Liver Disease

Investigators found that simultaneous infection with adeno-associated virus type 2 (AAV2) and certain other viruses is associated with the outbreak of mysterious pediatric hepatitis cases worldwide.

Coinfection with AAV2 and a human adenovirus (HAdV), in particular, appears to leave some children more vulnerable to this acute hepatitis of unknown origin, researchers reported in three studies published online in Nature. Coinfection with Epstein-Barr virus (EBV), herpes, and enterovirus also were found. Adeno-associated viruses are not considered pathogenic on their own and require a “helper” virus for productive infection.

“I am quite confident that we have identified the key viruses involved because we used a comprehensive metagenomic sequencing approach to look for potential infections from any virus or non-viral pathogen,” Charles Chiu, MD, PhD, senior author and professor of laboratory medicine and medicine/infectious diseases at the University of California, San Francisco, said in an interview.

Dr. Chiu and colleagues propose that lockdowns and social isolation during the COVID-19 pandemic left more children susceptible. A major aspect of immunity in childhood is the adaptive immune response – both cell-mediated and humoral – shaped in part by exposure to viruses and other pathogens early in life, Dr. Chiu said.

“Due to COVID-19, a large population of children did not experience this, so it is possible once restrictions were lifted, they were suddenly exposed over a short period of time to multiple viruses that, in a poorly trained immune system, would have increased their risk of developing severe disease,” he said.

This theory has been popular, especially because cases of unexplained acute hepatitis peaked during the height of the COVID-19 pandemic when isolation was common, William F. Balistreri, MD, who was not affiliated with the study, told this news organization. Dr. Balistreri is professor of pediatrics and director emeritus of the Pediatric Liver Care Center at Cincinnati Children’s Hospital Medical Center.
 

Identifying the culprits

Determining what factors might be involved was the main aim of the etiology study by Dr. Chiu and colleagues published online  in Nature.

The journal simultaneously published a genomic study confirming the presence of AAV2 and other suspected viruses and a genomic and laboratory study further corroborating the results.

More than 1,000 children worldwide had been diagnosed with unexplained acute pediatric hepatitis as of August 2022. In the United States, there have been 358 cases, including 22 in which the child required a liver transplant and 13 in which the child died.

This new form of hepatitis, first detected in October 2021, does not fit into existing classifications of types A through E, so some researchers refer to the condition as acute non–A-E hepatitis of unknown etiology.

The investigators started with an important clue based on previous research: the role adenovirus might play. Dr. Chiu and colleagues assessed 27 blood, stool, and other samples from 16 affected children who each previously tested positive for adenoviruses. The researchers included cases of the condition identified up until May 22, 2022. The median age was 3 years, and approximately half were boys.

They compared viruses present in these children with those in 113 controls without the mysterious hepatitis. The control group consisted of 15 children who were hospitalized with a nonhepatitis inflammatory condition, 27 with a noninflammatory condition, 30 with acute hepatitis of known origin, 12 with acute gastroenteritis and an HAdV-positive stool sample, and 11 with acute gastroenteritis and an HAdV-negative stool sample, as well as 18 blood donors. The median age was 7 years.

The researchers assessed samples using multiple technologies, including metagenomic sequencing, tiling multiplex polymerase chain reaction (PCR) amplicon sequencing, metagenomic sequencing with probe capture viral enrichment, and virus-specific PCR. Many of these advanced techniques were not even available 5-10 years ago, Dr. Chiu said.
 

Key findings

Blood samples were available for 14 of the 16 children with acute hepatitis of unknown origin. Among this study group, AAV2 was found in 13 (93%). No other adeno-associated viruses were found. HAdV was detected in all 14 children: HAdV-41 in 11 children and HAdV-40, HAdV-2, and an untypeable strain in one child each. This finding was not intuitive because HAdVs are not commonly associated with hepatitis, according to the study.

AAV2 was much less common in the control group. For example, it was found in none of the children with hepatitis of known origin and in only four children (3.5%) with acute gastroenteritis and HAdV-positive stool. Of note, neither AAV2 nor HAdV-41 was detected among the 30 pediatric controls with acute hepatitis of defined etiology nor 42 of the hospitalized children without hepatitis, the researchers wrote.

In the search for other viruses in the study group, metagenomic sequencing detected EBV, also known as human herpesvirus (HHV)–4, in two children, cytomegalovirus (CMV) in one child, and HAdV type C in one child.

Analysis of whole blood revealed enterovirus A71 in one patient. HAdV type C also was detected in one child on the basis of a nasopharyngeal swab, and picobirnavirus was found in a stool sample from another patient.

Researchers conducted virus-specific PCR tests on both patient groups to identify additional viruses that may be associated with the unexplained acute hepatitis. EBV/HHV-4 was detected in 11 children (79%) in the study group vs. in 1 child (0.88%) in the control group. HHV-6 was detected in seven children (50%) in the study group, compared with one case in the control group. CMV was not detected in any of the children in the study group versus vs. two children (1.8%) in the control group.

“Although we found significant differences in the relative proportions of EBV and HHV-6 in cases compared to controls, we do not believe that these viruses are the primary cause of acute severe hepatitis,” the researchers wrote. The viral load of the two herpes viruses were very low, so the positive results could represent integrated proviral DNA rather than bona fide low-level herpesvirus. In addition, herpesvirus can be reactivated by an inflammatory condition.

“Nevertheless, it is striking that among the 16 cases (in the study group), dual, triple, or quadruple infections with AAV2, adenovirus, and one or both herpesviruses were detected in whole blood from at least 12 cases (75%),” the researchers wrote.
 

Management of suspected hepatitis

The study’s key messages for parents and health care providers “are awareness and reassurance,” Dr. Balistreri said in an interview.

Vigilance also is warranted if a child develops prodromal symptoms including respiratory and/or gastrointestinal signs such as nausea, vomiting, diarrhea, and abdomen pain, he said. If jaundice or scleral icterus is noted, then hepatitis should be suspected.

Some patients need hospitalization and quickly recover. In very rare instances, the inflammation may progress to liver failure and transplantation, Dr. Balistreri said.

“Reassurance is based on the good news that most children with acute hepatitis get better. If a case arises, it is good practice to keep the child well hydrated, offer a normal diet, and avoid medications that may be cleared by the liver,” Dr. Balistreri added.

“Of course, COVID-19 vaccination is strongly suggested,” he said.

Some existing treatments could help against unexplained acute hepatitis, Dr. Chiu said. “The findings suggest that antiviral therapy might be effective in these cases.”

Cidofovir can be effective against adenovirus, according to a report in The Lancet . Similarly, ganciclovir or valganciclovir may have activity against EBV/HHV-4 or HHV-6, Dr. Chiu said. “However, antiviral therapy is not available for AAV2.”

The three studies published in Nature “offer compelling evidence, from disparate centers, of a linkage of outbreak cases to infection by AAV2,” Dr. Balistreri said. The studies also suggest that liver injury was related to abnormal immune responses. This is an important clinical distinction, indicating a potential therapeutic approach to future cases – immunosuppression rather than anti-adenoviral agents, he said.

“We await further studies of this important concept,” Dr. Balistreri said.

Many unanswered questions remain about the condition’s etiology, he added. Is there a synergy or shared susceptibility related to SARS-CoV-2? Is the COVID-19 virus helping to trigger these infections, or does it increase the risk once infected? Also, are other epigenetic factors or viruses involved?
 

Moving forward

The next steps in the research could go beyond identifying presence of these different viruses and determining which one(s) are contributing the most to the acute pediatric hepatitis, Dr. Chiu said.

The researchers also would like to test early results from the United Kingdom that identified a potential association of acute severe hepatitis with the presence of human leukocyte antigen genotype DRB1*04:01, he added.

They also might investigate other unintended potential clinical consequences of the COVID-19 pandemic, including long COVID and resurgence of infections from other viruses, such as respiratory syncytial virus, influenza, and enterovirus D68.

The study was supported by the Centers for Disease Control and Prevention, the National Institutes of Health, the Department of Homeland Security, and other grants. Dr. Chiu is a founder of Delve Bio and on the scientific advisory board for Delve Bio, Mammoth Biosciences, BiomeSense, and Poppy Health. Dr. Balistreri had no relevant disclosures.
 

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

Investigators found that simultaneous infection with adeno-associated virus type 2 (AAV2) and certain other viruses is associated with the outbreak of mysterious pediatric hepatitis cases worldwide.

Coinfection with AAV2 and a human adenovirus (HAdV), in particular, appears to leave some children more vulnerable to this acute hepatitis of unknown origin, researchers reported in three studies published online in Nature. Coinfection with Epstein-Barr virus (EBV), herpes, and enterovirus also were found. Adeno-associated viruses are not considered pathogenic on their own and require a “helper” virus for productive infection.

“I am quite confident that we have identified the key viruses involved because we used a comprehensive metagenomic sequencing approach to look for potential infections from any virus or non-viral pathogen,” Charles Chiu, MD, PhD, senior author and professor of laboratory medicine and medicine/infectious diseases at the University of California, San Francisco, said in an interview.

Dr. Chiu and colleagues propose that lockdowns and social isolation during the COVID-19 pandemic left more children susceptible. A major aspect of immunity in childhood is the adaptive immune response – both cell-mediated and humoral – shaped in part by exposure to viruses and other pathogens early in life, Dr. Chiu said.

“Due to COVID-19, a large population of children did not experience this, so it is possible once restrictions were lifted, they were suddenly exposed over a short period of time to multiple viruses that, in a poorly trained immune system, would have increased their risk of developing severe disease,” he said.

This theory has been popular, especially because cases of unexplained acute hepatitis peaked during the height of the COVID-19 pandemic when isolation was common, William F. Balistreri, MD, who was not affiliated with the study, told this news organization. Dr. Balistreri is professor of pediatrics and director emeritus of the Pediatric Liver Care Center at Cincinnati Children’s Hospital Medical Center.
 

Identifying the culprits

Determining what factors might be involved was the main aim of the etiology study by Dr. Chiu and colleagues published online  in Nature.

The journal simultaneously published a genomic study confirming the presence of AAV2 and other suspected viruses and a genomic and laboratory study further corroborating the results.

More than 1,000 children worldwide had been diagnosed with unexplained acute pediatric hepatitis as of August 2022. In the United States, there have been 358 cases, including 22 in which the child required a liver transplant and 13 in which the child died.

This new form of hepatitis, first detected in October 2021, does not fit into existing classifications of types A through E, so some researchers refer to the condition as acute non–A-E hepatitis of unknown etiology.

The investigators started with an important clue based on previous research: the role adenovirus might play. Dr. Chiu and colleagues assessed 27 blood, stool, and other samples from 16 affected children who each previously tested positive for adenoviruses. The researchers included cases of the condition identified up until May 22, 2022. The median age was 3 years, and approximately half were boys.

They compared viruses present in these children with those in 113 controls without the mysterious hepatitis. The control group consisted of 15 children who were hospitalized with a nonhepatitis inflammatory condition, 27 with a noninflammatory condition, 30 with acute hepatitis of known origin, 12 with acute gastroenteritis and an HAdV-positive stool sample, and 11 with acute gastroenteritis and an HAdV-negative stool sample, as well as 18 blood donors. The median age was 7 years.

The researchers assessed samples using multiple technologies, including metagenomic sequencing, tiling multiplex polymerase chain reaction (PCR) amplicon sequencing, metagenomic sequencing with probe capture viral enrichment, and virus-specific PCR. Many of these advanced techniques were not even available 5-10 years ago, Dr. Chiu said.
 

Key findings

Blood samples were available for 14 of the 16 children with acute hepatitis of unknown origin. Among this study group, AAV2 was found in 13 (93%). No other adeno-associated viruses were found. HAdV was detected in all 14 children: HAdV-41 in 11 children and HAdV-40, HAdV-2, and an untypeable strain in one child each. This finding was not intuitive because HAdVs are not commonly associated with hepatitis, according to the study.

AAV2 was much less common in the control group. For example, it was found in none of the children with hepatitis of known origin and in only four children (3.5%) with acute gastroenteritis and HAdV-positive stool. Of note, neither AAV2 nor HAdV-41 was detected among the 30 pediatric controls with acute hepatitis of defined etiology nor 42 of the hospitalized children without hepatitis, the researchers wrote.

In the search for other viruses in the study group, metagenomic sequencing detected EBV, also known as human herpesvirus (HHV)–4, in two children, cytomegalovirus (CMV) in one child, and HAdV type C in one child.

Analysis of whole blood revealed enterovirus A71 in one patient. HAdV type C also was detected in one child on the basis of a nasopharyngeal swab, and picobirnavirus was found in a stool sample from another patient.

Researchers conducted virus-specific PCR tests on both patient groups to identify additional viruses that may be associated with the unexplained acute hepatitis. EBV/HHV-4 was detected in 11 children (79%) in the study group vs. in 1 child (0.88%) in the control group. HHV-6 was detected in seven children (50%) in the study group, compared with one case in the control group. CMV was not detected in any of the children in the study group versus vs. two children (1.8%) in the control group.

“Although we found significant differences in the relative proportions of EBV and HHV-6 in cases compared to controls, we do not believe that these viruses are the primary cause of acute severe hepatitis,” the researchers wrote. The viral load of the two herpes viruses were very low, so the positive results could represent integrated proviral DNA rather than bona fide low-level herpesvirus. In addition, herpesvirus can be reactivated by an inflammatory condition.

“Nevertheless, it is striking that among the 16 cases (in the study group), dual, triple, or quadruple infections with AAV2, adenovirus, and one or both herpesviruses were detected in whole blood from at least 12 cases (75%),” the researchers wrote.
 

Management of suspected hepatitis

The study’s key messages for parents and health care providers “are awareness and reassurance,” Dr. Balistreri said in an interview.

Vigilance also is warranted if a child develops prodromal symptoms including respiratory and/or gastrointestinal signs such as nausea, vomiting, diarrhea, and abdomen pain, he said. If jaundice or scleral icterus is noted, then hepatitis should be suspected.

Some patients need hospitalization and quickly recover. In very rare instances, the inflammation may progress to liver failure and transplantation, Dr. Balistreri said.

“Reassurance is based on the good news that most children with acute hepatitis get better. If a case arises, it is good practice to keep the child well hydrated, offer a normal diet, and avoid medications that may be cleared by the liver,” Dr. Balistreri added.

“Of course, COVID-19 vaccination is strongly suggested,” he said.

Some existing treatments could help against unexplained acute hepatitis, Dr. Chiu said. “The findings suggest that antiviral therapy might be effective in these cases.”

Cidofovir can be effective against adenovirus, according to a report in The Lancet . Similarly, ganciclovir or valganciclovir may have activity against EBV/HHV-4 or HHV-6, Dr. Chiu said. “However, antiviral therapy is not available for AAV2.”

The three studies published in Nature “offer compelling evidence, from disparate centers, of a linkage of outbreak cases to infection by AAV2,” Dr. Balistreri said. The studies also suggest that liver injury was related to abnormal immune responses. This is an important clinical distinction, indicating a potential therapeutic approach to future cases – immunosuppression rather than anti-adenoviral agents, he said.

“We await further studies of this important concept,” Dr. Balistreri said.

Many unanswered questions remain about the condition’s etiology, he added. Is there a synergy or shared susceptibility related to SARS-CoV-2? Is the COVID-19 virus helping to trigger these infections, or does it increase the risk once infected? Also, are other epigenetic factors or viruses involved?
 

Moving forward

The next steps in the research could go beyond identifying presence of these different viruses and determining which one(s) are contributing the most to the acute pediatric hepatitis, Dr. Chiu said.

The researchers also would like to test early results from the United Kingdom that identified a potential association of acute severe hepatitis with the presence of human leukocyte antigen genotype DRB1*04:01, he added.

They also might investigate other unintended potential clinical consequences of the COVID-19 pandemic, including long COVID and resurgence of infections from other viruses, such as respiratory syncytial virus, influenza, and enterovirus D68.

The study was supported by the Centers for Disease Control and Prevention, the National Institutes of Health, the Department of Homeland Security, and other grants. Dr. Chiu is a founder of Delve Bio and on the scientific advisory board for Delve Bio, Mammoth Biosciences, BiomeSense, and Poppy Health. Dr. Balistreri had no relevant disclosures.
 

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

Investigators found that simultaneous infection with adeno-associated virus type 2 (AAV2) and certain other viruses is associated with the outbreak of mysterious pediatric hepatitis cases worldwide.

Coinfection with AAV2 and a human adenovirus (HAdV), in particular, appears to leave some children more vulnerable to this acute hepatitis of unknown origin, researchers reported in three studies published online in Nature. Coinfection with Epstein-Barr virus (EBV), herpes, and enterovirus also were found. Adeno-associated viruses are not considered pathogenic on their own and require a “helper” virus for productive infection.

“I am quite confident that we have identified the key viruses involved because we used a comprehensive metagenomic sequencing approach to look for potential infections from any virus or non-viral pathogen,” Charles Chiu, MD, PhD, senior author and professor of laboratory medicine and medicine/infectious diseases at the University of California, San Francisco, said in an interview.

Dr. Chiu and colleagues propose that lockdowns and social isolation during the COVID-19 pandemic left more children susceptible. A major aspect of immunity in childhood is the adaptive immune response – both cell-mediated and humoral – shaped in part by exposure to viruses and other pathogens early in life, Dr. Chiu said.

“Due to COVID-19, a large population of children did not experience this, so it is possible once restrictions were lifted, they were suddenly exposed over a short period of time to multiple viruses that, in a poorly trained immune system, would have increased their risk of developing severe disease,” he said.

This theory has been popular, especially because cases of unexplained acute hepatitis peaked during the height of the COVID-19 pandemic when isolation was common, William F. Balistreri, MD, who was not affiliated with the study, told this news organization. Dr. Balistreri is professor of pediatrics and director emeritus of the Pediatric Liver Care Center at Cincinnati Children’s Hospital Medical Center.
 

Identifying the culprits

Determining what factors might be involved was the main aim of the etiology study by Dr. Chiu and colleagues published online  in Nature.

The journal simultaneously published a genomic study confirming the presence of AAV2 and other suspected viruses and a genomic and laboratory study further corroborating the results.

More than 1,000 children worldwide had been diagnosed with unexplained acute pediatric hepatitis as of August 2022. In the United States, there have been 358 cases, including 22 in which the child required a liver transplant and 13 in which the child died.

This new form of hepatitis, first detected in October 2021, does not fit into existing classifications of types A through E, so some researchers refer to the condition as acute non–A-E hepatitis of unknown etiology.

The investigators started with an important clue based on previous research: the role adenovirus might play. Dr. Chiu and colleagues assessed 27 blood, stool, and other samples from 16 affected children who each previously tested positive for adenoviruses. The researchers included cases of the condition identified up until May 22, 2022. The median age was 3 years, and approximately half were boys.

They compared viruses present in these children with those in 113 controls without the mysterious hepatitis. The control group consisted of 15 children who were hospitalized with a nonhepatitis inflammatory condition, 27 with a noninflammatory condition, 30 with acute hepatitis of known origin, 12 with acute gastroenteritis and an HAdV-positive stool sample, and 11 with acute gastroenteritis and an HAdV-negative stool sample, as well as 18 blood donors. The median age was 7 years.

The researchers assessed samples using multiple technologies, including metagenomic sequencing, tiling multiplex polymerase chain reaction (PCR) amplicon sequencing, metagenomic sequencing with probe capture viral enrichment, and virus-specific PCR. Many of these advanced techniques were not even available 5-10 years ago, Dr. Chiu said.
 

Key findings

Blood samples were available for 14 of the 16 children with acute hepatitis of unknown origin. Among this study group, AAV2 was found in 13 (93%). No other adeno-associated viruses were found. HAdV was detected in all 14 children: HAdV-41 in 11 children and HAdV-40, HAdV-2, and an untypeable strain in one child each. This finding was not intuitive because HAdVs are not commonly associated with hepatitis, according to the study.

AAV2 was much less common in the control group. For example, it was found in none of the children with hepatitis of known origin and in only four children (3.5%) with acute gastroenteritis and HAdV-positive stool. Of note, neither AAV2 nor HAdV-41 was detected among the 30 pediatric controls with acute hepatitis of defined etiology nor 42 of the hospitalized children without hepatitis, the researchers wrote.

In the search for other viruses in the study group, metagenomic sequencing detected EBV, also known as human herpesvirus (HHV)–4, in two children, cytomegalovirus (CMV) in one child, and HAdV type C in one child.

Analysis of whole blood revealed enterovirus A71 in one patient. HAdV type C also was detected in one child on the basis of a nasopharyngeal swab, and picobirnavirus was found in a stool sample from another patient.

Researchers conducted virus-specific PCR tests on both patient groups to identify additional viruses that may be associated with the unexplained acute hepatitis. EBV/HHV-4 was detected in 11 children (79%) in the study group vs. in 1 child (0.88%) in the control group. HHV-6 was detected in seven children (50%) in the study group, compared with one case in the control group. CMV was not detected in any of the children in the study group versus vs. two children (1.8%) in the control group.

“Although we found significant differences in the relative proportions of EBV and HHV-6 in cases compared to controls, we do not believe that these viruses are the primary cause of acute severe hepatitis,” the researchers wrote. The viral load of the two herpes viruses were very low, so the positive results could represent integrated proviral DNA rather than bona fide low-level herpesvirus. In addition, herpesvirus can be reactivated by an inflammatory condition.

“Nevertheless, it is striking that among the 16 cases (in the study group), dual, triple, or quadruple infections with AAV2, adenovirus, and one or both herpesviruses were detected in whole blood from at least 12 cases (75%),” the researchers wrote.
 

Management of suspected hepatitis

The study’s key messages for parents and health care providers “are awareness and reassurance,” Dr. Balistreri said in an interview.

Vigilance also is warranted if a child develops prodromal symptoms including respiratory and/or gastrointestinal signs such as nausea, vomiting, diarrhea, and abdomen pain, he said. If jaundice or scleral icterus is noted, then hepatitis should be suspected.

Some patients need hospitalization and quickly recover. In very rare instances, the inflammation may progress to liver failure and transplantation, Dr. Balistreri said.

“Reassurance is based on the good news that most children with acute hepatitis get better. If a case arises, it is good practice to keep the child well hydrated, offer a normal diet, and avoid medications that may be cleared by the liver,” Dr. Balistreri added.

“Of course, COVID-19 vaccination is strongly suggested,” he said.

Some existing treatments could help against unexplained acute hepatitis, Dr. Chiu said. “The findings suggest that antiviral therapy might be effective in these cases.”

Cidofovir can be effective against adenovirus, according to a report in The Lancet . Similarly, ganciclovir or valganciclovir may have activity against EBV/HHV-4 or HHV-6, Dr. Chiu said. “However, antiviral therapy is not available for AAV2.”

The three studies published in Nature “offer compelling evidence, from disparate centers, of a linkage of outbreak cases to infection by AAV2,” Dr. Balistreri said. The studies also suggest that liver injury was related to abnormal immune responses. This is an important clinical distinction, indicating a potential therapeutic approach to future cases – immunosuppression rather than anti-adenoviral agents, he said.

“We await further studies of this important concept,” Dr. Balistreri said.

Many unanswered questions remain about the condition’s etiology, he added. Is there a synergy or shared susceptibility related to SARS-CoV-2? Is the COVID-19 virus helping to trigger these infections, or does it increase the risk once infected? Also, are other epigenetic factors or viruses involved?
 

Moving forward

The next steps in the research could go beyond identifying presence of these different viruses and determining which one(s) are contributing the most to the acute pediatric hepatitis, Dr. Chiu said.

The researchers also would like to test early results from the United Kingdom that identified a potential association of acute severe hepatitis with the presence of human leukocyte antigen genotype DRB1*04:01, he added.

They also might investigate other unintended potential clinical consequences of the COVID-19 pandemic, including long COVID and resurgence of infections from other viruses, such as respiratory syncytial virus, influenza, and enterovirus D68.

The study was supported by the Centers for Disease Control and Prevention, the National Institutes of Health, the Department of Homeland Security, and other grants. Dr. Chiu is a founder of Delve Bio and on the scientific advisory board for Delve Bio, Mammoth Biosciences, BiomeSense, and Poppy Health. Dr. Balistreri had no relevant disclosures.
 

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

Patients with nonalcoholic fatty liver disease (NAFLD) who carry two copies of the PNPLA3 p.I148M variant, may exhibit faster progression to cirrhosis, while those with this genotype who also have diabetes and indeterminate Fibrosis-4 (FIB4) scores may have the same risk of cirrhosis as patients with a high FIB4, according to investigators.

These findings suggest that NAFLD patients with indeterminate FIB4 and metabolic risk factors should routinely undergo PNPLA3 genotyping, lead author Vincent L. Chen, MD, of the University of Michigan, Ann Arbor, and colleagues reported.

Michigan Medicine

“Whether incorporating genetics into risk stratification results in meaningful improvement over clinical predictors, such as FIB4, diabetes, and obesity status, is unknown,” the investigators wrote in Gastroenterology. “Improved understanding of how genetics influences the rate of disease progression and how it interacts with established risk factors for advanced liver disease is crucial for genetic testing to be applicable in clinical practice.”

To evaluate the risk presented by the PNPLA3 p.I148M variant, Dr. Chen and colleagues analyzed data from two independent cohorts with 7,893 patients and 46,880 patients each.

They first characterized the relationship between PNPLA3 genotype and cirrhosis via univariable and multivariable analyses. These efforts revealed that the genotype predicted cirrhosis in both cohorts, with associations also detected for well-documented clinical risk factors, including diabetes, obesity, and high ALT. Of note, PNPLA3 genotype demonstrated an additive effect for cirrhosis when detected in conjunction with these risks.

Further analysis revealed that homozygous carriers of PNPLA3 p.I148M with indeterminate FIB4 scores (1.3-2.67) and diabetes had an incidence rate of cirrhosis on par with patients who had high-risk FIB4 (greater than 2.67).

The effects of the risk allele were also made evident by comparing patients with diabetes and indeterminate FIB4 based on presence or absence of the marker – those testing positive for h PNPLA3 p.I148M had 2.9-4.8 times greater risk of cirrhosis. Conversely, patients with FIB4 scores less than 1.3, regardless of other risk factors, had little change in cirrhosis rate regardless of PNPLA3 status.

“We found that PNPLA3 genotyping in conjunction with clinical risk factors may improve risk stratification in patients with NAFLD,” the investigators concluded. “Although it may be possible to develop more complex polygenic risk scores for cirrhosis, these findings suggest that genotyping of PNPLA3 alone, which is less expensive than genomewide genotyping and easier to understand, may have similar clinical applicability for NAFLD.”

Dr. Chen and colleagues therefore recommended that NAFLD patients with metabolic risk factors (particularly diabetes) and indeterminate FIB4 routinely undergo PNPLA3 genotyping, with referral to hepatology if positive for two risk alleles.

The study was supported by the American Association for the Study of Liver Diseases, National Institutes of Health, and the University of Michigan department of internal medicine. The investigators disclosed no conflicts of interest.

Patients with nonalcoholic fatty liver disease (NAFLD) who carry two copies of the PNPLA3 p.I148M variant, may exhibit faster progression to cirrhosis, while those with this genotype who also have diabetes and indeterminate Fibrosis-4 (FIB4) scores may have the same risk of cirrhosis as patients with a high FIB4, according to investigators.

These findings suggest that NAFLD patients with indeterminate FIB4 and metabolic risk factors should routinely undergo PNPLA3 genotyping, lead author Vincent L. Chen, MD, of the University of Michigan, Ann Arbor, and colleagues reported.

Michigan Medicine

“Whether incorporating genetics into risk stratification results in meaningful improvement over clinical predictors, such as FIB4, diabetes, and obesity status, is unknown,” the investigators wrote in Gastroenterology. “Improved understanding of how genetics influences the rate of disease progression and how it interacts with established risk factors for advanced liver disease is crucial for genetic testing to be applicable in clinical practice.”

To evaluate the risk presented by the PNPLA3 p.I148M variant, Dr. Chen and colleagues analyzed data from two independent cohorts with 7,893 patients and 46,880 patients each.

They first characterized the relationship between PNPLA3 genotype and cirrhosis via univariable and multivariable analyses. These efforts revealed that the genotype predicted cirrhosis in both cohorts, with associations also detected for well-documented clinical risk factors, including diabetes, obesity, and high ALT. Of note, PNPLA3 genotype demonstrated an additive effect for cirrhosis when detected in conjunction with these risks.

Further analysis revealed that homozygous carriers of PNPLA3 p.I148M with indeterminate FIB4 scores (1.3-2.67) and diabetes had an incidence rate of cirrhosis on par with patients who had high-risk FIB4 (greater than 2.67).

The effects of the risk allele were also made evident by comparing patients with diabetes and indeterminate FIB4 based on presence or absence of the marker – those testing positive for h PNPLA3 p.I148M had 2.9-4.8 times greater risk of cirrhosis. Conversely, patients with FIB4 scores less than 1.3, regardless of other risk factors, had little change in cirrhosis rate regardless of PNPLA3 status.

“We found that PNPLA3 genotyping in conjunction with clinical risk factors may improve risk stratification in patients with NAFLD,” the investigators concluded. “Although it may be possible to develop more complex polygenic risk scores for cirrhosis, these findings suggest that genotyping of PNPLA3 alone, which is less expensive than genomewide genotyping and easier to understand, may have similar clinical applicability for NAFLD.”

Dr. Chen and colleagues therefore recommended that NAFLD patients with metabolic risk factors (particularly diabetes) and indeterminate FIB4 routinely undergo PNPLA3 genotyping, with referral to hepatology if positive for two risk alleles.

The study was supported by the American Association for the Study of Liver Diseases, National Institutes of Health, and the University of Michigan department of internal medicine. The investigators disclosed no conflicts of interest.

Patients with nonalcoholic fatty liver disease (NAFLD) who carry two copies of the PNPLA3 p.I148M variant, may exhibit faster progression to cirrhosis, while those with this genotype who also have diabetes and indeterminate Fibrosis-4 (FIB4) scores may have the same risk of cirrhosis as patients with a high FIB4, according to investigators.

These findings suggest that NAFLD patients with indeterminate FIB4 and metabolic risk factors should routinely undergo PNPLA3 genotyping, lead author Vincent L. Chen, MD, of the University of Michigan, Ann Arbor, and colleagues reported.

Michigan Medicine

“Whether incorporating genetics into risk stratification results in meaningful improvement over clinical predictors, such as FIB4, diabetes, and obesity status, is unknown,” the investigators wrote in Gastroenterology. “Improved understanding of how genetics influences the rate of disease progression and how it interacts with established risk factors for advanced liver disease is crucial for genetic testing to be applicable in clinical practice.”

To evaluate the risk presented by the PNPLA3 p.I148M variant, Dr. Chen and colleagues analyzed data from two independent cohorts with 7,893 patients and 46,880 patients each.

They first characterized the relationship between PNPLA3 genotype and cirrhosis via univariable and multivariable analyses. These efforts revealed that the genotype predicted cirrhosis in both cohorts, with associations also detected for well-documented clinical risk factors, including diabetes, obesity, and high ALT. Of note, PNPLA3 genotype demonstrated an additive effect for cirrhosis when detected in conjunction with these risks.

Further analysis revealed that homozygous carriers of PNPLA3 p.I148M with indeterminate FIB4 scores (1.3-2.67) and diabetes had an incidence rate of cirrhosis on par with patients who had high-risk FIB4 (greater than 2.67).

The effects of the risk allele were also made evident by comparing patients with diabetes and indeterminate FIB4 based on presence or absence of the marker – those testing positive for h PNPLA3 p.I148M had 2.9-4.8 times greater risk of cirrhosis. Conversely, patients with FIB4 scores less than 1.3, regardless of other risk factors, had little change in cirrhosis rate regardless of PNPLA3 status.

“We found that PNPLA3 genotyping in conjunction with clinical risk factors may improve risk stratification in patients with NAFLD,” the investigators concluded. “Although it may be possible to develop more complex polygenic risk scores for cirrhosis, these findings suggest that genotyping of PNPLA3 alone, which is less expensive than genomewide genotyping and easier to understand, may have similar clinical applicability for NAFLD.”

Dr. Chen and colleagues therefore recommended that NAFLD patients with metabolic risk factors (particularly diabetes) and indeterminate FIB4 routinely undergo PNPLA3 genotyping, with referral to hepatology if positive for two risk alleles.

The study was supported by the American Association for the Study of Liver Diseases, National Institutes of Health, and the University of Michigan department of internal medicine. The investigators disclosed no conflicts of interest.

All adults should be tested for hepatitis B virus (HBV) at least once in their lifetime, according to updated guidelines from the Centers for Disease Control and Prevention.

This is the first update to HBV screening guidelines since 2008, the agency said.

“Risk-based testing alone has not identified most persons living with chronic HBV infection and is considered inefficient for providers to implement,” the authors wrote in the new guidance, published in the CDC’s Morbidity and Mortality Weekly Report. “Universal screening of adults for HBV infection is cost-effective, compared with risk-based screening and averts liver disease and death. Although a curative treatment is not yet available, early diagnosis and treatment of chronic HBV infections reduces the risk for cirrhosis, liver cancer, and death.”

Howard Lee, MD, an assistant professor in the section of gastroenterology and hepatology at Baylor College of Medicine in Houston, agreed that risk-based screening has not been effective. A universal screening approach “is the way to go,” he said. With this new screening approach, patients can get tested without having to admit that they may be at risk for a chronic disease like HIV and HBV, which can be stigmatizing, said Dr. Lee, who was not involved with making these recommendations.

An estimated 580,000 to 2.4 million individuals are living with HBV infection in the United States, and two-thirds may be unaware they are infected, according to the CDC. The virus spreads through contact with blood, semen, and other body fluids of an infected person.

The guidance now recommends using the triple panel (HBsAg, anti-HBs, total anti-HBc) for initial screening.

“It can help identify persons who have an active HBV infection and could be linked to care; have resolved infection and might be susceptible to reactivation (for example, immunosuppressed persons); are susceptible and need vaccination; or are vaccinated,” the authors wrote.

Patients with previous HBV infection can have the infection reactivated with immunosuppressive treatments, Dr. Lee said, which is why detecting prior infection via the triple panel screening is important.

Women who are pregnant should be screened, ideally, in the first trimester of each pregnancy, regardless of vaccination status or testing history. If they have already received timely triple panel screening for hepatitis B and have no new HBV exposures, pregnant women only need HBsAg screening, the guidelines state.

The guidelines also specify that higher risk groups, specifically those incarcerated or formerly incarcerated, adults with current or past hepatitis C virus infection, and those with current or past sexually transmitted infections and multiple sex partners.

People who are susceptible for infection, refuse vaccination and are at higher risk for HBV should be screened periodically, but how often they should be screened should be based on shared decision-making between the provider and patient as well as individual risk and immune status.

Additional research into the optimal frequency of periodic testing is necessary, the authors say.

“Along with vaccination strategies, universal screening of adults and appropriate testing of persons at increased risk for HBV infection will improve health outcomes, reduce the prevalence of HBV infection in the United States, and advance viral hepatitis elimination goals,” the authors wrote.

The new recommendations now contrast with the 2020 screening guidelines issued by the U.S. Preventive Services Task Force (USPSTF) that recommend risk-based screening for hepatitis B.

“When that recommendation was published, the Task Force was aligned with several other organizations, including the CDC, in supporting screening for hepatitis B in high-risk populations — and importantly, we’re all still aligned in making sure that people get the care that they need,” said Michael Barry, MD, chair of the USPSTF, in an emailed statement. “The evidence on clinical preventive services is always changing, and the Task Force aims to keep all recommendations current, updating each recommendation approximately every 5 years.”

“In the meantime, we always encourage clinicians to use their judgment as they provide care for their patients — including those who may benefit from screening for hepatitis B — and to decide together with each patient which preventive services can best help them live a long and healthy life,” Dr. Barry said.

The American Association for the Study of Liver Diseases is currently updating their HBV screening recommendations, Dr. Lee said, and he expects other professional societies to follow the CDC recommendations.

“It’s not uncommon that we see the CDC or societies making recommendations and the USPSTF following along, so hopefully that’s the case for hepatitis B as well,” he said.

The authors reported no potential conflicts of interest.

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

All adults should be tested for hepatitis B virus (HBV) at least once in their lifetime, according to updated guidelines from the Centers for Disease Control and Prevention.

This is the first update to HBV screening guidelines since 2008, the agency said.

“Risk-based testing alone has not identified most persons living with chronic HBV infection and is considered inefficient for providers to implement,” the authors wrote in the new guidance, published in the CDC’s Morbidity and Mortality Weekly Report. “Universal screening of adults for HBV infection is cost-effective, compared with risk-based screening and averts liver disease and death. Although a curative treatment is not yet available, early diagnosis and treatment of chronic HBV infections reduces the risk for cirrhosis, liver cancer, and death.”

Howard Lee, MD, an assistant professor in the section of gastroenterology and hepatology at Baylor College of Medicine in Houston, agreed that risk-based screening has not been effective. A universal screening approach “is the way to go,” he said. With this new screening approach, patients can get tested without having to admit that they may be at risk for a chronic disease like HIV and HBV, which can be stigmatizing, said Dr. Lee, who was not involved with making these recommendations.

An estimated 580,000 to 2.4 million individuals are living with HBV infection in the United States, and two-thirds may be unaware they are infected, according to the CDC. The virus spreads through contact with blood, semen, and other body fluids of an infected person.

The guidance now recommends using the triple panel (HBsAg, anti-HBs, total anti-HBc) for initial screening.

“It can help identify persons who have an active HBV infection and could be linked to care; have resolved infection and might be susceptible to reactivation (for example, immunosuppressed persons); are susceptible and need vaccination; or are vaccinated,” the authors wrote.

Patients with previous HBV infection can have the infection reactivated with immunosuppressive treatments, Dr. Lee said, which is why detecting prior infection via the triple panel screening is important.

Women who are pregnant should be screened, ideally, in the first trimester of each pregnancy, regardless of vaccination status or testing history. If they have already received timely triple panel screening for hepatitis B and have no new HBV exposures, pregnant women only need HBsAg screening, the guidelines state.

The guidelines also specify that higher risk groups, specifically those incarcerated or formerly incarcerated, adults with current or past hepatitis C virus infection, and those with current or past sexually transmitted infections and multiple sex partners.

People who are susceptible for infection, refuse vaccination and are at higher risk for HBV should be screened periodically, but how often they should be screened should be based on shared decision-making between the provider and patient as well as individual risk and immune status.

Additional research into the optimal frequency of periodic testing is necessary, the authors say.

“Along with vaccination strategies, universal screening of adults and appropriate testing of persons at increased risk for HBV infection will improve health outcomes, reduce the prevalence of HBV infection in the United States, and advance viral hepatitis elimination goals,” the authors wrote.

The new recommendations now contrast with the 2020 screening guidelines issued by the U.S. Preventive Services Task Force (USPSTF) that recommend risk-based screening for hepatitis B.

“When that recommendation was published, the Task Force was aligned with several other organizations, including the CDC, in supporting screening for hepatitis B in high-risk populations — and importantly, we’re all still aligned in making sure that people get the care that they need,” said Michael Barry, MD, chair of the USPSTF, in an emailed statement. “The evidence on clinical preventive services is always changing, and the Task Force aims to keep all recommendations current, updating each recommendation approximately every 5 years.”

“In the meantime, we always encourage clinicians to use their judgment as they provide care for their patients — including those who may benefit from screening for hepatitis B — and to decide together with each patient which preventive services can best help them live a long and healthy life,” Dr. Barry said.

The American Association for the Study of Liver Diseases is currently updating their HBV screening recommendations, Dr. Lee said, and he expects other professional societies to follow the CDC recommendations.

“It’s not uncommon that we see the CDC or societies making recommendations and the USPSTF following along, so hopefully that’s the case for hepatitis B as well,” he said.

The authors reported no potential conflicts of interest.

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

All adults should be tested for hepatitis B virus (HBV) at least once in their lifetime, according to updated guidelines from the Centers for Disease Control and Prevention.

This is the first update to HBV screening guidelines since 2008, the agency said.

“Risk-based testing alone has not identified most persons living with chronic HBV infection and is considered inefficient for providers to implement,” the authors wrote in the new guidance, published in the CDC’s Morbidity and Mortality Weekly Report. “Universal screening of adults for HBV infection is cost-effective, compared with risk-based screening and averts liver disease and death. Although a curative treatment is not yet available, early diagnosis and treatment of chronic HBV infections reduces the risk for cirrhosis, liver cancer, and death.”

Howard Lee, MD, an assistant professor in the section of gastroenterology and hepatology at Baylor College of Medicine in Houston, agreed that risk-based screening has not been effective. A universal screening approach “is the way to go,” he said. With this new screening approach, patients can get tested without having to admit that they may be at risk for a chronic disease like HIV and HBV, which can be stigmatizing, said Dr. Lee, who was not involved with making these recommendations.

An estimated 580,000 to 2.4 million individuals are living with HBV infection in the United States, and two-thirds may be unaware they are infected, according to the CDC. The virus spreads through contact with blood, semen, and other body fluids of an infected person.

The guidance now recommends using the triple panel (HBsAg, anti-HBs, total anti-HBc) for initial screening.

“It can help identify persons who have an active HBV infection and could be linked to care; have resolved infection and might be susceptible to reactivation (for example, immunosuppressed persons); are susceptible and need vaccination; or are vaccinated,” the authors wrote.

Patients with previous HBV infection can have the infection reactivated with immunosuppressive treatments, Dr. Lee said, which is why detecting prior infection via the triple panel screening is important.

Women who are pregnant should be screened, ideally, in the first trimester of each pregnancy, regardless of vaccination status or testing history. If they have already received timely triple panel screening for hepatitis B and have no new HBV exposures, pregnant women only need HBsAg screening, the guidelines state.

The guidelines also specify that higher risk groups, specifically those incarcerated or formerly incarcerated, adults with current or past hepatitis C virus infection, and those with current or past sexually transmitted infections and multiple sex partners.

People who are susceptible for infection, refuse vaccination and are at higher risk for HBV should be screened periodically, but how often they should be screened should be based on shared decision-making between the provider and patient as well as individual risk and immune status.

Additional research into the optimal frequency of periodic testing is necessary, the authors say.

“Along with vaccination strategies, universal screening of adults and appropriate testing of persons at increased risk for HBV infection will improve health outcomes, reduce the prevalence of HBV infection in the United States, and advance viral hepatitis elimination goals,” the authors wrote.

The new recommendations now contrast with the 2020 screening guidelines issued by the U.S. Preventive Services Task Force (USPSTF) that recommend risk-based screening for hepatitis B.

“When that recommendation was published, the Task Force was aligned with several other organizations, including the CDC, in supporting screening for hepatitis B in high-risk populations — and importantly, we’re all still aligned in making sure that people get the care that they need,” said Michael Barry, MD, chair of the USPSTF, in an emailed statement. “The evidence on clinical preventive services is always changing, and the Task Force aims to keep all recommendations current, updating each recommendation approximately every 5 years.”

“In the meantime, we always encourage clinicians to use their judgment as they provide care for their patients — including those who may benefit from screening for hepatitis B — and to decide together with each patient which preventive services can best help them live a long and healthy life,” Dr. Barry said.

The American Association for the Study of Liver Diseases is currently updating their HBV screening recommendations, Dr. Lee said, and he expects other professional societies to follow the CDC recommendations.

“It’s not uncommon that we see the CDC or societies making recommendations and the USPSTF following along, so hopefully that’s the case for hepatitis B as well,” he said.

The authors reported no potential conflicts of interest.

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

Low serum levels of the hepatitis B core-related antigen (HBcrAg) could be an early biomarker of a functional cure of a hepatitis B infection, according to new findings from a retrospective study.

A drop in HBcrAg predicted the seroclearance of hepatitis B surface antigen (HBsAg), the widely accepted measure of optimal liver-related outcomes in patient care and clinical trials, long before HBsAg levels actually fell.

“In a large retrospective cohort study of chronic hepatitis B patients, we found lower levels of HBcrAg were associated with higher probability of clearing HBsAg,” wrote Tai-Chung Tseng and coauthors at National Taiwan University Hospital in Taipei. “Reduction of HBcrAg developed 10 years before decline of HBsAg in patients with high HBsAg levels at baseline.”

Nearly 300 million people worldwide are estimated to be positive for the HBsAg antigen, a marker of active hepatitis B virus (HBV) infection. Chronic HBV puts individuals at greater risk of cirrhosis, hepatocellular carcinoma (HCC), and other liver complications.

Seroclearance of HBsAg is generally regarded as signaling a functional cure, because it is associated with low viral activity and good clinical outcomes. Patients with low HBsAg levels may transition to complete clearance, while those with levels of 1,000 IU/mL or higher rarely achieve clearance either spontaneously or through treatment.

As with HBsAg, higher serum levels of HBcrAg have been linked to a raised risk of adverse events, including increased viral activity and heightened risk of developing hepatitis B e antigen-negative hepatitis, cirrhosis, and HCC. Lower HBcrAg levels are associated with a greater likelihood of HBsAg seroclearance in chronic hepatitis B patients who discontinued antiviral therapy.

In a study published in Gastroenterology, researchers conducted a retrospective Taiwanese cohort study of 2,614 untreated patients with hepatitis B who underwent long-term follow-up at National Taiwan University Hospital. The median age was 38.2 years, and 60.6% were men. At baseline, 14.8% had HBsAg levels of less than 100 IU/mL, and 47.7% had HBcrAg levels less than 10,000 IU/mL. Most (77.5%) were infected with HBV genotype B. From stored serum samples, the researchers quantified levels of HBV DNA, HBsAg, and HBcrAg and evaluated the relationships with spontaneous HBsAg seroclearance.

Over an average follow-up of about 12 years, 465 patients cleared HBsAg, an incidence of 1.43% per year. Researchers stratified patients by levels of viral markers. Compared to those with the highest HBcrAg levels (> 100,000 IU/mL), lower levels of HBcrAg were associated with greater likelihood of HBsAg clearance.

Specifically, intermediate levels (10,000-99,999 IU/mL) were associated with nearly double the chance of HBsAg clearance (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.44-2.65), and the lowest levels (< 10,000 IU/mL) were associated with just over triple the chance of clearance (HR, 3.15; 95% CI, 2.45-4.05). These associations held up with multivariable analyses, and HBV DNA levels were not significantly associated with HBsAg clearance.

“Not surprisingly, HBsAg levels still serve as a better predictor than the other two biomarkers,” the authors wrote. “Notably, the HBsAg levels are more like a short-term predictor” (within 5 years).

For patients with higher HBsAg levels (> 1,000 IU/mL), it took a median of 16 years to achieve HBsAg clearance. A subanalysis of the 1,539 patients with HbsAg levels > 1,000 IU/mL found that only HBcrAg levels below 10,000 IU/mL predicted HBsAg seroclearance versus 100,000 U/mL or higher (adjusted HR, 1.95; 95% CI, 1.16-3.27).

HBsAg levels began to decline later, often between 5 and 9 years before HBsAg seroclearance occurs. However, HBcrAg levels became undetectable 10-14 years before HBsAg seroclearance. Among patients achieving undetectable levels of HBcrAg, the annual HBsAg seroclearance rate was higher in the second decade of follow-up than in the first decade (3.75% versus 0.97%).

HBcrAg levels reflect the transcriptional activity of covalently closed circular DNA (cccDNA), the authors noted, while HBsAg can come from cccDNA and HBV-DNA integrated into the host genome. Several novel hepatitis B therapies in development target cccDNA transcription, but it isn’t known if the strategy will result in HBsAg clearance.

In the discussion section, the authors speculated about the possible pathology and treatment implications for several chronic hepatitis B scenarios. For example, the finding that HBcrAg clearance usually precedes HBsAg clearance suggests that reduction of cccDNA transcription is a requirement for curing hepatitis B, the authors speculate, but it also suggests that add-on treatment may need to target HBsAg transcribed from the integrated viral genome for a functional cure.

The researchers noted several study limitations, including that the cohort included only Asians largely with HBV genotypes B or C and that “further validation from Caucasian patients infected with genotypes types A or D is mandatory.”

Tai-Chung Tseng disclosed financial conflicts with Fujirebio, Bristol-Myers Squibb, and Gilead Sciences. The remaining authors had no conflicts of interest. The study received grant support from several institutions, including National Taiwan University Hospital.

Low serum levels of the hepatitis B core-related antigen (HBcrAg) could be an early biomarker of a functional cure of a hepatitis B infection, according to new findings from a retrospective study.

A drop in HBcrAg predicted the seroclearance of hepatitis B surface antigen (HBsAg), the widely accepted measure of optimal liver-related outcomes in patient care and clinical trials, long before HBsAg levels actually fell.

“In a large retrospective cohort study of chronic hepatitis B patients, we found lower levels of HBcrAg were associated with higher probability of clearing HBsAg,” wrote Tai-Chung Tseng and coauthors at National Taiwan University Hospital in Taipei. “Reduction of HBcrAg developed 10 years before decline of HBsAg in patients with high HBsAg levels at baseline.”

Nearly 300 million people worldwide are estimated to be positive for the HBsAg antigen, a marker of active hepatitis B virus (HBV) infection. Chronic HBV puts individuals at greater risk of cirrhosis, hepatocellular carcinoma (HCC), and other liver complications.

Seroclearance of HBsAg is generally regarded as signaling a functional cure, because it is associated with low viral activity and good clinical outcomes. Patients with low HBsAg levels may transition to complete clearance, while those with levels of 1,000 IU/mL or higher rarely achieve clearance either spontaneously or through treatment.

As with HBsAg, higher serum levels of HBcrAg have been linked to a raised risk of adverse events, including increased viral activity and heightened risk of developing hepatitis B e antigen-negative hepatitis, cirrhosis, and HCC. Lower HBcrAg levels are associated with a greater likelihood of HBsAg seroclearance in chronic hepatitis B patients who discontinued antiviral therapy.

In a study published in Gastroenterology, researchers conducted a retrospective Taiwanese cohort study of 2,614 untreated patients with hepatitis B who underwent long-term follow-up at National Taiwan University Hospital. The median age was 38.2 years, and 60.6% were men. At baseline, 14.8% had HBsAg levels of less than 100 IU/mL, and 47.7% had HBcrAg levels less than 10,000 IU/mL. Most (77.5%) were infected with HBV genotype B. From stored serum samples, the researchers quantified levels of HBV DNA, HBsAg, and HBcrAg and evaluated the relationships with spontaneous HBsAg seroclearance.

Over an average follow-up of about 12 years, 465 patients cleared HBsAg, an incidence of 1.43% per year. Researchers stratified patients by levels of viral markers. Compared to those with the highest HBcrAg levels (> 100,000 IU/mL), lower levels of HBcrAg were associated with greater likelihood of HBsAg clearance.

Specifically, intermediate levels (10,000-99,999 IU/mL) were associated with nearly double the chance of HBsAg clearance (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.44-2.65), and the lowest levels (< 10,000 IU/mL) were associated with just over triple the chance of clearance (HR, 3.15; 95% CI, 2.45-4.05). These associations held up with multivariable analyses, and HBV DNA levels were not significantly associated with HBsAg clearance.

“Not surprisingly, HBsAg levels still serve as a better predictor than the other two biomarkers,” the authors wrote. “Notably, the HBsAg levels are more like a short-term predictor” (within 5 years).

For patients with higher HBsAg levels (> 1,000 IU/mL), it took a median of 16 years to achieve HBsAg clearance. A subanalysis of the 1,539 patients with HbsAg levels > 1,000 IU/mL found that only HBcrAg levels below 10,000 IU/mL predicted HBsAg seroclearance versus 100,000 U/mL or higher (adjusted HR, 1.95; 95% CI, 1.16-3.27).

HBsAg levels began to decline later, often between 5 and 9 years before HBsAg seroclearance occurs. However, HBcrAg levels became undetectable 10-14 years before HBsAg seroclearance. Among patients achieving undetectable levels of HBcrAg, the annual HBsAg seroclearance rate was higher in the second decade of follow-up than in the first decade (3.75% versus 0.97%).

HBcrAg levels reflect the transcriptional activity of covalently closed circular DNA (cccDNA), the authors noted, while HBsAg can come from cccDNA and HBV-DNA integrated into the host genome. Several novel hepatitis B therapies in development target cccDNA transcription, but it isn’t known if the strategy will result in HBsAg clearance.

In the discussion section, the authors speculated about the possible pathology and treatment implications for several chronic hepatitis B scenarios. For example, the finding that HBcrAg clearance usually precedes HBsAg clearance suggests that reduction of cccDNA transcription is a requirement for curing hepatitis B, the authors speculate, but it also suggests that add-on treatment may need to target HBsAg transcribed from the integrated viral genome for a functional cure.

The researchers noted several study limitations, including that the cohort included only Asians largely with HBV genotypes B or C and that “further validation from Caucasian patients infected with genotypes types A or D is mandatory.”

Tai-Chung Tseng disclosed financial conflicts with Fujirebio, Bristol-Myers Squibb, and Gilead Sciences. The remaining authors had no conflicts of interest. The study received grant support from several institutions, including National Taiwan University Hospital.

Low serum levels of the hepatitis B core-related antigen (HBcrAg) could be an early biomarker of a functional cure of a hepatitis B infection, according to new findings from a retrospective study.

A drop in HBcrAg predicted the seroclearance of hepatitis B surface antigen (HBsAg), the widely accepted measure of optimal liver-related outcomes in patient care and clinical trials, long before HBsAg levels actually fell.

“In a large retrospective cohort study of chronic hepatitis B patients, we found lower levels of HBcrAg were associated with higher probability of clearing HBsAg,” wrote Tai-Chung Tseng and coauthors at National Taiwan University Hospital in Taipei. “Reduction of HBcrAg developed 10 years before decline of HBsAg in patients with high HBsAg levels at baseline.”

Nearly 300 million people worldwide are estimated to be positive for the HBsAg antigen, a marker of active hepatitis B virus (HBV) infection. Chronic HBV puts individuals at greater risk of cirrhosis, hepatocellular carcinoma (HCC), and other liver complications.

Seroclearance of HBsAg is generally regarded as signaling a functional cure, because it is associated with low viral activity and good clinical outcomes. Patients with low HBsAg levels may transition to complete clearance, while those with levels of 1,000 IU/mL or higher rarely achieve clearance either spontaneously or through treatment.

As with HBsAg, higher serum levels of HBcrAg have been linked to a raised risk of adverse events, including increased viral activity and heightened risk of developing hepatitis B e antigen-negative hepatitis, cirrhosis, and HCC. Lower HBcrAg levels are associated with a greater likelihood of HBsAg seroclearance in chronic hepatitis B patients who discontinued antiviral therapy.

In a study published in Gastroenterology, researchers conducted a retrospective Taiwanese cohort study of 2,614 untreated patients with hepatitis B who underwent long-term follow-up at National Taiwan University Hospital. The median age was 38.2 years, and 60.6% were men. At baseline, 14.8% had HBsAg levels of less than 100 IU/mL, and 47.7% had HBcrAg levels less than 10,000 IU/mL. Most (77.5%) were infected with HBV genotype B. From stored serum samples, the researchers quantified levels of HBV DNA, HBsAg, and HBcrAg and evaluated the relationships with spontaneous HBsAg seroclearance.

Over an average follow-up of about 12 years, 465 patients cleared HBsAg, an incidence of 1.43% per year. Researchers stratified patients by levels of viral markers. Compared to those with the highest HBcrAg levels (> 100,000 IU/mL), lower levels of HBcrAg were associated with greater likelihood of HBsAg clearance.

Specifically, intermediate levels (10,000-99,999 IU/mL) were associated with nearly double the chance of HBsAg clearance (hazard ratio [HR], 1.95; 95% confidence interval [CI], 1.44-2.65), and the lowest levels (< 10,000 IU/mL) were associated with just over triple the chance of clearance (HR, 3.15; 95% CI, 2.45-4.05). These associations held up with multivariable analyses, and HBV DNA levels were not significantly associated with HBsAg clearance.

“Not surprisingly, HBsAg levels still serve as a better predictor than the other two biomarkers,” the authors wrote. “Notably, the HBsAg levels are more like a short-term predictor” (within 5 years).

For patients with higher HBsAg levels (> 1,000 IU/mL), it took a median of 16 years to achieve HBsAg clearance. A subanalysis of the 1,539 patients with HbsAg levels > 1,000 IU/mL found that only HBcrAg levels below 10,000 IU/mL predicted HBsAg seroclearance versus 100,000 U/mL or higher (adjusted HR, 1.95; 95% CI, 1.16-3.27).

HBsAg levels began to decline later, often between 5 and 9 years before HBsAg seroclearance occurs. However, HBcrAg levels became undetectable 10-14 years before HBsAg seroclearance. Among patients achieving undetectable levels of HBcrAg, the annual HBsAg seroclearance rate was higher in the second decade of follow-up than in the first decade (3.75% versus 0.97%).

HBcrAg levels reflect the transcriptional activity of covalently closed circular DNA (cccDNA), the authors noted, while HBsAg can come from cccDNA and HBV-DNA integrated into the host genome. Several novel hepatitis B therapies in development target cccDNA transcription, but it isn’t known if the strategy will result in HBsAg clearance.

In the discussion section, the authors speculated about the possible pathology and treatment implications for several chronic hepatitis B scenarios. For example, the finding that HBcrAg clearance usually precedes HBsAg clearance suggests that reduction of cccDNA transcription is a requirement for curing hepatitis B, the authors speculate, but it also suggests that add-on treatment may need to target HBsAg transcribed from the integrated viral genome for a functional cure.

The researchers noted several study limitations, including that the cohort included only Asians largely with HBV genotypes B or C and that “further validation from Caucasian patients infected with genotypes types A or D is mandatory.”

Tai-Chung Tseng disclosed financial conflicts with Fujirebio, Bristol-Myers Squibb, and Gilead Sciences. The remaining authors had no conflicts of interest. The study received grant support from several institutions, including National Taiwan University Hospital.

Liver transplant recipients with nonalcoholic steatohepatitis (NASH) who received grafts from older donors are at higher risk for posttransplant death, especially from infection, according to a new study.

All-cause mortality was twice as high and death from an infectious cause was more than three times as high for patients with NASH who received liver grafts from octogenarian donors than for those who received a liver from someone younger than 50.

“The findings from this study implicate a critical need to investigate donor age as an important risk factor for poorer host and graft survival,” wrote the authors, led by David Lee, MD, of the University of Maryland, Baltimore.

“Given the possibility of infectious graft complications, post–liver transplant follow-ups may need to be more comprehensive and frequent in these individuals who receive grafts from older donors,” they add.

The study was published online in Digestive and Liver Disease.
 

Donor age trends

Dr. Lee and colleagues pulled data from the United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research database, a national database of deidentified donor and recipient transplant data. The analysis excluded recipients younger than 18, those with a living donor, those who had hepatocellular carcinoma prior to transplant, and those who had been diagnosed with additional liver disorders apart from NASH.

The team identified 8,88 recipients with NASH who received a liver transplant from 2005–2019. They stratified recipients by donor age. The 5,187 patients who received livers from donors who were younger than 50 served as the reference group. The remainder were placed into four cohorts – 1,842 whose donors were in their 50s, 1,290 whose donors were in their 60s, 504 whose donors were in their 70s, and 65 whose donors were in their 80s.

The researchers found that in comparison with the reference group, the average age of recipients in each donor-age cohort was progressively older. Two donor-age cohorts had significantly higher proportions of recipients with diabetes than the 46.5% in the reference group – the sexagenarian cohort (51.7%) and the octogenarian group (66.2%).

The median follow-up time ranged from 2.35–3.61 years across all age groups.

The researchers found that for all donor-age groups excluding donors in their 60s, recipients had higher risk of all-cause mortality after transplant than the reference group. Recipients with donors in their 50s had a 16% greater risk for death (P = .01), and recipients with donors in their 70s had a 20% greater risk (P = .05). For recipients with octogenarian donors, the adjusted hazard ratio for all-cause mortality was 2.01 (P < .001).

Only recipients in the octogenarian donor cohort were at increased risk of graft failure, compared with the reference group (aHR, 3.72; P = .002).

As donor age increased, the recipient’s risk of dying from sepsis and infectious causes rose, compared with the reference group. Recipients’ likelihood of sepsis death increased by 71% (P = .001) with donors in their 50s, 73% (P = .003) with donors in their 60s, and 76% (P = .03) with donors in their 70s. For recipients with octogenarian donors, the risk more than tripled (aHR, 3.58; P = .007). Likewise, recipients with donors in their 70s were 73% more likely to die from infectious causes. That risk nearly quadrupled among those with donors in their 80s.
 

Recipient factors at play?

While the study found a relationship between liver donor age and recipient outcomes, it is not clear whether any other recipient factors may have contributed to the higher risk of all-cause mortality, sad Nancy Reau, MD, chief of the hepatology section at Rush University Medical Center, Chicago. The researchers did not parse out whether younger recipients did better with older organs than older recipients or whether older recipients fared worse with younger organs, she said in an interview.

“I wasn’t convinced that they had demonstrated that the recipient may not have played a role in that,” said Dr. Reau, who wasn’t involved with the study.

The analysis only a found an increased risk of graft failure among recipients who received organs from octogenarian donors, so factors other than liver transplant may have contributed to all-cause mortality, she noted.

The UNOS database has some limitations, noted Timothy Pruett, MD, who directs the liver transplant program at the University of Minnesota, Minneapolis. Because the database pulls information from transplantation centers across the country, it can be difficult to standardize specific patient variables in the data.

While it’s clear that a patient died, it’s less certain whether an infection was the cause of death and whether that infection was somehow associated with the liver, noted Dr. Pruett, who wasn’t involved in the research. For example, a patient could have had broken a hip, gone to the hospital, and contracted pneumonia, which led to their death.

“There’s just not much granularity in the database, and we can’t overextrapolate what we see,” Dr. Pruett said in an interview.
 

Knowledge gaps

Dr. Lee agreed that more research is needed to understand what may be driving higher mortality rates among patients who receive older organs. “There are still a lot of gaps in knowledge with respect to why.”

Dr. Reau said she is curious as to whether certain comorbidities, such as previous infection, diabetes, or obesity, could predict worse outcomes for recipients with older organs.

“We would love to give all of our patients younger organs, but if that leads to even more disparity in need [compared] to availability and the alternative is not surviving, I think you have to place [this work] into context,” she said.

The study findings shouldn’t be used to deter patients with NASH from considering older organs, Dr. Reau said. More insight as to which populations might want to be choosier owing to an elevated risk would be beneficial, she added.

Dr. Lee, Dr. Pruett, and Dr. Reau reported no relevant financial relationships.

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

Liver transplant recipients with nonalcoholic steatohepatitis (NASH) who received grafts from older donors are at higher risk for posttransplant death, especially from infection, according to a new study.

All-cause mortality was twice as high and death from an infectious cause was more than three times as high for patients with NASH who received liver grafts from octogenarian donors than for those who received a liver from someone younger than 50.

“The findings from this study implicate a critical need to investigate donor age as an important risk factor for poorer host and graft survival,” wrote the authors, led by David Lee, MD, of the University of Maryland, Baltimore.

“Given the possibility of infectious graft complications, post–liver transplant follow-ups may need to be more comprehensive and frequent in these individuals who receive grafts from older donors,” they add.

The study was published online in Digestive and Liver Disease.
 

Donor age trends

Dr. Lee and colleagues pulled data from the United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research database, a national database of deidentified donor and recipient transplant data. The analysis excluded recipients younger than 18, those with a living donor, those who had hepatocellular carcinoma prior to transplant, and those who had been diagnosed with additional liver disorders apart from NASH.

The team identified 8,88 recipients with NASH who received a liver transplant from 2005–2019. They stratified recipients by donor age. The 5,187 patients who received livers from donors who were younger than 50 served as the reference group. The remainder were placed into four cohorts – 1,842 whose donors were in their 50s, 1,290 whose donors were in their 60s, 504 whose donors were in their 70s, and 65 whose donors were in their 80s.

The researchers found that in comparison with the reference group, the average age of recipients in each donor-age cohort was progressively older. Two donor-age cohorts had significantly higher proportions of recipients with diabetes than the 46.5% in the reference group – the sexagenarian cohort (51.7%) and the octogenarian group (66.2%).

The median follow-up time ranged from 2.35–3.61 years across all age groups.

The researchers found that for all donor-age groups excluding donors in their 60s, recipients had higher risk of all-cause mortality after transplant than the reference group. Recipients with donors in their 50s had a 16% greater risk for death (P = .01), and recipients with donors in their 70s had a 20% greater risk (P = .05). For recipients with octogenarian donors, the adjusted hazard ratio for all-cause mortality was 2.01 (P < .001).

Only recipients in the octogenarian donor cohort were at increased risk of graft failure, compared with the reference group (aHR, 3.72; P = .002).

As donor age increased, the recipient’s risk of dying from sepsis and infectious causes rose, compared with the reference group. Recipients’ likelihood of sepsis death increased by 71% (P = .001) with donors in their 50s, 73% (P = .003) with donors in their 60s, and 76% (P = .03) with donors in their 70s. For recipients with octogenarian donors, the risk more than tripled (aHR, 3.58; P = .007). Likewise, recipients with donors in their 70s were 73% more likely to die from infectious causes. That risk nearly quadrupled among those with donors in their 80s.
 

Recipient factors at play?

While the study found a relationship between liver donor age and recipient outcomes, it is not clear whether any other recipient factors may have contributed to the higher risk of all-cause mortality, sad Nancy Reau, MD, chief of the hepatology section at Rush University Medical Center, Chicago. The researchers did not parse out whether younger recipients did better with older organs than older recipients or whether older recipients fared worse with younger organs, she said in an interview.

“I wasn’t convinced that they had demonstrated that the recipient may not have played a role in that,” said Dr. Reau, who wasn’t involved with the study.

The analysis only a found an increased risk of graft failure among recipients who received organs from octogenarian donors, so factors other than liver transplant may have contributed to all-cause mortality, she noted.

The UNOS database has some limitations, noted Timothy Pruett, MD, who directs the liver transplant program at the University of Minnesota, Minneapolis. Because the database pulls information from transplantation centers across the country, it can be difficult to standardize specific patient variables in the data.

While it’s clear that a patient died, it’s less certain whether an infection was the cause of death and whether that infection was somehow associated with the liver, noted Dr. Pruett, who wasn’t involved in the research. For example, a patient could have had broken a hip, gone to the hospital, and contracted pneumonia, which led to their death.

“There’s just not much granularity in the database, and we can’t overextrapolate what we see,” Dr. Pruett said in an interview.
 

Knowledge gaps

Dr. Lee agreed that more research is needed to understand what may be driving higher mortality rates among patients who receive older organs. “There are still a lot of gaps in knowledge with respect to why.”

Dr. Reau said she is curious as to whether certain comorbidities, such as previous infection, diabetes, or obesity, could predict worse outcomes for recipients with older organs.

“We would love to give all of our patients younger organs, but if that leads to even more disparity in need [compared] to availability and the alternative is not surviving, I think you have to place [this work] into context,” she said.

The study findings shouldn’t be used to deter patients with NASH from considering older organs, Dr. Reau said. More insight as to which populations might want to be choosier owing to an elevated risk would be beneficial, she added.

Dr. Lee, Dr. Pruett, and Dr. Reau reported no relevant financial relationships.

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

Liver transplant recipients with nonalcoholic steatohepatitis (NASH) who received grafts from older donors are at higher risk for posttransplant death, especially from infection, according to a new study.

All-cause mortality was twice as high and death from an infectious cause was more than three times as high for patients with NASH who received liver grafts from octogenarian donors than for those who received a liver from someone younger than 50.

“The findings from this study implicate a critical need to investigate donor age as an important risk factor for poorer host and graft survival,” wrote the authors, led by David Lee, MD, of the University of Maryland, Baltimore.

“Given the possibility of infectious graft complications, post–liver transplant follow-ups may need to be more comprehensive and frequent in these individuals who receive grafts from older donors,” they add.

The study was published online in Digestive and Liver Disease.
 

Donor age trends

Dr. Lee and colleagues pulled data from the United Network for Organ Sharing (UNOS) Standard Transplant Analysis and Research database, a national database of deidentified donor and recipient transplant data. The analysis excluded recipients younger than 18, those with a living donor, those who had hepatocellular carcinoma prior to transplant, and those who had been diagnosed with additional liver disorders apart from NASH.

The team identified 8,88 recipients with NASH who received a liver transplant from 2005–2019. They stratified recipients by donor age. The 5,187 patients who received livers from donors who were younger than 50 served as the reference group. The remainder were placed into four cohorts – 1,842 whose donors were in their 50s, 1,290 whose donors were in their 60s, 504 whose donors were in their 70s, and 65 whose donors were in their 80s.

The researchers found that in comparison with the reference group, the average age of recipients in each donor-age cohort was progressively older. Two donor-age cohorts had significantly higher proportions of recipients with diabetes than the 46.5% in the reference group – the sexagenarian cohort (51.7%) and the octogenarian group (66.2%).

The median follow-up time ranged from 2.35–3.61 years across all age groups.

The researchers found that for all donor-age groups excluding donors in their 60s, recipients had higher risk of all-cause mortality after transplant than the reference group. Recipients with donors in their 50s had a 16% greater risk for death (P = .01), and recipients with donors in their 70s had a 20% greater risk (P = .05). For recipients with octogenarian donors, the adjusted hazard ratio for all-cause mortality was 2.01 (P < .001).

Only recipients in the octogenarian donor cohort were at increased risk of graft failure, compared with the reference group (aHR, 3.72; P = .002).

As donor age increased, the recipient’s risk of dying from sepsis and infectious causes rose, compared with the reference group. Recipients’ likelihood of sepsis death increased by 71% (P = .001) with donors in their 50s, 73% (P = .003) with donors in their 60s, and 76% (P = .03) with donors in their 70s. For recipients with octogenarian donors, the risk more than tripled (aHR, 3.58; P = .007). Likewise, recipients with donors in their 70s were 73% more likely to die from infectious causes. That risk nearly quadrupled among those with donors in their 80s.
 

Recipient factors at play?

While the study found a relationship between liver donor age and recipient outcomes, it is not clear whether any other recipient factors may have contributed to the higher risk of all-cause mortality, sad Nancy Reau, MD, chief of the hepatology section at Rush University Medical Center, Chicago. The researchers did not parse out whether younger recipients did better with older organs than older recipients or whether older recipients fared worse with younger organs, she said in an interview.

“I wasn’t convinced that they had demonstrated that the recipient may not have played a role in that,” said Dr. Reau, who wasn’t involved with the study.

The analysis only a found an increased risk of graft failure among recipients who received organs from octogenarian donors, so factors other than liver transplant may have contributed to all-cause mortality, she noted.

The UNOS database has some limitations, noted Timothy Pruett, MD, who directs the liver transplant program at the University of Minnesota, Minneapolis. Because the database pulls information from transplantation centers across the country, it can be difficult to standardize specific patient variables in the data.

While it’s clear that a patient died, it’s less certain whether an infection was the cause of death and whether that infection was somehow associated with the liver, noted Dr. Pruett, who wasn’t involved in the research. For example, a patient could have had broken a hip, gone to the hospital, and contracted pneumonia, which led to their death.

“There’s just not much granularity in the database, and we can’t overextrapolate what we see,” Dr. Pruett said in an interview.
 

Knowledge gaps

Dr. Lee agreed that more research is needed to understand what may be driving higher mortality rates among patients who receive older organs. “There are still a lot of gaps in knowledge with respect to why.”

Dr. Reau said she is curious as to whether certain comorbidities, such as previous infection, diabetes, or obesity, could predict worse outcomes for recipients with older organs.

“We would love to give all of our patients younger organs, but if that leads to even more disparity in need [compared] to availability and the alternative is not surviving, I think you have to place [this work] into context,” she said.

The study findings shouldn’t be used to deter patients with NASH from considering older organs, Dr. Reau said. More insight as to which populations might want to be choosier owing to an elevated risk would be beneficial, she added.

Dr. Lee, Dr. Pruett, and Dr. Reau reported no relevant financial relationships.

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

The risks of all-cause and liver-related mortality increase substantially based on fibrosis stage in biopsy-confirmed nonalcoholic fatty liver disease (NAFLD), according to a study published in Clinical Gastroenterology and Hepatology.

In particular, patients with NAFLD and advanced fibrosis have a threefold higher risk of all-cause mortality and 10-fold higher risk of liver-related mortality, as compared with patients with NAFLD but not advanced fibrosis, Cheng Han Ng, with the National University of Singapore, and colleagues wrote.

“These data provide high-level evidence that provides prognostication for each stage of fibrosis to inform care providers and patients,” they wrote. “In addition, these findings have important implications for clinical trial design and highlight the importance of developing therapeutics.”

Although previous studies have found higher risks of all-cause and liver-related mortality in patients with NAFLD with increasing fibrosis stages, they examined the risk of mortality in reference to stage 0 fibrosis and didn’t include comparisons across different stages of fibrosis. In addition, the studies typically used pooled risk ratios, didn’t account for time-to-event analysis, or incorporate the most recent data.

The study investigators conducted an updated time-to-event meta-analysis to understand the impact of fibrosis stage on all-cause and liver-related mortality in biopsy-confirmed NAFLD. In addition, they pooled the survival estimates of individual fibrosis stages based on reconstructed individual patient data and compared mortality between fibrosis stages.

In 14 included studies, 17,301 patients had biopsy-proven NAFLD, including 6,069 assessed for overall mortality and 3,421 for liver-related mortality. The studies were conducted in the United States, Canada, Sweden, Israel, Japan, and Hong Kong, with four multicenter studies across multiple regions. The median follow-up duration was 7.7 years, and the average age of patients was 50.5.

For nonadvanced fibrosis (F0-F2), the 1-, 3-, 5-, 8-, and 10-year all-cause mortality were 0.1%, 1.9%, 3.3%, 6%, and 7.7%, respectively. For clinically significant fibrosis (F2-F4), the rates were 0.3%, 8.4%, 14%, 23.7%, and 29.3%, respectively. For advanced fibrosis (F3-F4), the rates were 0.3%, 8.8%, 14.9%, 25.5%, and 32.2%, respectively. For cirrhosis (F4), the rates were 0.3%, 13%, 20.6%, 33.3%, and 41.5%, respectively.

Compared with F0 as a reference, there were no statistically significant differences in all-cause mortality for F1. However, the risk significantly increased for F2 (HR, 1.46; 95% confidence interval, 1.08-1.98; P 1⁄4 .01), F3 (HR, 1.96; 95% CI, 1.41-2.72; P < .01), and F4 (HR, 3.66; 95% CI, 2.65-5.05; P < .01). In addition, early fibrosis (F1-F2) resulted in a statistically significant increase in all-cause mortality, as did the presence of clinically significant fibrosis or advanced fibrosis.

Compared with non–clinically significant fibrosis (F0-F1), clinically significant fibrosis (F2-F4) resulted in a statistically significant increase in mortality (HR, 2.06; 95% CI, 1.52-2.81; P < .01).

Compared with nonadvanced fibrosis (F0-F2), advanced fibrosis (F3-F4) resulted in a significantly increased risk of mortality (HR, 3.32; 95% CI, 2.38-4.65; P < .01).

In a comparison between F3 and F4, F4 resulted in a statistically significant increase in mortality (HR, 2.67; 95% CI, 1.47-4.83; P < .01). In a sensitivity analysis with three studies including nonalcoholic steatohepatitis, patients with NASH had a significantly increased risk of mortality in F4 (HR, 5.08; 95% CI, 2.70-9.55; P < .01).

For liver-related mortality, F1 didn’t result in a statistically significant increase, as compared with F0. However, increased risks were found for F2 (HR, 4.07; 95% CI, 1.44-11.5; P < .01), F3 (HR, 7.59; 95% CI, 2.80-20.5; P < .01), and F4 (HR, 15.1; 95% CI, 5.27-43.4; P < .01). In addition, any fibrosis (F1-F4) resulted in an increased risk of mortality, early fibrosis resulted in a borderline nonsignificant increase, and clinically significant or advanced fibrosis led to an increased risk.

Compared with non–clinically significant fibrosis (F0-F1), clinically significant fibrosis (F2-F4) resulted in an increase in liver-related mortality (HR, 6.49; 95% CI, 3.30-12.8; P < .01).

Compared with nonadvanced fibrosis (F0-F2), advanced fibrosis (F3-F4) resulted in a statistically significant increase in liver-related mortality (HR, 10.4; 95% CI, 6.18-17.5; P < .01).

In a comparison between F3 and F4, F4 resulted in a significant increase in liver-related mortality (HR, 2.57; 95% CI, 1.22-5.42; P < .01).

Although the presence of F4 leads to the greatest risk of mortality, selection criteria in NASH clinical trials have predominately targeted patients with F0-F3, the authors wrote.

“NASH is currently the fastest growing cause for liver transplant and [transplant] remains the only known curative treatment for cirrhosis,” they wrote. “However, with the global shortage of suitable grafts for transplant and lack of viable treatment, our results highlight that there is an urgent need for an efficacious treatment for patients with NASH and F4.”

The researchers outlined several limitations of their study. The development of hepatocellular carcinoma and its effects on survival were outside the scope of the study, they wrote. Analysis of liver-related mortality by proportion was not conducted because of insufficient studies. Data were insufficient to perform subgroup analyses by gender, age, study design, medication use, and diagnostic modality for fibrosis stage.

The authors reported funding support from several national U.S. grants and disclosed consultant and advisory rules for numerous pharmaceutical companies.

The risks of all-cause and liver-related mortality increase substantially based on fibrosis stage in biopsy-confirmed nonalcoholic fatty liver disease (NAFLD), according to a study published in Clinical Gastroenterology and Hepatology.

In particular, patients with NAFLD and advanced fibrosis have a threefold higher risk of all-cause mortality and 10-fold higher risk of liver-related mortality, as compared with patients with NAFLD but not advanced fibrosis, Cheng Han Ng, with the National University of Singapore, and colleagues wrote.

“These data provide high-level evidence that provides prognostication for each stage of fibrosis to inform care providers and patients,” they wrote. “In addition, these findings have important implications for clinical trial design and highlight the importance of developing therapeutics.”

Although previous studies have found higher risks of all-cause and liver-related mortality in patients with NAFLD with increasing fibrosis stages, they examined the risk of mortality in reference to stage 0 fibrosis and didn’t include comparisons across different stages of fibrosis. In addition, the studies typically used pooled risk ratios, didn’t account for time-to-event analysis, or incorporate the most recent data.

The study investigators conducted an updated time-to-event meta-analysis to understand the impact of fibrosis stage on all-cause and liver-related mortality in biopsy-confirmed NAFLD. In addition, they pooled the survival estimates of individual fibrosis stages based on reconstructed individual patient data and compared mortality between fibrosis stages.

In 14 included studies, 17,301 patients had biopsy-proven NAFLD, including 6,069 assessed for overall mortality and 3,421 for liver-related mortality. The studies were conducted in the United States, Canada, Sweden, Israel, Japan, and Hong Kong, with four multicenter studies across multiple regions. The median follow-up duration was 7.7 years, and the average age of patients was 50.5.

For nonadvanced fibrosis (F0-F2), the 1-, 3-, 5-, 8-, and 10-year all-cause mortality were 0.1%, 1.9%, 3.3%, 6%, and 7.7%, respectively. For clinically significant fibrosis (F2-F4), the rates were 0.3%, 8.4%, 14%, 23.7%, and 29.3%, respectively. For advanced fibrosis (F3-F4), the rates were 0.3%, 8.8%, 14.9%, 25.5%, and 32.2%, respectively. For cirrhosis (F4), the rates were 0.3%, 13%, 20.6%, 33.3%, and 41.5%, respectively.

Compared with F0 as a reference, there were no statistically significant differences in all-cause mortality for F1. However, the risk significantly increased for F2 (HR, 1.46; 95% confidence interval, 1.08-1.98; P 1⁄4 .01), F3 (HR, 1.96; 95% CI, 1.41-2.72; P < .01), and F4 (HR, 3.66; 95% CI, 2.65-5.05; P < .01). In addition, early fibrosis (F1-F2) resulted in a statistically significant increase in all-cause mortality, as did the presence of clinically significant fibrosis or advanced fibrosis.

Compared with non–clinically significant fibrosis (F0-F1), clinically significant fibrosis (F2-F4) resulted in a statistically significant increase in mortality (HR, 2.06; 95% CI, 1.52-2.81; P < .01).

Compared with nonadvanced fibrosis (F0-F2), advanced fibrosis (F3-F4) resulted in a significantly increased risk of mortality (HR, 3.32; 95% CI, 2.38-4.65; P < .01).

In a comparison between F3 and F4, F4 resulted in a statistically significant increase in mortality (HR, 2.67; 95% CI, 1.47-4.83; P < .01). In a sensitivity analysis with three studies including nonalcoholic steatohepatitis, patients with NASH had a significantly increased risk of mortality in F4 (HR, 5.08; 95% CI, 2.70-9.55; P < .01).

For liver-related mortality, F1 didn’t result in a statistically significant increase, as compared with F0. However, increased risks were found for F2 (HR, 4.07; 95% CI, 1.44-11.5; P < .01), F3 (HR, 7.59; 95% CI, 2.80-20.5; P < .01), and F4 (HR, 15.1; 95% CI, 5.27-43.4; P < .01). In addition, any fibrosis (F1-F4) resulted in an increased risk of mortality, early fibrosis resulted in a borderline nonsignificant increase, and clinically significant or advanced fibrosis led to an increased risk.

Compared with non–clinically significant fibrosis (F0-F1), clinically significant fibrosis (F2-F4) resulted in an increase in liver-related mortality (HR, 6.49; 95% CI, 3.30-12.8; P < .01).

Compared with nonadvanced fibrosis (F0-F2), advanced fibrosis (F3-F4) resulted in a statistically significant increase in liver-related mortality (HR, 10.4; 95% CI, 6.18-17.5; P < .01).

In a comparison between F3 and F4, F4 resulted in a significant increase in liver-related mortality (HR, 2.57; 95% CI, 1.22-5.42; P < .01).

Although the presence of F4 leads to the greatest risk of mortality, selection criteria in NASH clinical trials have predominately targeted patients with F0-F3, the authors wrote.

“NASH is currently the fastest growing cause for liver transplant and [transplant] remains the only known curative treatment for cirrhosis,” they wrote. “However, with the global shortage of suitable grafts for transplant and lack of viable treatment, our results highlight that there is an urgent need for an efficacious treatment for patients with NASH and F4.”

The researchers outlined several limitations of their study. The development of hepatocellular carcinoma and its effects on survival were outside the scope of the study, they wrote. Analysis of liver-related mortality by proportion was not conducted because of insufficient studies. Data were insufficient to perform subgroup analyses by gender, age, study design, medication use, and diagnostic modality for fibrosis stage.

The authors reported funding support from several national U.S. grants and disclosed consultant and advisory rules for numerous pharmaceutical companies.

The risks of all-cause and liver-related mortality increase substantially based on fibrosis stage in biopsy-confirmed nonalcoholic fatty liver disease (NAFLD), according to a study published in Clinical Gastroenterology and Hepatology.

In particular, patients with NAFLD and advanced fibrosis have a threefold higher risk of all-cause mortality and 10-fold higher risk of liver-related mortality, as compared with patients with NAFLD but not advanced fibrosis, Cheng Han Ng, with the National University of Singapore, and colleagues wrote.

“These data provide high-level evidence that provides prognostication for each stage of fibrosis to inform care providers and patients,” they wrote. “In addition, these findings have important implications for clinical trial design and highlight the importance of developing therapeutics.”

Although previous studies have found higher risks of all-cause and liver-related mortality in patients with NAFLD with increasing fibrosis stages, they examined the risk of mortality in reference to stage 0 fibrosis and didn’t include comparisons across different stages of fibrosis. In addition, the studies typically used pooled risk ratios, didn’t account for time-to-event analysis, or incorporate the most recent data.

The study investigators conducted an updated time-to-event meta-analysis to understand the impact of fibrosis stage on all-cause and liver-related mortality in biopsy-confirmed NAFLD. In addition, they pooled the survival estimates of individual fibrosis stages based on reconstructed individual patient data and compared mortality between fibrosis stages.

In 14 included studies, 17,301 patients had biopsy-proven NAFLD, including 6,069 assessed for overall mortality and 3,421 for liver-related mortality. The studies were conducted in the United States, Canada, Sweden, Israel, Japan, and Hong Kong, with four multicenter studies across multiple regions. The median follow-up duration was 7.7 years, and the average age of patients was 50.5.

For nonadvanced fibrosis (F0-F2), the 1-, 3-, 5-, 8-, and 10-year all-cause mortality were 0.1%, 1.9%, 3.3%, 6%, and 7.7%, respectively. For clinically significant fibrosis (F2-F4), the rates were 0.3%, 8.4%, 14%, 23.7%, and 29.3%, respectively. For advanced fibrosis (F3-F4), the rates were 0.3%, 8.8%, 14.9%, 25.5%, and 32.2%, respectively. For cirrhosis (F4), the rates were 0.3%, 13%, 20.6%, 33.3%, and 41.5%, respectively.

Compared with F0 as a reference, there were no statistically significant differences in all-cause mortality for F1. However, the risk significantly increased for F2 (HR, 1.46; 95% confidence interval, 1.08-1.98; P 1⁄4 .01), F3 (HR, 1.96; 95% CI, 1.41-2.72; P < .01), and F4 (HR, 3.66; 95% CI, 2.65-5.05; P < .01). In addition, early fibrosis (F1-F2) resulted in a statistically significant increase in all-cause mortality, as did the presence of clinically significant fibrosis or advanced fibrosis.

Compared with non–clinically significant fibrosis (F0-F1), clinically significant fibrosis (F2-F4) resulted in a statistically significant increase in mortality (HR, 2.06; 95% CI, 1.52-2.81; P < .01).

Compared with nonadvanced fibrosis (F0-F2), advanced fibrosis (F3-F4) resulted in a significantly increased risk of mortality (HR, 3.32; 95% CI, 2.38-4.65; P < .01).

In a comparison between F3 and F4, F4 resulted in a statistically significant increase in mortality (HR, 2.67; 95% CI, 1.47-4.83; P < .01). In a sensitivity analysis with three studies including nonalcoholic steatohepatitis, patients with NASH had a significantly increased risk of mortality in F4 (HR, 5.08; 95% CI, 2.70-9.55; P < .01).

For liver-related mortality, F1 didn’t result in a statistically significant increase, as compared with F0. However, increased risks were found for F2 (HR, 4.07; 95% CI, 1.44-11.5; P < .01), F3 (HR, 7.59; 95% CI, 2.80-20.5; P < .01), and F4 (HR, 15.1; 95% CI, 5.27-43.4; P < .01). In addition, any fibrosis (F1-F4) resulted in an increased risk of mortality, early fibrosis resulted in a borderline nonsignificant increase, and clinically significant or advanced fibrosis led to an increased risk.

Compared with non–clinically significant fibrosis (F0-F1), clinically significant fibrosis (F2-F4) resulted in an increase in liver-related mortality (HR, 6.49; 95% CI, 3.30-12.8; P < .01).

Compared with nonadvanced fibrosis (F0-F2), advanced fibrosis (F3-F4) resulted in a statistically significant increase in liver-related mortality (HR, 10.4; 95% CI, 6.18-17.5; P < .01).

In a comparison between F3 and F4, F4 resulted in a significant increase in liver-related mortality (HR, 2.57; 95% CI, 1.22-5.42; P < .01).

Although the presence of F4 leads to the greatest risk of mortality, selection criteria in NASH clinical trials have predominately targeted patients with F0-F3, the authors wrote.

“NASH is currently the fastest growing cause for liver transplant and [transplant] remains the only known curative treatment for cirrhosis,” they wrote. “However, with the global shortage of suitable grafts for transplant and lack of viable treatment, our results highlight that there is an urgent need for an efficacious treatment for patients with NASH and F4.”

The researchers outlined several limitations of their study. The development of hepatocellular carcinoma and its effects on survival were outside the scope of the study, they wrote. Analysis of liver-related mortality by proportion was not conducted because of insufficient studies. Data were insufficient to perform subgroup analyses by gender, age, study design, medication use, and diagnostic modality for fibrosis stage.

The authors reported funding support from several national U.S. grants and disclosed consultant and advisory rules for numerous pharmaceutical companies.

People at high risk for nonalcoholic fatty liver disease (NAFLD), such as those with type 2 diabetes or medically complicated obesity, should be screened for advanced fibrosis, says new guidance from the American Association for the Study of Liver Diseases.

The guidance, published online in Hepatology, also reflects recent advances in the diagnosis and management of NAFLD, particularly noninvasive testing, lead author Mary E. Rinella, MD, University of Chicago, told this news organization.

The “biggest change” from the previous guidance, published 5 years ago, is “that we are explicitly recommending that people in high-risk categories get screened in primary care,” she said.

NAFLD is “a silent disease ... you could easily have somebody develop cirrhosis,” Dr. Rinella said. By identifying patients earlier, physicians would be able to “prevent or reduce the number of people turning up decompensated or at an advanced stage,” she added.

The other message that Dr. Rinella wants clinicians to take away from the guidance is that “something can be done” for patients with NAFLD. “It’s very common, and the often-cited reason why patients aren’t referred to specialty care is that there’s ‘nothing that can be done.’ ”

Although there is no U.S. Food and Drug Administration–approved drug for NAFLD, clinicians can still support their patients and suggest lifestyle changes, she added.

The guidelines also are designed to prepare the groundwork for novel drugs in the pipeline, as well as discuss those that are already available for conditions such as obesity and diabetes and that benefit people with liver disease, Dr. Rinella said.
 

Screening and evaluation

The guidance covers all aspects of NAFLD, including the latest developments in understanding of the epidemiology and natural history of the disease, and its molecular and cellular pathogenesis.

The guidance continues to recommend against population-based screening for NAFLD. In addition to the aforementioned screening for advanced fibrosis in high-risk individuals, it calls for a primary risk assessment with FIB-4 to be performed every 1-2 years in patients with pre-diabetes, type 2 diabetes, two or more metabolic risk factors, or imaging evidence of hepatic steatosis.

Patients with nonalcoholic steatohepatitis (NASH) cirrhosis require routine monitoring, as they are at the highest risk for liver-related outcomes, the guidance adds. Those with suspected NASH should be referred for evaluation by a specialist.

In assessments of liver fibrosis in patients, findings such as highly elevated liver stiffness, FIB-4, and enhanced liver fibrosis scores can predict an increased risk for hepatic decompensation and mortality, the authors write.
 

Intervention guidance

Patients with NAFLD who are overweight or obese should be prescribed a reduced calorie diet in a multidisciplinary setting because weight loss “improves hepatic steatosis, NASH, and hepatic fibrosis in a dose-dependent manner,” the guidance states.

Bariatric surgery should be considered in appropriate patients because of its effectiveness in resolving NAFLD and NASH in most patients without cirrhosis, the guidance says. However, in patients with well-compensated NASH cirrhosis, the type, safety, and efficacy of bariatric surgery is not established, so a “careful benefit-risk assessment by a multidisciplinary team of experts that includes a hepatologist” is needed, the authors note.

The guidance discusses alcohol consumption’s role in the progression of fatty liver disease and recommends that intake be assessed on a regular basis in patients with NAFLD. Patients with clinically significant hepatic fibrosis should abstain completely, it adds. Abstinence, particularly for patients with moderate to heavy alcohol intake, may lower the risk of fibrosis progression and hepatic and extrahepatic malignancies, the authors note.

Additionally, drinking at least three cups of coffee, caffeinated or not, per day is “associated with less-advanced liver disease,” they write.

The guidance also sets out key considerations for people with comorbid conditions. It states that patients with NAFLD should be screened for type 2 diabetes and that statins can be safely used for cardiovascular risk reduction “across the disease spectrum, including compensated cirrhosis.”

While noting the lack of approved medications for NAFLD, the guidance states that some drugs prescribed for comorbidities also benefit patients with NASH. These are glucagon-like peptide 1 agonist semaglutide, pioglitazone, and vitamin E supplementation in select patients.

Available data on these same drugs, however, do not show an antifibrotic benefit and haven’t been studied in patients with cirrhosis, the guidance states.

Additionally, metformin, ursodeoxycholic acid, dipeptidyl peptidase-4 inhibitors, silymarin, and statins do not offer meaningful histologic benefit and shouldn’t be used as a treatment for NASH.
 

Help against an ‘evolving epidemic’

The guidance is “timely and long awaited,” Jamile Wakim-Fleming, MD, director of the fatty liver disease program at the Cleveland Clinic, said in an interview. NAFLD is an “evolving epidemic,” she added.

Numerous recent studies have “led to new modalities for diagnosis and therapy, and a better understanding” of the epidemiology and pathophysiology of NAFLD, she said. “More specifically, advancements in noninvasive testing, risk stratifications, and therapeutic modalities are now available and worth disseminating.”

NAFLD’s complexity and the lack of an FDA-approved therapy specifically targeting the liver means that managing the disease “requires expertise in multiple disciplines and knowledge of the latest developments,” Dr. Wakim-Fleming noted.

“This guidance describes preventive and treatment strategies for the metabolic conditions associated with NAFLD and is very useful for physicians in different specialties who treat individuals with these conditions,” she said.

No funding was declared. Dr. Rinella and Dr. Wakim-Fleming have disclosed no relevant financial relationships.

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


The AGA’s Clinical Practice Update on the Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Lean Individuals is available online.

People at high risk for nonalcoholic fatty liver disease (NAFLD), such as those with type 2 diabetes or medically complicated obesity, should be screened for advanced fibrosis, says new guidance from the American Association for the Study of Liver Diseases.

The guidance, published online in Hepatology, also reflects recent advances in the diagnosis and management of NAFLD, particularly noninvasive testing, lead author Mary E. Rinella, MD, University of Chicago, told this news organization.

The “biggest change” from the previous guidance, published 5 years ago, is “that we are explicitly recommending that people in high-risk categories get screened in primary care,” she said.

NAFLD is “a silent disease ... you could easily have somebody develop cirrhosis,” Dr. Rinella said. By identifying patients earlier, physicians would be able to “prevent or reduce the number of people turning up decompensated or at an advanced stage,” she added.

The other message that Dr. Rinella wants clinicians to take away from the guidance is that “something can be done” for patients with NAFLD. “It’s very common, and the often-cited reason why patients aren’t referred to specialty care is that there’s ‘nothing that can be done.’ ”

Although there is no U.S. Food and Drug Administration–approved drug for NAFLD, clinicians can still support their patients and suggest lifestyle changes, she added.

The guidelines also are designed to prepare the groundwork for novel drugs in the pipeline, as well as discuss those that are already available for conditions such as obesity and diabetes and that benefit people with liver disease, Dr. Rinella said.
 

Screening and evaluation

The guidance covers all aspects of NAFLD, including the latest developments in understanding of the epidemiology and natural history of the disease, and its molecular and cellular pathogenesis.

The guidance continues to recommend against population-based screening for NAFLD. In addition to the aforementioned screening for advanced fibrosis in high-risk individuals, it calls for a primary risk assessment with FIB-4 to be performed every 1-2 years in patients with pre-diabetes, type 2 diabetes, two or more metabolic risk factors, or imaging evidence of hepatic steatosis.

Patients with nonalcoholic steatohepatitis (NASH) cirrhosis require routine monitoring, as they are at the highest risk for liver-related outcomes, the guidance adds. Those with suspected NASH should be referred for evaluation by a specialist.

In assessments of liver fibrosis in patients, findings such as highly elevated liver stiffness, FIB-4, and enhanced liver fibrosis scores can predict an increased risk for hepatic decompensation and mortality, the authors write.
 

Intervention guidance

Patients with NAFLD who are overweight or obese should be prescribed a reduced calorie diet in a multidisciplinary setting because weight loss “improves hepatic steatosis, NASH, and hepatic fibrosis in a dose-dependent manner,” the guidance states.

Bariatric surgery should be considered in appropriate patients because of its effectiveness in resolving NAFLD and NASH in most patients without cirrhosis, the guidance says. However, in patients with well-compensated NASH cirrhosis, the type, safety, and efficacy of bariatric surgery is not established, so a “careful benefit-risk assessment by a multidisciplinary team of experts that includes a hepatologist” is needed, the authors note.

The guidance discusses alcohol consumption’s role in the progression of fatty liver disease and recommends that intake be assessed on a regular basis in patients with NAFLD. Patients with clinically significant hepatic fibrosis should abstain completely, it adds. Abstinence, particularly for patients with moderate to heavy alcohol intake, may lower the risk of fibrosis progression and hepatic and extrahepatic malignancies, the authors note.

Additionally, drinking at least three cups of coffee, caffeinated or not, per day is “associated with less-advanced liver disease,” they write.

The guidance also sets out key considerations for people with comorbid conditions. It states that patients with NAFLD should be screened for type 2 diabetes and that statins can be safely used for cardiovascular risk reduction “across the disease spectrum, including compensated cirrhosis.”

While noting the lack of approved medications for NAFLD, the guidance states that some drugs prescribed for comorbidities also benefit patients with NASH. These are glucagon-like peptide 1 agonist semaglutide, pioglitazone, and vitamin E supplementation in select patients.

Available data on these same drugs, however, do not show an antifibrotic benefit and haven’t been studied in patients with cirrhosis, the guidance states.

Additionally, metformin, ursodeoxycholic acid, dipeptidyl peptidase-4 inhibitors, silymarin, and statins do not offer meaningful histologic benefit and shouldn’t be used as a treatment for NASH.
 

Help against an ‘evolving epidemic’

The guidance is “timely and long awaited,” Jamile Wakim-Fleming, MD, director of the fatty liver disease program at the Cleveland Clinic, said in an interview. NAFLD is an “evolving epidemic,” she added.

Numerous recent studies have “led to new modalities for diagnosis and therapy, and a better understanding” of the epidemiology and pathophysiology of NAFLD, she said. “More specifically, advancements in noninvasive testing, risk stratifications, and therapeutic modalities are now available and worth disseminating.”

NAFLD’s complexity and the lack of an FDA-approved therapy specifically targeting the liver means that managing the disease “requires expertise in multiple disciplines and knowledge of the latest developments,” Dr. Wakim-Fleming noted.

“This guidance describes preventive and treatment strategies for the metabolic conditions associated with NAFLD and is very useful for physicians in different specialties who treat individuals with these conditions,” she said.

No funding was declared. Dr. Rinella and Dr. Wakim-Fleming have disclosed no relevant financial relationships.

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


The AGA’s Clinical Practice Update on the Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Lean Individuals is available online.

People at high risk for nonalcoholic fatty liver disease (NAFLD), such as those with type 2 diabetes or medically complicated obesity, should be screened for advanced fibrosis, says new guidance from the American Association for the Study of Liver Diseases.

The guidance, published online in Hepatology, also reflects recent advances in the diagnosis and management of NAFLD, particularly noninvasive testing, lead author Mary E. Rinella, MD, University of Chicago, told this news organization.

The “biggest change” from the previous guidance, published 5 years ago, is “that we are explicitly recommending that people in high-risk categories get screened in primary care,” she said.

NAFLD is “a silent disease ... you could easily have somebody develop cirrhosis,” Dr. Rinella said. By identifying patients earlier, physicians would be able to “prevent or reduce the number of people turning up decompensated or at an advanced stage,” she added.

The other message that Dr. Rinella wants clinicians to take away from the guidance is that “something can be done” for patients with NAFLD. “It’s very common, and the often-cited reason why patients aren’t referred to specialty care is that there’s ‘nothing that can be done.’ ”

Although there is no U.S. Food and Drug Administration–approved drug for NAFLD, clinicians can still support their patients and suggest lifestyle changes, she added.

The guidelines also are designed to prepare the groundwork for novel drugs in the pipeline, as well as discuss those that are already available for conditions such as obesity and diabetes and that benefit people with liver disease, Dr. Rinella said.
 

Screening and evaluation

The guidance covers all aspects of NAFLD, including the latest developments in understanding of the epidemiology and natural history of the disease, and its molecular and cellular pathogenesis.

The guidance continues to recommend against population-based screening for NAFLD. In addition to the aforementioned screening for advanced fibrosis in high-risk individuals, it calls for a primary risk assessment with FIB-4 to be performed every 1-2 years in patients with pre-diabetes, type 2 diabetes, two or more metabolic risk factors, or imaging evidence of hepatic steatosis.

Patients with nonalcoholic steatohepatitis (NASH) cirrhosis require routine monitoring, as they are at the highest risk for liver-related outcomes, the guidance adds. Those with suspected NASH should be referred for evaluation by a specialist.

In assessments of liver fibrosis in patients, findings such as highly elevated liver stiffness, FIB-4, and enhanced liver fibrosis scores can predict an increased risk for hepatic decompensation and mortality, the authors write.
 

Intervention guidance

Patients with NAFLD who are overweight or obese should be prescribed a reduced calorie diet in a multidisciplinary setting because weight loss “improves hepatic steatosis, NASH, and hepatic fibrosis in a dose-dependent manner,” the guidance states.

Bariatric surgery should be considered in appropriate patients because of its effectiveness in resolving NAFLD and NASH in most patients without cirrhosis, the guidance says. However, in patients with well-compensated NASH cirrhosis, the type, safety, and efficacy of bariatric surgery is not established, so a “careful benefit-risk assessment by a multidisciplinary team of experts that includes a hepatologist” is needed, the authors note.

The guidance discusses alcohol consumption’s role in the progression of fatty liver disease and recommends that intake be assessed on a regular basis in patients with NAFLD. Patients with clinically significant hepatic fibrosis should abstain completely, it adds. Abstinence, particularly for patients with moderate to heavy alcohol intake, may lower the risk of fibrosis progression and hepatic and extrahepatic malignancies, the authors note.

Additionally, drinking at least three cups of coffee, caffeinated or not, per day is “associated with less-advanced liver disease,” they write.

The guidance also sets out key considerations for people with comorbid conditions. It states that patients with NAFLD should be screened for type 2 diabetes and that statins can be safely used for cardiovascular risk reduction “across the disease spectrum, including compensated cirrhosis.”

While noting the lack of approved medications for NAFLD, the guidance states that some drugs prescribed for comorbidities also benefit patients with NASH. These are glucagon-like peptide 1 agonist semaglutide, pioglitazone, and vitamin E supplementation in select patients.

Available data on these same drugs, however, do not show an antifibrotic benefit and haven’t been studied in patients with cirrhosis, the guidance states.

Additionally, metformin, ursodeoxycholic acid, dipeptidyl peptidase-4 inhibitors, silymarin, and statins do not offer meaningful histologic benefit and shouldn’t be used as a treatment for NASH.
 

Help against an ‘evolving epidemic’

The guidance is “timely and long awaited,” Jamile Wakim-Fleming, MD, director of the fatty liver disease program at the Cleveland Clinic, said in an interview. NAFLD is an “evolving epidemic,” she added.

Numerous recent studies have “led to new modalities for diagnosis and therapy, and a better understanding” of the epidemiology and pathophysiology of NAFLD, she said. “More specifically, advancements in noninvasive testing, risk stratifications, and therapeutic modalities are now available and worth disseminating.”

NAFLD’s complexity and the lack of an FDA-approved therapy specifically targeting the liver means that managing the disease “requires expertise in multiple disciplines and knowledge of the latest developments,” Dr. Wakim-Fleming noted.

“This guidance describes preventive and treatment strategies for the metabolic conditions associated with NAFLD and is very useful for physicians in different specialties who treat individuals with these conditions,” she said.

No funding was declared. Dr. Rinella and Dr. Wakim-Fleming have disclosed no relevant financial relationships.

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


The AGA’s Clinical Practice Update on the Diagnosis and Management of Nonalcoholic Fatty Liver Disease in Lean Individuals is available online.

In the first study to examine how intermittent fasting combined with exercise impacts nonalcoholic fatty liver disease (NAFLD), the combined strategy was more effective than aerobic exercise alone or no intervention (control).

However, the combined approach did not give significantly added benefit, compared with fasting alone, the researchers report.

Eighty patients with NAFLD were randomized to one of four lifestyle strategies (alternate-day fasting, aerobic exercise, both, or neither) for 3 months.

The primary outcome was change in intrahepatic triglyceride (IHTG) content from baseline to study end, measured by magnetic resonance imaging proton density fat fraction.

The results suggest that “combining intermittent fasting with exercise is effective for reducing hepatic steatosis [fatty liver] in patients with NAFLD but may offer no additional benefit versus fasting alone,” Mark Ezpeleta, PhD, formerly at the University of Illinois, Chicago, and now at the University of Colorado Anschutz Medical Campus, and colleagues conclude.

“Our findings also indicate that the combination intervention was effective for reducing body weight, fat mass, waist circumference, [the liver enzyme alanine transaminase (ALT)], fasting insulin, [and] insulin resistance and increasing insulin sensitivity, among patients with obesity and NAFLD versus controls,” the group reports.  

“When we compared the results of our study groups, we saw clearly that the most improved patients were in the group that followed the alternate-day fasting diet and exercised 5 days a week,” senior author Krista A. Varady, PhD, professor of nutrition, University of Illinois, said in a press release from the university.

“The people who only dieted or only exercised did not see the same improvements,” she added, “which reinforces the importance of these two relatively inexpensive lifestyle modifications on overall health and on combating chronic diseases like fatty liver disease.”

Moreover, “alternate-day fasting and exercise interventions can be difficult for people to stick to, and in prior studies we have seen significant dropout,” she noted. “It was very interesting to see that in this trial we had very high adherence to the interventions.”

The study was recently published in Cell Metabolism.  

An estimated 65% of people with obesity have NAFLD, or fat in the liver that is not the result of excessive alcohol consumption, which is strongly related to the development of insulin resistance and type 2 diabetes, the group writes.

Thiazolidinediones such as pioglitazone reduce hepatic steatosis, but there is mounting concern about the weight-gaining effect of these compounds.

Recent attention has focused on lifestyle interventions to resolve hepatic steatosis, and previous trials showed that alternate-day fasting was effective for certain outcomes in NAFLD, but those studies did not measure changes in IHTG content or include an exercise intervention.

The researchers enrolled 80 adults with obesity and NAFLD and randomized them to one of four groups for 3 months:

• Alternate day fasting group: Participants were instructed to consume 600 kcal at dinner between 5 PM and 8 PM on a fasting day alternating with food as desired on a feasting day.
• Exercise group: A 60-minute moderate-intensity aerobic exercise session 5 times a week.
• Fasting plus exercise group.
• Control group (no intervention).

Participants were age 23-65 (mean age, 44) and 81% were women.

Half were Hispanic, and the rest were Black (30%), White (11%), or Asian (9%).

They had a mean weight of 99 kg (218 lb) and a mean body mass index of 36 kg/m².

Dropout rates were minimal in the combination group (0%) and fasting groups (5%) and moderately high in the exercise group (25%).

IHTG content was reduced by a significantly greater amount in the combination group (–5.48%) than in the exercise alone group (–1.30%; P = .02) or in the control group (–0.17%; P < .01) and by a greater amount than in the fasting alone group, although this was not significant (–2.25%; P = .05).

Lean mass, aspartate transaminase (AST), A1c, blood pressure, plasma lipids, liver fibrosis score, and hepatokines (fetuin-A, FGF-21, and selenoprotein P) did not differ between groups.

Researchers acknowledge that although the combination intervention resulted in improved NAFLD parameters, IHTG and ALT did not reach the normal range.  

Participants likely had early stage NAFLD (their baseline IHTG was in the 16% to 18% range, where 5% to 33% is mild steatosis) and they were likely highly motivated (indicated by the low dropout rate), so the findings may not be generalizable.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Dr. Varady has reported receiving author fees from the Hachette Book Group for the book entitled “The Every Other Day Diet.” The other authors have reported no relevant financial relationships.

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

In the first study to examine how intermittent fasting combined with exercise impacts nonalcoholic fatty liver disease (NAFLD), the combined strategy was more effective than aerobic exercise alone or no intervention (control).

However, the combined approach did not give significantly added benefit, compared with fasting alone, the researchers report.

Eighty patients with NAFLD were randomized to one of four lifestyle strategies (alternate-day fasting, aerobic exercise, both, or neither) for 3 months.

The primary outcome was change in intrahepatic triglyceride (IHTG) content from baseline to study end, measured by magnetic resonance imaging proton density fat fraction.

The results suggest that “combining intermittent fasting with exercise is effective for reducing hepatic steatosis [fatty liver] in patients with NAFLD but may offer no additional benefit versus fasting alone,” Mark Ezpeleta, PhD, formerly at the University of Illinois, Chicago, and now at the University of Colorado Anschutz Medical Campus, and colleagues conclude.

“Our findings also indicate that the combination intervention was effective for reducing body weight, fat mass, waist circumference, [the liver enzyme alanine transaminase (ALT)], fasting insulin, [and] insulin resistance and increasing insulin sensitivity, among patients with obesity and NAFLD versus controls,” the group reports.  

“When we compared the results of our study groups, we saw clearly that the most improved patients were in the group that followed the alternate-day fasting diet and exercised 5 days a week,” senior author Krista A. Varady, PhD, professor of nutrition, University of Illinois, said in a press release from the university.

“The people who only dieted or only exercised did not see the same improvements,” she added, “which reinforces the importance of these two relatively inexpensive lifestyle modifications on overall health and on combating chronic diseases like fatty liver disease.”

Moreover, “alternate-day fasting and exercise interventions can be difficult for people to stick to, and in prior studies we have seen significant dropout,” she noted. “It was very interesting to see that in this trial we had very high adherence to the interventions.”

The study was recently published in Cell Metabolism.  

An estimated 65% of people with obesity have NAFLD, or fat in the liver that is not the result of excessive alcohol consumption, which is strongly related to the development of insulin resistance and type 2 diabetes, the group writes.

Thiazolidinediones such as pioglitazone reduce hepatic steatosis, but there is mounting concern about the weight-gaining effect of these compounds.

Recent attention has focused on lifestyle interventions to resolve hepatic steatosis, and previous trials showed that alternate-day fasting was effective for certain outcomes in NAFLD, but those studies did not measure changes in IHTG content or include an exercise intervention.

The researchers enrolled 80 adults with obesity and NAFLD and randomized them to one of four groups for 3 months:

• Alternate day fasting group: Participants were instructed to consume 600 kcal at dinner between 5 PM and 8 PM on a fasting day alternating with food as desired on a feasting day.
• Exercise group: A 60-minute moderate-intensity aerobic exercise session 5 times a week.
• Fasting plus exercise group.
• Control group (no intervention).

Participants were age 23-65 (mean age, 44) and 81% were women.

Half were Hispanic, and the rest were Black (30%), White (11%), or Asian (9%).

They had a mean weight of 99 kg (218 lb) and a mean body mass index of 36 kg/m².

Dropout rates were minimal in the combination group (0%) and fasting groups (5%) and moderately high in the exercise group (25%).

IHTG content was reduced by a significantly greater amount in the combination group (–5.48%) than in the exercise alone group (–1.30%; P = .02) or in the control group (–0.17%; P < .01) and by a greater amount than in the fasting alone group, although this was not significant (–2.25%; P = .05).

Lean mass, aspartate transaminase (AST), A1c, blood pressure, plasma lipids, liver fibrosis score, and hepatokines (fetuin-A, FGF-21, and selenoprotein P) did not differ between groups.

Researchers acknowledge that although the combination intervention resulted in improved NAFLD parameters, IHTG and ALT did not reach the normal range.  

Participants likely had early stage NAFLD (their baseline IHTG was in the 16% to 18% range, where 5% to 33% is mild steatosis) and they were likely highly motivated (indicated by the low dropout rate), so the findings may not be generalizable.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Dr. Varady has reported receiving author fees from the Hachette Book Group for the book entitled “The Every Other Day Diet.” The other authors have reported no relevant financial relationships.

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

In the first study to examine how intermittent fasting combined with exercise impacts nonalcoholic fatty liver disease (NAFLD), the combined strategy was more effective than aerobic exercise alone or no intervention (control).

However, the combined approach did not give significantly added benefit, compared with fasting alone, the researchers report.

Eighty patients with NAFLD were randomized to one of four lifestyle strategies (alternate-day fasting, aerobic exercise, both, or neither) for 3 months.

The primary outcome was change in intrahepatic triglyceride (IHTG) content from baseline to study end, measured by magnetic resonance imaging proton density fat fraction.

The results suggest that “combining intermittent fasting with exercise is effective for reducing hepatic steatosis [fatty liver] in patients with NAFLD but may offer no additional benefit versus fasting alone,” Mark Ezpeleta, PhD, formerly at the University of Illinois, Chicago, and now at the University of Colorado Anschutz Medical Campus, and colleagues conclude.

“Our findings also indicate that the combination intervention was effective for reducing body weight, fat mass, waist circumference, [the liver enzyme alanine transaminase (ALT)], fasting insulin, [and] insulin resistance and increasing insulin sensitivity, among patients with obesity and NAFLD versus controls,” the group reports.  

“When we compared the results of our study groups, we saw clearly that the most improved patients were in the group that followed the alternate-day fasting diet and exercised 5 days a week,” senior author Krista A. Varady, PhD, professor of nutrition, University of Illinois, said in a press release from the university.

“The people who only dieted or only exercised did not see the same improvements,” she added, “which reinforces the importance of these two relatively inexpensive lifestyle modifications on overall health and on combating chronic diseases like fatty liver disease.”

Moreover, “alternate-day fasting and exercise interventions can be difficult for people to stick to, and in prior studies we have seen significant dropout,” she noted. “It was very interesting to see that in this trial we had very high adherence to the interventions.”

The study was recently published in Cell Metabolism.  

An estimated 65% of people with obesity have NAFLD, or fat in the liver that is not the result of excessive alcohol consumption, which is strongly related to the development of insulin resistance and type 2 diabetes, the group writes.

Thiazolidinediones such as pioglitazone reduce hepatic steatosis, but there is mounting concern about the weight-gaining effect of these compounds.

Recent attention has focused on lifestyle interventions to resolve hepatic steatosis, and previous trials showed that alternate-day fasting was effective for certain outcomes in NAFLD, but those studies did not measure changes in IHTG content or include an exercise intervention.

The researchers enrolled 80 adults with obesity and NAFLD and randomized them to one of four groups for 3 months:

• Alternate day fasting group: Participants were instructed to consume 600 kcal at dinner between 5 PM and 8 PM on a fasting day alternating with food as desired on a feasting day.
• Exercise group: A 60-minute moderate-intensity aerobic exercise session 5 times a week.
• Fasting plus exercise group.
• Control group (no intervention).

Participants were age 23-65 (mean age, 44) and 81% were women.

Half were Hispanic, and the rest were Black (30%), White (11%), or Asian (9%).

They had a mean weight of 99 kg (218 lb) and a mean body mass index of 36 kg/m².

Dropout rates were minimal in the combination group (0%) and fasting groups (5%) and moderately high in the exercise group (25%).

IHTG content was reduced by a significantly greater amount in the combination group (–5.48%) than in the exercise alone group (–1.30%; P = .02) or in the control group (–0.17%; P < .01) and by a greater amount than in the fasting alone group, although this was not significant (–2.25%; P = .05).

Lean mass, aspartate transaminase (AST), A1c, blood pressure, plasma lipids, liver fibrosis score, and hepatokines (fetuin-A, FGF-21, and selenoprotein P) did not differ between groups.

Researchers acknowledge that although the combination intervention resulted in improved NAFLD parameters, IHTG and ALT did not reach the normal range.  

Participants likely had early stage NAFLD (their baseline IHTG was in the 16% to 18% range, where 5% to 33% is mild steatosis) and they were likely highly motivated (indicated by the low dropout rate), so the findings may not be generalizable.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health. Dr. Varady has reported receiving author fees from the Hachette Book Group for the book entitled “The Every Other Day Diet.” The other authors have reported no relevant financial relationships.

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

Exercise training is 3.5 times more likely to result in a clinically meaningful response in liver fat, compared with standard clinical care, for patients with nonalcoholic fatty liver disease (NAFLD), according to a new systematic review and meta-analysis.

An exercise dose of 750 metabolic equivalents of task (MET)–minutes per week – or 150 minutes per week of brisk walking – was required to achieve a treatment response, independently of weight loss.

“In the absence of a regulatory agency–approved drug treatment or a cure, lifestyle modification with dietary change and increased exercise is recommended for all patients with NAFLD,” first author Jonathan Stine, MD, an associate professor of medicine and public health sciences and director of the fatty liver program at the Penn State Health Milton S. Hershey Medical Center, Hershey, said in an interview.

“With that said, there are many key unanswered questions about how to best prescribe exercise as medicine to our patients with NAFLD, including whether the liver-specific benefit of exercise can be seen without any body weight loss,” Dr. Stine said. “And if found, what dose of exercise is required in order to achieve clinically meaningful benefit?” He noted that this analysis is a step toward helping to answer these questions.

The study by Dr. Stine and colleagues was published online in The American Journal of Gastroenterology.
 

Analyzing studies

Exercise training, which includes planned and structured physical activity intended to improve physical fitness, has been shown to provide multiple benefits for patients with NAFLD, the study authors wrote. The gains include improvements in liver fat, physical fitness, body composition, vascular biology, and health-related quality of life.

However, it has been unclear whether exercise training achieves a 30% or more relative reduction in liver fat, which is considered the minimal clinically important difference and is a surrogate for histologic response or improvement in liver fibrosis.

In their systematic review and meta-analysis, Dr. Stine and colleagues analyzed the evidence for MRI-measured liver reduction in response to exercise training across different doses, with a 30% or more relative reduction serving as the primary outcome. They included randomized controlled trials in adults with NAFLD who participated in exercise training programs.

The 14 studies included a total of 551 participants. The average age of the participants was 53 years, and the average body mass index was 31 kg/mg². The duration of the interventions ranged from 4 to 52 weeks and included different types of exercise, such as aerobic, high-intensity interval, resistance, and aerobic plus resistance training.

No study yielded the clinically significant weight loss required for histologic response (7%-10%). The average weight loss was about 2.8% among those who participated in exercise training.

Overall, seven studies with 152 participants had data for the 30% or more relative reduction in MRI-measured liver fat. The pooled rate was 34% for exercise training and 13% for the control condition.

In general, those who participated in exercise training were 3.5 times more likely to achieve a 30% or more relative reduction in MRI-measured liver fat than those in the control condition.

Among all participants, the mean change in absolute liver fat was –6.7% for the 338 participants enrolled in exercise training, compared with –0.8% for the 213 participants under the control condition. The pooled mean difference in absolute change in MRI-measured liver fat for exercise training versus the control was –5.8%.

For relative change in MRI-measured liver fat, researchers analyzed nine studies with 195 participants – 118 participants in exercise training, and 77 control participants. The mean relative change was –24.1% among the exercise training group and 7.3% among the control group. The pooled mean difference in relative change for exercise training versus the control was –26.4%.

For all 14 studies, an exercise dose of 750 or more MET-minutes per week resulted in a significant treatment response. This equates to 150 minutes per week of moderate-intensity exercise, such as brisk walking, or 75 minutes per week of vigorous-intensity exercise, such as jogging or cycling.

Among participants who had 750 MET-minutes per week, there was a –8% absolute and –28.9% relative mean difference in MRI-measured liver fat, compared with –4.1% and –22.8%, respectively, among those who had fewer than 750 MET-minutes per week.

An exercise dose of 750 or more MET-minutes per week led to a 30% or more relative reduction in MRI-measured liver fat in 39.3% of participants, compared with 25.7% who had fewer than that threshold.

The treatment response was independent of clinically significant body weight loss of more than 5%.

“Prior to our study, it was felt that body weight loss of at least 5% was required in order to significantly improve liver histology,” Dr. Stine said. “Our findings challenge this thought in that exercise training achieved rates of clinically significant liver fat reduction.”
 

Ongoing research

Dr. Stine and colleagues are continuing their research and are directly comparing exercise doses of 750 MET-minutes per week and 1,000 MET-minutes per week to standard clinical care in adults with biopsy-proven nonalcoholic steatohepatitis, or the progressive type of NAFLD.

“Importantly, this new study we’re undertaking is designed to mimic a real-world setting in which people’s daily schedules are highly variable,” he said. “Our experienced team of exercise professionals may vary frequency and time of exercise in a week so long as our study participant achieves the prescribed dose of exercise.”

Currently, leading professional societies have not reached consensus regarding the optimal physical activity program for patients with NAFLD, the study authors wrote. However, most clinical guidelines support at least 150 minutes per week of moderate-intensity aerobic activity.

Although more head-to-head clinical trials are needed, exercise training appears to reduce liver fat and provides other benefits, such as cardiorespiratory fitness, body composition changes, and improvements in vascular biology, they wrote.

“The important piece here is that this review shows that there does not have to be weight loss for improvements in fatty liver,” Jill Kanaley, PhD, a professor of nutrition and exercise physiology at University of Missouri–Columbia, said in an interview.

Dr. Kanaley, who wasn’t involved with this study, has researched exercise training among patients with NAFLD. She and her colleagues have found that moderate-and high-intensity exercise can decrease intrahepatic lipid content and NAFLD risk factors, independently of abdominal fat or body mass reductions.

“So often, people get frustrated with exercise if they do not see weight loss,” she said. “But in this case, there seems to be benefits of the exercise, even without weight loss.”

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The authors have received research funding and have had consultant roles with numerous pharmaceutical companies. Dr. Kanaley reported no relevant financial relationships.

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

Exercise training is 3.5 times more likely to result in a clinically meaningful response in liver fat, compared with standard clinical care, for patients with nonalcoholic fatty liver disease (NAFLD), according to a new systematic review and meta-analysis.

An exercise dose of 750 metabolic equivalents of task (MET)–minutes per week – or 150 minutes per week of brisk walking – was required to achieve a treatment response, independently of weight loss.

“In the absence of a regulatory agency–approved drug treatment or a cure, lifestyle modification with dietary change and increased exercise is recommended for all patients with NAFLD,” first author Jonathan Stine, MD, an associate professor of medicine and public health sciences and director of the fatty liver program at the Penn State Health Milton S. Hershey Medical Center, Hershey, said in an interview.

“With that said, there are many key unanswered questions about how to best prescribe exercise as medicine to our patients with NAFLD, including whether the liver-specific benefit of exercise can be seen without any body weight loss,” Dr. Stine said. “And if found, what dose of exercise is required in order to achieve clinically meaningful benefit?” He noted that this analysis is a step toward helping to answer these questions.

The study by Dr. Stine and colleagues was published online in The American Journal of Gastroenterology.
 

Analyzing studies

Exercise training, which includes planned and structured physical activity intended to improve physical fitness, has been shown to provide multiple benefits for patients with NAFLD, the study authors wrote. The gains include improvements in liver fat, physical fitness, body composition, vascular biology, and health-related quality of life.

However, it has been unclear whether exercise training achieves a 30% or more relative reduction in liver fat, which is considered the minimal clinically important difference and is a surrogate for histologic response or improvement in liver fibrosis.

In their systematic review and meta-analysis, Dr. Stine and colleagues analyzed the evidence for MRI-measured liver reduction in response to exercise training across different doses, with a 30% or more relative reduction serving as the primary outcome. They included randomized controlled trials in adults with NAFLD who participated in exercise training programs.

The 14 studies included a total of 551 participants. The average age of the participants was 53 years, and the average body mass index was 31 kg/mg². The duration of the interventions ranged from 4 to 52 weeks and included different types of exercise, such as aerobic, high-intensity interval, resistance, and aerobic plus resistance training.

No study yielded the clinically significant weight loss required for histologic response (7%-10%). The average weight loss was about 2.8% among those who participated in exercise training.

Overall, seven studies with 152 participants had data for the 30% or more relative reduction in MRI-measured liver fat. The pooled rate was 34% for exercise training and 13% for the control condition.

In general, those who participated in exercise training were 3.5 times more likely to achieve a 30% or more relative reduction in MRI-measured liver fat than those in the control condition.

Among all participants, the mean change in absolute liver fat was –6.7% for the 338 participants enrolled in exercise training, compared with –0.8% for the 213 participants under the control condition. The pooled mean difference in absolute change in MRI-measured liver fat for exercise training versus the control was –5.8%.

For relative change in MRI-measured liver fat, researchers analyzed nine studies with 195 participants – 118 participants in exercise training, and 77 control participants. The mean relative change was –24.1% among the exercise training group and 7.3% among the control group. The pooled mean difference in relative change for exercise training versus the control was –26.4%.

For all 14 studies, an exercise dose of 750 or more MET-minutes per week resulted in a significant treatment response. This equates to 150 minutes per week of moderate-intensity exercise, such as brisk walking, or 75 minutes per week of vigorous-intensity exercise, such as jogging or cycling.

Among participants who had 750 MET-minutes per week, there was a –8% absolute and –28.9% relative mean difference in MRI-measured liver fat, compared with –4.1% and –22.8%, respectively, among those who had fewer than 750 MET-minutes per week.

An exercise dose of 750 or more MET-minutes per week led to a 30% or more relative reduction in MRI-measured liver fat in 39.3% of participants, compared with 25.7% who had fewer than that threshold.

The treatment response was independent of clinically significant body weight loss of more than 5%.

“Prior to our study, it was felt that body weight loss of at least 5% was required in order to significantly improve liver histology,” Dr. Stine said. “Our findings challenge this thought in that exercise training achieved rates of clinically significant liver fat reduction.”
 

Ongoing research

Dr. Stine and colleagues are continuing their research and are directly comparing exercise doses of 750 MET-minutes per week and 1,000 MET-minutes per week to standard clinical care in adults with biopsy-proven nonalcoholic steatohepatitis, or the progressive type of NAFLD.

“Importantly, this new study we’re undertaking is designed to mimic a real-world setting in which people’s daily schedules are highly variable,” he said. “Our experienced team of exercise professionals may vary frequency and time of exercise in a week so long as our study participant achieves the prescribed dose of exercise.”

Currently, leading professional societies have not reached consensus regarding the optimal physical activity program for patients with NAFLD, the study authors wrote. However, most clinical guidelines support at least 150 minutes per week of moderate-intensity aerobic activity.

Although more head-to-head clinical trials are needed, exercise training appears to reduce liver fat and provides other benefits, such as cardiorespiratory fitness, body composition changes, and improvements in vascular biology, they wrote.

“The important piece here is that this review shows that there does not have to be weight loss for improvements in fatty liver,” Jill Kanaley, PhD, a professor of nutrition and exercise physiology at University of Missouri–Columbia, said in an interview.

Dr. Kanaley, who wasn’t involved with this study, has researched exercise training among patients with NAFLD. She and her colleagues have found that moderate-and high-intensity exercise can decrease intrahepatic lipid content and NAFLD risk factors, independently of abdominal fat or body mass reductions.

“So often, people get frustrated with exercise if they do not see weight loss,” she said. “But in this case, there seems to be benefits of the exercise, even without weight loss.”

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The authors have received research funding and have had consultant roles with numerous pharmaceutical companies. Dr. Kanaley reported no relevant financial relationships.

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

Exercise training is 3.5 times more likely to result in a clinically meaningful response in liver fat, compared with standard clinical care, for patients with nonalcoholic fatty liver disease (NAFLD), according to a new systematic review and meta-analysis.

An exercise dose of 750 metabolic equivalents of task (MET)–minutes per week – or 150 minutes per week of brisk walking – was required to achieve a treatment response, independently of weight loss.

“In the absence of a regulatory agency–approved drug treatment or a cure, lifestyle modification with dietary change and increased exercise is recommended for all patients with NAFLD,” first author Jonathan Stine, MD, an associate professor of medicine and public health sciences and director of the fatty liver program at the Penn State Health Milton S. Hershey Medical Center, Hershey, said in an interview.

“With that said, there are many key unanswered questions about how to best prescribe exercise as medicine to our patients with NAFLD, including whether the liver-specific benefit of exercise can be seen without any body weight loss,” Dr. Stine said. “And if found, what dose of exercise is required in order to achieve clinically meaningful benefit?” He noted that this analysis is a step toward helping to answer these questions.

The study by Dr. Stine and colleagues was published online in The American Journal of Gastroenterology.
 

Analyzing studies

Exercise training, which includes planned and structured physical activity intended to improve physical fitness, has been shown to provide multiple benefits for patients with NAFLD, the study authors wrote. The gains include improvements in liver fat, physical fitness, body composition, vascular biology, and health-related quality of life.

However, it has been unclear whether exercise training achieves a 30% or more relative reduction in liver fat, which is considered the minimal clinically important difference and is a surrogate for histologic response or improvement in liver fibrosis.

In their systematic review and meta-analysis, Dr. Stine and colleagues analyzed the evidence for MRI-measured liver reduction in response to exercise training across different doses, with a 30% or more relative reduction serving as the primary outcome. They included randomized controlled trials in adults with NAFLD who participated in exercise training programs.

The 14 studies included a total of 551 participants. The average age of the participants was 53 years, and the average body mass index was 31 kg/mg². The duration of the interventions ranged from 4 to 52 weeks and included different types of exercise, such as aerobic, high-intensity interval, resistance, and aerobic plus resistance training.

No study yielded the clinically significant weight loss required for histologic response (7%-10%). The average weight loss was about 2.8% among those who participated in exercise training.

Overall, seven studies with 152 participants had data for the 30% or more relative reduction in MRI-measured liver fat. The pooled rate was 34% for exercise training and 13% for the control condition.

In general, those who participated in exercise training were 3.5 times more likely to achieve a 30% or more relative reduction in MRI-measured liver fat than those in the control condition.

Among all participants, the mean change in absolute liver fat was –6.7% for the 338 participants enrolled in exercise training, compared with –0.8% for the 213 participants under the control condition. The pooled mean difference in absolute change in MRI-measured liver fat for exercise training versus the control was –5.8%.

For relative change in MRI-measured liver fat, researchers analyzed nine studies with 195 participants – 118 participants in exercise training, and 77 control participants. The mean relative change was –24.1% among the exercise training group and 7.3% among the control group. The pooled mean difference in relative change for exercise training versus the control was –26.4%.

For all 14 studies, an exercise dose of 750 or more MET-minutes per week resulted in a significant treatment response. This equates to 150 minutes per week of moderate-intensity exercise, such as brisk walking, or 75 minutes per week of vigorous-intensity exercise, such as jogging or cycling.

Among participants who had 750 MET-minutes per week, there was a –8% absolute and –28.9% relative mean difference in MRI-measured liver fat, compared with –4.1% and –22.8%, respectively, among those who had fewer than 750 MET-minutes per week.

An exercise dose of 750 or more MET-minutes per week led to a 30% or more relative reduction in MRI-measured liver fat in 39.3% of participants, compared with 25.7% who had fewer than that threshold.

The treatment response was independent of clinically significant body weight loss of more than 5%.

“Prior to our study, it was felt that body weight loss of at least 5% was required in order to significantly improve liver histology,” Dr. Stine said. “Our findings challenge this thought in that exercise training achieved rates of clinically significant liver fat reduction.”
 

Ongoing research

Dr. Stine and colleagues are continuing their research and are directly comparing exercise doses of 750 MET-minutes per week and 1,000 MET-minutes per week to standard clinical care in adults with biopsy-proven nonalcoholic steatohepatitis, or the progressive type of NAFLD.

“Importantly, this new study we’re undertaking is designed to mimic a real-world setting in which people’s daily schedules are highly variable,” he said. “Our experienced team of exercise professionals may vary frequency and time of exercise in a week so long as our study participant achieves the prescribed dose of exercise.”

Currently, leading professional societies have not reached consensus regarding the optimal physical activity program for patients with NAFLD, the study authors wrote. However, most clinical guidelines support at least 150 minutes per week of moderate-intensity aerobic activity.

Although more head-to-head clinical trials are needed, exercise training appears to reduce liver fat and provides other benefits, such as cardiorespiratory fitness, body composition changes, and improvements in vascular biology, they wrote.

“The important piece here is that this review shows that there does not have to be weight loss for improvements in fatty liver,” Jill Kanaley, PhD, a professor of nutrition and exercise physiology at University of Missouri–Columbia, said in an interview.

Dr. Kanaley, who wasn’t involved with this study, has researched exercise training among patients with NAFLD. She and her colleagues have found that moderate-and high-intensity exercise can decrease intrahepatic lipid content and NAFLD risk factors, independently of abdominal fat or body mass reductions.

“So often, people get frustrated with exercise if they do not see weight loss,” she said. “But in this case, there seems to be benefits of the exercise, even without weight loss.”

The study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases. The authors have received research funding and have had consultant roles with numerous pharmaceutical companies. Dr. Kanaley reported no relevant financial relationships.

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

Dementia frequently coexists with hepatic encephalopathy (HE) in patients with cirrhosis but doesn’t correlate with other decompensating events, according to a new study involving U.S. veterans.

The overlap between dementia and HE was also independent of alcohol use, brain injury, age, and other metabolic risk factors.

“The aging of patients with cirrhosis leads us to encounter several individuals who may be prone to both of these diseases,” senior author Jasmohan Bajaj, MD, a professor of gastroenterology, hepatology, and nutrition at Virginia Commonwealth University Medical Center and GI section of the Central Virginia Veterans Healthcare System in Richmond, said in an interview.

“Given the epidemic of metabolic syndrome and alcohol, consider excluding cirrhosis in your patient [for] whom the presumptive diagnosis is dementia, since they could have concomitant HE,” he said.

“On the flip side, in those with HE who have predominant long-term memory issues and persistent cognitive changes, consider consulting a neuropsychiatrist or neurologist to ensure there is a resolution of the underlying disease process,” Dr. Bajaj added.

The study was published online in The American Journal of Gastroenterology.
 

Analyzing associations

HE is a common decompensating event in patients with cirrhosis. Because of the aging population of patients with cirrhosis, however, it’s important to differentiate HE from nonhepatic etiologies of cognitive impairment, such as dementia, the authors note.

Using data from the VA Corporate Data Warehouse, Dr. Bajaj and colleagues identified veterans with cirrhosis who received VA care between October 2019 and September 2021 and compared baseline characteristics between the cohorts based on the presence or absence of dementia. The research team then evaluated factors associated with having a diagnosis of dementia, adjusting for demographics, comorbid illnesses, cirrhosis etiology, and cirrhosis complications.

Investigators identified 71,522 veterans with diagnostic codes for cirrhosis who were engaged in VA care in 2019. They were mostly men (96.2%) and had a median age of 66. The most common etiologies of cirrhosis were alcohol and hepatitis C, followed by nonalcoholic steatohepatitis (NASH). The group also included veterans with predominantly compensated cirrhosis and a median MELD-Na score of 9. The MELD-Na score gauges the severity of chronic liver disease using values such as serum bilirubin, serum creatinine, and the international normalized ratio for prothrombin time and sodium to predict survival.

Among those with cirrhosis, 5,647 (7.9%) also had dementia diagnosis codes. This rate is higher than the prevalence of dementia in the general population and equivalent to the rate of dementia in veterans without cirrhosis who are older than 65, the authors note.

In general, veterans with dementia tended to be older, to be White, to live in an urban area, and to have higher MELD-Na scores, and they were more frequently diagnosed with alcohol-related cirrhosis, alcohol and tobacco use disorder, diabetes, chronic kidney disease, chronic heart failure, brain trauma, and cerebrovascular disease.

In a multivariable analysis, the presence of any decompensating event was significantly associated with dementia. In subsequent analyses of individual decompensating events, however, the strongest association was with HE, while ascites or variceal bleeding did not add to the risk.

When HE was defined as patients who filled prescriptions for lactulose or rifaximin, the frequency of patients with HE decreased from 13.7% to 10.9%. In an analysis with HE as the decompensating event, the association between HE and dementia remained significant compared to when HE was defined by diagnostic codes alone.

“We were surprised by the high proportion of patients with dementia who also had cirrhosis, and given the genuine difficulty that clinicians have with defining HE vs. dementia, we were not very surprised at that overlap,” Dr. Bajaj said.

“We were also surprised at the specificity of this overlap only with HE and not with other decompensating events, which was also independent of head injury, alcohol use, and PTSD,” he added.
 

Additional research needed

Future research should look at the characteristics of HE, including the number of episodes or breakthrough episodes, and should focus on objective biomarkers to differentiate dementia and HE, the study authors write.

“The distinction and study of potential overlapping features among HE and dementia is important because HE is often treatable with medications and reverses after liver transplant, while this does not occur with dementia,” they add.

Dr. Bajaj and colleagues call for a greater awareness of disease processes and complications in older patients with cirrhosis, particularly since diagnostic imprecision can lead to patient and family confusion, distrust, and ineffective treatment.

The study will help physicians better understand the important overlap between dementia and HE, said Eric Orman, MD, an associate professor of medicine at Indiana University, Indianapolis.

Dr. Orman, who wasn’t involved with this study, has researched recent trends in the characteristics and outcomes of patients with newly diagnosed cirrhosis and has found that the proportion of older adults has increased, as well as those with alcoholic cirrhosis and NASH, which has implications for future patient care.

“It is important to recognize that both dementia and HE can occur either separately or concurrently in individuals with cirrhosis,” Dr. Orman told this news organization. “When seeing patients with cognitive impairment, having a high index of suspicion for both conditions is critical to ensure appropriate diagnosis and treatment.”

The study’s findings “represent the tip of the iceberg,” Neal Parikh, MD, an assistant professor of neurology and neuroscience at Weill Cornell Medicine in New York, said in an interview. “There is a tremendous amount left to be discovered regarding the role of the liver in brain health.”

Dr. Parikh, who wasn’t associated with this study, has researched the impact of chronic liver conditions on cognitive impairment and dementia. He is working on a project that addresses HE in detail.

“There is growing recognition of a so-called ‘liver-brain axis,’ with several researchers, including my group, showing that a range of chronic liver conditions may detrimentally impact cognitive function and increase the risk of dementia,” he said. “Studying the specific contributions of cirrhosis is critical for understanding the role of hepatic encephalopathy in age-related cognitive decline.”

The study received no financial support. The authors reported no potential competing interests.

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

Dementia frequently coexists with hepatic encephalopathy (HE) in patients with cirrhosis but doesn’t correlate with other decompensating events, according to a new study involving U.S. veterans.

The overlap between dementia and HE was also independent of alcohol use, brain injury, age, and other metabolic risk factors.

“The aging of patients with cirrhosis leads us to encounter several individuals who may be prone to both of these diseases,” senior author Jasmohan Bajaj, MD, a professor of gastroenterology, hepatology, and nutrition at Virginia Commonwealth University Medical Center and GI section of the Central Virginia Veterans Healthcare System in Richmond, said in an interview.

“Given the epidemic of metabolic syndrome and alcohol, consider excluding cirrhosis in your patient [for] whom the presumptive diagnosis is dementia, since they could have concomitant HE,” he said.

“On the flip side, in those with HE who have predominant long-term memory issues and persistent cognitive changes, consider consulting a neuropsychiatrist or neurologist to ensure there is a resolution of the underlying disease process,” Dr. Bajaj added.

The study was published online in The American Journal of Gastroenterology.
 

Analyzing associations

HE is a common decompensating event in patients with cirrhosis. Because of the aging population of patients with cirrhosis, however, it’s important to differentiate HE from nonhepatic etiologies of cognitive impairment, such as dementia, the authors note.

Using data from the VA Corporate Data Warehouse, Dr. Bajaj and colleagues identified veterans with cirrhosis who received VA care between October 2019 and September 2021 and compared baseline characteristics between the cohorts based on the presence or absence of dementia. The research team then evaluated factors associated with having a diagnosis of dementia, adjusting for demographics, comorbid illnesses, cirrhosis etiology, and cirrhosis complications.

Investigators identified 71,522 veterans with diagnostic codes for cirrhosis who were engaged in VA care in 2019. They were mostly men (96.2%) and had a median age of 66. The most common etiologies of cirrhosis were alcohol and hepatitis C, followed by nonalcoholic steatohepatitis (NASH). The group also included veterans with predominantly compensated cirrhosis and a median MELD-Na score of 9. The MELD-Na score gauges the severity of chronic liver disease using values such as serum bilirubin, serum creatinine, and the international normalized ratio for prothrombin time and sodium to predict survival.

Among those with cirrhosis, 5,647 (7.9%) also had dementia diagnosis codes. This rate is higher than the prevalence of dementia in the general population and equivalent to the rate of dementia in veterans without cirrhosis who are older than 65, the authors note.

In general, veterans with dementia tended to be older, to be White, to live in an urban area, and to have higher MELD-Na scores, and they were more frequently diagnosed with alcohol-related cirrhosis, alcohol and tobacco use disorder, diabetes, chronic kidney disease, chronic heart failure, brain trauma, and cerebrovascular disease.

In a multivariable analysis, the presence of any decompensating event was significantly associated with dementia. In subsequent analyses of individual decompensating events, however, the strongest association was with HE, while ascites or variceal bleeding did not add to the risk.

When HE was defined as patients who filled prescriptions for lactulose or rifaximin, the frequency of patients with HE decreased from 13.7% to 10.9%. In an analysis with HE as the decompensating event, the association between HE and dementia remained significant compared to when HE was defined by diagnostic codes alone.

“We were surprised by the high proportion of patients with dementia who also had cirrhosis, and given the genuine difficulty that clinicians have with defining HE vs. dementia, we were not very surprised at that overlap,” Dr. Bajaj said.

“We were also surprised at the specificity of this overlap only with HE and not with other decompensating events, which was also independent of head injury, alcohol use, and PTSD,” he added.
 

Additional research needed

Future research should look at the characteristics of HE, including the number of episodes or breakthrough episodes, and should focus on objective biomarkers to differentiate dementia and HE, the study authors write.

“The distinction and study of potential overlapping features among HE and dementia is important because HE is often treatable with medications and reverses after liver transplant, while this does not occur with dementia,” they add.

Dr. Bajaj and colleagues call for a greater awareness of disease processes and complications in older patients with cirrhosis, particularly since diagnostic imprecision can lead to patient and family confusion, distrust, and ineffective treatment.

The study will help physicians better understand the important overlap between dementia and HE, said Eric Orman, MD, an associate professor of medicine at Indiana University, Indianapolis.

Dr. Orman, who wasn’t involved with this study, has researched recent trends in the characteristics and outcomes of patients with newly diagnosed cirrhosis and has found that the proportion of older adults has increased, as well as those with alcoholic cirrhosis and NASH, which has implications for future patient care.

“It is important to recognize that both dementia and HE can occur either separately or concurrently in individuals with cirrhosis,” Dr. Orman told this news organization. “When seeing patients with cognitive impairment, having a high index of suspicion for both conditions is critical to ensure appropriate diagnosis and treatment.”

The study’s findings “represent the tip of the iceberg,” Neal Parikh, MD, an assistant professor of neurology and neuroscience at Weill Cornell Medicine in New York, said in an interview. “There is a tremendous amount left to be discovered regarding the role of the liver in brain health.”

Dr. Parikh, who wasn’t associated with this study, has researched the impact of chronic liver conditions on cognitive impairment and dementia. He is working on a project that addresses HE in detail.

“There is growing recognition of a so-called ‘liver-brain axis,’ with several researchers, including my group, showing that a range of chronic liver conditions may detrimentally impact cognitive function and increase the risk of dementia,” he said. “Studying the specific contributions of cirrhosis is critical for understanding the role of hepatic encephalopathy in age-related cognitive decline.”

The study received no financial support. The authors reported no potential competing interests.

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

Dementia frequently coexists with hepatic encephalopathy (HE) in patients with cirrhosis but doesn’t correlate with other decompensating events, according to a new study involving U.S. veterans.

The overlap between dementia and HE was also independent of alcohol use, brain injury, age, and other metabolic risk factors.

“The aging of patients with cirrhosis leads us to encounter several individuals who may be prone to both of these diseases,” senior author Jasmohan Bajaj, MD, a professor of gastroenterology, hepatology, and nutrition at Virginia Commonwealth University Medical Center and GI section of the Central Virginia Veterans Healthcare System in Richmond, said in an interview.

“Given the epidemic of metabolic syndrome and alcohol, consider excluding cirrhosis in your patient [for] whom the presumptive diagnosis is dementia, since they could have concomitant HE,” he said.

“On the flip side, in those with HE who have predominant long-term memory issues and persistent cognitive changes, consider consulting a neuropsychiatrist or neurologist to ensure there is a resolution of the underlying disease process,” Dr. Bajaj added.

The study was published online in The American Journal of Gastroenterology.
 

Analyzing associations

HE is a common decompensating event in patients with cirrhosis. Because of the aging population of patients with cirrhosis, however, it’s important to differentiate HE from nonhepatic etiologies of cognitive impairment, such as dementia, the authors note.

Using data from the VA Corporate Data Warehouse, Dr. Bajaj and colleagues identified veterans with cirrhosis who received VA care between October 2019 and September 2021 and compared baseline characteristics between the cohorts based on the presence or absence of dementia. The research team then evaluated factors associated with having a diagnosis of dementia, adjusting for demographics, comorbid illnesses, cirrhosis etiology, and cirrhosis complications.

Investigators identified 71,522 veterans with diagnostic codes for cirrhosis who were engaged in VA care in 2019. They were mostly men (96.2%) and had a median age of 66. The most common etiologies of cirrhosis were alcohol and hepatitis C, followed by nonalcoholic steatohepatitis (NASH). The group also included veterans with predominantly compensated cirrhosis and a median MELD-Na score of 9. The MELD-Na score gauges the severity of chronic liver disease using values such as serum bilirubin, serum creatinine, and the international normalized ratio for prothrombin time and sodium to predict survival.

Among those with cirrhosis, 5,647 (7.9%) also had dementia diagnosis codes. This rate is higher than the prevalence of dementia in the general population and equivalent to the rate of dementia in veterans without cirrhosis who are older than 65, the authors note.

In general, veterans with dementia tended to be older, to be White, to live in an urban area, and to have higher MELD-Na scores, and they were more frequently diagnosed with alcohol-related cirrhosis, alcohol and tobacco use disorder, diabetes, chronic kidney disease, chronic heart failure, brain trauma, and cerebrovascular disease.

In a multivariable analysis, the presence of any decompensating event was significantly associated with dementia. In subsequent analyses of individual decompensating events, however, the strongest association was with HE, while ascites or variceal bleeding did not add to the risk.

When HE was defined as patients who filled prescriptions for lactulose or rifaximin, the frequency of patients with HE decreased from 13.7% to 10.9%. In an analysis with HE as the decompensating event, the association between HE and dementia remained significant compared to when HE was defined by diagnostic codes alone.

“We were surprised by the high proportion of patients with dementia who also had cirrhosis, and given the genuine difficulty that clinicians have with defining HE vs. dementia, we were not very surprised at that overlap,” Dr. Bajaj said.

“We were also surprised at the specificity of this overlap only with HE and not with other decompensating events, which was also independent of head injury, alcohol use, and PTSD,” he added.
 

Additional research needed

Future research should look at the characteristics of HE, including the number of episodes or breakthrough episodes, and should focus on objective biomarkers to differentiate dementia and HE, the study authors write.

“The distinction and study of potential overlapping features among HE and dementia is important because HE is often treatable with medications and reverses after liver transplant, while this does not occur with dementia,” they add.

Dr. Bajaj and colleagues call for a greater awareness of disease processes and complications in older patients with cirrhosis, particularly since diagnostic imprecision can lead to patient and family confusion, distrust, and ineffective treatment.

The study will help physicians better understand the important overlap between dementia and HE, said Eric Orman, MD, an associate professor of medicine at Indiana University, Indianapolis.

Dr. Orman, who wasn’t involved with this study, has researched recent trends in the characteristics and outcomes of patients with newly diagnosed cirrhosis and has found that the proportion of older adults has increased, as well as those with alcoholic cirrhosis and NASH, which has implications for future patient care.

“It is important to recognize that both dementia and HE can occur either separately or concurrently in individuals with cirrhosis,” Dr. Orman told this news organization. “When seeing patients with cognitive impairment, having a high index of suspicion for both conditions is critical to ensure appropriate diagnosis and treatment.”

The study’s findings “represent the tip of the iceberg,” Neal Parikh, MD, an assistant professor of neurology and neuroscience at Weill Cornell Medicine in New York, said in an interview. “There is a tremendous amount left to be discovered regarding the role of the liver in brain health.”

Dr. Parikh, who wasn’t associated with this study, has researched the impact of chronic liver conditions on cognitive impairment and dementia. He is working on a project that addresses HE in detail.

“There is growing recognition of a so-called ‘liver-brain axis,’ with several researchers, including my group, showing that a range of chronic liver conditions may detrimentally impact cognitive function and increase the risk of dementia,” he said. “Studying the specific contributions of cirrhosis is critical for understanding the role of hepatic encephalopathy in age-related cognitive decline.”

The study received no financial support. The authors reported no potential competing interests.

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