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Histamine Pathway a Target for Erythropoietic Protoporphyria?
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.
Mutations in the ferrochelatase (FECH) gene cause erythropoietic porphyria. EPP is characterized biochemically by liver and bone marrow accumulation of protoporphyrin-IX (PP-IX), and is characterized clinically by hepatic dysfunction with progression in 1-4% to advanced liver disease.
A recent study by Kuo and colleagues exemplifies a bench-to-bedside evolution comprising pharmacological screening, mechanistic dissection, and ultimately translation of this mechanism to human subjects to treat EPP. They utilized high-throughput compound screening in a zebrafish model to identify the anti-histamine, chlorcyclizine (CCZ), as a candidate EPP therapy. Chlorciclizine lowered hepatocyte PP-IX in multiple EPP models by blocking peripheral histamine production, and by inducing hepatocyte PP-IX efflux. The data represent advances in the realms of both clinical therapeutics and molecular pathophysiological discovery.
From a discovery standpoint, strategic compound screening that utilizes the LOPAC (library of pharmaceutically active compounds) and Prestwick libraries offers at least two key characteristics. First, these compounds have largely known targets. The known pharmacology of chlorcyclizine provided immediate clues to validate mechanism rapidly in hepatic HPP, a relatively poorly understood disease. Moreover, screening libraries comprising FDA-approved drugs can minimize lag time between discovery and translation to interventional trials in human subjects.
Beyond such strategic discovery considerations, perhaps more exciting is the therapeutic potential for anti-histaminergic therapy to mitigate hepatic manifestations in EPP. Specifically, other porphyrias with hepatic complications have FDA-approved treatments, such as anti-ALAS1 siRNAs to treat acute hepatic porphyria (AHP). No such treatment currently exists for liver dysfunction in EPP, yet CCZ and other histamine-1 receptor blockers hold such promise. Indeed, the H1 inhibitor, cimetidine, is currently in an active phase 2 trial to treat EPP (NCT05020184).
Given the already widespread use of antihistamines to symptomatically treat cutaneous EPP, we may not be too distant from pivoting and deploying readily available H1Bs like cimetidine to treat EPP liver manifestations as well. Given recent data by Kuo and colleagues, such an outcome should not be too far-FECHed.
Brian DeBosch, MD, PhD, is Center Director of the nutrition & molecular metabolism research program, in the Division of Gastroenterology, Hepatology & Nutrition at Indiana University School of Medicine, Indianapolis. He declares no conflicts of interest.
Mutations in the ferrochelatase (FECH) gene cause erythropoietic porphyria. EPP is characterized biochemically by liver and bone marrow accumulation of protoporphyrin-IX (PP-IX), and is characterized clinically by hepatic dysfunction with progression in 1-4% to advanced liver disease.
A recent study by Kuo and colleagues exemplifies a bench-to-bedside evolution comprising pharmacological screening, mechanistic dissection, and ultimately translation of this mechanism to human subjects to treat EPP. They utilized high-throughput compound screening in a zebrafish model to identify the anti-histamine, chlorcyclizine (CCZ), as a candidate EPP therapy. Chlorciclizine lowered hepatocyte PP-IX in multiple EPP models by blocking peripheral histamine production, and by inducing hepatocyte PP-IX efflux. The data represent advances in the realms of both clinical therapeutics and molecular pathophysiological discovery.
From a discovery standpoint, strategic compound screening that utilizes the LOPAC (library of pharmaceutically active compounds) and Prestwick libraries offers at least two key characteristics. First, these compounds have largely known targets. The known pharmacology of chlorcyclizine provided immediate clues to validate mechanism rapidly in hepatic HPP, a relatively poorly understood disease. Moreover, screening libraries comprising FDA-approved drugs can minimize lag time between discovery and translation to interventional trials in human subjects.
Beyond such strategic discovery considerations, perhaps more exciting is the therapeutic potential for anti-histaminergic therapy to mitigate hepatic manifestations in EPP. Specifically, other porphyrias with hepatic complications have FDA-approved treatments, such as anti-ALAS1 siRNAs to treat acute hepatic porphyria (AHP). No such treatment currently exists for liver dysfunction in EPP, yet CCZ and other histamine-1 receptor blockers hold such promise. Indeed, the H1 inhibitor, cimetidine, is currently in an active phase 2 trial to treat EPP (NCT05020184).
Given the already widespread use of antihistamines to symptomatically treat cutaneous EPP, we may not be too distant from pivoting and deploying readily available H1Bs like cimetidine to treat EPP liver manifestations as well. Given recent data by Kuo and colleagues, such an outcome should not be too far-FECHed.
Brian DeBosch, MD, PhD, is Center Director of the nutrition & molecular metabolism research program, in the Division of Gastroenterology, Hepatology & Nutrition at Indiana University School of Medicine, Indianapolis. He declares no conflicts of interest.
Mutations in the ferrochelatase (FECH) gene cause erythropoietic porphyria. EPP is characterized biochemically by liver and bone marrow accumulation of protoporphyrin-IX (PP-IX), and is characterized clinically by hepatic dysfunction with progression in 1-4% to advanced liver disease.
A recent study by Kuo and colleagues exemplifies a bench-to-bedside evolution comprising pharmacological screening, mechanistic dissection, and ultimately translation of this mechanism to human subjects to treat EPP. They utilized high-throughput compound screening in a zebrafish model to identify the anti-histamine, chlorcyclizine (CCZ), as a candidate EPP therapy. Chlorciclizine lowered hepatocyte PP-IX in multiple EPP models by blocking peripheral histamine production, and by inducing hepatocyte PP-IX efflux. The data represent advances in the realms of both clinical therapeutics and molecular pathophysiological discovery.
From a discovery standpoint, strategic compound screening that utilizes the LOPAC (library of pharmaceutically active compounds) and Prestwick libraries offers at least two key characteristics. First, these compounds have largely known targets. The known pharmacology of chlorcyclizine provided immediate clues to validate mechanism rapidly in hepatic HPP, a relatively poorly understood disease. Moreover, screening libraries comprising FDA-approved drugs can minimize lag time between discovery and translation to interventional trials in human subjects.
Beyond such strategic discovery considerations, perhaps more exciting is the therapeutic potential for anti-histaminergic therapy to mitigate hepatic manifestations in EPP. Specifically, other porphyrias with hepatic complications have FDA-approved treatments, such as anti-ALAS1 siRNAs to treat acute hepatic porphyria (AHP). No such treatment currently exists for liver dysfunction in EPP, yet CCZ and other histamine-1 receptor blockers hold such promise. Indeed, the H1 inhibitor, cimetidine, is currently in an active phase 2 trial to treat EPP (NCT05020184).
Given the already widespread use of antihistamines to symptomatically treat cutaneous EPP, we may not be too distant from pivoting and deploying readily available H1Bs like cimetidine to treat EPP liver manifestations as well. Given recent data by Kuo and colleagues, such an outcome should not be too far-FECHed.
Brian DeBosch, MD, PhD, is Center Director of the nutrition & molecular metabolism research program, in the Division of Gastroenterology, Hepatology & Nutrition at Indiana University School of Medicine, Indianapolis. He declares no conflicts of interest.
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.
From Cellular and Molecular Gastroenterology and Hepatology
Weekend Workout, Regular Exercise Are Equals at Lowering GI Disease Risk
SAN DIEGO — The session started with a question that many in the audience at Digestive Disease Week (DDW) 2025 seemed to relate to: “How many of you find yourself squeezing workouts into a weekend after a hectic work week?”
Although regular exercise three or more times a week is often viewed as preferable, Shiyi Yu, MD, a resident physician in the Department of Gastroenterology at Guangdong Provincial People’s Hospital in Guangzhou, China, had good news for weekend warriors.
Both patterns reduce digestive disease almost equally.
Her study compared weekend warriors with those she called “active regulars” and sedentary folks to see how activity patterns affect digestive disease risks.
Her bottom line: “Your gut does not care about your schedule.”
The researchers analyzed wrist-based accelerometer data from 89,595 participants in the UK Biobank. To categorize participants as active or inactive, they used the World Health Organization 2020 guidelines for physical activity, which recommend at least 150-300 minutes of moderate-intensity aerobic physical activity or at least 75-150 minutes of vigorous-intensity aerobic physical activity, or an equivalent combination throughout the week. Median age of participants was 63.3 years and 48.8% were men.
They divided participants into three groups:
- About 43% were weekend warriors who met or exceeded 150 minutes of moderate to vigorous physical activity (MVPA), with 50% or more of total MVPA achieved in 1-2 days.
- About 23% were active regulars who met or exceeded 150 minutes a week but spread over more days.
- About 34% were inactive participants who were active less than 150 minutes a week.
The researchers followed the participants for a median of 7.9 years, looking for the incidence of multiple digestive diseases, identified using the International Classification of Diseases, 10th Revision, codes. These included diverticulosis, constipation, metabolic dysfunction–associated steatotic liver disease, cholelithiasis, and gastroesophageal reflux disease.
,” Yu said. At the threshold ≥ 150 minutes, for instance, hazard ratios for any digestive disease were 0.83 for weekend warriors and 0.79 for active regulars, compared with sedentary participants.
The analysis was repeated using a median threshold ≥ 230.4 minutes of MVPA a week, and the researchers found the same results.
As a validation cohort, the researchers used more than 6,000 participants from the National Institutes of Health’s All of Us Research Program with over 6 months of wrist-based accelerometer data.
A recent meta-epidemiology study found that the weekend warrior pattern offers other health benefits, including reducing the risk for cardiovascular disease mortality, mental disorders, and metabolic syndrome.
A Pleasant Surprise
The digestive disease study’s findings were “a surprise and a pleasant one,” said Aasma Shaukat, MD, MPH, AGAF, professor of medicine and a gastroenterologist at NYU Grossman School of Medicine, New York City.
“We often think if we’re not able to exercise regularly, then there’s no hope for us,” said Shaukat, who moderated the session. “But this implies that even if we have time only during the weekend to engage in physical activity, it still confers benefits in reducing our risk of any GI health disorder, as well as cardiovascular or other health disorders, compared to people inactive at baseline.”
“It gives us flexibility in terms of how we structure our exercise. Obviously, people should try to get into the habit of doing regular activity; it’s more sustainable. But a good alternative, according to this research, is that packing all of that in over the weekend seems to confer benefit. So all is not lost.”
Will this change her conversation with patients moving forward? Absolutely, Shaukat said. She generally recommends physical activity for at least 30 minutes three times a week. Now Shaukat said she can tell patients: “If that’s not possible, take that time out during the weekend for your health”.
This study was funded by grants from the National Natural Science Foundation of China and its Regional Innovation and Development Joint Foundation. Yu and Shaukat reported no disclosures.
A version of this article appeared on Medscape.com.
SAN DIEGO — The session started with a question that many in the audience at Digestive Disease Week (DDW) 2025 seemed to relate to: “How many of you find yourself squeezing workouts into a weekend after a hectic work week?”
Although regular exercise three or more times a week is often viewed as preferable, Shiyi Yu, MD, a resident physician in the Department of Gastroenterology at Guangdong Provincial People’s Hospital in Guangzhou, China, had good news for weekend warriors.
Both patterns reduce digestive disease almost equally.
Her study compared weekend warriors with those she called “active regulars” and sedentary folks to see how activity patterns affect digestive disease risks.
Her bottom line: “Your gut does not care about your schedule.”
The researchers analyzed wrist-based accelerometer data from 89,595 participants in the UK Biobank. To categorize participants as active or inactive, they used the World Health Organization 2020 guidelines for physical activity, which recommend at least 150-300 minutes of moderate-intensity aerobic physical activity or at least 75-150 minutes of vigorous-intensity aerobic physical activity, or an equivalent combination throughout the week. Median age of participants was 63.3 years and 48.8% were men.
They divided participants into three groups:
- About 43% were weekend warriors who met or exceeded 150 minutes of moderate to vigorous physical activity (MVPA), with 50% or more of total MVPA achieved in 1-2 days.
- About 23% were active regulars who met or exceeded 150 minutes a week but spread over more days.
- About 34% were inactive participants who were active less than 150 minutes a week.
The researchers followed the participants for a median of 7.9 years, looking for the incidence of multiple digestive diseases, identified using the International Classification of Diseases, 10th Revision, codes. These included diverticulosis, constipation, metabolic dysfunction–associated steatotic liver disease, cholelithiasis, and gastroesophageal reflux disease.
,” Yu said. At the threshold ≥ 150 minutes, for instance, hazard ratios for any digestive disease were 0.83 for weekend warriors and 0.79 for active regulars, compared with sedentary participants.
The analysis was repeated using a median threshold ≥ 230.4 minutes of MVPA a week, and the researchers found the same results.
As a validation cohort, the researchers used more than 6,000 participants from the National Institutes of Health’s All of Us Research Program with over 6 months of wrist-based accelerometer data.
A recent meta-epidemiology study found that the weekend warrior pattern offers other health benefits, including reducing the risk for cardiovascular disease mortality, mental disorders, and metabolic syndrome.
A Pleasant Surprise
The digestive disease study’s findings were “a surprise and a pleasant one,” said Aasma Shaukat, MD, MPH, AGAF, professor of medicine and a gastroenterologist at NYU Grossman School of Medicine, New York City.
“We often think if we’re not able to exercise regularly, then there’s no hope for us,” said Shaukat, who moderated the session. “But this implies that even if we have time only during the weekend to engage in physical activity, it still confers benefits in reducing our risk of any GI health disorder, as well as cardiovascular or other health disorders, compared to people inactive at baseline.”
“It gives us flexibility in terms of how we structure our exercise. Obviously, people should try to get into the habit of doing regular activity; it’s more sustainable. But a good alternative, according to this research, is that packing all of that in over the weekend seems to confer benefit. So all is not lost.”
Will this change her conversation with patients moving forward? Absolutely, Shaukat said. She generally recommends physical activity for at least 30 minutes three times a week. Now Shaukat said she can tell patients: “If that’s not possible, take that time out during the weekend for your health”.
This study was funded by grants from the National Natural Science Foundation of China and its Regional Innovation and Development Joint Foundation. Yu and Shaukat reported no disclosures.
A version of this article appeared on Medscape.com.
SAN DIEGO — The session started with a question that many in the audience at Digestive Disease Week (DDW) 2025 seemed to relate to: “How many of you find yourself squeezing workouts into a weekend after a hectic work week?”
Although regular exercise three or more times a week is often viewed as preferable, Shiyi Yu, MD, a resident physician in the Department of Gastroenterology at Guangdong Provincial People’s Hospital in Guangzhou, China, had good news for weekend warriors.
Both patterns reduce digestive disease almost equally.
Her study compared weekend warriors with those she called “active regulars” and sedentary folks to see how activity patterns affect digestive disease risks.
Her bottom line: “Your gut does not care about your schedule.”
The researchers analyzed wrist-based accelerometer data from 89,595 participants in the UK Biobank. To categorize participants as active or inactive, they used the World Health Organization 2020 guidelines for physical activity, which recommend at least 150-300 minutes of moderate-intensity aerobic physical activity or at least 75-150 minutes of vigorous-intensity aerobic physical activity, or an equivalent combination throughout the week. Median age of participants was 63.3 years and 48.8% were men.
They divided participants into three groups:
- About 43% were weekend warriors who met or exceeded 150 minutes of moderate to vigorous physical activity (MVPA), with 50% or more of total MVPA achieved in 1-2 days.
- About 23% were active regulars who met or exceeded 150 minutes a week but spread over more days.
- About 34% were inactive participants who were active less than 150 minutes a week.
The researchers followed the participants for a median of 7.9 years, looking for the incidence of multiple digestive diseases, identified using the International Classification of Diseases, 10th Revision, codes. These included diverticulosis, constipation, metabolic dysfunction–associated steatotic liver disease, cholelithiasis, and gastroesophageal reflux disease.
,” Yu said. At the threshold ≥ 150 minutes, for instance, hazard ratios for any digestive disease were 0.83 for weekend warriors and 0.79 for active regulars, compared with sedentary participants.
The analysis was repeated using a median threshold ≥ 230.4 minutes of MVPA a week, and the researchers found the same results.
As a validation cohort, the researchers used more than 6,000 participants from the National Institutes of Health’s All of Us Research Program with over 6 months of wrist-based accelerometer data.
A recent meta-epidemiology study found that the weekend warrior pattern offers other health benefits, including reducing the risk for cardiovascular disease mortality, mental disorders, and metabolic syndrome.
A Pleasant Surprise
The digestive disease study’s findings were “a surprise and a pleasant one,” said Aasma Shaukat, MD, MPH, AGAF, professor of medicine and a gastroenterologist at NYU Grossman School of Medicine, New York City.
“We often think if we’re not able to exercise regularly, then there’s no hope for us,” said Shaukat, who moderated the session. “But this implies that even if we have time only during the weekend to engage in physical activity, it still confers benefits in reducing our risk of any GI health disorder, as well as cardiovascular or other health disorders, compared to people inactive at baseline.”
“It gives us flexibility in terms of how we structure our exercise. Obviously, people should try to get into the habit of doing regular activity; it’s more sustainable. But a good alternative, according to this research, is that packing all of that in over the weekend seems to confer benefit. So all is not lost.”
Will this change her conversation with patients moving forward? Absolutely, Shaukat said. She generally recommends physical activity for at least 30 minutes three times a week. Now Shaukat said she can tell patients: “If that’s not possible, take that time out during the weekend for your health”.
This study was funded by grants from the National Natural Science Foundation of China and its Regional Innovation and Development Joint Foundation. Yu and Shaukat reported no disclosures.
A version of this article appeared on Medscape.com.
FROM DDW 2025
SGLT2 Inhibitors Reduce Portal Hypertension From Cirrhosis
SAN DIEGO — , new research shows.
“Our study found that SGLT2 inhibitors were associated with fewer portal hypertension complications and lower mortality, suggesting they may be a valuable addition to cirrhosis management,” first author Abhinav K. Rao, MD, of the Medical University of South Carolina, Charleston, South Carolina, told GI & Hepatology News.
The findings were presented at Digestive Disease Week (DDW) 2025.
Portal hypertension, a potentially life-threatening complication of cirrhosis, can be a key driver of additional complications including ascites and gastro-esophageal varices in cirrhosis.
Current treatments such as beta-blockers can prevent some complications, however, more effective therapies are needed.
SGLT2 inhibitors are often used in the treatment of cardiovascular disease as well as metabolic dysfunction–associated steatohepatitis (MASH)–mediated liver disease; research is lacking regarding their effects in portal hypertension in the broader population of people with cirrhosis.
“The therapeutic efficacy of SGLT2 inhibitors might be related to their ability to improve vascular function, making them attractive in portal hypertension,” Rao explained.
To investigate, Rao and colleagues evaluated data on 637,079 patients with cirrhosis in the TriNetX database, which includes patients in the United States from 66 healthcare organizations.
Patients were divided into three subgroups, including those with MASH, alcohol-associated, and other etiologies of cirrhosis.
Using robust 1:1 propensity score matching, patients in each subgroup were stratified as either having or not having been treated with SGLT2 inhibitors, limited to those who initiated the drugs within 1 year of their cirrhosis diagnosis to prevent immortal time bias. Patients were matched on other characteristics.
For the primary outcome of all-cause mortality, with an overall median follow-up of 2 years, patients prescribed SGLT2 inhibitors in the MASH cirrhosis (n = 47,385), alcohol-associated cirrhosis (n = 107,844), and other etiologies of cirrhosis (n = 59,499) groups all had a significantly lower risk for all-cause mortality than those not prescribed SGLT2 inhibitors (P < .05 for all).
SGLT2 Inhibitors in MASH Cirrhosis
Specifically looking at the MASH cirrhosis group, Rao described outcomes of the two groups of 3026 patients each who were and were not treated with SGLT2 inhibitors.
The patients had similar rates of esophageal varices (25% in the SGLT2 group and 22% in the no SGLT2 group), ascites (19% in each group), and a similar rate of 19% had hepatic encephalopathy (HE).
About 57% of patients in each treatment group used beta-blockers and 33% used glucagon-like peptide 1 (GLP-1) receptor agonists. Those with a history of liver transplantation, hemodialysis, or transjugular intrahepatic portosystemic shunt placement were excluded.
The secondary outcome results in those patients showed that treatment with SGLT2 inhibitors was associated with significantly reduced risks of developing portal hypertension complications including ascites, HE, spontaneous bacterial peritonitis (SBP), and hepatorenal syndrome (P < .05 for all).
Esophageal variceal bleeding was also reduced with SGLT-2 inhibitors; however the difference was not statistically significant.
Effects Diminished With Beta-Blocker Treatment
In a secondary analysis of patients in the MASH cirrhosis group treated with one type of a nonselective beta-blockers (n = 509) and another nonselective beta-blockers (n = 2561), the beneficial effects of SGLT2 inhibitors on portal hypertension, with the exception of HE and SBP, were found to be somewhat diminished, likely because patients were already benefitting from the beta-blockers, Rao noted.
Other Groups
In outcomes of the non–MASH-related cirrhosis groups, patients prescribed SGLT2 inhibitors also had a reduced risk for specific, as well as any portal hypertension complications (P < .05), Rao noted.
Overall, the findings add to previous studies on SGLT2 inhibitors in MASH and expand on the possible benefits, he said.
“Our findings validate these [previous] results and suggest potential benefits across for patients with other types of liver disease and raise the possibility of a beneficial effect in portal hypertension,” he said.
“Given the marked reduction in portal hypertension complications after SGLT2 inhibitor initiation, the associated survival benefit may not be surprising,” he noted.
“However, we were intrigued by the consistent reduction in portal hypertension complications across all cirrhosis types, especially since SGLT-2 inhibitors are most commonly used in patients with diabetes who have MASH-mediated liver disease.”
‘Real World Glimpse’ at SGLT2 Inhibitors; Limitations Need Noting
Commenting on the study, Rotonya M. Carr, MD, Division Head of Gastroenterology at the University of Washington, Seattle, said the study sheds important light on an issue previously addressed only in smaller cohorts.
“To date, there have only been a few small prospective, retrospective, and case series studies investigating SGTL2 inhibitors in patients with cirrhosis,” she told GI & Hepatology Newsv.
“This retrospective study is a real-world glimpse at how patients with cirrhosis may fare on these drugs — very exciting data.”
Carr cautioned, however, that, in addition to the retrospective study design, limitations included that the study doesn’t provide details on the duration of therapy, preventing an understanding of whether the results represent chronic, sustained use of SGLT2 inhibitors.
“[Therefore], we cannot interpret these results to mean that chronic, sustained use of SGTL2 inh is beneficial, or does not cause harm, in patients with cirrhosis.”
“While these data are provocative, more work needs to be done before we understand the full safety and efficacy of SGTL2 inhibitors for patients with cirrhosis,” Carr added.
“However, these data are very encouraging, and I am optimistic that we will indeed see both SGTL2 inhibitors and GLP-1s among the group of medications we use in the future for the primary management of patients with liver disease.”
The authors had no disclosures to report. Carr’s disclosures included relationships with Intercept and Novo Nordisk and research funding from Merck.
A version of this article appeared on Medscape.com.
SAN DIEGO — , new research shows.
“Our study found that SGLT2 inhibitors were associated with fewer portal hypertension complications and lower mortality, suggesting they may be a valuable addition to cirrhosis management,” first author Abhinav K. Rao, MD, of the Medical University of South Carolina, Charleston, South Carolina, told GI & Hepatology News.
The findings were presented at Digestive Disease Week (DDW) 2025.
Portal hypertension, a potentially life-threatening complication of cirrhosis, can be a key driver of additional complications including ascites and gastro-esophageal varices in cirrhosis.
Current treatments such as beta-blockers can prevent some complications, however, more effective therapies are needed.
SGLT2 inhibitors are often used in the treatment of cardiovascular disease as well as metabolic dysfunction–associated steatohepatitis (MASH)–mediated liver disease; research is lacking regarding their effects in portal hypertension in the broader population of people with cirrhosis.
“The therapeutic efficacy of SGLT2 inhibitors might be related to their ability to improve vascular function, making them attractive in portal hypertension,” Rao explained.
To investigate, Rao and colleagues evaluated data on 637,079 patients with cirrhosis in the TriNetX database, which includes patients in the United States from 66 healthcare organizations.
Patients were divided into three subgroups, including those with MASH, alcohol-associated, and other etiologies of cirrhosis.
Using robust 1:1 propensity score matching, patients in each subgroup were stratified as either having or not having been treated with SGLT2 inhibitors, limited to those who initiated the drugs within 1 year of their cirrhosis diagnosis to prevent immortal time bias. Patients were matched on other characteristics.
For the primary outcome of all-cause mortality, with an overall median follow-up of 2 years, patients prescribed SGLT2 inhibitors in the MASH cirrhosis (n = 47,385), alcohol-associated cirrhosis (n = 107,844), and other etiologies of cirrhosis (n = 59,499) groups all had a significantly lower risk for all-cause mortality than those not prescribed SGLT2 inhibitors (P < .05 for all).
SGLT2 Inhibitors in MASH Cirrhosis
Specifically looking at the MASH cirrhosis group, Rao described outcomes of the two groups of 3026 patients each who were and were not treated with SGLT2 inhibitors.
The patients had similar rates of esophageal varices (25% in the SGLT2 group and 22% in the no SGLT2 group), ascites (19% in each group), and a similar rate of 19% had hepatic encephalopathy (HE).
About 57% of patients in each treatment group used beta-blockers and 33% used glucagon-like peptide 1 (GLP-1) receptor agonists. Those with a history of liver transplantation, hemodialysis, or transjugular intrahepatic portosystemic shunt placement were excluded.
The secondary outcome results in those patients showed that treatment with SGLT2 inhibitors was associated with significantly reduced risks of developing portal hypertension complications including ascites, HE, spontaneous bacterial peritonitis (SBP), and hepatorenal syndrome (P < .05 for all).
Esophageal variceal bleeding was also reduced with SGLT-2 inhibitors; however the difference was not statistically significant.
Effects Diminished With Beta-Blocker Treatment
In a secondary analysis of patients in the MASH cirrhosis group treated with one type of a nonselective beta-blockers (n = 509) and another nonselective beta-blockers (n = 2561), the beneficial effects of SGLT2 inhibitors on portal hypertension, with the exception of HE and SBP, were found to be somewhat diminished, likely because patients were already benefitting from the beta-blockers, Rao noted.
Other Groups
In outcomes of the non–MASH-related cirrhosis groups, patients prescribed SGLT2 inhibitors also had a reduced risk for specific, as well as any portal hypertension complications (P < .05), Rao noted.
Overall, the findings add to previous studies on SGLT2 inhibitors in MASH and expand on the possible benefits, he said.
“Our findings validate these [previous] results and suggest potential benefits across for patients with other types of liver disease and raise the possibility of a beneficial effect in portal hypertension,” he said.
“Given the marked reduction in portal hypertension complications after SGLT2 inhibitor initiation, the associated survival benefit may not be surprising,” he noted.
“However, we were intrigued by the consistent reduction in portal hypertension complications across all cirrhosis types, especially since SGLT-2 inhibitors are most commonly used in patients with diabetes who have MASH-mediated liver disease.”
‘Real World Glimpse’ at SGLT2 Inhibitors; Limitations Need Noting
Commenting on the study, Rotonya M. Carr, MD, Division Head of Gastroenterology at the University of Washington, Seattle, said the study sheds important light on an issue previously addressed only in smaller cohorts.
“To date, there have only been a few small prospective, retrospective, and case series studies investigating SGTL2 inhibitors in patients with cirrhosis,” she told GI & Hepatology Newsv.
“This retrospective study is a real-world glimpse at how patients with cirrhosis may fare on these drugs — very exciting data.”
Carr cautioned, however, that, in addition to the retrospective study design, limitations included that the study doesn’t provide details on the duration of therapy, preventing an understanding of whether the results represent chronic, sustained use of SGLT2 inhibitors.
“[Therefore], we cannot interpret these results to mean that chronic, sustained use of SGTL2 inh is beneficial, or does not cause harm, in patients with cirrhosis.”
“While these data are provocative, more work needs to be done before we understand the full safety and efficacy of SGTL2 inhibitors for patients with cirrhosis,” Carr added.
“However, these data are very encouraging, and I am optimistic that we will indeed see both SGTL2 inhibitors and GLP-1s among the group of medications we use in the future for the primary management of patients with liver disease.”
The authors had no disclosures to report. Carr’s disclosures included relationships with Intercept and Novo Nordisk and research funding from Merck.
A version of this article appeared on Medscape.com.
SAN DIEGO — , new research shows.
“Our study found that SGLT2 inhibitors were associated with fewer portal hypertension complications and lower mortality, suggesting they may be a valuable addition to cirrhosis management,” first author Abhinav K. Rao, MD, of the Medical University of South Carolina, Charleston, South Carolina, told GI & Hepatology News.
The findings were presented at Digestive Disease Week (DDW) 2025.
Portal hypertension, a potentially life-threatening complication of cirrhosis, can be a key driver of additional complications including ascites and gastro-esophageal varices in cirrhosis.
Current treatments such as beta-blockers can prevent some complications, however, more effective therapies are needed.
SGLT2 inhibitors are often used in the treatment of cardiovascular disease as well as metabolic dysfunction–associated steatohepatitis (MASH)–mediated liver disease; research is lacking regarding their effects in portal hypertension in the broader population of people with cirrhosis.
“The therapeutic efficacy of SGLT2 inhibitors might be related to their ability to improve vascular function, making them attractive in portal hypertension,” Rao explained.
To investigate, Rao and colleagues evaluated data on 637,079 patients with cirrhosis in the TriNetX database, which includes patients in the United States from 66 healthcare organizations.
Patients were divided into three subgroups, including those with MASH, alcohol-associated, and other etiologies of cirrhosis.
Using robust 1:1 propensity score matching, patients in each subgroup were stratified as either having or not having been treated with SGLT2 inhibitors, limited to those who initiated the drugs within 1 year of their cirrhosis diagnosis to prevent immortal time bias. Patients were matched on other characteristics.
For the primary outcome of all-cause mortality, with an overall median follow-up of 2 years, patients prescribed SGLT2 inhibitors in the MASH cirrhosis (n = 47,385), alcohol-associated cirrhosis (n = 107,844), and other etiologies of cirrhosis (n = 59,499) groups all had a significantly lower risk for all-cause mortality than those not prescribed SGLT2 inhibitors (P < .05 for all).
SGLT2 Inhibitors in MASH Cirrhosis
Specifically looking at the MASH cirrhosis group, Rao described outcomes of the two groups of 3026 patients each who were and were not treated with SGLT2 inhibitors.
The patients had similar rates of esophageal varices (25% in the SGLT2 group and 22% in the no SGLT2 group), ascites (19% in each group), and a similar rate of 19% had hepatic encephalopathy (HE).
About 57% of patients in each treatment group used beta-blockers and 33% used glucagon-like peptide 1 (GLP-1) receptor agonists. Those with a history of liver transplantation, hemodialysis, or transjugular intrahepatic portosystemic shunt placement were excluded.
The secondary outcome results in those patients showed that treatment with SGLT2 inhibitors was associated with significantly reduced risks of developing portal hypertension complications including ascites, HE, spontaneous bacterial peritonitis (SBP), and hepatorenal syndrome (P < .05 for all).
Esophageal variceal bleeding was also reduced with SGLT-2 inhibitors; however the difference was not statistically significant.
Effects Diminished With Beta-Blocker Treatment
In a secondary analysis of patients in the MASH cirrhosis group treated with one type of a nonselective beta-blockers (n = 509) and another nonselective beta-blockers (n = 2561), the beneficial effects of SGLT2 inhibitors on portal hypertension, with the exception of HE and SBP, were found to be somewhat diminished, likely because patients were already benefitting from the beta-blockers, Rao noted.
Other Groups
In outcomes of the non–MASH-related cirrhosis groups, patients prescribed SGLT2 inhibitors also had a reduced risk for specific, as well as any portal hypertension complications (P < .05), Rao noted.
Overall, the findings add to previous studies on SGLT2 inhibitors in MASH and expand on the possible benefits, he said.
“Our findings validate these [previous] results and suggest potential benefits across for patients with other types of liver disease and raise the possibility of a beneficial effect in portal hypertension,” he said.
“Given the marked reduction in portal hypertension complications after SGLT2 inhibitor initiation, the associated survival benefit may not be surprising,” he noted.
“However, we were intrigued by the consistent reduction in portal hypertension complications across all cirrhosis types, especially since SGLT-2 inhibitors are most commonly used in patients with diabetes who have MASH-mediated liver disease.”
‘Real World Glimpse’ at SGLT2 Inhibitors; Limitations Need Noting
Commenting on the study, Rotonya M. Carr, MD, Division Head of Gastroenterology at the University of Washington, Seattle, said the study sheds important light on an issue previously addressed only in smaller cohorts.
“To date, there have only been a few small prospective, retrospective, and case series studies investigating SGTL2 inhibitors in patients with cirrhosis,” she told GI & Hepatology Newsv.
“This retrospective study is a real-world glimpse at how patients with cirrhosis may fare on these drugs — very exciting data.”
Carr cautioned, however, that, in addition to the retrospective study design, limitations included that the study doesn’t provide details on the duration of therapy, preventing an understanding of whether the results represent chronic, sustained use of SGLT2 inhibitors.
“[Therefore], we cannot interpret these results to mean that chronic, sustained use of SGTL2 inh is beneficial, or does not cause harm, in patients with cirrhosis.”
“While these data are provocative, more work needs to be done before we understand the full safety and efficacy of SGTL2 inhibitors for patients with cirrhosis,” Carr added.
“However, these data are very encouraging, and I am optimistic that we will indeed see both SGTL2 inhibitors and GLP-1s among the group of medications we use in the future for the primary management of patients with liver disease.”
The authors had no disclosures to report. Carr’s disclosures included relationships with Intercept and Novo Nordisk and research funding from Merck.
A version of this article appeared on Medscape.com.
FROM DDW 2025
Experts Recommend Medication for Pediatric MASLD Management
, according to a new joint perspective paper.
Pediatric MASLD is the number-one cause of chronic liver disease in children and the number-one reason for liver transplant listing in young adults aged 18-40 years, said corresponding author Jennifer A. Panganiban, MD, Children’s Hospital of Philadelphia, Philadelphia.
The paper, published in Obesity Pillars, represents “a call to action that has been long overdue,” Panganiban told GI & Hepatology News.
The goal of the authors was to bring global awareness to the recent changes in the pediatric MASLD landscape — especially in medication use — and to empower clinicians treating the disease, she explained.
The recommendations are based on a combination of the latest published evidence and clinical expertise from eight hepatologists/gastroenterologists and two physicians from the Obesity Medicine Association, Centennial, Colorado.
One of the major barriers to MASLD management in children is suboptimal screening resulting in underdiagnosis, said Panganiban. “Unfortunately, only up to 30% of children are being screened in their pediatrician’s office.”
The new guideline outlines the patient care process from screening, referral to a subspecialist, and workup; however, the primary focus is on treatment with medication options that were previously not available or underutilized, she said.
Successful and Sustainable Weight Loss
Adiposity and weight gain make MASLD worse, but weight reduction has been shown to improve the condition, the authors noted. Previous strategies for curbing MASLD in children with obesity have focused mainly on lifestyle changes, but with limited success.
Nevertheless, the authors recommend continuing physical activity and nutrition as treatments for MASLD in children, with a plan tailored specifically to the patient.
In addition, however, they suggest that anti-obesity medications started early in the disease may help reduce costs and improve future outcomes.
Although glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have not yet been studied specifically for pediatric MASLD, data from studies of pediatric obesity, diabetes, and other retrospective studies are encouraging, the authors wrote.
The GLP-1 RAs liraglutide and semaglutide are both approved by the US Food and Drug Administration (FDA) for managing obesity in children and adolescents aged 12 years or older, they noted. And a recent phase 3a randomized trial showed that liraglutide, not yet approved for children younger than 12 years, led to a mean change in body mass index of 5.8% from baseline to 56 weeks in children aged 6-11 years with obesity.
GLP-1 RAs not only are effective for weight management but also improve other metabolic dysfunction indicators including cholesterol and blood pressure, which makes these medications an even more beneficial option for individuals with obesity and MASLD, Panganiban and colleagues wrote.
For example, a recent single-center study of 111 children with MASLD (mean age, 15 years) showed a significant improvement in alanine aminotransferase levels with the use of GLP-1 RAs, although body mass index and weight were unchanged.
Regaining weight after discontinuing GLP-1 RAs is the main barrier to their use for MASLD, the authors noted. In addition, GLP-1 RAs are contraindicated in some situations, such as in those with a history of serious hypersensitivity, and in patients with a personal or family history of either medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 based on animal studies showing an association with the medications and thyroid C–cell tumors.
Other FDA-approved medication options for obesity in children include metformin, topiramate, and phentermine, as well as bupropion, lisdexamfetamine, and setmelanotide, the authors said.
Resmetirom, a thyroid hormone receptor-beta agonist, which is another significant breakthrough in MASLD for adults, has not yet been tested or approved for pediatric use.
In addition to medications, metabolic bariatric surgery has shown effectiveness in children with obesity and/or MASLD by reducing liver fat and reversing fibrosis, as shown in the Teen-LABS study, the authors wrote. However, long-term data on fibrosis reversal are limited, and cost and access remain barriers.
More Research Needed
The joint expert review is intended as an educational tool that may require updates and should not be interpreted as rules for individual patient care, the authors cautioned. And physical activity and nutrition remain the primary treatment of MASLD and should be continued in conjunction with other treatment modalities, they emphasized.
Looking ahead, research is needed to develop accurate and reliable noninvasive biomarkers to diagnose and assess obesity treatment efficacy, Panganiban told GI & Hepatology News.
Also needed are multicenter randomized control trials in children with obesity involving different medications that have been successful in the treatment of metabolic dysfunction–associated steatohepatitis/fibrosis in adults, such as GLP-1 RAs or resmetirom, she added.
Educating Clinicians on Early Identification
When obesity occurs in childhood, it starts a process of additional complications that arise in earlier ages in adults, said Saul J. Karpen, MD, chief scientific officer at the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University, Richmond, Virginia, in an interview.“Given the epidemic of obesity, altered diets, and reduced physical activities during younger ages, it is not easy to identify which children are at greater risk of MASLD,” said Karpen.
“It requires insight from the care providers and often imaging, a blood test, or a referral to a pediatric hepatologist, and not every region has easy access to such expertise,” Karpen said.
The new review is important because it highlights the fact that obesity and its consequences are not limited to adulthood, and that educated clinicians are in a position to get an early start on treatment in children, Karpen noted.
The guideline received no outside funding. Panganiban and Karpen had no financial conflicts to disclose.
A version of this article appeared on Medscape.com.
, according to a new joint perspective paper.
Pediatric MASLD is the number-one cause of chronic liver disease in children and the number-one reason for liver transplant listing in young adults aged 18-40 years, said corresponding author Jennifer A. Panganiban, MD, Children’s Hospital of Philadelphia, Philadelphia.
The paper, published in Obesity Pillars, represents “a call to action that has been long overdue,” Panganiban told GI & Hepatology News.
The goal of the authors was to bring global awareness to the recent changes in the pediatric MASLD landscape — especially in medication use — and to empower clinicians treating the disease, she explained.
The recommendations are based on a combination of the latest published evidence and clinical expertise from eight hepatologists/gastroenterologists and two physicians from the Obesity Medicine Association, Centennial, Colorado.
One of the major barriers to MASLD management in children is suboptimal screening resulting in underdiagnosis, said Panganiban. “Unfortunately, only up to 30% of children are being screened in their pediatrician’s office.”
The new guideline outlines the patient care process from screening, referral to a subspecialist, and workup; however, the primary focus is on treatment with medication options that were previously not available or underutilized, she said.
Successful and Sustainable Weight Loss
Adiposity and weight gain make MASLD worse, but weight reduction has been shown to improve the condition, the authors noted. Previous strategies for curbing MASLD in children with obesity have focused mainly on lifestyle changes, but with limited success.
Nevertheless, the authors recommend continuing physical activity and nutrition as treatments for MASLD in children, with a plan tailored specifically to the patient.
In addition, however, they suggest that anti-obesity medications started early in the disease may help reduce costs and improve future outcomes.
Although glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have not yet been studied specifically for pediatric MASLD, data from studies of pediatric obesity, diabetes, and other retrospective studies are encouraging, the authors wrote.
The GLP-1 RAs liraglutide and semaglutide are both approved by the US Food and Drug Administration (FDA) for managing obesity in children and adolescents aged 12 years or older, they noted. And a recent phase 3a randomized trial showed that liraglutide, not yet approved for children younger than 12 years, led to a mean change in body mass index of 5.8% from baseline to 56 weeks in children aged 6-11 years with obesity.
GLP-1 RAs not only are effective for weight management but also improve other metabolic dysfunction indicators including cholesterol and blood pressure, which makes these medications an even more beneficial option for individuals with obesity and MASLD, Panganiban and colleagues wrote.
For example, a recent single-center study of 111 children with MASLD (mean age, 15 years) showed a significant improvement in alanine aminotransferase levels with the use of GLP-1 RAs, although body mass index and weight were unchanged.
Regaining weight after discontinuing GLP-1 RAs is the main barrier to their use for MASLD, the authors noted. In addition, GLP-1 RAs are contraindicated in some situations, such as in those with a history of serious hypersensitivity, and in patients with a personal or family history of either medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 based on animal studies showing an association with the medications and thyroid C–cell tumors.
Other FDA-approved medication options for obesity in children include metformin, topiramate, and phentermine, as well as bupropion, lisdexamfetamine, and setmelanotide, the authors said.
Resmetirom, a thyroid hormone receptor-beta agonist, which is another significant breakthrough in MASLD for adults, has not yet been tested or approved for pediatric use.
In addition to medications, metabolic bariatric surgery has shown effectiveness in children with obesity and/or MASLD by reducing liver fat and reversing fibrosis, as shown in the Teen-LABS study, the authors wrote. However, long-term data on fibrosis reversal are limited, and cost and access remain barriers.
More Research Needed
The joint expert review is intended as an educational tool that may require updates and should not be interpreted as rules for individual patient care, the authors cautioned. And physical activity and nutrition remain the primary treatment of MASLD and should be continued in conjunction with other treatment modalities, they emphasized.
Looking ahead, research is needed to develop accurate and reliable noninvasive biomarkers to diagnose and assess obesity treatment efficacy, Panganiban told GI & Hepatology News.
Also needed are multicenter randomized control trials in children with obesity involving different medications that have been successful in the treatment of metabolic dysfunction–associated steatohepatitis/fibrosis in adults, such as GLP-1 RAs or resmetirom, she added.
Educating Clinicians on Early Identification
When obesity occurs in childhood, it starts a process of additional complications that arise in earlier ages in adults, said Saul J. Karpen, MD, chief scientific officer at the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University, Richmond, Virginia, in an interview.“Given the epidemic of obesity, altered diets, and reduced physical activities during younger ages, it is not easy to identify which children are at greater risk of MASLD,” said Karpen.
“It requires insight from the care providers and often imaging, a blood test, or a referral to a pediatric hepatologist, and not every region has easy access to such expertise,” Karpen said.
The new review is important because it highlights the fact that obesity and its consequences are not limited to adulthood, and that educated clinicians are in a position to get an early start on treatment in children, Karpen noted.
The guideline received no outside funding. Panganiban and Karpen had no financial conflicts to disclose.
A version of this article appeared on Medscape.com.
, according to a new joint perspective paper.
Pediatric MASLD is the number-one cause of chronic liver disease in children and the number-one reason for liver transplant listing in young adults aged 18-40 years, said corresponding author Jennifer A. Panganiban, MD, Children’s Hospital of Philadelphia, Philadelphia.
The paper, published in Obesity Pillars, represents “a call to action that has been long overdue,” Panganiban told GI & Hepatology News.
The goal of the authors was to bring global awareness to the recent changes in the pediatric MASLD landscape — especially in medication use — and to empower clinicians treating the disease, she explained.
The recommendations are based on a combination of the latest published evidence and clinical expertise from eight hepatologists/gastroenterologists and two physicians from the Obesity Medicine Association, Centennial, Colorado.
One of the major barriers to MASLD management in children is suboptimal screening resulting in underdiagnosis, said Panganiban. “Unfortunately, only up to 30% of children are being screened in their pediatrician’s office.”
The new guideline outlines the patient care process from screening, referral to a subspecialist, and workup; however, the primary focus is on treatment with medication options that were previously not available or underutilized, she said.
Successful and Sustainable Weight Loss
Adiposity and weight gain make MASLD worse, but weight reduction has been shown to improve the condition, the authors noted. Previous strategies for curbing MASLD in children with obesity have focused mainly on lifestyle changes, but with limited success.
Nevertheless, the authors recommend continuing physical activity and nutrition as treatments for MASLD in children, with a plan tailored specifically to the patient.
In addition, however, they suggest that anti-obesity medications started early in the disease may help reduce costs and improve future outcomes.
Although glucagon-like peptide 1 receptor agonists (GLP-1 RAs) have not yet been studied specifically for pediatric MASLD, data from studies of pediatric obesity, diabetes, and other retrospective studies are encouraging, the authors wrote.
The GLP-1 RAs liraglutide and semaglutide are both approved by the US Food and Drug Administration (FDA) for managing obesity in children and adolescents aged 12 years or older, they noted. And a recent phase 3a randomized trial showed that liraglutide, not yet approved for children younger than 12 years, led to a mean change in body mass index of 5.8% from baseline to 56 weeks in children aged 6-11 years with obesity.
GLP-1 RAs not only are effective for weight management but also improve other metabolic dysfunction indicators including cholesterol and blood pressure, which makes these medications an even more beneficial option for individuals with obesity and MASLD, Panganiban and colleagues wrote.
For example, a recent single-center study of 111 children with MASLD (mean age, 15 years) showed a significant improvement in alanine aminotransferase levels with the use of GLP-1 RAs, although body mass index and weight were unchanged.
Regaining weight after discontinuing GLP-1 RAs is the main barrier to their use for MASLD, the authors noted. In addition, GLP-1 RAs are contraindicated in some situations, such as in those with a history of serious hypersensitivity, and in patients with a personal or family history of either medullary thyroid carcinoma or multiple endocrine neoplasia syndrome type 2 based on animal studies showing an association with the medications and thyroid C–cell tumors.
Other FDA-approved medication options for obesity in children include metformin, topiramate, and phentermine, as well as bupropion, lisdexamfetamine, and setmelanotide, the authors said.
Resmetirom, a thyroid hormone receptor-beta agonist, which is another significant breakthrough in MASLD for adults, has not yet been tested or approved for pediatric use.
In addition to medications, metabolic bariatric surgery has shown effectiveness in children with obesity and/or MASLD by reducing liver fat and reversing fibrosis, as shown in the Teen-LABS study, the authors wrote. However, long-term data on fibrosis reversal are limited, and cost and access remain barriers.
More Research Needed
The joint expert review is intended as an educational tool that may require updates and should not be interpreted as rules for individual patient care, the authors cautioned. And physical activity and nutrition remain the primary treatment of MASLD and should be continued in conjunction with other treatment modalities, they emphasized.
Looking ahead, research is needed to develop accurate and reliable noninvasive biomarkers to diagnose and assess obesity treatment efficacy, Panganiban told GI & Hepatology News.
Also needed are multicenter randomized control trials in children with obesity involving different medications that have been successful in the treatment of metabolic dysfunction–associated steatohepatitis/fibrosis in adults, such as GLP-1 RAs or resmetirom, she added.
Educating Clinicians on Early Identification
When obesity occurs in childhood, it starts a process of additional complications that arise in earlier ages in adults, said Saul J. Karpen, MD, chief scientific officer at the Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University, Richmond, Virginia, in an interview.“Given the epidemic of obesity, altered diets, and reduced physical activities during younger ages, it is not easy to identify which children are at greater risk of MASLD,” said Karpen.
“It requires insight from the care providers and often imaging, a blood test, or a referral to a pediatric hepatologist, and not every region has easy access to such expertise,” Karpen said.
The new review is important because it highlights the fact that obesity and its consequences are not limited to adulthood, and that educated clinicians are in a position to get an early start on treatment in children, Karpen noted.
The guideline received no outside funding. Panganiban and Karpen had no financial conflicts to disclose.
A version of this article appeared on Medscape.com.
Key Blood Proteins Predict MASLD Up to 16 Years in Advance
SAN DIEGO –
“This represents the first high-performance, ultra-early (16 years) predictive model for MASLD,” said first author Shiyi Yu, MD, resident physician in the department of gastroenterology, Guangdong Provincial People’s Hospital in China.
“The findings could be a game-changer for how we screen for and intervene in liver disease,” Yu said at a press briefing for Digestive Disease Week® (DDW) 2025.
“Instead of waiting for symptoms or irreversible damage, we can [identify] high-risk individuals early and take steps to prevent MASLD from developing, which is particularly important because MASLD often progresses silently until advanced stages,” she added.
MASLD is the most common liver disorder in the world and carries a high risk of morbidity and mortality, with a mortality rate that is doubled compared with those without MASLD.
To identify any long-term predictive markers that could be used in simple predictive models, Yu and colleagues evaluated data on 52,952 participants enrolled in the UK Biobank between 2006 and 2010 who did not have MASLD at baseline and were followed up for up to 16.6 years.
Overall, 782 participants were diagnosed with MASLD over the course of the study.
A total of 2,737 blood proteins were analyzed, and among them, the five that emerged as being robust predictive biomarkers for development of MASLD within 5 years included CDHR2 (area under the curve [AUC] = 0.825), FUOM (AUC = 0.815), KRT18 (AUC = 0.810), ACY1 (AUC = 0.803), and GGT1 (AUC = 0.797).
Deviations of the proteins in plasma concentrations were observed up to 16 years prior to MASLD onset, with higher levels of the proteins at baseline associated with up to a nearly 10-times higher risk of MASLD (hazard ratios, 7.05-9.81).
A combination of the five proteins was predictive of incident MASLD at all time frames, including at 5-years (AUC = 0.857), 10-years (AUC = 0.775), and at all time points (AUC = 0.758).
The combined proteins gained even stronger predictive performance when added to key clinical biomarkers such as BMI and daily exercise, with an accuracy of 90.4% at 5 years and 82.2% at 16 years, “surpassing all existing short-term prediction models,” Yu reported.
Similar results were observed with the predictive model in a separate, smaller cohort of 100 participants in China, “further supporting the robustness of the model and showing it can be effective across diverse populations,” she noted in the press briefing.
Potential for Interventions ‘Years Before’ Damage Begins
Yu underscored the potential benefits of informing patients of their risk of MASLD.
“Too often, people do not find out they are at risk for liver disease before they are diagnosed and coping with symptoms,” she said.
A protein-based risk score could “profoundly transform early intervention strategies, triggering personalized lifestyle interventions for high-risk individuals” she said.
With obesity, type 2 diabetes, and high cholesterol levels among key risk factors for MASLD, such personalized interventions could include “counseling on diet, physical activity, and other factors years before liver damage begins, potentially averting disease progression altogether,” Yu noted.
Instead of waiting for abnormal liver function tests or imaging findings, patients could receive more frequent monitoring with annual elastography or ultrasound, for example, she explained.
In addition, “knowing one’s individualized protein-based risk may be more effective than abstract measures such as BMI or liver enzymes in motivating patients, facilitating better patient engagement and adherence,” Yu said.While noting that more work is needed to understand the biology behind the biomarkers, Yu underscored that “this is a big step toward personalized prevention.”
“By finding at-risk patients early, we hope to help stop MASLD before it starts,” she concluded.
Predictive Performance Impressive
Commenting on the study at the press briefing, Loren A. Laine, MD, AGAF, professor of medicine and chief of the Section of Digestive Diseases at the Yale School of Medicine, New Haven, Conn., and council chair of DDW 2025, noted that — as far as AUCs go — even a ranking in the 80% range is considered good. “So, for this to have an accuracy up to the 90s indicates a really excellent [predictive] performance,” he explained.
Laine agreed that the study findings have “the potential value to identify individuals at increased risk,” allowing for early monitoring and interventions.
The interventions “could be either general, such as things like diet and lifestyle, or more specific,” based on the function of these proteins, he added.
Rotonya Carr, MD, the division head of gastroenterology at the University of Washington, Seattle, further highlighted the pressing need for better predictive tools in MASLD.
“The predictions are that if we don’t do anything, as many as 122 million people will be impacted by MASLD” in the US by 2050, she told GI & Hepatology News.
“So, I am very excited about this work because we really don’t have anything right now that predicts who is going to get MASLD,” she said. “We are going to need tools like this, where people have information about their future health in order to make decisions.”
MASLD is known to be a significant risk factor for cardiovascular disease (CVD), and Carr speculated that the findings could lead to the types of predictive tools already available for CVD.
“I see this as being akin to what cardiology has had for quite some time, where they have cardiovascular risk disease calculators in which patients or their physicians can enter data and then estimate their risk of developing cardiovascular disease over, for instance, 10 years,” she said.
Laine’s disclosures include consulting and/or relationships with Medtronic, Phathom Pharmaceuticals, Biohaven, Celgene, Intercept, Merck, and Pfizer. Carr’s disclosures include relationships with Intercept and Novo Nordisk and research funding from Merck.
A version of this article appeared on Medscape.com.
SAN DIEGO –
“This represents the first high-performance, ultra-early (16 years) predictive model for MASLD,” said first author Shiyi Yu, MD, resident physician in the department of gastroenterology, Guangdong Provincial People’s Hospital in China.
“The findings could be a game-changer for how we screen for and intervene in liver disease,” Yu said at a press briefing for Digestive Disease Week® (DDW) 2025.
“Instead of waiting for symptoms or irreversible damage, we can [identify] high-risk individuals early and take steps to prevent MASLD from developing, which is particularly important because MASLD often progresses silently until advanced stages,” she added.
MASLD is the most common liver disorder in the world and carries a high risk of morbidity and mortality, with a mortality rate that is doubled compared with those without MASLD.
To identify any long-term predictive markers that could be used in simple predictive models, Yu and colleagues evaluated data on 52,952 participants enrolled in the UK Biobank between 2006 and 2010 who did not have MASLD at baseline and were followed up for up to 16.6 years.
Overall, 782 participants were diagnosed with MASLD over the course of the study.
A total of 2,737 blood proteins were analyzed, and among them, the five that emerged as being robust predictive biomarkers for development of MASLD within 5 years included CDHR2 (area under the curve [AUC] = 0.825), FUOM (AUC = 0.815), KRT18 (AUC = 0.810), ACY1 (AUC = 0.803), and GGT1 (AUC = 0.797).
Deviations of the proteins in plasma concentrations were observed up to 16 years prior to MASLD onset, with higher levels of the proteins at baseline associated with up to a nearly 10-times higher risk of MASLD (hazard ratios, 7.05-9.81).
A combination of the five proteins was predictive of incident MASLD at all time frames, including at 5-years (AUC = 0.857), 10-years (AUC = 0.775), and at all time points (AUC = 0.758).
The combined proteins gained even stronger predictive performance when added to key clinical biomarkers such as BMI and daily exercise, with an accuracy of 90.4% at 5 years and 82.2% at 16 years, “surpassing all existing short-term prediction models,” Yu reported.
Similar results were observed with the predictive model in a separate, smaller cohort of 100 participants in China, “further supporting the robustness of the model and showing it can be effective across diverse populations,” she noted in the press briefing.
Potential for Interventions ‘Years Before’ Damage Begins
Yu underscored the potential benefits of informing patients of their risk of MASLD.
“Too often, people do not find out they are at risk for liver disease before they are diagnosed and coping with symptoms,” she said.
A protein-based risk score could “profoundly transform early intervention strategies, triggering personalized lifestyle interventions for high-risk individuals” she said.
With obesity, type 2 diabetes, and high cholesterol levels among key risk factors for MASLD, such personalized interventions could include “counseling on diet, physical activity, and other factors years before liver damage begins, potentially averting disease progression altogether,” Yu noted.
Instead of waiting for abnormal liver function tests or imaging findings, patients could receive more frequent monitoring with annual elastography or ultrasound, for example, she explained.
In addition, “knowing one’s individualized protein-based risk may be more effective than abstract measures such as BMI or liver enzymes in motivating patients, facilitating better patient engagement and adherence,” Yu said.While noting that more work is needed to understand the biology behind the biomarkers, Yu underscored that “this is a big step toward personalized prevention.”
“By finding at-risk patients early, we hope to help stop MASLD before it starts,” she concluded.
Predictive Performance Impressive
Commenting on the study at the press briefing, Loren A. Laine, MD, AGAF, professor of medicine and chief of the Section of Digestive Diseases at the Yale School of Medicine, New Haven, Conn., and council chair of DDW 2025, noted that — as far as AUCs go — even a ranking in the 80% range is considered good. “So, for this to have an accuracy up to the 90s indicates a really excellent [predictive] performance,” he explained.
Laine agreed that the study findings have “the potential value to identify individuals at increased risk,” allowing for early monitoring and interventions.
The interventions “could be either general, such as things like diet and lifestyle, or more specific,” based on the function of these proteins, he added.
Rotonya Carr, MD, the division head of gastroenterology at the University of Washington, Seattle, further highlighted the pressing need for better predictive tools in MASLD.
“The predictions are that if we don’t do anything, as many as 122 million people will be impacted by MASLD” in the US by 2050, she told GI & Hepatology News.
“So, I am very excited about this work because we really don’t have anything right now that predicts who is going to get MASLD,” she said. “We are going to need tools like this, where people have information about their future health in order to make decisions.”
MASLD is known to be a significant risk factor for cardiovascular disease (CVD), and Carr speculated that the findings could lead to the types of predictive tools already available for CVD.
“I see this as being akin to what cardiology has had for quite some time, where they have cardiovascular risk disease calculators in which patients or their physicians can enter data and then estimate their risk of developing cardiovascular disease over, for instance, 10 years,” she said.
Laine’s disclosures include consulting and/or relationships with Medtronic, Phathom Pharmaceuticals, Biohaven, Celgene, Intercept, Merck, and Pfizer. Carr’s disclosures include relationships with Intercept and Novo Nordisk and research funding from Merck.
A version of this article appeared on Medscape.com.
SAN DIEGO –
“This represents the first high-performance, ultra-early (16 years) predictive model for MASLD,” said first author Shiyi Yu, MD, resident physician in the department of gastroenterology, Guangdong Provincial People’s Hospital in China.
“The findings could be a game-changer for how we screen for and intervene in liver disease,” Yu said at a press briefing for Digestive Disease Week® (DDW) 2025.
“Instead of waiting for symptoms or irreversible damage, we can [identify] high-risk individuals early and take steps to prevent MASLD from developing, which is particularly important because MASLD often progresses silently until advanced stages,” she added.
MASLD is the most common liver disorder in the world and carries a high risk of morbidity and mortality, with a mortality rate that is doubled compared with those without MASLD.
To identify any long-term predictive markers that could be used in simple predictive models, Yu and colleagues evaluated data on 52,952 participants enrolled in the UK Biobank between 2006 and 2010 who did not have MASLD at baseline and were followed up for up to 16.6 years.
Overall, 782 participants were diagnosed with MASLD over the course of the study.
A total of 2,737 blood proteins were analyzed, and among them, the five that emerged as being robust predictive biomarkers for development of MASLD within 5 years included CDHR2 (area under the curve [AUC] = 0.825), FUOM (AUC = 0.815), KRT18 (AUC = 0.810), ACY1 (AUC = 0.803), and GGT1 (AUC = 0.797).
Deviations of the proteins in plasma concentrations were observed up to 16 years prior to MASLD onset, with higher levels of the proteins at baseline associated with up to a nearly 10-times higher risk of MASLD (hazard ratios, 7.05-9.81).
A combination of the five proteins was predictive of incident MASLD at all time frames, including at 5-years (AUC = 0.857), 10-years (AUC = 0.775), and at all time points (AUC = 0.758).
The combined proteins gained even stronger predictive performance when added to key clinical biomarkers such as BMI and daily exercise, with an accuracy of 90.4% at 5 years and 82.2% at 16 years, “surpassing all existing short-term prediction models,” Yu reported.
Similar results were observed with the predictive model in a separate, smaller cohort of 100 participants in China, “further supporting the robustness of the model and showing it can be effective across diverse populations,” she noted in the press briefing.
Potential for Interventions ‘Years Before’ Damage Begins
Yu underscored the potential benefits of informing patients of their risk of MASLD.
“Too often, people do not find out they are at risk for liver disease before they are diagnosed and coping with symptoms,” she said.
A protein-based risk score could “profoundly transform early intervention strategies, triggering personalized lifestyle interventions for high-risk individuals” she said.
With obesity, type 2 diabetes, and high cholesterol levels among key risk factors for MASLD, such personalized interventions could include “counseling on diet, physical activity, and other factors years before liver damage begins, potentially averting disease progression altogether,” Yu noted.
Instead of waiting for abnormal liver function tests or imaging findings, patients could receive more frequent monitoring with annual elastography or ultrasound, for example, she explained.
In addition, “knowing one’s individualized protein-based risk may be more effective than abstract measures such as BMI or liver enzymes in motivating patients, facilitating better patient engagement and adherence,” Yu said.While noting that more work is needed to understand the biology behind the biomarkers, Yu underscored that “this is a big step toward personalized prevention.”
“By finding at-risk patients early, we hope to help stop MASLD before it starts,” she concluded.
Predictive Performance Impressive
Commenting on the study at the press briefing, Loren A. Laine, MD, AGAF, professor of medicine and chief of the Section of Digestive Diseases at the Yale School of Medicine, New Haven, Conn., and council chair of DDW 2025, noted that — as far as AUCs go — even a ranking in the 80% range is considered good. “So, for this to have an accuracy up to the 90s indicates a really excellent [predictive] performance,” he explained.
Laine agreed that the study findings have “the potential value to identify individuals at increased risk,” allowing for early monitoring and interventions.
The interventions “could be either general, such as things like diet and lifestyle, or more specific,” based on the function of these proteins, he added.
Rotonya Carr, MD, the division head of gastroenterology at the University of Washington, Seattle, further highlighted the pressing need for better predictive tools in MASLD.
“The predictions are that if we don’t do anything, as many as 122 million people will be impacted by MASLD” in the US by 2050, she told GI & Hepatology News.
“So, I am very excited about this work because we really don’t have anything right now that predicts who is going to get MASLD,” she said. “We are going to need tools like this, where people have information about their future health in order to make decisions.”
MASLD is known to be a significant risk factor for cardiovascular disease (CVD), and Carr speculated that the findings could lead to the types of predictive tools already available for CVD.
“I see this as being akin to what cardiology has had for quite some time, where they have cardiovascular risk disease calculators in which patients or their physicians can enter data and then estimate their risk of developing cardiovascular disease over, for instance, 10 years,” she said.
Laine’s disclosures include consulting and/or relationships with Medtronic, Phathom Pharmaceuticals, Biohaven, Celgene, Intercept, Merck, and Pfizer. Carr’s disclosures include relationships with Intercept and Novo Nordisk and research funding from Merck.
A version of this article appeared on Medscape.com.
FROM DDW 2025
Auto-Brewery Syndrome Explained: New Patient Cohort Identifies Culprit Bacteria, Fermentation
WASHINGTON — When a published case of auto-brewery syndrome (ABS) in China — caused by Klebsiella pneumoniae — received widespread publicity in 2019, patients reacted, sending emails to lead author Jing Yuan, in Beijing, China. Many of these inquiries were from patients in the United States who believed they might have ABS.
“Can you check to see if I have ABS?” patients asked Yuan.
For help, Yuan contacted Bernd Schnabl, MD, AGAF, at the University of California, San Diego, whose research was addressing alcohol-associated liver disease and who was also interested in the gut-liver axis and the role of gut microbiome–derived ethanol in metabolic dysfunction–associated steatotic liver disease (MASLD).
“She asked me, ‘Are you interested in looking into ABS?” Schnabl recalled at the Gut Microbiota for Health (GMFH) World Summit 2025. He dug in and formed what may be the largest research cohort thus far of patients with ABS — a group of 22 patients with their diagnosis confirmed through observed glucose challenge.
His soon-to-be-published
ABS is considered a rare condition, but “I’d argue that it’s rarely diagnosed because many physicians don’t know of the diagnosis, and many are actually very skeptical about the disease,” Schnabl said at the meeting, convened by AGA and the European Society of Neurogastroenterology and Motility.
Patients experience symptoms of intoxication when ethanol produced by dysregulated gut microbiota exceeds the capacity of the liver to metabolize it and accumulates in the blood, he explained.
“Patients constantly talk about brain fog; they can’t concentrate, and it can be very severe,” he said. “They don’t get a firm diagnosis and go from one medical center to another, and they also suffer from complications of alcohol use disorder including serious family, social, and legal problems.”
Advancing Knowledge, Findings From the Cohort
The phenomenon of ethanol production by gut microbiota has been known for over a century, Schnabl wrote with two co-authors in a 2024 review in Nature Reviews Gastroenterology & Hepatology of “endogenous ethanol production in health and disease.”
And in recent decades, he said at the meeting, research has linked endogenous ethanol production to MASLD, positioning it as a potential contributor to disease pathogenesis. In one of the most recently published studies, patients with MASLD had higher concentrations of ethanol in their systemic circulation after a mixed meal test than did healthy controls — and even higher ethanol concentrations in their portal vein blood, “suggesting that this ethanol is coming from the gut microbiome,” Schnabl said.
The paper from China that led Schnabl to establish his cohort was spurred on by a patient with both ABS and MASLD cirrhosis. The patient was found to have strains of high alcohol–producing K pneumoniae in the gut microbiome. When the researchers transplanted these strains into mice via fecal microbiota transplantation (FMT), the mice developed MASLD.
Schnabl’s study focused just on ABS, which is alternatively sometimes called gut fermentation syndrome. The 22 patients in his ABS cohort — each of whom provided stool samples corresponding to remission or flare of ABS symptoms — had a median age of 45 years and were predominantly men, slightly overweight and not obese, and without liver disease. (About 48 patients with suspected ABS were screened, and 20 were excluded after an observed glucose challenge failed to establish a diagnosis; 6 withdrew from the study.)
During remission (no symptoms), patients’ mean blood alcohol content (BAC) level was zero, but during a flare, the mean BAC level was 136 mg/dL. “To put it into perspective, the legal limit for driving in the US is 80 mg/dL,” Schnabl said. Within a mean of 4 hours after the oral glucose load used for diagnosis, patients’ mean BAC level was 73 mg/dL, he noted.
To assess ethanol production by the patients’ microbiota, Schnabl and his team cultured the stool samples — anaerobically adding glucose and measuring ethanol production — and compared the results with findings from stool samples collected from household partners who generally were of the opposite sex. Among their findings: cultures of stool from patients experiencing a flare produced significantly more ethanol than stool from household partners and samples from patients in remission.
To assess whether ethanol was produced by bacteria or fungi, the researchers measured ethanol production in cultures treated with either the antifungal amphotericin B or the antibiotic chloramphenicol. “Chloramphenicol clearly decreased the ethanol production,” Schnabl said. “So at least in this culture test, bacteria produced most of the alcohol in our patients.”
Taxonomic profiling, moreover, revealed “significantly elevated levels” of proteobacteria — with relative abundance of Escherichia coli and K pneumoniae — in patients who were flaring, he said. And functional profiling of the fecal microbiota showed much higher activity of fermentation pathways during patients’ flares than in household partners or healthy controls. (Healthy controls were incorporated into the taxonomic and functional profiling parts of the research.)
A Clinical Approach to ABS
Schnabl said at the meeting that stool cultures of both household partners and patients in long-term remission “all produced some low amount of ethanol, which was initially puzzling to us” but became less surprising as he and his colleagues reviewed more of the literature.
Asked during a discussion period whether ABS could explain chronic fatigue, a commonly reported chronic symptom in populations, Schnabl said it’s possible. And in an interview after the meeting, he elaborated. “The literature clearly says ABS is a rare disease, but I argue that more patients may have ABS; they just don’t know it. And I suspect some may have mild symptoms, like brain fog, feeling tired,” he said. “But at this point, this is complete speculation.”
Physicians should “be aware that if a patient has unexplained symptoms that could be aligned with ABS, checking the blood alcohol level” may be warranted, he said in the interview. A PEth (phosphatidylethanol) test — a biomarker test used to check for longer-term alcohol consumption — is an option, but it is important to appreciate it will not discriminate between exogenous alcohol drinking and endogenous ethanol production.
There are no standardized diagnostic tests for ABS, but at the meeting, Schnabl outlined a clinical approach, starting with a standardized oral glucose tolerance challenge test to detect elevated ethanol concentrations.
A fecal yeast test is warranted for diagnosed patients on the basis of some case reports in which ABS symptoms have improved with antifungal treatments. When the fecal yeast test is negative, “ideally you want to identify the ethanol-producing intestinal bacteria in the patient,” he said, using cultures and fecal metagenomics sequencing.
Treatment could then be tailored to the identified microbial strain, with options being selective antibiotics, probiotics and/or prebiotics, and — likely in the future — phages or FMT, he said. (These options, all aimed at restoring gut homeostasis, are also discussed in his 2024 review.)
Schnabl and his team recently performed FMT in a patient with ABS in whom E coli was determined to be producing excessive ethanol. The FMT, performed after antibiotic pretreatment, resulted in decreases in the relative abundance of proteobacteria and E coli levels, lower blood alcohol levels and fermentation enrichment pathways, and normalized liver enzymes.
After 6 months, however, the patient relapsed, and the measurements reversed. “We decided to do FMT every month, and we treated the patient for 6 months,” Schnabl said, noting that ABS had rendered the patient dysfunctional and unable to work. “He has been out of treatment for over a year now and is not flaring any longer.”
Schnabl and Elizabeth Hohmann, MD, at Massachusetts General Hospital, Boston, are currently recruiting patients with confirmed ABS for a National Institutes of Health–funded phase 1 safety and tolerability study of FMT for ABS.
Schnabl disclosed serving as an external scientific advisor/consultant to Ambys Medicines, Boehringer Ingelheim, Gelesis, Mabwell Therapeutics, Surrozen, and Takeda; and as the founder/BOD/BEO of Nterica Bio.
A version of this article appeared on Medscape.com.
WASHINGTON — When a published case of auto-brewery syndrome (ABS) in China — caused by Klebsiella pneumoniae — received widespread publicity in 2019, patients reacted, sending emails to lead author Jing Yuan, in Beijing, China. Many of these inquiries were from patients in the United States who believed they might have ABS.
“Can you check to see if I have ABS?” patients asked Yuan.
For help, Yuan contacted Bernd Schnabl, MD, AGAF, at the University of California, San Diego, whose research was addressing alcohol-associated liver disease and who was also interested in the gut-liver axis and the role of gut microbiome–derived ethanol in metabolic dysfunction–associated steatotic liver disease (MASLD).
“She asked me, ‘Are you interested in looking into ABS?” Schnabl recalled at the Gut Microbiota for Health (GMFH) World Summit 2025. He dug in and formed what may be the largest research cohort thus far of patients with ABS — a group of 22 patients with their diagnosis confirmed through observed glucose challenge.
His soon-to-be-published
ABS is considered a rare condition, but “I’d argue that it’s rarely diagnosed because many physicians don’t know of the diagnosis, and many are actually very skeptical about the disease,” Schnabl said at the meeting, convened by AGA and the European Society of Neurogastroenterology and Motility.
Patients experience symptoms of intoxication when ethanol produced by dysregulated gut microbiota exceeds the capacity of the liver to metabolize it and accumulates in the blood, he explained.
“Patients constantly talk about brain fog; they can’t concentrate, and it can be very severe,” he said. “They don’t get a firm diagnosis and go from one medical center to another, and they also suffer from complications of alcohol use disorder including serious family, social, and legal problems.”
Advancing Knowledge, Findings From the Cohort
The phenomenon of ethanol production by gut microbiota has been known for over a century, Schnabl wrote with two co-authors in a 2024 review in Nature Reviews Gastroenterology & Hepatology of “endogenous ethanol production in health and disease.”
And in recent decades, he said at the meeting, research has linked endogenous ethanol production to MASLD, positioning it as a potential contributor to disease pathogenesis. In one of the most recently published studies, patients with MASLD had higher concentrations of ethanol in their systemic circulation after a mixed meal test than did healthy controls — and even higher ethanol concentrations in their portal vein blood, “suggesting that this ethanol is coming from the gut microbiome,” Schnabl said.
The paper from China that led Schnabl to establish his cohort was spurred on by a patient with both ABS and MASLD cirrhosis. The patient was found to have strains of high alcohol–producing K pneumoniae in the gut microbiome. When the researchers transplanted these strains into mice via fecal microbiota transplantation (FMT), the mice developed MASLD.
Schnabl’s study focused just on ABS, which is alternatively sometimes called gut fermentation syndrome. The 22 patients in his ABS cohort — each of whom provided stool samples corresponding to remission or flare of ABS symptoms — had a median age of 45 years and were predominantly men, slightly overweight and not obese, and without liver disease. (About 48 patients with suspected ABS were screened, and 20 were excluded after an observed glucose challenge failed to establish a diagnosis; 6 withdrew from the study.)
During remission (no symptoms), patients’ mean blood alcohol content (BAC) level was zero, but during a flare, the mean BAC level was 136 mg/dL. “To put it into perspective, the legal limit for driving in the US is 80 mg/dL,” Schnabl said. Within a mean of 4 hours after the oral glucose load used for diagnosis, patients’ mean BAC level was 73 mg/dL, he noted.
To assess ethanol production by the patients’ microbiota, Schnabl and his team cultured the stool samples — anaerobically adding glucose and measuring ethanol production — and compared the results with findings from stool samples collected from household partners who generally were of the opposite sex. Among their findings: cultures of stool from patients experiencing a flare produced significantly more ethanol than stool from household partners and samples from patients in remission.
To assess whether ethanol was produced by bacteria or fungi, the researchers measured ethanol production in cultures treated with either the antifungal amphotericin B or the antibiotic chloramphenicol. “Chloramphenicol clearly decreased the ethanol production,” Schnabl said. “So at least in this culture test, bacteria produced most of the alcohol in our patients.”
Taxonomic profiling, moreover, revealed “significantly elevated levels” of proteobacteria — with relative abundance of Escherichia coli and K pneumoniae — in patients who were flaring, he said. And functional profiling of the fecal microbiota showed much higher activity of fermentation pathways during patients’ flares than in household partners or healthy controls. (Healthy controls were incorporated into the taxonomic and functional profiling parts of the research.)
A Clinical Approach to ABS
Schnabl said at the meeting that stool cultures of both household partners and patients in long-term remission “all produced some low amount of ethanol, which was initially puzzling to us” but became less surprising as he and his colleagues reviewed more of the literature.
Asked during a discussion period whether ABS could explain chronic fatigue, a commonly reported chronic symptom in populations, Schnabl said it’s possible. And in an interview after the meeting, he elaborated. “The literature clearly says ABS is a rare disease, but I argue that more patients may have ABS; they just don’t know it. And I suspect some may have mild symptoms, like brain fog, feeling tired,” he said. “But at this point, this is complete speculation.”
Physicians should “be aware that if a patient has unexplained symptoms that could be aligned with ABS, checking the blood alcohol level” may be warranted, he said in the interview. A PEth (phosphatidylethanol) test — a biomarker test used to check for longer-term alcohol consumption — is an option, but it is important to appreciate it will not discriminate between exogenous alcohol drinking and endogenous ethanol production.
There are no standardized diagnostic tests for ABS, but at the meeting, Schnabl outlined a clinical approach, starting with a standardized oral glucose tolerance challenge test to detect elevated ethanol concentrations.
A fecal yeast test is warranted for diagnosed patients on the basis of some case reports in which ABS symptoms have improved with antifungal treatments. When the fecal yeast test is negative, “ideally you want to identify the ethanol-producing intestinal bacteria in the patient,” he said, using cultures and fecal metagenomics sequencing.
Treatment could then be tailored to the identified microbial strain, with options being selective antibiotics, probiotics and/or prebiotics, and — likely in the future — phages or FMT, he said. (These options, all aimed at restoring gut homeostasis, are also discussed in his 2024 review.)
Schnabl and his team recently performed FMT in a patient with ABS in whom E coli was determined to be producing excessive ethanol. The FMT, performed after antibiotic pretreatment, resulted in decreases in the relative abundance of proteobacteria and E coli levels, lower blood alcohol levels and fermentation enrichment pathways, and normalized liver enzymes.
After 6 months, however, the patient relapsed, and the measurements reversed. “We decided to do FMT every month, and we treated the patient for 6 months,” Schnabl said, noting that ABS had rendered the patient dysfunctional and unable to work. “He has been out of treatment for over a year now and is not flaring any longer.”
Schnabl and Elizabeth Hohmann, MD, at Massachusetts General Hospital, Boston, are currently recruiting patients with confirmed ABS for a National Institutes of Health–funded phase 1 safety and tolerability study of FMT for ABS.
Schnabl disclosed serving as an external scientific advisor/consultant to Ambys Medicines, Boehringer Ingelheim, Gelesis, Mabwell Therapeutics, Surrozen, and Takeda; and as the founder/BOD/BEO of Nterica Bio.
A version of this article appeared on Medscape.com.
WASHINGTON — When a published case of auto-brewery syndrome (ABS) in China — caused by Klebsiella pneumoniae — received widespread publicity in 2019, patients reacted, sending emails to lead author Jing Yuan, in Beijing, China. Many of these inquiries were from patients in the United States who believed they might have ABS.
“Can you check to see if I have ABS?” patients asked Yuan.
For help, Yuan contacted Bernd Schnabl, MD, AGAF, at the University of California, San Diego, whose research was addressing alcohol-associated liver disease and who was also interested in the gut-liver axis and the role of gut microbiome–derived ethanol in metabolic dysfunction–associated steatotic liver disease (MASLD).
“She asked me, ‘Are you interested in looking into ABS?” Schnabl recalled at the Gut Microbiota for Health (GMFH) World Summit 2025. He dug in and formed what may be the largest research cohort thus far of patients with ABS — a group of 22 patients with their diagnosis confirmed through observed glucose challenge.
His soon-to-be-published
ABS is considered a rare condition, but “I’d argue that it’s rarely diagnosed because many physicians don’t know of the diagnosis, and many are actually very skeptical about the disease,” Schnabl said at the meeting, convened by AGA and the European Society of Neurogastroenterology and Motility.
Patients experience symptoms of intoxication when ethanol produced by dysregulated gut microbiota exceeds the capacity of the liver to metabolize it and accumulates in the blood, he explained.
“Patients constantly talk about brain fog; they can’t concentrate, and it can be very severe,” he said. “They don’t get a firm diagnosis and go from one medical center to another, and they also suffer from complications of alcohol use disorder including serious family, social, and legal problems.”
Advancing Knowledge, Findings From the Cohort
The phenomenon of ethanol production by gut microbiota has been known for over a century, Schnabl wrote with two co-authors in a 2024 review in Nature Reviews Gastroenterology & Hepatology of “endogenous ethanol production in health and disease.”
And in recent decades, he said at the meeting, research has linked endogenous ethanol production to MASLD, positioning it as a potential contributor to disease pathogenesis. In one of the most recently published studies, patients with MASLD had higher concentrations of ethanol in their systemic circulation after a mixed meal test than did healthy controls — and even higher ethanol concentrations in their portal vein blood, “suggesting that this ethanol is coming from the gut microbiome,” Schnabl said.
The paper from China that led Schnabl to establish his cohort was spurred on by a patient with both ABS and MASLD cirrhosis. The patient was found to have strains of high alcohol–producing K pneumoniae in the gut microbiome. When the researchers transplanted these strains into mice via fecal microbiota transplantation (FMT), the mice developed MASLD.
Schnabl’s study focused just on ABS, which is alternatively sometimes called gut fermentation syndrome. The 22 patients in his ABS cohort — each of whom provided stool samples corresponding to remission or flare of ABS symptoms — had a median age of 45 years and were predominantly men, slightly overweight and not obese, and without liver disease. (About 48 patients with suspected ABS were screened, and 20 were excluded after an observed glucose challenge failed to establish a diagnosis; 6 withdrew from the study.)
During remission (no symptoms), patients’ mean blood alcohol content (BAC) level was zero, but during a flare, the mean BAC level was 136 mg/dL. “To put it into perspective, the legal limit for driving in the US is 80 mg/dL,” Schnabl said. Within a mean of 4 hours after the oral glucose load used for diagnosis, patients’ mean BAC level was 73 mg/dL, he noted.
To assess ethanol production by the patients’ microbiota, Schnabl and his team cultured the stool samples — anaerobically adding glucose and measuring ethanol production — and compared the results with findings from stool samples collected from household partners who generally were of the opposite sex. Among their findings: cultures of stool from patients experiencing a flare produced significantly more ethanol than stool from household partners and samples from patients in remission.
To assess whether ethanol was produced by bacteria or fungi, the researchers measured ethanol production in cultures treated with either the antifungal amphotericin B or the antibiotic chloramphenicol. “Chloramphenicol clearly decreased the ethanol production,” Schnabl said. “So at least in this culture test, bacteria produced most of the alcohol in our patients.”
Taxonomic profiling, moreover, revealed “significantly elevated levels” of proteobacteria — with relative abundance of Escherichia coli and K pneumoniae — in patients who were flaring, he said. And functional profiling of the fecal microbiota showed much higher activity of fermentation pathways during patients’ flares than in household partners or healthy controls. (Healthy controls were incorporated into the taxonomic and functional profiling parts of the research.)
A Clinical Approach to ABS
Schnabl said at the meeting that stool cultures of both household partners and patients in long-term remission “all produced some low amount of ethanol, which was initially puzzling to us” but became less surprising as he and his colleagues reviewed more of the literature.
Asked during a discussion period whether ABS could explain chronic fatigue, a commonly reported chronic symptom in populations, Schnabl said it’s possible. And in an interview after the meeting, he elaborated. “The literature clearly says ABS is a rare disease, but I argue that more patients may have ABS; they just don’t know it. And I suspect some may have mild symptoms, like brain fog, feeling tired,” he said. “But at this point, this is complete speculation.”
Physicians should “be aware that if a patient has unexplained symptoms that could be aligned with ABS, checking the blood alcohol level” may be warranted, he said in the interview. A PEth (phosphatidylethanol) test — a biomarker test used to check for longer-term alcohol consumption — is an option, but it is important to appreciate it will not discriminate between exogenous alcohol drinking and endogenous ethanol production.
There are no standardized diagnostic tests for ABS, but at the meeting, Schnabl outlined a clinical approach, starting with a standardized oral glucose tolerance challenge test to detect elevated ethanol concentrations.
A fecal yeast test is warranted for diagnosed patients on the basis of some case reports in which ABS symptoms have improved with antifungal treatments. When the fecal yeast test is negative, “ideally you want to identify the ethanol-producing intestinal bacteria in the patient,” he said, using cultures and fecal metagenomics sequencing.
Treatment could then be tailored to the identified microbial strain, with options being selective antibiotics, probiotics and/or prebiotics, and — likely in the future — phages or FMT, he said. (These options, all aimed at restoring gut homeostasis, are also discussed in his 2024 review.)
Schnabl and his team recently performed FMT in a patient with ABS in whom E coli was determined to be producing excessive ethanol. The FMT, performed after antibiotic pretreatment, resulted in decreases in the relative abundance of proteobacteria and E coli levels, lower blood alcohol levels and fermentation enrichment pathways, and normalized liver enzymes.
After 6 months, however, the patient relapsed, and the measurements reversed. “We decided to do FMT every month, and we treated the patient for 6 months,” Schnabl said, noting that ABS had rendered the patient dysfunctional and unable to work. “He has been out of treatment for over a year now and is not flaring any longer.”
Schnabl and Elizabeth Hohmann, MD, at Massachusetts General Hospital, Boston, are currently recruiting patients with confirmed ABS for a National Institutes of Health–funded phase 1 safety and tolerability study of FMT for ABS.
Schnabl disclosed serving as an external scientific advisor/consultant to Ambys Medicines, Boehringer Ingelheim, Gelesis, Mabwell Therapeutics, Surrozen, and Takeda; and as the founder/BOD/BEO of Nterica Bio.
A version of this article appeared on Medscape.com.
FROM GMFH 2025
The Extra-Bacterial Gut Ecosystem: The Influence of Phages and Fungi in the Microbiome
WASHINGTON, DC — Research on the gut microbiome — and clinical attention to it — has focused mainly on bacteria, but bacteriophages and fungi play critical roles as well, with significant influences on health and disease, experts said at the Gut Microbiota for Health (GMFH) World Summit 2025.
Fungi account for < 1% of the total genetic material in the microbiome but 1%-2% of its total biomass. “Despite their relative rarity, they have an important and outsized influence on gut health” — an impact that results from their unique interface with the immune system, said Kyla Ost, PhD, of the Anschutz Medical Campus, University of Colorado, in Denver, whose research focuses on this interface.
And bacteriophages — viruses that infect and kill bacteria — are highly abundant in the gut. “Bacteriophages begin to colonize our GI [gastrointestinal] tract at the same time we develop our own microbiome shortly after birth, and from that time on, they interact with the bacteria in our GI tract, shaping [and being shaped by] the bacterial species we carry with us,” said Robert (Chip) Schooley, MD, distinguished professor of medicine at the University of California San Diego School of Medicine.
“We’ve been talking about things that affect the gut microbiome — diet, genetics, immune response — but probably the biggest influence on what grows in the GI tract are bacteriophages,” said Schooley, co-director of the Center for Innovative Phage Applications and Therapeutics, in a session on the extra-bacterial gut ecosystem.
Among the current questions:
‘New life’ for Phage Therapy
Bacteriophages represent a promising approach for the treatment of multidrug resistant bacterial pathogens in an era of increasing resistance and a dried-up antibiotic discovery pipeline, Schooley said. (In 2019, an estimated 4.95 million deaths around the world were associated with bacterial antimicrobial resistance, and by 2050, it has been forecast that this number will rise to an estimated 8.22 million deaths.)
But in addition to suppressing bacterial pathogens causing direct morbidity, phage therapy has the potential to suppress bacteria believed to contribute to chronic diseases, he said. “We have proof-of-concept studies about the ability of phage to modulate bacteria in the digestive tract,” and an increasing number of clinical trials of the use of phages in GI and other diseases are underway, he said.
Phages were discovered just over a century ago, but phage therapy was widely abandoned once antibiotics were developed, except for in Russia and the former Eastern Bloc countries, where phage therapy continued to be used.
Phage therapy “got new life” in the West, Schooley said, about 10-15 years ago with an increasing number of detailed and high-profile case reports, including one in which a UC San Diego colleague, Tom Patterson, PhD, contracted a deadly multidrug resistant bacterial infection in Egypt and was eventually saved with bacteriophage therapy. (The case was the subject of the book The Perfect Predator).
Since then, as described in case reports and studies in the literature, “hundreds of people have been treated with bacteriophages here and in Europe,” most commonly for pulmonary infections and infections in implanted vascular and orthopedic devices, said Schooley, who coauthored a review in Cell in 2023 that describes phage biology and advances and future directions in phage therapy.
The use of bacteriophages to prevent systemic infections during high-risk periods — such as during chemotherapeutic regimens for hematological regimens — is an area of interest, he said at the meeting.
In research that is making its way to a clinical trial of patients undergoing allogeneic hematopoietic stem cell transplant (HSCT), researchers screened a library of phages to identify those with broad coverage of Escherichia coli. Using tail fiber engineering and CRISPR technology, they then engineered a combination of the four most complementary bacteriophages to selectively kill E coli — including fluoroquinolone-resistant strains that, in patients whose GI tracts are colonized with these strains, can translocate from the gut into the bloodstream, causing sepsis, during chemotherapeutic regimens for HSCT.
In a mouse model, the CRISPR-enhanced four-phage cocktail (SNIPR001) led to a steady reduction in the E coli colony counts in stool, “showing you can modulate these bacteria in the gut by using bacteriophages to kill them,” Schooley said. Moreover, the CRISPR enhancement strengthened the phages’ ability to break up biofilms, he said, showing “that you can engineer bacteriophages to make them better killers.” A phase 1b/2a study is being planned.
Other Niches for Therapeutic Phages, Challenges
Bacteriophages also could be used to target a gut bacterium that has been shown to attenuate alcoholic liver disease. Patients with alcoholic hepatitis “have a gut microbiome that is different in distribution,” Schooley said, often with increased numbers of Enterococcus faecalis that produce cytolysin, an exotoxin that exacerbates liver injury and is associated with increased mortality.
In published research led by investigators at UC San Diego, stool from cytolysin-positive patients with alcoholic hepatitis was found to exacerbate ethanol-induced liver disease in gnotobiotic mice, and phage therapy against cytolytic E faecalis was found to abolish it, Schooley shared.
Research is also exploring the potential of phage therapy to selectively target adherent invasive E coli in Crohn’s disease, and Klebsiella pneumoniae in the gut microbiome as an exacerbator of inflammatory bowel disease (IBD), he said.
And investigators in Japan, he noted, have reported that bacteriophage therapy against K pneumoniae can ameliorate liver inflammation and disease severity in primary sclerosing cholangitis.
Challenges in the therapeutic use of phages include the narrow host range of phages and an uncertain predictive value of in vitro phage susceptibility testing. “We don’t know yet how to do resistance testing as well as we do with antibiotics,” he said.
In addition, most phages tend to be acid labile, requiring strategies to mitigate inactivation by gastric acid, and there are “major knowledge gaps” relating to phage pharmacology. “We also know that adaptive immune responses to phages can but often doesn’t impact therapy, and we want to understand that better in clinical trials,” Schooley said.
Phages that have a “lysogenic” lifestyle — as opposed to lytic phages which are used therapeutically — can contribute to antibiotic resistance by facilitating the interchange of bacterial resistance genes, he noted.
A Window Into the Mycobiome
The human gut mycobiome is primarily composed of fungi in the Saccharomyces, Candida, and Malassezia genera, with Candida species dominating. Fungal cells harbor distinct immune-stimulatory molecules and activate distinct immune pathways compared with bacteria and other members of the microbiome, said Ost, assistant professor in the immunology and microbiology department of CU Anschutz.
Some fungi, including those in the Candida genus, activate adaptive and innate immune responses that promote metabolic health and protect against infection. A recently published study in Science, for instance, demonstrated that colonization with C dubliniensis in very young mice who had been exposed to broad-spectrum antibiotics promoted “the expansion and development of beta cells in the pancreas” in a macrophage dependent manner, improving metabolic health and reducing diabetes incidence, she shared.
On the one hand, fungi can “exacerbate and perpetuate the pathogenic inflammation that’s found in a growing list of inflammatory diseases” such as IBD. And “in fact, a lot of the benefits and detriments are driven by the exact same species of fungi,” said Ost. “This is particularly true of Candida,” which is a “lifelong colonizer of intestinal microbiota that rarely causes disease but can be quite pathogenic when it does.”
A 2023 review in Nature Reviews Gastroenterology & Hepatology coauthored by Ost describes the role of commensal fungi in intestinal diseases, including IBD, colorectal cancer, and pancreatic cancer.
The pathogenic potential of commensal fungi is largely dependent on its strain, its morphology and its expression of virulence factors, researchers are learning. Ost has studied C albicans, which has been associated with intestinal inflammation and IBD. Like some other Candida species, C albicans are “fascinating shape shifters,” she said, transitioning between a less pathogenic “yeast” morphology and an elongated, adhesive “hyphae” shape that is more pathogenic.
It turns out, according to research by Ost and others, that the C albicans hyphal morphotype — and the adhesins (sticky proteins that facilitate adherence to epithelial cells) and a cytolytic toxin it produces — are preferentially targeted and suppressed by immunoglobulin A (IgA) in the gut.
“Our gut is protected by a large quantity of IgA antibodies…and these IgA interact with the microbiota and play a big role in what microbes are there and the biology of the microbes,” Ost said. Indeed, symptomatic IgA deficiency in humans has been shown to be associated with C albicans overgrowth.
Leveraging the hyphal-specific IgA response to protect against disease seems possible, she said, referring to an experimental anti-Candida fungal vaccine (NDV-3A) designed to induce an adhesin-specific immune response. In a mouse model of colitis, the vaccine protected against C albicans-associated damage. “We saw an immediate IgA response that targeted C albicans in the intestinal contents,” Ost said.
C glabrata, which has also been associated with intestinal inflammation and IBD, does not form hyphae but — depending on the strain — may also induce intestinal IgA responses, she said in describing her recent research.
Ost reported having no disclosures. Schooley disclosed being a consultant for SNIPR Biome, BiomX, Locus, MicrobiotiX, Amazon Data Monitoring Committee: Merck.
A version of this article appeared on Medscape.com.
WASHINGTON, DC — Research on the gut microbiome — and clinical attention to it — has focused mainly on bacteria, but bacteriophages and fungi play critical roles as well, with significant influences on health and disease, experts said at the Gut Microbiota for Health (GMFH) World Summit 2025.
Fungi account for < 1% of the total genetic material in the microbiome but 1%-2% of its total biomass. “Despite their relative rarity, they have an important and outsized influence on gut health” — an impact that results from their unique interface with the immune system, said Kyla Ost, PhD, of the Anschutz Medical Campus, University of Colorado, in Denver, whose research focuses on this interface.
And bacteriophages — viruses that infect and kill bacteria — are highly abundant in the gut. “Bacteriophages begin to colonize our GI [gastrointestinal] tract at the same time we develop our own microbiome shortly after birth, and from that time on, they interact with the bacteria in our GI tract, shaping [and being shaped by] the bacterial species we carry with us,” said Robert (Chip) Schooley, MD, distinguished professor of medicine at the University of California San Diego School of Medicine.
“We’ve been talking about things that affect the gut microbiome — diet, genetics, immune response — but probably the biggest influence on what grows in the GI tract are bacteriophages,” said Schooley, co-director of the Center for Innovative Phage Applications and Therapeutics, in a session on the extra-bacterial gut ecosystem.
Among the current questions:
‘New life’ for Phage Therapy
Bacteriophages represent a promising approach for the treatment of multidrug resistant bacterial pathogens in an era of increasing resistance and a dried-up antibiotic discovery pipeline, Schooley said. (In 2019, an estimated 4.95 million deaths around the world were associated with bacterial antimicrobial resistance, and by 2050, it has been forecast that this number will rise to an estimated 8.22 million deaths.)
But in addition to suppressing bacterial pathogens causing direct morbidity, phage therapy has the potential to suppress bacteria believed to contribute to chronic diseases, he said. “We have proof-of-concept studies about the ability of phage to modulate bacteria in the digestive tract,” and an increasing number of clinical trials of the use of phages in GI and other diseases are underway, he said.
Phages were discovered just over a century ago, but phage therapy was widely abandoned once antibiotics were developed, except for in Russia and the former Eastern Bloc countries, where phage therapy continued to be used.
Phage therapy “got new life” in the West, Schooley said, about 10-15 years ago with an increasing number of detailed and high-profile case reports, including one in which a UC San Diego colleague, Tom Patterson, PhD, contracted a deadly multidrug resistant bacterial infection in Egypt and was eventually saved with bacteriophage therapy. (The case was the subject of the book The Perfect Predator).
Since then, as described in case reports and studies in the literature, “hundreds of people have been treated with bacteriophages here and in Europe,” most commonly for pulmonary infections and infections in implanted vascular and orthopedic devices, said Schooley, who coauthored a review in Cell in 2023 that describes phage biology and advances and future directions in phage therapy.
The use of bacteriophages to prevent systemic infections during high-risk periods — such as during chemotherapeutic regimens for hematological regimens — is an area of interest, he said at the meeting.
In research that is making its way to a clinical trial of patients undergoing allogeneic hematopoietic stem cell transplant (HSCT), researchers screened a library of phages to identify those with broad coverage of Escherichia coli. Using tail fiber engineering and CRISPR technology, they then engineered a combination of the four most complementary bacteriophages to selectively kill E coli — including fluoroquinolone-resistant strains that, in patients whose GI tracts are colonized with these strains, can translocate from the gut into the bloodstream, causing sepsis, during chemotherapeutic regimens for HSCT.
In a mouse model, the CRISPR-enhanced four-phage cocktail (SNIPR001) led to a steady reduction in the E coli colony counts in stool, “showing you can modulate these bacteria in the gut by using bacteriophages to kill them,” Schooley said. Moreover, the CRISPR enhancement strengthened the phages’ ability to break up biofilms, he said, showing “that you can engineer bacteriophages to make them better killers.” A phase 1b/2a study is being planned.
Other Niches for Therapeutic Phages, Challenges
Bacteriophages also could be used to target a gut bacterium that has been shown to attenuate alcoholic liver disease. Patients with alcoholic hepatitis “have a gut microbiome that is different in distribution,” Schooley said, often with increased numbers of Enterococcus faecalis that produce cytolysin, an exotoxin that exacerbates liver injury and is associated with increased mortality.
In published research led by investigators at UC San Diego, stool from cytolysin-positive patients with alcoholic hepatitis was found to exacerbate ethanol-induced liver disease in gnotobiotic mice, and phage therapy against cytolytic E faecalis was found to abolish it, Schooley shared.
Research is also exploring the potential of phage therapy to selectively target adherent invasive E coli in Crohn’s disease, and Klebsiella pneumoniae in the gut microbiome as an exacerbator of inflammatory bowel disease (IBD), he said.
And investigators in Japan, he noted, have reported that bacteriophage therapy against K pneumoniae can ameliorate liver inflammation and disease severity in primary sclerosing cholangitis.
Challenges in the therapeutic use of phages include the narrow host range of phages and an uncertain predictive value of in vitro phage susceptibility testing. “We don’t know yet how to do resistance testing as well as we do with antibiotics,” he said.
In addition, most phages tend to be acid labile, requiring strategies to mitigate inactivation by gastric acid, and there are “major knowledge gaps” relating to phage pharmacology. “We also know that adaptive immune responses to phages can but often doesn’t impact therapy, and we want to understand that better in clinical trials,” Schooley said.
Phages that have a “lysogenic” lifestyle — as opposed to lytic phages which are used therapeutically — can contribute to antibiotic resistance by facilitating the interchange of bacterial resistance genes, he noted.
A Window Into the Mycobiome
The human gut mycobiome is primarily composed of fungi in the Saccharomyces, Candida, and Malassezia genera, with Candida species dominating. Fungal cells harbor distinct immune-stimulatory molecules and activate distinct immune pathways compared with bacteria and other members of the microbiome, said Ost, assistant professor in the immunology and microbiology department of CU Anschutz.
Some fungi, including those in the Candida genus, activate adaptive and innate immune responses that promote metabolic health and protect against infection. A recently published study in Science, for instance, demonstrated that colonization with C dubliniensis in very young mice who had been exposed to broad-spectrum antibiotics promoted “the expansion and development of beta cells in the pancreas” in a macrophage dependent manner, improving metabolic health and reducing diabetes incidence, she shared.
On the one hand, fungi can “exacerbate and perpetuate the pathogenic inflammation that’s found in a growing list of inflammatory diseases” such as IBD. And “in fact, a lot of the benefits and detriments are driven by the exact same species of fungi,” said Ost. “This is particularly true of Candida,” which is a “lifelong colonizer of intestinal microbiota that rarely causes disease but can be quite pathogenic when it does.”
A 2023 review in Nature Reviews Gastroenterology & Hepatology coauthored by Ost describes the role of commensal fungi in intestinal diseases, including IBD, colorectal cancer, and pancreatic cancer.
The pathogenic potential of commensal fungi is largely dependent on its strain, its morphology and its expression of virulence factors, researchers are learning. Ost has studied C albicans, which has been associated with intestinal inflammation and IBD. Like some other Candida species, C albicans are “fascinating shape shifters,” she said, transitioning between a less pathogenic “yeast” morphology and an elongated, adhesive “hyphae” shape that is more pathogenic.
It turns out, according to research by Ost and others, that the C albicans hyphal morphotype — and the adhesins (sticky proteins that facilitate adherence to epithelial cells) and a cytolytic toxin it produces — are preferentially targeted and suppressed by immunoglobulin A (IgA) in the gut.
“Our gut is protected by a large quantity of IgA antibodies…and these IgA interact with the microbiota and play a big role in what microbes are there and the biology of the microbes,” Ost said. Indeed, symptomatic IgA deficiency in humans has been shown to be associated with C albicans overgrowth.
Leveraging the hyphal-specific IgA response to protect against disease seems possible, she said, referring to an experimental anti-Candida fungal vaccine (NDV-3A) designed to induce an adhesin-specific immune response. In a mouse model of colitis, the vaccine protected against C albicans-associated damage. “We saw an immediate IgA response that targeted C albicans in the intestinal contents,” Ost said.
C glabrata, which has also been associated with intestinal inflammation and IBD, does not form hyphae but — depending on the strain — may also induce intestinal IgA responses, she said in describing her recent research.
Ost reported having no disclosures. Schooley disclosed being a consultant for SNIPR Biome, BiomX, Locus, MicrobiotiX, Amazon Data Monitoring Committee: Merck.
A version of this article appeared on Medscape.com.
WASHINGTON, DC — Research on the gut microbiome — and clinical attention to it — has focused mainly on bacteria, but bacteriophages and fungi play critical roles as well, with significant influences on health and disease, experts said at the Gut Microbiota for Health (GMFH) World Summit 2025.
Fungi account for < 1% of the total genetic material in the microbiome but 1%-2% of its total biomass. “Despite their relative rarity, they have an important and outsized influence on gut health” — an impact that results from their unique interface with the immune system, said Kyla Ost, PhD, of the Anschutz Medical Campus, University of Colorado, in Denver, whose research focuses on this interface.
And bacteriophages — viruses that infect and kill bacteria — are highly abundant in the gut. “Bacteriophages begin to colonize our GI [gastrointestinal] tract at the same time we develop our own microbiome shortly after birth, and from that time on, they interact with the bacteria in our GI tract, shaping [and being shaped by] the bacterial species we carry with us,” said Robert (Chip) Schooley, MD, distinguished professor of medicine at the University of California San Diego School of Medicine.
“We’ve been talking about things that affect the gut microbiome — diet, genetics, immune response — but probably the biggest influence on what grows in the GI tract are bacteriophages,” said Schooley, co-director of the Center for Innovative Phage Applications and Therapeutics, in a session on the extra-bacterial gut ecosystem.
Among the current questions:
‘New life’ for Phage Therapy
Bacteriophages represent a promising approach for the treatment of multidrug resistant bacterial pathogens in an era of increasing resistance and a dried-up antibiotic discovery pipeline, Schooley said. (In 2019, an estimated 4.95 million deaths around the world were associated with bacterial antimicrobial resistance, and by 2050, it has been forecast that this number will rise to an estimated 8.22 million deaths.)
But in addition to suppressing bacterial pathogens causing direct morbidity, phage therapy has the potential to suppress bacteria believed to contribute to chronic diseases, he said. “We have proof-of-concept studies about the ability of phage to modulate bacteria in the digestive tract,” and an increasing number of clinical trials of the use of phages in GI and other diseases are underway, he said.
Phages were discovered just over a century ago, but phage therapy was widely abandoned once antibiotics were developed, except for in Russia and the former Eastern Bloc countries, where phage therapy continued to be used.
Phage therapy “got new life” in the West, Schooley said, about 10-15 years ago with an increasing number of detailed and high-profile case reports, including one in which a UC San Diego colleague, Tom Patterson, PhD, contracted a deadly multidrug resistant bacterial infection in Egypt and was eventually saved with bacteriophage therapy. (The case was the subject of the book The Perfect Predator).
Since then, as described in case reports and studies in the literature, “hundreds of people have been treated with bacteriophages here and in Europe,” most commonly for pulmonary infections and infections in implanted vascular and orthopedic devices, said Schooley, who coauthored a review in Cell in 2023 that describes phage biology and advances and future directions in phage therapy.
The use of bacteriophages to prevent systemic infections during high-risk periods — such as during chemotherapeutic regimens for hematological regimens — is an area of interest, he said at the meeting.
In research that is making its way to a clinical trial of patients undergoing allogeneic hematopoietic stem cell transplant (HSCT), researchers screened a library of phages to identify those with broad coverage of Escherichia coli. Using tail fiber engineering and CRISPR technology, they then engineered a combination of the four most complementary bacteriophages to selectively kill E coli — including fluoroquinolone-resistant strains that, in patients whose GI tracts are colonized with these strains, can translocate from the gut into the bloodstream, causing sepsis, during chemotherapeutic regimens for HSCT.
In a mouse model, the CRISPR-enhanced four-phage cocktail (SNIPR001) led to a steady reduction in the E coli colony counts in stool, “showing you can modulate these bacteria in the gut by using bacteriophages to kill them,” Schooley said. Moreover, the CRISPR enhancement strengthened the phages’ ability to break up biofilms, he said, showing “that you can engineer bacteriophages to make them better killers.” A phase 1b/2a study is being planned.
Other Niches for Therapeutic Phages, Challenges
Bacteriophages also could be used to target a gut bacterium that has been shown to attenuate alcoholic liver disease. Patients with alcoholic hepatitis “have a gut microbiome that is different in distribution,” Schooley said, often with increased numbers of Enterococcus faecalis that produce cytolysin, an exotoxin that exacerbates liver injury and is associated with increased mortality.
In published research led by investigators at UC San Diego, stool from cytolysin-positive patients with alcoholic hepatitis was found to exacerbate ethanol-induced liver disease in gnotobiotic mice, and phage therapy against cytolytic E faecalis was found to abolish it, Schooley shared.
Research is also exploring the potential of phage therapy to selectively target adherent invasive E coli in Crohn’s disease, and Klebsiella pneumoniae in the gut microbiome as an exacerbator of inflammatory bowel disease (IBD), he said.
And investigators in Japan, he noted, have reported that bacteriophage therapy against K pneumoniae can ameliorate liver inflammation and disease severity in primary sclerosing cholangitis.
Challenges in the therapeutic use of phages include the narrow host range of phages and an uncertain predictive value of in vitro phage susceptibility testing. “We don’t know yet how to do resistance testing as well as we do with antibiotics,” he said.
In addition, most phages tend to be acid labile, requiring strategies to mitigate inactivation by gastric acid, and there are “major knowledge gaps” relating to phage pharmacology. “We also know that adaptive immune responses to phages can but often doesn’t impact therapy, and we want to understand that better in clinical trials,” Schooley said.
Phages that have a “lysogenic” lifestyle — as opposed to lytic phages which are used therapeutically — can contribute to antibiotic resistance by facilitating the interchange of bacterial resistance genes, he noted.
A Window Into the Mycobiome
The human gut mycobiome is primarily composed of fungi in the Saccharomyces, Candida, and Malassezia genera, with Candida species dominating. Fungal cells harbor distinct immune-stimulatory molecules and activate distinct immune pathways compared with bacteria and other members of the microbiome, said Ost, assistant professor in the immunology and microbiology department of CU Anschutz.
Some fungi, including those in the Candida genus, activate adaptive and innate immune responses that promote metabolic health and protect against infection. A recently published study in Science, for instance, demonstrated that colonization with C dubliniensis in very young mice who had been exposed to broad-spectrum antibiotics promoted “the expansion and development of beta cells in the pancreas” in a macrophage dependent manner, improving metabolic health and reducing diabetes incidence, she shared.
On the one hand, fungi can “exacerbate and perpetuate the pathogenic inflammation that’s found in a growing list of inflammatory diseases” such as IBD. And “in fact, a lot of the benefits and detriments are driven by the exact same species of fungi,” said Ost. “This is particularly true of Candida,” which is a “lifelong colonizer of intestinal microbiota that rarely causes disease but can be quite pathogenic when it does.”
A 2023 review in Nature Reviews Gastroenterology & Hepatology coauthored by Ost describes the role of commensal fungi in intestinal diseases, including IBD, colorectal cancer, and pancreatic cancer.
The pathogenic potential of commensal fungi is largely dependent on its strain, its morphology and its expression of virulence factors, researchers are learning. Ost has studied C albicans, which has been associated with intestinal inflammation and IBD. Like some other Candida species, C albicans are “fascinating shape shifters,” she said, transitioning between a less pathogenic “yeast” morphology and an elongated, adhesive “hyphae” shape that is more pathogenic.
It turns out, according to research by Ost and others, that the C albicans hyphal morphotype — and the adhesins (sticky proteins that facilitate adherence to epithelial cells) and a cytolytic toxin it produces — are preferentially targeted and suppressed by immunoglobulin A (IgA) in the gut.
“Our gut is protected by a large quantity of IgA antibodies…and these IgA interact with the microbiota and play a big role in what microbes are there and the biology of the microbes,” Ost said. Indeed, symptomatic IgA deficiency in humans has been shown to be associated with C albicans overgrowth.
Leveraging the hyphal-specific IgA response to protect against disease seems possible, she said, referring to an experimental anti-Candida fungal vaccine (NDV-3A) designed to induce an adhesin-specific immune response. In a mouse model of colitis, the vaccine protected against C albicans-associated damage. “We saw an immediate IgA response that targeted C albicans in the intestinal contents,” Ost said.
C glabrata, which has also been associated with intestinal inflammation and IBD, does not form hyphae but — depending on the strain — may also induce intestinal IgA responses, she said in describing her recent research.
Ost reported having no disclosures. Schooley disclosed being a consultant for SNIPR Biome, BiomX, Locus, MicrobiotiX, Amazon Data Monitoring Committee: Merck.
A version of this article appeared on Medscape.com.
FROM GMFH 2025
Statin-Antibiotic Combo Fails in Decompensated Cirrhosis
, a European randomized trial found.
Published in JAMA, the double-blind, placebo-controlled, phase 3 LIVERHOPE trial was conducted in 14 European hospitals from January 2019 to December 2022, the last date of follow-up.
Investigators led by Elisa Pose, MD, PhD, a research fellow in the Liver Unit at the Hospital Clínic de Barcelona in Barcelona, Spain, randomly assigned 237 patients with advanced, mostly alcohol-related liver disease to receive either simvastatin 20 mg/d plus rifaximin 1200 mg/d (n = 117) or an identical-appearing placebo (n = 120) for 12 months. Patients also received standard therapy, stratified according to Child-Pugh class B or C.
A previous simvastatin trial demonstrated a benefit in cirrhosis death. And with rifaximin, a large randomized controlled trial (RCT) “showed positive results for prevention of recurrent hepatic encephalopathy in cirrhosis,” Pose told GI & Hepatology News. “Rifaximin targets bacterial translocation from the gut in patients with cirrhosis. Simvastatin lowers portal pressure, the main pathogenetic cause of decompensation in cirrhosis, and may reduce systemic inflammation.”
“Randomized clinical trials showed that not only did 40 mg of simvastatin daily significantly reduce portal hypertension but it also improved survival in patients with cirrhosis who recovered from variceal bleeding compared with placebo,” added study co-author Ruben Hernaez, MD, MPH, PhD, an associate professor of medicine – gastroenterology at Baylor College of Medicine in Houston. “With rifaximin, one could expect not only improvement in hepatic encephalopathy but also a decreased infection rate, the most common trigger of acute-on-chronic liver failure [ACLF].”
In addition to lowering serum cholesterol, statins have pleiotropic effects via their anti-inflammatory properties, which make them an attractive option for decompensated cirrhosis, the authors explained, and their effect on portal hypertension may diminish complications and increase survival.
“The hypothesis is that simvastatin could improve intrahepatic circulation through an increase in nitric oxide synthesis or due to anti-inflammatory effects,” said Hernaez. “Cirrhosis, similar to any other chronic condition, suffers from an enhanced systemic inflammation, which increases as the disease progresses.”
Cirrhosis is also associated with increased gut permeability and bacterial translocation, which can foster hepatic encephalopathy, bacterial infection, and ACLF. Rifaximin has been shown to reduce the risk for recurrent hepatic encephalopathy and modulate the gut microbiome.
Commenting on the study but not involved in it, Meena B. Bansal, MD, a professor of medicine at the Icahn School of Medicine at Mount Sinai and system chief of the Division of Liver Diseases at Mount Sinai Health System, both in New York City, cautioned that previous studies were limited by confounding by indication because those with poor liver function already have low cholesterol and thus may not have been prescribed statins. In the current study, the authors prospectively used a statin independent of cholesterol levels and combined it with an antibiotic, which may help decrease microbial translocation and ACLF.
“There is a great need to prevent ACLF/decompensating events, and thus, the negative results of this study are disappointing,” Bansal said.
Study Details
The trial’s primary endpoint was the incidence of severe complications of liver cirrhosis associated with organ failure meeting criteria for ACLF. Secondary outcomes included transplant or death and a composite endpoint of cirrhotic complications, including ascites, hepatic encephalopathy, variceal bleeding, acute kidney injury, and infection.
The 237 participants had Child-Pugh class B (n = 194) or class C (n = 43), 72% were men, more than 90% were White, and 79.8% had alcohol-related cirrhosis.
The study found no significant differences between the treatment and placebo arms in the following outcomes:
- ACLF: 17.9% vs 14.2% (hazard ratio [HR], 1.23, 95% CI, 0.65-2.34; P =.52)
- Transplant or death: 18.8% vs 24.2% (HR, 0.75; 95% CI, 0.43-1.32; P =.32)
- Complications of cirrhosis: 42.7% vs 45.8% (HR, 0.93; 95% CI, 0.63-1.36; P =.70)
Also, the benefits were not observed in any patient subgroup, although this type of analysis was not part of the endpoints. The incidence of adverse events was similar in both arms at 426 vs 419 (P =.59), but three patients in the treatment group (2.6%) developed rhabdomyolysis.
The results suggest, however, that this statin/antibiotic combination is at least not harmful in this patient population, Hernaez said.
The lack of benefit observed likely related to the advanced state of liver disease in the cohort. “When you look at the MELD [Model for End-Stage Liver Disease] score, the most-used measure to assess liver function and prognosis, it is higher in this cohort than in patients from the previous trial showing positive results in survival,” Pose said. “The rest of the studies showing positive results were mostly retrospective cohort studies or small RCTs showing effects on portal pressure. We think it is likely that studies at earlier stages — maybe patients with compensated liver disease — may have more positive results.”
Pose added that statins will not be prescribed at her center beyond the lipid-lowering indication. And in her view, the question of add-on therapy is closed for patients with advanced disease “but may be open for earlier stages of cirrhosis.”
Unanswered questions remain, however, Hernaez said. “For example, patients with metabolic dysfunction–associated steatotic liver disease may have a different intensity of the inflammatory milieu compared to the majority of patients in our study [whose disease] was alcohol-related.” Furthermore, is a simvastatin dose of 20 mg enough, and what would be the effect if patients had less advanced disease or compensated cirrhosis? “Hence, while we proved with a well-conducted negative randomized clinical trial the combination is not affecting this outcome and population, the question is still unanswered for other types of patient populations and/or dose.” Hernaez said.
Bansal, too, pointed to the need for further studies in more diverse populations with varying etiologies of liver disease. “About 80% of this European population had alcohol-associated liver disease,” she said, agreeing that the study population likely had too-advanced disease. “The beneficial effects of these drugs may only be seen in those with less advanced cirrhosis, which warrants further study.” Based on these findings, Bansal added, statins should not be prescribed to prevent ACLF but reserved for patients with eligible cardiovascular risk factors, and rifaximin for those who meet criteria for the treatment of hepatic encephalopathy.
This work was supported by a grant from the Horizon 20/20 program.
Pose, Hernaez, and Bansal had no relevant competing interests to disclose. Multiple coauthors, including co–senior author Pere Ginès, reported having financial ties such as receiving research funding from; receiving advisory, consulting, or speaker’s fees from; and holding stocks and patents in multiple private-sector companies.
A version of this article appeared on Medscape.com.
, a European randomized trial found.
Published in JAMA, the double-blind, placebo-controlled, phase 3 LIVERHOPE trial was conducted in 14 European hospitals from January 2019 to December 2022, the last date of follow-up.
Investigators led by Elisa Pose, MD, PhD, a research fellow in the Liver Unit at the Hospital Clínic de Barcelona in Barcelona, Spain, randomly assigned 237 patients with advanced, mostly alcohol-related liver disease to receive either simvastatin 20 mg/d plus rifaximin 1200 mg/d (n = 117) or an identical-appearing placebo (n = 120) for 12 months. Patients also received standard therapy, stratified according to Child-Pugh class B or C.
A previous simvastatin trial demonstrated a benefit in cirrhosis death. And with rifaximin, a large randomized controlled trial (RCT) “showed positive results for prevention of recurrent hepatic encephalopathy in cirrhosis,” Pose told GI & Hepatology News. “Rifaximin targets bacterial translocation from the gut in patients with cirrhosis. Simvastatin lowers portal pressure, the main pathogenetic cause of decompensation in cirrhosis, and may reduce systemic inflammation.”
“Randomized clinical trials showed that not only did 40 mg of simvastatin daily significantly reduce portal hypertension but it also improved survival in patients with cirrhosis who recovered from variceal bleeding compared with placebo,” added study co-author Ruben Hernaez, MD, MPH, PhD, an associate professor of medicine – gastroenterology at Baylor College of Medicine in Houston. “With rifaximin, one could expect not only improvement in hepatic encephalopathy but also a decreased infection rate, the most common trigger of acute-on-chronic liver failure [ACLF].”
In addition to lowering serum cholesterol, statins have pleiotropic effects via their anti-inflammatory properties, which make them an attractive option for decompensated cirrhosis, the authors explained, and their effect on portal hypertension may diminish complications and increase survival.
“The hypothesis is that simvastatin could improve intrahepatic circulation through an increase in nitric oxide synthesis or due to anti-inflammatory effects,” said Hernaez. “Cirrhosis, similar to any other chronic condition, suffers from an enhanced systemic inflammation, which increases as the disease progresses.”
Cirrhosis is also associated with increased gut permeability and bacterial translocation, which can foster hepatic encephalopathy, bacterial infection, and ACLF. Rifaximin has been shown to reduce the risk for recurrent hepatic encephalopathy and modulate the gut microbiome.
Commenting on the study but not involved in it, Meena B. Bansal, MD, a professor of medicine at the Icahn School of Medicine at Mount Sinai and system chief of the Division of Liver Diseases at Mount Sinai Health System, both in New York City, cautioned that previous studies were limited by confounding by indication because those with poor liver function already have low cholesterol and thus may not have been prescribed statins. In the current study, the authors prospectively used a statin independent of cholesterol levels and combined it with an antibiotic, which may help decrease microbial translocation and ACLF.
“There is a great need to prevent ACLF/decompensating events, and thus, the negative results of this study are disappointing,” Bansal said.
Study Details
The trial’s primary endpoint was the incidence of severe complications of liver cirrhosis associated with organ failure meeting criteria for ACLF. Secondary outcomes included transplant or death and a composite endpoint of cirrhotic complications, including ascites, hepatic encephalopathy, variceal bleeding, acute kidney injury, and infection.
The 237 participants had Child-Pugh class B (n = 194) or class C (n = 43), 72% were men, more than 90% were White, and 79.8% had alcohol-related cirrhosis.
The study found no significant differences between the treatment and placebo arms in the following outcomes:
- ACLF: 17.9% vs 14.2% (hazard ratio [HR], 1.23, 95% CI, 0.65-2.34; P =.52)
- Transplant or death: 18.8% vs 24.2% (HR, 0.75; 95% CI, 0.43-1.32; P =.32)
- Complications of cirrhosis: 42.7% vs 45.8% (HR, 0.93; 95% CI, 0.63-1.36; P =.70)
Also, the benefits were not observed in any patient subgroup, although this type of analysis was not part of the endpoints. The incidence of adverse events was similar in both arms at 426 vs 419 (P =.59), but three patients in the treatment group (2.6%) developed rhabdomyolysis.
The results suggest, however, that this statin/antibiotic combination is at least not harmful in this patient population, Hernaez said.
The lack of benefit observed likely related to the advanced state of liver disease in the cohort. “When you look at the MELD [Model for End-Stage Liver Disease] score, the most-used measure to assess liver function and prognosis, it is higher in this cohort than in patients from the previous trial showing positive results in survival,” Pose said. “The rest of the studies showing positive results were mostly retrospective cohort studies or small RCTs showing effects on portal pressure. We think it is likely that studies at earlier stages — maybe patients with compensated liver disease — may have more positive results.”
Pose added that statins will not be prescribed at her center beyond the lipid-lowering indication. And in her view, the question of add-on therapy is closed for patients with advanced disease “but may be open for earlier stages of cirrhosis.”
Unanswered questions remain, however, Hernaez said. “For example, patients with metabolic dysfunction–associated steatotic liver disease may have a different intensity of the inflammatory milieu compared to the majority of patients in our study [whose disease] was alcohol-related.” Furthermore, is a simvastatin dose of 20 mg enough, and what would be the effect if patients had less advanced disease or compensated cirrhosis? “Hence, while we proved with a well-conducted negative randomized clinical trial the combination is not affecting this outcome and population, the question is still unanswered for other types of patient populations and/or dose.” Hernaez said.
Bansal, too, pointed to the need for further studies in more diverse populations with varying etiologies of liver disease. “About 80% of this European population had alcohol-associated liver disease,” she said, agreeing that the study population likely had too-advanced disease. “The beneficial effects of these drugs may only be seen in those with less advanced cirrhosis, which warrants further study.” Based on these findings, Bansal added, statins should not be prescribed to prevent ACLF but reserved for patients with eligible cardiovascular risk factors, and rifaximin for those who meet criteria for the treatment of hepatic encephalopathy.
This work was supported by a grant from the Horizon 20/20 program.
Pose, Hernaez, and Bansal had no relevant competing interests to disclose. Multiple coauthors, including co–senior author Pere Ginès, reported having financial ties such as receiving research funding from; receiving advisory, consulting, or speaker’s fees from; and holding stocks and patents in multiple private-sector companies.
A version of this article appeared on Medscape.com.
, a European randomized trial found.
Published in JAMA, the double-blind, placebo-controlled, phase 3 LIVERHOPE trial was conducted in 14 European hospitals from January 2019 to December 2022, the last date of follow-up.
Investigators led by Elisa Pose, MD, PhD, a research fellow in the Liver Unit at the Hospital Clínic de Barcelona in Barcelona, Spain, randomly assigned 237 patients with advanced, mostly alcohol-related liver disease to receive either simvastatin 20 mg/d plus rifaximin 1200 mg/d (n = 117) or an identical-appearing placebo (n = 120) for 12 months. Patients also received standard therapy, stratified according to Child-Pugh class B or C.
A previous simvastatin trial demonstrated a benefit in cirrhosis death. And with rifaximin, a large randomized controlled trial (RCT) “showed positive results for prevention of recurrent hepatic encephalopathy in cirrhosis,” Pose told GI & Hepatology News. “Rifaximin targets bacterial translocation from the gut in patients with cirrhosis. Simvastatin lowers portal pressure, the main pathogenetic cause of decompensation in cirrhosis, and may reduce systemic inflammation.”
“Randomized clinical trials showed that not only did 40 mg of simvastatin daily significantly reduce portal hypertension but it also improved survival in patients with cirrhosis who recovered from variceal bleeding compared with placebo,” added study co-author Ruben Hernaez, MD, MPH, PhD, an associate professor of medicine – gastroenterology at Baylor College of Medicine in Houston. “With rifaximin, one could expect not only improvement in hepatic encephalopathy but also a decreased infection rate, the most common trigger of acute-on-chronic liver failure [ACLF].”
In addition to lowering serum cholesterol, statins have pleiotropic effects via their anti-inflammatory properties, which make them an attractive option for decompensated cirrhosis, the authors explained, and their effect on portal hypertension may diminish complications and increase survival.
“The hypothesis is that simvastatin could improve intrahepatic circulation through an increase in nitric oxide synthesis or due to anti-inflammatory effects,” said Hernaez. “Cirrhosis, similar to any other chronic condition, suffers from an enhanced systemic inflammation, which increases as the disease progresses.”
Cirrhosis is also associated with increased gut permeability and bacterial translocation, which can foster hepatic encephalopathy, bacterial infection, and ACLF. Rifaximin has been shown to reduce the risk for recurrent hepatic encephalopathy and modulate the gut microbiome.
Commenting on the study but not involved in it, Meena B. Bansal, MD, a professor of medicine at the Icahn School of Medicine at Mount Sinai and system chief of the Division of Liver Diseases at Mount Sinai Health System, both in New York City, cautioned that previous studies were limited by confounding by indication because those with poor liver function already have low cholesterol and thus may not have been prescribed statins. In the current study, the authors prospectively used a statin independent of cholesterol levels and combined it with an antibiotic, which may help decrease microbial translocation and ACLF.
“There is a great need to prevent ACLF/decompensating events, and thus, the negative results of this study are disappointing,” Bansal said.
Study Details
The trial’s primary endpoint was the incidence of severe complications of liver cirrhosis associated with organ failure meeting criteria for ACLF. Secondary outcomes included transplant or death and a composite endpoint of cirrhotic complications, including ascites, hepatic encephalopathy, variceal bleeding, acute kidney injury, and infection.
The 237 participants had Child-Pugh class B (n = 194) or class C (n = 43), 72% were men, more than 90% were White, and 79.8% had alcohol-related cirrhosis.
The study found no significant differences between the treatment and placebo arms in the following outcomes:
- ACLF: 17.9% vs 14.2% (hazard ratio [HR], 1.23, 95% CI, 0.65-2.34; P =.52)
- Transplant or death: 18.8% vs 24.2% (HR, 0.75; 95% CI, 0.43-1.32; P =.32)
- Complications of cirrhosis: 42.7% vs 45.8% (HR, 0.93; 95% CI, 0.63-1.36; P =.70)
Also, the benefits were not observed in any patient subgroup, although this type of analysis was not part of the endpoints. The incidence of adverse events was similar in both arms at 426 vs 419 (P =.59), but three patients in the treatment group (2.6%) developed rhabdomyolysis.
The results suggest, however, that this statin/antibiotic combination is at least not harmful in this patient population, Hernaez said.
The lack of benefit observed likely related to the advanced state of liver disease in the cohort. “When you look at the MELD [Model for End-Stage Liver Disease] score, the most-used measure to assess liver function and prognosis, it is higher in this cohort than in patients from the previous trial showing positive results in survival,” Pose said. “The rest of the studies showing positive results were mostly retrospective cohort studies or small RCTs showing effects on portal pressure. We think it is likely that studies at earlier stages — maybe patients with compensated liver disease — may have more positive results.”
Pose added that statins will not be prescribed at her center beyond the lipid-lowering indication. And in her view, the question of add-on therapy is closed for patients with advanced disease “but may be open for earlier stages of cirrhosis.”
Unanswered questions remain, however, Hernaez said. “For example, patients with metabolic dysfunction–associated steatotic liver disease may have a different intensity of the inflammatory milieu compared to the majority of patients in our study [whose disease] was alcohol-related.” Furthermore, is a simvastatin dose of 20 mg enough, and what would be the effect if patients had less advanced disease or compensated cirrhosis? “Hence, while we proved with a well-conducted negative randomized clinical trial the combination is not affecting this outcome and population, the question is still unanswered for other types of patient populations and/or dose.” Hernaez said.
Bansal, too, pointed to the need for further studies in more diverse populations with varying etiologies of liver disease. “About 80% of this European population had alcohol-associated liver disease,” she said, agreeing that the study population likely had too-advanced disease. “The beneficial effects of these drugs may only be seen in those with less advanced cirrhosis, which warrants further study.” Based on these findings, Bansal added, statins should not be prescribed to prevent ACLF but reserved for patients with eligible cardiovascular risk factors, and rifaximin for those who meet criteria for the treatment of hepatic encephalopathy.
This work was supported by a grant from the Horizon 20/20 program.
Pose, Hernaez, and Bansal had no relevant competing interests to disclose. Multiple coauthors, including co–senior author Pere Ginès, reported having financial ties such as receiving research funding from; receiving advisory, consulting, or speaker’s fees from; and holding stocks and patents in multiple private-sector companies.
A version of this article appeared on Medscape.com.
Low-Quality Food Environments Increase MASLD-related Mortality
according to investigators.
These findings highlight the importance of addressing disparities in food environments and social determinants of health to help reduce MASLD-related mortality, lead author Annette Paik, MD, of Inova Health System, Falls Church, Virginia, and colleagues reported.
“Recent studies indicate that food swamps and deserts, as surrogates for food insecurity, are linked to poor glycemic control and higher adult obesity rates,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Understanding the intersection of these factors with sociodemographic and clinical variables offers insights into MASLD-related outcomes, including mortality.”
To this end, the present study examined the association between food environments and MASLD-related mortality across more than 2,195 US counties. County-level mortality data were obtained from the CDC WONDER database (2016-2020) and linked to food environment data from the US Department of Agriculture Food Environment Atlas using Federal Information Processing Standards (FIPS) codes. Food deserts were defined as low-income areas with limited access to grocery stores, while food swamps were characterized by a predominance of unhealthy food outlets relative to healthy ones.
Additional data on obesity, type 2 diabetes (T2D), and nine social determinants of health were obtained from CDC PLACES and other publicly available datasets. Counties were stratified into quartiles based on MASLD-related mortality rates. Population-weighted mixed-effects linear regression models were used to evaluate associations between food environment exposures and MASLD mortality, adjusting for region, rural-urban status, age, sex, race, insurance coverage, chronic dis-ease prevalence, SNAP participation, and access to exercise facilities.
Counties with the worst food environments had significantly higher MASLD-related mortality, even after adjusting for clinical and sociodemographic factors. Compared with counties in the lowest quartile of MASLD mortality, those in the highest quartile had a greater proportion of food deserts (22.3% vs 14.9%; P < .001) and food swamps (73.1% vs 65.7%; P < .001). They also had a significantly higher prevalence of obesity (40.5% vs 32.5%), type 2 diabetes (15.8% vs 11.4%), and physical inactivity (33.7% vs 24.9%).
Demographically, counties with higher MASLD mortality had significantly larger proportions of Black and Hispanic residents, and were more likely to be rural and located in the South. These counties also had significantly lower median household incomes, higher poverty rates, fewer adults with a college education, lower access to exercise opportunities, greater SNAP participation, less broadband access, and more uninsured adults.
In multivariable regression models, both food deserts and food swamps remained independently associated with MASLD mortality. Counties in the highest quartile of food desert exposure had a 14.5% higher MASLD mortality rate, compared with the lowest quartile (P = .001), and those in the highest quartile for food swamp exposure had a 13.9% higher mortality rate (P = .005).
Type 2 diabetes, physical inactivity, and lack of health insurance were also independently associated with increased MASLD-related mortality.
“Implementing public health interventions that address the specific environmental factors of each county can help US policymakers promote access to healthy, culturally appropriate food choices at affordable prices and reduce the consumption of poor-quality food,” the investigators wrote. “Moreover, improving access to parks and exercise facilities can further enhance the impact of healthy nutrition. These strategies could help curb the growing epidemic of metabolic diseases, including MASLD and related mortality.”
This study was supported by King Faisal Specialist Hospital & Research Center, the Global NASH Council, Center for Outcomes Research in Liver Diseases, and the Beatty Liver and Obesity Research Fund, Inova Health System. The investigators disclosed no conflicts of interest.
A healthy lifestyle continues to be foundational to the management of metabolic dysfunction–associated steatotic liver disease (MASLD). Poor diet quality is a risk factor for developing MASLD in the US general population. Food deserts and food swamps are symptoms of socioeconomic hardship, as they both are characterized by limited access to healthy food (as described by the US Department of Agriculture Dietary Guidelines for Americans) owing to the absence of grocery stores/supermarkets. However, food swamps suffer from abundant access to unhealthy, energy-dense, yet nutritionally sparse (EDYNS) foods.
The article by Paik et al shows that food deserts and food swamps are not only associated with the burden of MASLD in the United States but also with MASLD-related mortality. The counties with the highest MASLD-related mortality carried higher food swamps and food deserts, poverty, unemployment, household crowding, absence of broadband internet access, lack of high school education, and elderly, Hispanic residents and likely to be located in the South.
MASLD appears to have origins in the dark underbelly of socioeconomic hardship that might preclude many of our patients from complying with lifestyle changes. Policy changes are urgently needed at a national level, from increasing incentives to establish grocery stores in the food deserts to limiting the proportion of EDYNS foods in grocery stores and conspicuous labeling by the Food and Drug Administration of EDYNS foods. At an individual practice level, supporting MASLD patients in the clinic with a dietitian, educational material, and, where possible, utilizing applications to assist healthy dietary habits to empower them in choosing healthy food options.
Niharika Samala, MD, is assistant professor of medicine, associate program director of the GI Fellowship, and director of the IUH MASLD/NAFLD Clinic at the Indiana University School of Medicine, Indianapolis. She reported no relevant conflicts of interest.
A healthy lifestyle continues to be foundational to the management of metabolic dysfunction–associated steatotic liver disease (MASLD). Poor diet quality is a risk factor for developing MASLD in the US general population. Food deserts and food swamps are symptoms of socioeconomic hardship, as they both are characterized by limited access to healthy food (as described by the US Department of Agriculture Dietary Guidelines for Americans) owing to the absence of grocery stores/supermarkets. However, food swamps suffer from abundant access to unhealthy, energy-dense, yet nutritionally sparse (EDYNS) foods.
The article by Paik et al shows that food deserts and food swamps are not only associated with the burden of MASLD in the United States but also with MASLD-related mortality. The counties with the highest MASLD-related mortality carried higher food swamps and food deserts, poverty, unemployment, household crowding, absence of broadband internet access, lack of high school education, and elderly, Hispanic residents and likely to be located in the South.
MASLD appears to have origins in the dark underbelly of socioeconomic hardship that might preclude many of our patients from complying with lifestyle changes. Policy changes are urgently needed at a national level, from increasing incentives to establish grocery stores in the food deserts to limiting the proportion of EDYNS foods in grocery stores and conspicuous labeling by the Food and Drug Administration of EDYNS foods. At an individual practice level, supporting MASLD patients in the clinic with a dietitian, educational material, and, where possible, utilizing applications to assist healthy dietary habits to empower them in choosing healthy food options.
Niharika Samala, MD, is assistant professor of medicine, associate program director of the GI Fellowship, and director of the IUH MASLD/NAFLD Clinic at the Indiana University School of Medicine, Indianapolis. She reported no relevant conflicts of interest.
A healthy lifestyle continues to be foundational to the management of metabolic dysfunction–associated steatotic liver disease (MASLD). Poor diet quality is a risk factor for developing MASLD in the US general population. Food deserts and food swamps are symptoms of socioeconomic hardship, as they both are characterized by limited access to healthy food (as described by the US Department of Agriculture Dietary Guidelines for Americans) owing to the absence of grocery stores/supermarkets. However, food swamps suffer from abundant access to unhealthy, energy-dense, yet nutritionally sparse (EDYNS) foods.
The article by Paik et al shows that food deserts and food swamps are not only associated with the burden of MASLD in the United States but also with MASLD-related mortality. The counties with the highest MASLD-related mortality carried higher food swamps and food deserts, poverty, unemployment, household crowding, absence of broadband internet access, lack of high school education, and elderly, Hispanic residents and likely to be located in the South.
MASLD appears to have origins in the dark underbelly of socioeconomic hardship that might preclude many of our patients from complying with lifestyle changes. Policy changes are urgently needed at a national level, from increasing incentives to establish grocery stores in the food deserts to limiting the proportion of EDYNS foods in grocery stores and conspicuous labeling by the Food and Drug Administration of EDYNS foods. At an individual practice level, supporting MASLD patients in the clinic with a dietitian, educational material, and, where possible, utilizing applications to assist healthy dietary habits to empower them in choosing healthy food options.
Niharika Samala, MD, is assistant professor of medicine, associate program director of the GI Fellowship, and director of the IUH MASLD/NAFLD Clinic at the Indiana University School of Medicine, Indianapolis. She reported no relevant conflicts of interest.
according to investigators.
These findings highlight the importance of addressing disparities in food environments and social determinants of health to help reduce MASLD-related mortality, lead author Annette Paik, MD, of Inova Health System, Falls Church, Virginia, and colleagues reported.
“Recent studies indicate that food swamps and deserts, as surrogates for food insecurity, are linked to poor glycemic control and higher adult obesity rates,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Understanding the intersection of these factors with sociodemographic and clinical variables offers insights into MASLD-related outcomes, including mortality.”
To this end, the present study examined the association between food environments and MASLD-related mortality across more than 2,195 US counties. County-level mortality data were obtained from the CDC WONDER database (2016-2020) and linked to food environment data from the US Department of Agriculture Food Environment Atlas using Federal Information Processing Standards (FIPS) codes. Food deserts were defined as low-income areas with limited access to grocery stores, while food swamps were characterized by a predominance of unhealthy food outlets relative to healthy ones.
Additional data on obesity, type 2 diabetes (T2D), and nine social determinants of health were obtained from CDC PLACES and other publicly available datasets. Counties were stratified into quartiles based on MASLD-related mortality rates. Population-weighted mixed-effects linear regression models were used to evaluate associations between food environment exposures and MASLD mortality, adjusting for region, rural-urban status, age, sex, race, insurance coverage, chronic dis-ease prevalence, SNAP participation, and access to exercise facilities.
Counties with the worst food environments had significantly higher MASLD-related mortality, even after adjusting for clinical and sociodemographic factors. Compared with counties in the lowest quartile of MASLD mortality, those in the highest quartile had a greater proportion of food deserts (22.3% vs 14.9%; P < .001) and food swamps (73.1% vs 65.7%; P < .001). They also had a significantly higher prevalence of obesity (40.5% vs 32.5%), type 2 diabetes (15.8% vs 11.4%), and physical inactivity (33.7% vs 24.9%).
Demographically, counties with higher MASLD mortality had significantly larger proportions of Black and Hispanic residents, and were more likely to be rural and located in the South. These counties also had significantly lower median household incomes, higher poverty rates, fewer adults with a college education, lower access to exercise opportunities, greater SNAP participation, less broadband access, and more uninsured adults.
In multivariable regression models, both food deserts and food swamps remained independently associated with MASLD mortality. Counties in the highest quartile of food desert exposure had a 14.5% higher MASLD mortality rate, compared with the lowest quartile (P = .001), and those in the highest quartile for food swamp exposure had a 13.9% higher mortality rate (P = .005).
Type 2 diabetes, physical inactivity, and lack of health insurance were also independently associated with increased MASLD-related mortality.
“Implementing public health interventions that address the specific environmental factors of each county can help US policymakers promote access to healthy, culturally appropriate food choices at affordable prices and reduce the consumption of poor-quality food,” the investigators wrote. “Moreover, improving access to parks and exercise facilities can further enhance the impact of healthy nutrition. These strategies could help curb the growing epidemic of metabolic diseases, including MASLD and related mortality.”
This study was supported by King Faisal Specialist Hospital & Research Center, the Global NASH Council, Center for Outcomes Research in Liver Diseases, and the Beatty Liver and Obesity Research Fund, Inova Health System. The investigators disclosed no conflicts of interest.
according to investigators.
These findings highlight the importance of addressing disparities in food environments and social determinants of health to help reduce MASLD-related mortality, lead author Annette Paik, MD, of Inova Health System, Falls Church, Virginia, and colleagues reported.
“Recent studies indicate that food swamps and deserts, as surrogates for food insecurity, are linked to poor glycemic control and higher adult obesity rates,” the investigators wrote in Clinical Gastroenterology and Hepatology. “Understanding the intersection of these factors with sociodemographic and clinical variables offers insights into MASLD-related outcomes, including mortality.”
To this end, the present study examined the association between food environments and MASLD-related mortality across more than 2,195 US counties. County-level mortality data were obtained from the CDC WONDER database (2016-2020) and linked to food environment data from the US Department of Agriculture Food Environment Atlas using Federal Information Processing Standards (FIPS) codes. Food deserts were defined as low-income areas with limited access to grocery stores, while food swamps were characterized by a predominance of unhealthy food outlets relative to healthy ones.
Additional data on obesity, type 2 diabetes (T2D), and nine social determinants of health were obtained from CDC PLACES and other publicly available datasets. Counties were stratified into quartiles based on MASLD-related mortality rates. Population-weighted mixed-effects linear regression models were used to evaluate associations between food environment exposures and MASLD mortality, adjusting for region, rural-urban status, age, sex, race, insurance coverage, chronic dis-ease prevalence, SNAP participation, and access to exercise facilities.
Counties with the worst food environments had significantly higher MASLD-related mortality, even after adjusting for clinical and sociodemographic factors. Compared with counties in the lowest quartile of MASLD mortality, those in the highest quartile had a greater proportion of food deserts (22.3% vs 14.9%; P < .001) and food swamps (73.1% vs 65.7%; P < .001). They also had a significantly higher prevalence of obesity (40.5% vs 32.5%), type 2 diabetes (15.8% vs 11.4%), and physical inactivity (33.7% vs 24.9%).
Demographically, counties with higher MASLD mortality had significantly larger proportions of Black and Hispanic residents, and were more likely to be rural and located in the South. These counties also had significantly lower median household incomes, higher poverty rates, fewer adults with a college education, lower access to exercise opportunities, greater SNAP participation, less broadband access, and more uninsured adults.
In multivariable regression models, both food deserts and food swamps remained independently associated with MASLD mortality. Counties in the highest quartile of food desert exposure had a 14.5% higher MASLD mortality rate, compared with the lowest quartile (P = .001), and those in the highest quartile for food swamp exposure had a 13.9% higher mortality rate (P = .005).
Type 2 diabetes, physical inactivity, and lack of health insurance were also independently associated with increased MASLD-related mortality.
“Implementing public health interventions that address the specific environmental factors of each county can help US policymakers promote access to healthy, culturally appropriate food choices at affordable prices and reduce the consumption of poor-quality food,” the investigators wrote. “Moreover, improving access to parks and exercise facilities can further enhance the impact of healthy nutrition. These strategies could help curb the growing epidemic of metabolic diseases, including MASLD and related mortality.”
This study was supported by King Faisal Specialist Hospital & Research Center, the Global NASH Council, Center for Outcomes Research in Liver Diseases, and the Beatty Liver and Obesity Research Fund, Inova Health System. The investigators disclosed no conflicts of interest.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
Infrequent HDV Testing Raises Concern for Worse Liver Outcomes
—according to new findings.
The low testing rate suggests limited awareness of HDV-associated risks in patients with CHB, and underscores the need for earlier testing and diagnosis, lead author Robert J. Wong, MD, of Stanford University School of Medicine, Stanford, California, and colleagues, reported.
“Data among US populations are lacking to describe the epidemiology and long-term outcomes of patients with CHB and concurrent HDV infection,” the investigators wrote in Gastro Hep Advances (2025 Oct. doi: 10.1016/j.gastha.2024.10.015).
Prior studies have found that only 6% to 19% of patients with CHB get tested for HDV, and among those tested, the prevalence is relatively low—between 2% and 4.6%. Although relatively uncommon, HDV carries a substantial clinical and economic burden, Dr. Wong and colleagues noted, highlighting the importance of clinical awareness and accurate epidemiologic data.
The present study analyzed data from the Veterans Affairs (VA) Corporate Data Warehouse between 2010 and 2023. Adults with CHB were identified based on laboratory-confirmed markers and ICD-9/10 codes. HDV testing (anti-HDV antibody and HDV RNA) was assessed, and predictors of testing were evaluated using multivariable logistic regression.
To examine liver-related outcomes, patients who tested positive for HDV were propensity score–matched 1:2 with CHB patients who tested negative. Matching accounted for age, sex, race/ethnicity, HBeAg status, antiviral treatment, HCV and HIV coinfection, diabetes, and alcohol use. Patients with cirrhosis or hepatocellular carcinoma (HCC) at base-line were excluded. Incidence of cirrhosis, hepatic decompensation, and HCC was estimated using competing risks Nelson-Aalen methods.
Among 27,548 veterans with CHB, only 16.1% underwent HDV testing. Of those tested, 3.25% were HDV positive. Testing rates were higher among patients who were HBeAg positive, on antiviral therapy, or identified as Asian or Pacific Islander.
Conversely, testing was significantly less common among patients with high-risk alcohol use, past or current drug use, cirrhosis at diagnosis, or HCV coinfection. In contrast, HIV coinfection was associated with increased odds of being tested.
Among those tested, HDV positivity was more likely in patients with HCV coinfection, cirrhosis, or a history of drug use. On multivariable analysis, these factors were independent predictors of HDV positivity.
In the matched cohort of 71 HDV-positive patients and 140 HDV-negative controls, the incidence of cirrhosis was more than 3-fold higher in HDV-positive patients (4.39 vs 1.30 per 100,000 person-years; P less than .01), and hepatic decompensation was over 5 times more common (2.18 vs 0.41 per 100,000 person-years; P = .01). There was also a non-significant trend toward increased HCC risk in the HDV group.
“These findings align with existing studies and confirm that among a predominantly non-Asian US cohort of CHB patients, presence of concurrent HDV is associated with more severe liver disease progression,” the investigators wrote. “These observations, taken together with the low rates of HDV testing overall and particularly among high-risk individuals, emphasizes the need for greater awareness and novel strategies on how to improve HDV testing and diagnosis, particularly given that novel HDV therapies are on the near horizon.”
The study was supported by Gilead. The investigators disclosed additional relationships with Exact Sciences, GSK, Novo Nordisk, and others.
Hepatitis D virus (HDV) is an RNA “sub-virus” that infects patients with co-existing hepatitis B virus (HBV) infections. HDV infection currently affects approximately 15-20 million people worldwide but is an orphan disease in the United States with fewer than 100,000 individuals infected today.
Those with HDV have a 70% lifetime risk of hepatocellular carcinoma (HCC), cirrhosis, liver failure, death, or liver transplant. But there are no current treatments in the US that are Food and Drug Administration (FDA)-approved for the treatment of HDV, and only one therapy in the European Union with full approval by the European Medicines Agency.
Despite HDV severity and limited treatment options, screening for HDV remains severely inadequate, often only testing those individuals at high risk sequentially. HDV screening, would benefit from a revamped approach that automatically reflexes testing when individuals are diagnosed with HBV if positive for hepatitis B surface antigen (HBsAg+), then proceeds to anti-HDV antibody total testing, and then double reflexed to HDV-RNA polymerase chain reaction (PCR) quantitation. This is especially true in the Veterans Administration (VA)’s hospitals and clinics, where Wong and colleagues found very low rates of HDV testing among a national cohort of US Veterans with chronic HBV.
This study highlights the importance of timely HDV testing using reflex tools to improve diagnosis and HDV treatment, reducing long-term risks of liver-related morbidity and mortality.
Robert G. Gish, MD, AGAF, is principal at Robert G Gish Consultants LLC, clinical professor of medicine at Loma Linda University, Loma Linda, Calif., and medical director of the Hepatitis B Foundation. His complete list of disclosures can be found at www.robertgish.com/about.
Hepatitis D virus (HDV) is an RNA “sub-virus” that infects patients with co-existing hepatitis B virus (HBV) infections. HDV infection currently affects approximately 15-20 million people worldwide but is an orphan disease in the United States with fewer than 100,000 individuals infected today.
Those with HDV have a 70% lifetime risk of hepatocellular carcinoma (HCC), cirrhosis, liver failure, death, or liver transplant. But there are no current treatments in the US that are Food and Drug Administration (FDA)-approved for the treatment of HDV, and only one therapy in the European Union with full approval by the European Medicines Agency.
Despite HDV severity and limited treatment options, screening for HDV remains severely inadequate, often only testing those individuals at high risk sequentially. HDV screening, would benefit from a revamped approach that automatically reflexes testing when individuals are diagnosed with HBV if positive for hepatitis B surface antigen (HBsAg+), then proceeds to anti-HDV antibody total testing, and then double reflexed to HDV-RNA polymerase chain reaction (PCR) quantitation. This is especially true in the Veterans Administration (VA)’s hospitals and clinics, where Wong and colleagues found very low rates of HDV testing among a national cohort of US Veterans with chronic HBV.
This study highlights the importance of timely HDV testing using reflex tools to improve diagnosis and HDV treatment, reducing long-term risks of liver-related morbidity and mortality.
Robert G. Gish, MD, AGAF, is principal at Robert G Gish Consultants LLC, clinical professor of medicine at Loma Linda University, Loma Linda, Calif., and medical director of the Hepatitis B Foundation. His complete list of disclosures can be found at www.robertgish.com/about.
Hepatitis D virus (HDV) is an RNA “sub-virus” that infects patients with co-existing hepatitis B virus (HBV) infections. HDV infection currently affects approximately 15-20 million people worldwide but is an orphan disease in the United States with fewer than 100,000 individuals infected today.
Those with HDV have a 70% lifetime risk of hepatocellular carcinoma (HCC), cirrhosis, liver failure, death, or liver transplant. But there are no current treatments in the US that are Food and Drug Administration (FDA)-approved for the treatment of HDV, and only one therapy in the European Union with full approval by the European Medicines Agency.
Despite HDV severity and limited treatment options, screening for HDV remains severely inadequate, often only testing those individuals at high risk sequentially. HDV screening, would benefit from a revamped approach that automatically reflexes testing when individuals are diagnosed with HBV if positive for hepatitis B surface antigen (HBsAg+), then proceeds to anti-HDV antibody total testing, and then double reflexed to HDV-RNA polymerase chain reaction (PCR) quantitation. This is especially true in the Veterans Administration (VA)’s hospitals and clinics, where Wong and colleagues found very low rates of HDV testing among a national cohort of US Veterans with chronic HBV.
This study highlights the importance of timely HDV testing using reflex tools to improve diagnosis and HDV treatment, reducing long-term risks of liver-related morbidity and mortality.
Robert G. Gish, MD, AGAF, is principal at Robert G Gish Consultants LLC, clinical professor of medicine at Loma Linda University, Loma Linda, Calif., and medical director of the Hepatitis B Foundation. His complete list of disclosures can be found at www.robertgish.com/about.
—according to new findings.
The low testing rate suggests limited awareness of HDV-associated risks in patients with CHB, and underscores the need for earlier testing and diagnosis, lead author Robert J. Wong, MD, of Stanford University School of Medicine, Stanford, California, and colleagues, reported.
“Data among US populations are lacking to describe the epidemiology and long-term outcomes of patients with CHB and concurrent HDV infection,” the investigators wrote in Gastro Hep Advances (2025 Oct. doi: 10.1016/j.gastha.2024.10.015).
Prior studies have found that only 6% to 19% of patients with CHB get tested for HDV, and among those tested, the prevalence is relatively low—between 2% and 4.6%. Although relatively uncommon, HDV carries a substantial clinical and economic burden, Dr. Wong and colleagues noted, highlighting the importance of clinical awareness and accurate epidemiologic data.
The present study analyzed data from the Veterans Affairs (VA) Corporate Data Warehouse between 2010 and 2023. Adults with CHB were identified based on laboratory-confirmed markers and ICD-9/10 codes. HDV testing (anti-HDV antibody and HDV RNA) was assessed, and predictors of testing were evaluated using multivariable logistic regression.
To examine liver-related outcomes, patients who tested positive for HDV were propensity score–matched 1:2 with CHB patients who tested negative. Matching accounted for age, sex, race/ethnicity, HBeAg status, antiviral treatment, HCV and HIV coinfection, diabetes, and alcohol use. Patients with cirrhosis or hepatocellular carcinoma (HCC) at base-line were excluded. Incidence of cirrhosis, hepatic decompensation, and HCC was estimated using competing risks Nelson-Aalen methods.
Among 27,548 veterans with CHB, only 16.1% underwent HDV testing. Of those tested, 3.25% were HDV positive. Testing rates were higher among patients who were HBeAg positive, on antiviral therapy, or identified as Asian or Pacific Islander.
Conversely, testing was significantly less common among patients with high-risk alcohol use, past or current drug use, cirrhosis at diagnosis, or HCV coinfection. In contrast, HIV coinfection was associated with increased odds of being tested.
Among those tested, HDV positivity was more likely in patients with HCV coinfection, cirrhosis, or a history of drug use. On multivariable analysis, these factors were independent predictors of HDV positivity.
In the matched cohort of 71 HDV-positive patients and 140 HDV-negative controls, the incidence of cirrhosis was more than 3-fold higher in HDV-positive patients (4.39 vs 1.30 per 100,000 person-years; P less than .01), and hepatic decompensation was over 5 times more common (2.18 vs 0.41 per 100,000 person-years; P = .01). There was also a non-significant trend toward increased HCC risk in the HDV group.
“These findings align with existing studies and confirm that among a predominantly non-Asian US cohort of CHB patients, presence of concurrent HDV is associated with more severe liver disease progression,” the investigators wrote. “These observations, taken together with the low rates of HDV testing overall and particularly among high-risk individuals, emphasizes the need for greater awareness and novel strategies on how to improve HDV testing and diagnosis, particularly given that novel HDV therapies are on the near horizon.”
The study was supported by Gilead. The investigators disclosed additional relationships with Exact Sciences, GSK, Novo Nordisk, and others.
—according to new findings.
The low testing rate suggests limited awareness of HDV-associated risks in patients with CHB, and underscores the need for earlier testing and diagnosis, lead author Robert J. Wong, MD, of Stanford University School of Medicine, Stanford, California, and colleagues, reported.
“Data among US populations are lacking to describe the epidemiology and long-term outcomes of patients with CHB and concurrent HDV infection,” the investigators wrote in Gastro Hep Advances (2025 Oct. doi: 10.1016/j.gastha.2024.10.015).
Prior studies have found that only 6% to 19% of patients with CHB get tested for HDV, and among those tested, the prevalence is relatively low—between 2% and 4.6%. Although relatively uncommon, HDV carries a substantial clinical and economic burden, Dr. Wong and colleagues noted, highlighting the importance of clinical awareness and accurate epidemiologic data.
The present study analyzed data from the Veterans Affairs (VA) Corporate Data Warehouse between 2010 and 2023. Adults with CHB were identified based on laboratory-confirmed markers and ICD-9/10 codes. HDV testing (anti-HDV antibody and HDV RNA) was assessed, and predictors of testing were evaluated using multivariable logistic regression.
To examine liver-related outcomes, patients who tested positive for HDV were propensity score–matched 1:2 with CHB patients who tested negative. Matching accounted for age, sex, race/ethnicity, HBeAg status, antiviral treatment, HCV and HIV coinfection, diabetes, and alcohol use. Patients with cirrhosis or hepatocellular carcinoma (HCC) at base-line were excluded. Incidence of cirrhosis, hepatic decompensation, and HCC was estimated using competing risks Nelson-Aalen methods.
Among 27,548 veterans with CHB, only 16.1% underwent HDV testing. Of those tested, 3.25% were HDV positive. Testing rates were higher among patients who were HBeAg positive, on antiviral therapy, or identified as Asian or Pacific Islander.
Conversely, testing was significantly less common among patients with high-risk alcohol use, past or current drug use, cirrhosis at diagnosis, or HCV coinfection. In contrast, HIV coinfection was associated with increased odds of being tested.
Among those tested, HDV positivity was more likely in patients with HCV coinfection, cirrhosis, or a history of drug use. On multivariable analysis, these factors were independent predictors of HDV positivity.
In the matched cohort of 71 HDV-positive patients and 140 HDV-negative controls, the incidence of cirrhosis was more than 3-fold higher in HDV-positive patients (4.39 vs 1.30 per 100,000 person-years; P less than .01), and hepatic decompensation was over 5 times more common (2.18 vs 0.41 per 100,000 person-years; P = .01). There was also a non-significant trend toward increased HCC risk in the HDV group.
“These findings align with existing studies and confirm that among a predominantly non-Asian US cohort of CHB patients, presence of concurrent HDV is associated with more severe liver disease progression,” the investigators wrote. “These observations, taken together with the low rates of HDV testing overall and particularly among high-risk individuals, emphasizes the need for greater awareness and novel strategies on how to improve HDV testing and diagnosis, particularly given that novel HDV therapies are on the near horizon.”
The study was supported by Gilead. The investigators disclosed additional relationships with Exact Sciences, GSK, Novo Nordisk, and others.
FROM GASTRO HEP ADVANCES