Liver Disease

Researchers studying differences in treatment initiation for chronic hepatitis B (CHB) among a large, multiracial cohort in North America did not find evidence of disparities by race or socioeconomic status.

Instead, they observed a similar gap across races between the number of people eligible for treatment and those receiving it.

That gap suggests that treatment guidelines need to be simplified and that efforts to increase hepatitis B virus (HBV) awareness and train more clinicians are needed to achieve the World Health Organization’s goal of eliminating HBV by 2030, the researchers write.

The Hepatitis B Research Network study was published online in JAMA Network Open.

The prevalence of CHB in the United States is estimated at 2.4 million. It disproportionately affects persons of Asian or African descent, the investigators note. Their study examined whether treatment initiation and outcomes differ between African American and Black, Asian, and White participants, as well as between African American and Black participants born in North America and East or West Africa.

The research involved 1,550 adult patients: 1,157 Asian American, 193 African American or Black (39 born in the United States, 90 in East Africa, 53 in West Africa, and 11 elsewhere), 157 White, and 43 who identified as being of “other races.” All had CHB but were not receiving antiviral treatment at enrollment.

Participants came from 20 centers in the United States and one in Canada. They underwent clinical and laboratory assessments and could receive anti-HBV treatment after they enrolled. Enrollment was from Jan. 14, 2011, to Jan. 28, 2018. Participants were followed at 12 and 24 weeks and every 24 weeks thereafter in the longitudinal cohort study by Mandana Khalili, MD, division of gastroenterology and hepatology, University of California, San Francisco, and colleagues.

Information on patients’ country of birth, duration of U.S. or Canadian residency, educational level, employment, insurance, prior antiviral treatment, family history of HBV or hepatocellular carcinoma (HCC), and mode of transmission were collected by research coordinators.
 

Treatment initiation

During the study period, slightly fewer than one-third (32.5%) of the participants initiated treatment. The incidences were 4.8 per 100 person-years in African American or Black participants, 9.9 per 100 person-years in Asian participants, 6.6 per 100 person-years in White participants, and 7.9 per 100 person-years in those of other races (P < .001).

A lower percentage of African American and Black participants (14%) met the American Association for the Study of Liver Diseases treatment criteria, compared with Asian (22%) and White (27%) participants (P = .01).

When the researchers compared cumulative probability of initiating treatment by race for those who met criteria for treatment, they found no significant differences by race.

At 72 weeks, initiation probability was 0.45 for African American and Black patients and 0.51 for Asian and White patients (P = .68). Similarly, among African American and Black participants who met treatment criteria, there were no significant differences in cumulative probability of treatment by region of birth.

The cumulative percentage of treatment initiation for those who met guideline-based criteria was 62%.

“Among participants with a treatment indication, treatment rates did not differ significantly by race, despite marked differences in educational level, income, and type of health care insurance across the racial groups,” the researchers write. “Moreover, race was not an independent estimator of treatment initiation when adjusting for known factors associated with a higher risk of adverse clinical outcomes, namely, HBV DNA, disease severity, sex, and age.”

Adverse liver outcomes (hepatic decompensation, HCC, liver transplant, and death) were rare and did not vary significantly by race, the researchers write.

One study limitation is that participants were linked to specialty liver clinics, so the findings may not be generalizable to patients who receive care in other settings, the authors note.

The results are “reassuring,” said senior author Anna S. Lok, MD, division of gastroenterology and hepatology at University of Michigan in Ann Arbor. However, she noted, study participants had already overcome barriers to receiving care at major academic centers.

“Once you get into the big academic liver centers, then maybe everything is equal, but in the real world, a lot of people don’t ever get to the big liver centers,” she said. The question becomes: “Are we serving only a portion of the patient population?”

Many factors drive the decision to undergo treatment, including the doctor’s opinion as to need and the patient’s desire to receive treatment, she said.

The study participants who were more likely to get treated were those with higher-level disease who had a stronger indication for treatment, Dr. Lok said.
 

Finding the disparities

Centers for Disease Control and Prevention statistics show that Black people are 3.9 times more likely to have CHB and 2.5 times more likely to die from it than White people, notes H. Nina Kim, MD, with the department of medicine, University of Washington, Seattle, in an accompanying invited commentary.

“The fact that we have not observed racial disparities in treatment initiation does not mean none exist; it means we have to look harder to find them,” she writes.

“We need to examine whether our guidelines for HBV treatment are so complex that it becomes the purview of specialists, thereby restricting access and deepening inequities,” Dr. Kim adds. “We should look closely at retention in care, the step that precedes treatment, and stratify this outcome by race and ethnicity.”

Primary care physicians in some regions might find it difficult to manage patients who have hepatitis B because they see so few of them, Dr. Lok noted.

Dr. Khalili has received grants and consulting fees from Gilead Sciences Inc and grants from Intercept Pharmaceuticals outside the submitted work. Dr. Lok has received grants from Target and consultant fees from Abbott, Ambys, Arbutus, Chroma, Clear B, Enanta, Enochian, GNI, GlaxoSmithKline, Eli Lilly, and Virion outside the submitted work. Coauthors have received grants, consulting fees, or personal fees from Bayer, Boston Scientific, Exact Sciences, Fujifilm Medical Sciences, Gilead Sciences, Glycotest, Redhill Biopharma, Target RWE, MedEd Design, Pontifax, Global Life, the Lynx Group, AstraZeneca, Eisai, Novartis Venture Fund, Grail, QED Therapeutics, Genentech, Hepion Pharmaceuticals, Roche, Abbott, AbbVie, and Pfizer. Dr. Kim has received grants from Gilead Sciences (paid to her institution) outside the submitted work.

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

Researchers studying differences in treatment initiation for chronic hepatitis B (CHB) among a large, multiracial cohort in North America did not find evidence of disparities by race or socioeconomic status.

Instead, they observed a similar gap across races between the number of people eligible for treatment and those receiving it.

That gap suggests that treatment guidelines need to be simplified and that efforts to increase hepatitis B virus (HBV) awareness and train more clinicians are needed to achieve the World Health Organization’s goal of eliminating HBV by 2030, the researchers write.

The Hepatitis B Research Network study was published online in JAMA Network Open.

The prevalence of CHB in the United States is estimated at 2.4 million. It disproportionately affects persons of Asian or African descent, the investigators note. Their study examined whether treatment initiation and outcomes differ between African American and Black, Asian, and White participants, as well as between African American and Black participants born in North America and East or West Africa.

The research involved 1,550 adult patients: 1,157 Asian American, 193 African American or Black (39 born in the United States, 90 in East Africa, 53 in West Africa, and 11 elsewhere), 157 White, and 43 who identified as being of “other races.” All had CHB but were not receiving antiviral treatment at enrollment.

Participants came from 20 centers in the United States and one in Canada. They underwent clinical and laboratory assessments and could receive anti-HBV treatment after they enrolled. Enrollment was from Jan. 14, 2011, to Jan. 28, 2018. Participants were followed at 12 and 24 weeks and every 24 weeks thereafter in the longitudinal cohort study by Mandana Khalili, MD, division of gastroenterology and hepatology, University of California, San Francisco, and colleagues.

Information on patients’ country of birth, duration of U.S. or Canadian residency, educational level, employment, insurance, prior antiviral treatment, family history of HBV or hepatocellular carcinoma (HCC), and mode of transmission were collected by research coordinators.
 

Treatment initiation

During the study period, slightly fewer than one-third (32.5%) of the participants initiated treatment. The incidences were 4.8 per 100 person-years in African American or Black participants, 9.9 per 100 person-years in Asian participants, 6.6 per 100 person-years in White participants, and 7.9 per 100 person-years in those of other races (P < .001).

A lower percentage of African American and Black participants (14%) met the American Association for the Study of Liver Diseases treatment criteria, compared with Asian (22%) and White (27%) participants (P = .01).

When the researchers compared cumulative probability of initiating treatment by race for those who met criteria for treatment, they found no significant differences by race.

At 72 weeks, initiation probability was 0.45 for African American and Black patients and 0.51 for Asian and White patients (P = .68). Similarly, among African American and Black participants who met treatment criteria, there were no significant differences in cumulative probability of treatment by region of birth.

The cumulative percentage of treatment initiation for those who met guideline-based criteria was 62%.

“Among participants with a treatment indication, treatment rates did not differ significantly by race, despite marked differences in educational level, income, and type of health care insurance across the racial groups,” the researchers write. “Moreover, race was not an independent estimator of treatment initiation when adjusting for known factors associated with a higher risk of adverse clinical outcomes, namely, HBV DNA, disease severity, sex, and age.”

Adverse liver outcomes (hepatic decompensation, HCC, liver transplant, and death) were rare and did not vary significantly by race, the researchers write.

One study limitation is that participants were linked to specialty liver clinics, so the findings may not be generalizable to patients who receive care in other settings, the authors note.

The results are “reassuring,” said senior author Anna S. Lok, MD, division of gastroenterology and hepatology at University of Michigan in Ann Arbor. However, she noted, study participants had already overcome barriers to receiving care at major academic centers.

“Once you get into the big academic liver centers, then maybe everything is equal, but in the real world, a lot of people don’t ever get to the big liver centers,” she said. The question becomes: “Are we serving only a portion of the patient population?”

Many factors drive the decision to undergo treatment, including the doctor’s opinion as to need and the patient’s desire to receive treatment, she said.

The study participants who were more likely to get treated were those with higher-level disease who had a stronger indication for treatment, Dr. Lok said.
 

Finding the disparities

Centers for Disease Control and Prevention statistics show that Black people are 3.9 times more likely to have CHB and 2.5 times more likely to die from it than White people, notes H. Nina Kim, MD, with the department of medicine, University of Washington, Seattle, in an accompanying invited commentary.

“The fact that we have not observed racial disparities in treatment initiation does not mean none exist; it means we have to look harder to find them,” she writes.

“We need to examine whether our guidelines for HBV treatment are so complex that it becomes the purview of specialists, thereby restricting access and deepening inequities,” Dr. Kim adds. “We should look closely at retention in care, the step that precedes treatment, and stratify this outcome by race and ethnicity.”

Primary care physicians in some regions might find it difficult to manage patients who have hepatitis B because they see so few of them, Dr. Lok noted.

Dr. Khalili has received grants and consulting fees from Gilead Sciences Inc and grants from Intercept Pharmaceuticals outside the submitted work. Dr. Lok has received grants from Target and consultant fees from Abbott, Ambys, Arbutus, Chroma, Clear B, Enanta, Enochian, GNI, GlaxoSmithKline, Eli Lilly, and Virion outside the submitted work. Coauthors have received grants, consulting fees, or personal fees from Bayer, Boston Scientific, Exact Sciences, Fujifilm Medical Sciences, Gilead Sciences, Glycotest, Redhill Biopharma, Target RWE, MedEd Design, Pontifax, Global Life, the Lynx Group, AstraZeneca, Eisai, Novartis Venture Fund, Grail, QED Therapeutics, Genentech, Hepion Pharmaceuticals, Roche, Abbott, AbbVie, and Pfizer. Dr. Kim has received grants from Gilead Sciences (paid to her institution) outside the submitted work.

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

Researchers studying differences in treatment initiation for chronic hepatitis B (CHB) among a large, multiracial cohort in North America did not find evidence of disparities by race or socioeconomic status.

Instead, they observed a similar gap across races between the number of people eligible for treatment and those receiving it.

That gap suggests that treatment guidelines need to be simplified and that efforts to increase hepatitis B virus (HBV) awareness and train more clinicians are needed to achieve the World Health Organization’s goal of eliminating HBV by 2030, the researchers write.

The Hepatitis B Research Network study was published online in JAMA Network Open.

The prevalence of CHB in the United States is estimated at 2.4 million. It disproportionately affects persons of Asian or African descent, the investigators note. Their study examined whether treatment initiation and outcomes differ between African American and Black, Asian, and White participants, as well as between African American and Black participants born in North America and East or West Africa.

The research involved 1,550 adult patients: 1,157 Asian American, 193 African American or Black (39 born in the United States, 90 in East Africa, 53 in West Africa, and 11 elsewhere), 157 White, and 43 who identified as being of “other races.” All had CHB but were not receiving antiviral treatment at enrollment.

Participants came from 20 centers in the United States and one in Canada. They underwent clinical and laboratory assessments and could receive anti-HBV treatment after they enrolled. Enrollment was from Jan. 14, 2011, to Jan. 28, 2018. Participants were followed at 12 and 24 weeks and every 24 weeks thereafter in the longitudinal cohort study by Mandana Khalili, MD, division of gastroenterology and hepatology, University of California, San Francisco, and colleagues.

Information on patients’ country of birth, duration of U.S. or Canadian residency, educational level, employment, insurance, prior antiviral treatment, family history of HBV or hepatocellular carcinoma (HCC), and mode of transmission were collected by research coordinators.
 

Treatment initiation

During the study period, slightly fewer than one-third (32.5%) of the participants initiated treatment. The incidences were 4.8 per 100 person-years in African American or Black participants, 9.9 per 100 person-years in Asian participants, 6.6 per 100 person-years in White participants, and 7.9 per 100 person-years in those of other races (P < .001).

A lower percentage of African American and Black participants (14%) met the American Association for the Study of Liver Diseases treatment criteria, compared with Asian (22%) and White (27%) participants (P = .01).

When the researchers compared cumulative probability of initiating treatment by race for those who met criteria for treatment, they found no significant differences by race.

At 72 weeks, initiation probability was 0.45 for African American and Black patients and 0.51 for Asian and White patients (P = .68). Similarly, among African American and Black participants who met treatment criteria, there were no significant differences in cumulative probability of treatment by region of birth.

The cumulative percentage of treatment initiation for those who met guideline-based criteria was 62%.

“Among participants with a treatment indication, treatment rates did not differ significantly by race, despite marked differences in educational level, income, and type of health care insurance across the racial groups,” the researchers write. “Moreover, race was not an independent estimator of treatment initiation when adjusting for known factors associated with a higher risk of adverse clinical outcomes, namely, HBV DNA, disease severity, sex, and age.”

Adverse liver outcomes (hepatic decompensation, HCC, liver transplant, and death) were rare and did not vary significantly by race, the researchers write.

One study limitation is that participants were linked to specialty liver clinics, so the findings may not be generalizable to patients who receive care in other settings, the authors note.

The results are “reassuring,” said senior author Anna S. Lok, MD, division of gastroenterology and hepatology at University of Michigan in Ann Arbor. However, she noted, study participants had already overcome barriers to receiving care at major academic centers.

“Once you get into the big academic liver centers, then maybe everything is equal, but in the real world, a lot of people don’t ever get to the big liver centers,” she said. The question becomes: “Are we serving only a portion of the patient population?”

Many factors drive the decision to undergo treatment, including the doctor’s opinion as to need and the patient’s desire to receive treatment, she said.

The study participants who were more likely to get treated were those with higher-level disease who had a stronger indication for treatment, Dr. Lok said.
 

Finding the disparities

Centers for Disease Control and Prevention statistics show that Black people are 3.9 times more likely to have CHB and 2.5 times more likely to die from it than White people, notes H. Nina Kim, MD, with the department of medicine, University of Washington, Seattle, in an accompanying invited commentary.

“The fact that we have not observed racial disparities in treatment initiation does not mean none exist; it means we have to look harder to find them,” she writes.

“We need to examine whether our guidelines for HBV treatment are so complex that it becomes the purview of specialists, thereby restricting access and deepening inequities,” Dr. Kim adds. “We should look closely at retention in care, the step that precedes treatment, and stratify this outcome by race and ethnicity.”

Primary care physicians in some regions might find it difficult to manage patients who have hepatitis B because they see so few of them, Dr. Lok noted.

Dr. Khalili has received grants and consulting fees from Gilead Sciences Inc and grants from Intercept Pharmaceuticals outside the submitted work. Dr. Lok has received grants from Target and consultant fees from Abbott, Ambys, Arbutus, Chroma, Clear B, Enanta, Enochian, GNI, GlaxoSmithKline, Eli Lilly, and Virion outside the submitted work. Coauthors have received grants, consulting fees, or personal fees from Bayer, Boston Scientific, Exact Sciences, Fujifilm Medical Sciences, Gilead Sciences, Glycotest, Redhill Biopharma, Target RWE, MedEd Design, Pontifax, Global Life, the Lynx Group, AstraZeneca, Eisai, Novartis Venture Fund, Grail, QED Therapeutics, Genentech, Hepion Pharmaceuticals, Roche, Abbott, AbbVie, and Pfizer. Dr. Kim has received grants from Gilead Sciences (paid to her institution) outside the submitted work.

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

Hepatocellular carcinoma (HCC) is relatively common among patients with alcohol-associated cirrhosis, reaching a cumulative incidence of 9% at the 10-year mark, shows a large pooled analysis.

Incidence rates were higher for cohorts that underwent HCC surveillance versus those that did not undergo surveillance, suggesting that such programs offer significant benefit, lead author Daniel Q. Huang, MBBS, of the University of California, San Diego, and colleagues reported.

National University of Singapore

“A systematic review of the incidence of HCC among patients with alcohol-associated cirrhosis has not been reported,” the investigators wrote in Clinical Gastroenterology and Hepatology, prompting the present research.

Previous studies have described a broad range of annual incidence findings for HCC in this population, from 0.6% to 5.6%, suggesting that a systematic approach was needed.

To this end, Dr. Huang and colleagues analyzed data from 18 studies that involved 148,333 patients with alcohol-associated cirrhosis. The primary analysis aimed to determine cumulative incidence rates over time, while the secondary analysis characterized the impact of participation in HCC surveillance programs.

“This meta-analysis used reconstructed individual participant data, which is considered to be the gold standard for reporting survival data because it accounts for censoring of events,” the investigators noted. “The current study provides important data that are useful for clinical practice and clinical trial design.”

The cumulative incidence rates of HCC were 1%, 3%, and 9% at 1 year, 5 years, and 10 years, respectively. Among 12 of the risk factors studied, smoking, diabetes, and decompensation were all significantly associated with rate of HCC.

“Therefore, patients with alcohol-associated cirrhosis should be screened for diabetes to identify the patients at high risk for HCC development,” the investigators wrote. “In addition, patients with alcohol-associated cirrhosis should be advised to stop smoking, while patients with hepatic decompensation should be monitored carefully for the development of HCC if clinically appropriate.”

The secondary analysis showed that HCC incidence rates were higher among patients participating in HCC surveillance programs than those who did not participate (18.6 vs. 4.8 per 1,000 person-years; P = .001).

“Patients with alcohol-associated cirrhosis are known to have lower HCC surveillance rates, which may be related to poor disease awareness, clinic time constraints caused by other active medical issues, and provider beliefs regarding the likelihood of adherence,” the investigators noted.

Increased efforts are needed to promote surveillance in this population, they added, suggesting a range of communication pathways, including social media, traditional news outlets, and direct mailing.

Dr. Huang and colleagues also suggested that the findings should be validated in large prospective studies.

The study was funded by the National Institute on Alcohol Abuse and Alcoholism, the National Institute of Environmental Health Sciences, the National Center for Advancing Translational Sciences, and others. Dr. Huang disclosed funding from the Singapore Ministry of Health’s National Medical Research Council.

Hepatocellular carcinoma (HCC) is relatively common among patients with alcohol-associated cirrhosis, reaching a cumulative incidence of 9% at the 10-year mark, shows a large pooled analysis.

Incidence rates were higher for cohorts that underwent HCC surveillance versus those that did not undergo surveillance, suggesting that such programs offer significant benefit, lead author Daniel Q. Huang, MBBS, of the University of California, San Diego, and colleagues reported.

National University of Singapore

“A systematic review of the incidence of HCC among patients with alcohol-associated cirrhosis has not been reported,” the investigators wrote in Clinical Gastroenterology and Hepatology, prompting the present research.

Previous studies have described a broad range of annual incidence findings for HCC in this population, from 0.6% to 5.6%, suggesting that a systematic approach was needed.

To this end, Dr. Huang and colleagues analyzed data from 18 studies that involved 148,333 patients with alcohol-associated cirrhosis. The primary analysis aimed to determine cumulative incidence rates over time, while the secondary analysis characterized the impact of participation in HCC surveillance programs.

“This meta-analysis used reconstructed individual participant data, which is considered to be the gold standard for reporting survival data because it accounts for censoring of events,” the investigators noted. “The current study provides important data that are useful for clinical practice and clinical trial design.”

The cumulative incidence rates of HCC were 1%, 3%, and 9% at 1 year, 5 years, and 10 years, respectively. Among 12 of the risk factors studied, smoking, diabetes, and decompensation were all significantly associated with rate of HCC.

“Therefore, patients with alcohol-associated cirrhosis should be screened for diabetes to identify the patients at high risk for HCC development,” the investigators wrote. “In addition, patients with alcohol-associated cirrhosis should be advised to stop smoking, while patients with hepatic decompensation should be monitored carefully for the development of HCC if clinically appropriate.”

The secondary analysis showed that HCC incidence rates were higher among patients participating in HCC surveillance programs than those who did not participate (18.6 vs. 4.8 per 1,000 person-years; P = .001).

“Patients with alcohol-associated cirrhosis are known to have lower HCC surveillance rates, which may be related to poor disease awareness, clinic time constraints caused by other active medical issues, and provider beliefs regarding the likelihood of adherence,” the investigators noted.

Increased efforts are needed to promote surveillance in this population, they added, suggesting a range of communication pathways, including social media, traditional news outlets, and direct mailing.

Dr. Huang and colleagues also suggested that the findings should be validated in large prospective studies.

The study was funded by the National Institute on Alcohol Abuse and Alcoholism, the National Institute of Environmental Health Sciences, the National Center for Advancing Translational Sciences, and others. Dr. Huang disclosed funding from the Singapore Ministry of Health’s National Medical Research Council.

Hepatocellular carcinoma (HCC) is relatively common among patients with alcohol-associated cirrhosis, reaching a cumulative incidence of 9% at the 10-year mark, shows a large pooled analysis.

Incidence rates were higher for cohorts that underwent HCC surveillance versus those that did not undergo surveillance, suggesting that such programs offer significant benefit, lead author Daniel Q. Huang, MBBS, of the University of California, San Diego, and colleagues reported.

National University of Singapore

“A systematic review of the incidence of HCC among patients with alcohol-associated cirrhosis has not been reported,” the investigators wrote in Clinical Gastroenterology and Hepatology, prompting the present research.

Previous studies have described a broad range of annual incidence findings for HCC in this population, from 0.6% to 5.6%, suggesting that a systematic approach was needed.

To this end, Dr. Huang and colleagues analyzed data from 18 studies that involved 148,333 patients with alcohol-associated cirrhosis. The primary analysis aimed to determine cumulative incidence rates over time, while the secondary analysis characterized the impact of participation in HCC surveillance programs.

“This meta-analysis used reconstructed individual participant data, which is considered to be the gold standard for reporting survival data because it accounts for censoring of events,” the investigators noted. “The current study provides important data that are useful for clinical practice and clinical trial design.”

The cumulative incidence rates of HCC were 1%, 3%, and 9% at 1 year, 5 years, and 10 years, respectively. Among 12 of the risk factors studied, smoking, diabetes, and decompensation were all significantly associated with rate of HCC.

“Therefore, patients with alcohol-associated cirrhosis should be screened for diabetes to identify the patients at high risk for HCC development,” the investigators wrote. “In addition, patients with alcohol-associated cirrhosis should be advised to stop smoking, while patients with hepatic decompensation should be monitored carefully for the development of HCC if clinically appropriate.”

The secondary analysis showed that HCC incidence rates were higher among patients participating in HCC surveillance programs than those who did not participate (18.6 vs. 4.8 per 1,000 person-years; P = .001).

“Patients with alcohol-associated cirrhosis are known to have lower HCC surveillance rates, which may be related to poor disease awareness, clinic time constraints caused by other active medical issues, and provider beliefs regarding the likelihood of adherence,” the investigators noted.

Increased efforts are needed to promote surveillance in this population, they added, suggesting a range of communication pathways, including social media, traditional news outlets, and direct mailing.

Dr. Huang and colleagues also suggested that the findings should be validated in large prospective studies.

The study was funded by the National Institute on Alcohol Abuse and Alcoholism, the National Institute of Environmental Health Sciences, the National Center for Advancing Translational Sciences, and others. Dr. Huang disclosed funding from the Singapore Ministry of Health’s National Medical Research Council.

Antibiotic pretreatment may protect against liver ischemia/reperfusion (I/R) injury through altered gut microbiota, glutamine levels, and glutamine downstream products in circulation, according to a recent study in Cellular and Molecular Gastroenterology and Hepatology.

The findings show that gut microbiota and their metabolites play critical roles in hepatic I/R injury by modulating macrophage metabolic reprogramming, wrote Tianfei Lu, with the Abdominal Transplant Surgery Center at Ruijin Hospital and Shanghai Jiao Tong University, China, and colleagues.

“Potential therapies that target macrophage metabolism, including antibiotic therapies and novel immunometabolism modulators, can be exploited for the treatment of liver I/R injury,” the authors wrote.

Liver I/R injury is a common complication of liver resection, transplantation, trauma, and hemorrhagic shock. Previous studies have noted the important role of gut microbiota in liver disease progression, yet the mechanisms in liver I/R injury remain unknown.

The researchers pretreated mice with an antibiotic cocktail to modify the gut microbiome. They found that the pretreatment showed protective effects against hepatic I/R injury, with reductions in serum alanine aminotransferase (ALT), interleukin-1 beta, tumor necrosis factor–alpha, IL-6, IL-12b, and CXCL10.

Through histologic analysis of liver tissues, they also found that the area of necrosis, the degree of congestion and edema, and the presence of vacuole-like lesions were alleviated in the preconditioned mice. Inflammation and necrosis of the liver were also lower, according to both qualitative and quantitative data.

Then, through fecal microbiota transplantation into germ-free mice, they found that the protection from I/R injury was transferable. This finding indicated that the altered gut microbiome, rather than the antibiotic treatment itself, exerted the protective effect.

Because altered gut microbiota can cause changes in metabolites, the researchers used ultra-performance liquid chromatography coupled to tandem mass spectrometry to explore the changes of gut microbiota and metabolites in both feces and portal blood, as well as analyze the mechanisms underlying their protective effects in liver I/R injury.

The researchers found that glutamine and its downstream product called alpha-ketoglutarate (AKG) were present in higher concentrations in feces and blood in the mice with antibiotic pretreatment. Glutamate levels were significantly lower, indicating that glutamine is converted into AKG through glutamate after entering the blood.

In addition, there were increased levels of intermediate products of the tricarboxylic acid (TCA) cycle, as well as pyruvate produced by glycolysis. That led to an increase in M2 macrophages, which are responsible for anti-inflammatory processes and tissue repair.

The authors concluded that elevated glutamine levels in the intestine cause an increase in AKG levels in the blood, and AKG can promote M2 macrophage polarization by fueling the TCA cycle. In turn, the increased number of M2 macrophages can repair hepatic I/R injury.

Finally, the researchers tested oligomycin A, which can block the OXPHOS metabolic pathway and inhibit the mitochondrial ATP synthase. As expected, they wrote, the protective effect of antibiotic pretreatment reversed, M2 macrophages decreased, and serum ALT levels increased.

“The immunometabolism and polarization of macrophages play an important role in host homeostasis and the development of various diseases,” the authors wrote. “The relationship between antibiotics treatment, altered gut microbiota, and liver I/R injury are complex and worthy of further study.”

The study was supported by the China National Science and Technology Major Project, National Natural Science Foundation of China, and Natural Science Foundation exploration project of Zhejiang Province. The authors disclosed no conflicts.

Antibiotic pretreatment may protect against liver ischemia/reperfusion (I/R) injury through altered gut microbiota, glutamine levels, and glutamine downstream products in circulation, according to a recent study in Cellular and Molecular Gastroenterology and Hepatology.

The findings show that gut microbiota and their metabolites play critical roles in hepatic I/R injury by modulating macrophage metabolic reprogramming, wrote Tianfei Lu, with the Abdominal Transplant Surgery Center at Ruijin Hospital and Shanghai Jiao Tong University, China, and colleagues.

“Potential therapies that target macrophage metabolism, including antibiotic therapies and novel immunometabolism modulators, can be exploited for the treatment of liver I/R injury,” the authors wrote.

Liver I/R injury is a common complication of liver resection, transplantation, trauma, and hemorrhagic shock. Previous studies have noted the important role of gut microbiota in liver disease progression, yet the mechanisms in liver I/R injury remain unknown.

The researchers pretreated mice with an antibiotic cocktail to modify the gut microbiome. They found that the pretreatment showed protective effects against hepatic I/R injury, with reductions in serum alanine aminotransferase (ALT), interleukin-1 beta, tumor necrosis factor–alpha, IL-6, IL-12b, and CXCL10.

Through histologic analysis of liver tissues, they also found that the area of necrosis, the degree of congestion and edema, and the presence of vacuole-like lesions were alleviated in the preconditioned mice. Inflammation and necrosis of the liver were also lower, according to both qualitative and quantitative data.

Then, through fecal microbiota transplantation into germ-free mice, they found that the protection from I/R injury was transferable. This finding indicated that the altered gut microbiome, rather than the antibiotic treatment itself, exerted the protective effect.

Because altered gut microbiota can cause changes in metabolites, the researchers used ultra-performance liquid chromatography coupled to tandem mass spectrometry to explore the changes of gut microbiota and metabolites in both feces and portal blood, as well as analyze the mechanisms underlying their protective effects in liver I/R injury.

The researchers found that glutamine and its downstream product called alpha-ketoglutarate (AKG) were present in higher concentrations in feces and blood in the mice with antibiotic pretreatment. Glutamate levels were significantly lower, indicating that glutamine is converted into AKG through glutamate after entering the blood.

In addition, there were increased levels of intermediate products of the tricarboxylic acid (TCA) cycle, as well as pyruvate produced by glycolysis. That led to an increase in M2 macrophages, which are responsible for anti-inflammatory processes and tissue repair.

The authors concluded that elevated glutamine levels in the intestine cause an increase in AKG levels in the blood, and AKG can promote M2 macrophage polarization by fueling the TCA cycle. In turn, the increased number of M2 macrophages can repair hepatic I/R injury.

Finally, the researchers tested oligomycin A, which can block the OXPHOS metabolic pathway and inhibit the mitochondrial ATP synthase. As expected, they wrote, the protective effect of antibiotic pretreatment reversed, M2 macrophages decreased, and serum ALT levels increased.

“The immunometabolism and polarization of macrophages play an important role in host homeostasis and the development of various diseases,” the authors wrote. “The relationship between antibiotics treatment, altered gut microbiota, and liver I/R injury are complex and worthy of further study.”

The study was supported by the China National Science and Technology Major Project, National Natural Science Foundation of China, and Natural Science Foundation exploration project of Zhejiang Province. The authors disclosed no conflicts.

Antibiotic pretreatment may protect against liver ischemia/reperfusion (I/R) injury through altered gut microbiota, glutamine levels, and glutamine downstream products in circulation, according to a recent study in Cellular and Molecular Gastroenterology and Hepatology.

The findings show that gut microbiota and their metabolites play critical roles in hepatic I/R injury by modulating macrophage metabolic reprogramming, wrote Tianfei Lu, with the Abdominal Transplant Surgery Center at Ruijin Hospital and Shanghai Jiao Tong University, China, and colleagues.

“Potential therapies that target macrophage metabolism, including antibiotic therapies and novel immunometabolism modulators, can be exploited for the treatment of liver I/R injury,” the authors wrote.

Liver I/R injury is a common complication of liver resection, transplantation, trauma, and hemorrhagic shock. Previous studies have noted the important role of gut microbiota in liver disease progression, yet the mechanisms in liver I/R injury remain unknown.

The researchers pretreated mice with an antibiotic cocktail to modify the gut microbiome. They found that the pretreatment showed protective effects against hepatic I/R injury, with reductions in serum alanine aminotransferase (ALT), interleukin-1 beta, tumor necrosis factor–alpha, IL-6, IL-12b, and CXCL10.

Through histologic analysis of liver tissues, they also found that the area of necrosis, the degree of congestion and edema, and the presence of vacuole-like lesions were alleviated in the preconditioned mice. Inflammation and necrosis of the liver were also lower, according to both qualitative and quantitative data.

Then, through fecal microbiota transplantation into germ-free mice, they found that the protection from I/R injury was transferable. This finding indicated that the altered gut microbiome, rather than the antibiotic treatment itself, exerted the protective effect.

Because altered gut microbiota can cause changes in metabolites, the researchers used ultra-performance liquid chromatography coupled to tandem mass spectrometry to explore the changes of gut microbiota and metabolites in both feces and portal blood, as well as analyze the mechanisms underlying their protective effects in liver I/R injury.

The researchers found that glutamine and its downstream product called alpha-ketoglutarate (AKG) were present in higher concentrations in feces and blood in the mice with antibiotic pretreatment. Glutamate levels were significantly lower, indicating that glutamine is converted into AKG through glutamate after entering the blood.

In addition, there were increased levels of intermediate products of the tricarboxylic acid (TCA) cycle, as well as pyruvate produced by glycolysis. That led to an increase in M2 macrophages, which are responsible for anti-inflammatory processes and tissue repair.

The authors concluded that elevated glutamine levels in the intestine cause an increase in AKG levels in the blood, and AKG can promote M2 macrophage polarization by fueling the TCA cycle. In turn, the increased number of M2 macrophages can repair hepatic I/R injury.

Finally, the researchers tested oligomycin A, which can block the OXPHOS metabolic pathway and inhibit the mitochondrial ATP synthase. As expected, they wrote, the protective effect of antibiotic pretreatment reversed, M2 macrophages decreased, and serum ALT levels increased.

“The immunometabolism and polarization of macrophages play an important role in host homeostasis and the development of various diseases,” the authors wrote. “The relationship between antibiotics treatment, altered gut microbiota, and liver I/R injury are complex and worthy of further study.”

The study was supported by the China National Science and Technology Major Project, National Natural Science Foundation of China, and Natural Science Foundation exploration project of Zhejiang Province. The authors disclosed no conflicts.

Adding time-restricted eating to a calorie-restricted diet did not provide added benefits in adults with obesity and nonalcoholic fatty liver disease (NAFLD), according to the results of a randomized controlled trial conducted in China.

With the same calorie restrictions, an 8-hour time-restricted eating (TRE) pattern was no more effective in lowering intrahepatic triglyceride content or achieving resolution of NAFLD than daily calorie restriction (DCR) without time constraints (habitual meal timing).

TRE also did not provide additional benefits over DCR for reducing body fat or metabolic risk factors.

Calorie intake restriction seems to explain most of the beneficial effects of TRE and supports the importance of calorie restriction in a TRE regimen in adults with obesity and NAFLD, say the investigators, led by Xueyun Wei, MD, with Southern Medical University, Guangzhou (China).

The study “supports some other recent data that kind of disproves that intermittent fasting actually works that well and that it basically comes down to calorie restriction,” said Lisa Ganjhu, DO, who wasn’t involved in the research.

“It doesn’t matter when you are calorie restricting; it’s just that you are restricting calories to a certain amount. We know that works,” Dr. Ganjhu, a clinical associate professor in the division of gastroenterology and hepatology at NYU Grossman School of Medicine, told this news organization.

Results of the TREATY-FLD study were published online  in JAMA Network Open.
 

Calorie reduction is key

NAFLD has become a major worldwide public health challenge, affecting roughly 20%-30% of adults in the general population and more than 70% of adults with obesity and diabetes.

Weight loss through lifestyle modifications has been shown to improve liver fat and metabolic disorders. TRE, a type of intermittent fasting, has garnered attention as a potential alternative to DCR for weight loss. “However, most of the reported benefits of TRE are either ‘untested or under tested’ and can’t isolate the effects of TRE itself,” Dr. Wei and colleagues note.

In the TREATY-FLD study, 88 adults (mean age, 32 years; 56% male) with obesity and NAFLD and similar baseline characteristics were randomly allocated to a TRE or DCR group.

All participants were instructed to maintain a diet of 1,500-1,800 kcal per day for men and 1,200-1,500 kcal per day for women for 12 months. The diets consisted of 40%-55% carbohydrate, 15%-20% protein, and 20%-30% fat. Participants were also given one protein shake per day for the first 6 months and received dietary counseling throughout the study.

Participants in the TRE group were told to eat only between 8 AM and 4 PM each day. Only noncaloric beverages were permitted outside of the daily eating window. Participants in the DCR group had no restrictions on when they could eat.

Investigators found no significant between-group differences in change in MRI-measured IHTG content from baseline to 6 or 12 months (the primary outcome).

At 6 months, IHTG content was reduced by 8.3% in the TRE group and by 8.1% in the DRC group. At 12 months, IHTG content was reduced by 6.9% and 7.9%, respectively. The net change in IHTG content was not significantly different between the groups at 6 months (percentage point difference: −0.2; P = .86) or 12 months (percentage point difference: 1; P = .45)

Liver stiffness was reduced by 2.1 kPa in the TRE group and 1.7 kPa in the DCR group at 12 months, with no significant difference between the groups (P = .33). A percentage of participants in the TRE and DCR groups had resolution of NAFLD (defined as IHTG content less than 5%) at 12 months (33% vs. 49%; P = .31).

During the 12-month intervention, body weight was significantly reduced by 8.4 kg in the TRE group and 7.8 kg in the DCR group, with no significant between-group differences (P = .69).

In addition, waist circumference, body fat percentage, fat mass, lean mass, total abdominal fat, subcutaneous fat, visceral fat, and visceral to subcutaneous fat ratio were all significantly and comparably reduced in the two groups.

Both groups also saw significant and comparable improvement over 12 months in metabolic risk factors, including systolic and diastolic blood pressure, pulse rate, and total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol levels.

However, TRE might be more effective in improving insulin sensitivity than DCR. Both diets significantly reduced fasting plasma glucose level, hemoglobin A1c, and homeostasis model assessment of insulin resistance (HOMA-IR) at 6 months. TRE significantly reduced HOMA-IR, compared with DCR at 12 months.

Both diets significantly reduced levels of liver enzymes, including serum alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase, with no significant between-group differences.
 

Eat less, exercise more

Although the study found no additional benefit from TRE, it’s still good advice to skip snacking in the evening, Dr. Ganjhu said in an interview. “No one snacks on anything healthy at night. I mean, who’s chewing on celery?” she added.

Eating late at night can trigger reflux, so “not eating anything for several hours before bed or better yet going for a walk after dinner to kickstart your metabolism is good advice,” Dr. Ganjhu said.

For obesity and fatty liver disease, it really comes down to diet and exercise, she noted.

“For all the money that is going into pharmaceuticals, the long and the short of it is you just have to eat less and work out more and manage all the other factors like diabetes, high blood pressure, and metabolic syndrome. But getting people to follow that is tough,” Dr. Ganjhu said.

The study was supported by grants from the National Key Research and Development Project, Joint Funds of the National Natural Science Foundation of China, and Key-Area Clinical Research Program of Southern Medical University. Dr. Wei and Dr. Ganjhu report no relevant financial relationships.

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

Adding time-restricted eating to a calorie-restricted diet did not provide added benefits in adults with obesity and nonalcoholic fatty liver disease (NAFLD), according to the results of a randomized controlled trial conducted in China.

With the same calorie restrictions, an 8-hour time-restricted eating (TRE) pattern was no more effective in lowering intrahepatic triglyceride content or achieving resolution of NAFLD than daily calorie restriction (DCR) without time constraints (habitual meal timing).

TRE also did not provide additional benefits over DCR for reducing body fat or metabolic risk factors.

Calorie intake restriction seems to explain most of the beneficial effects of TRE and supports the importance of calorie restriction in a TRE regimen in adults with obesity and NAFLD, say the investigators, led by Xueyun Wei, MD, with Southern Medical University, Guangzhou (China).

The study “supports some other recent data that kind of disproves that intermittent fasting actually works that well and that it basically comes down to calorie restriction,” said Lisa Ganjhu, DO, who wasn’t involved in the research.

“It doesn’t matter when you are calorie restricting; it’s just that you are restricting calories to a certain amount. We know that works,” Dr. Ganjhu, a clinical associate professor in the division of gastroenterology and hepatology at NYU Grossman School of Medicine, told this news organization.

Results of the TREATY-FLD study were published online  in JAMA Network Open.
 

Calorie reduction is key

NAFLD has become a major worldwide public health challenge, affecting roughly 20%-30% of adults in the general population and more than 70% of adults with obesity and diabetes.

Weight loss through lifestyle modifications has been shown to improve liver fat and metabolic disorders. TRE, a type of intermittent fasting, has garnered attention as a potential alternative to DCR for weight loss. “However, most of the reported benefits of TRE are either ‘untested or under tested’ and can’t isolate the effects of TRE itself,” Dr. Wei and colleagues note.

In the TREATY-FLD study, 88 adults (mean age, 32 years; 56% male) with obesity and NAFLD and similar baseline characteristics were randomly allocated to a TRE or DCR group.

All participants were instructed to maintain a diet of 1,500-1,800 kcal per day for men and 1,200-1,500 kcal per day for women for 12 months. The diets consisted of 40%-55% carbohydrate, 15%-20% protein, and 20%-30% fat. Participants were also given one protein shake per day for the first 6 months and received dietary counseling throughout the study.

Participants in the TRE group were told to eat only between 8 AM and 4 PM each day. Only noncaloric beverages were permitted outside of the daily eating window. Participants in the DCR group had no restrictions on when they could eat.

Investigators found no significant between-group differences in change in MRI-measured IHTG content from baseline to 6 or 12 months (the primary outcome).

At 6 months, IHTG content was reduced by 8.3% in the TRE group and by 8.1% in the DRC group. At 12 months, IHTG content was reduced by 6.9% and 7.9%, respectively. The net change in IHTG content was not significantly different between the groups at 6 months (percentage point difference: −0.2; P = .86) or 12 months (percentage point difference: 1; P = .45)

Liver stiffness was reduced by 2.1 kPa in the TRE group and 1.7 kPa in the DCR group at 12 months, with no significant difference between the groups (P = .33). A percentage of participants in the TRE and DCR groups had resolution of NAFLD (defined as IHTG content less than 5%) at 12 months (33% vs. 49%; P = .31).

During the 12-month intervention, body weight was significantly reduced by 8.4 kg in the TRE group and 7.8 kg in the DCR group, with no significant between-group differences (P = .69).

In addition, waist circumference, body fat percentage, fat mass, lean mass, total abdominal fat, subcutaneous fat, visceral fat, and visceral to subcutaneous fat ratio were all significantly and comparably reduced in the two groups.

Both groups also saw significant and comparable improvement over 12 months in metabolic risk factors, including systolic and diastolic blood pressure, pulse rate, and total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol levels.

However, TRE might be more effective in improving insulin sensitivity than DCR. Both diets significantly reduced fasting plasma glucose level, hemoglobin A1c, and homeostasis model assessment of insulin resistance (HOMA-IR) at 6 months. TRE significantly reduced HOMA-IR, compared with DCR at 12 months.

Both diets significantly reduced levels of liver enzymes, including serum alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase, with no significant between-group differences.
 

Eat less, exercise more

Although the study found no additional benefit from TRE, it’s still good advice to skip snacking in the evening, Dr. Ganjhu said in an interview. “No one snacks on anything healthy at night. I mean, who’s chewing on celery?” she added.

Eating late at night can trigger reflux, so “not eating anything for several hours before bed or better yet going for a walk after dinner to kickstart your metabolism is good advice,” Dr. Ganjhu said.

For obesity and fatty liver disease, it really comes down to diet and exercise, she noted.

“For all the money that is going into pharmaceuticals, the long and the short of it is you just have to eat less and work out more and manage all the other factors like diabetes, high blood pressure, and metabolic syndrome. But getting people to follow that is tough,” Dr. Ganjhu said.

The study was supported by grants from the National Key Research and Development Project, Joint Funds of the National Natural Science Foundation of China, and Key-Area Clinical Research Program of Southern Medical University. Dr. Wei and Dr. Ganjhu report no relevant financial relationships.

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

Adding time-restricted eating to a calorie-restricted diet did not provide added benefits in adults with obesity and nonalcoholic fatty liver disease (NAFLD), according to the results of a randomized controlled trial conducted in China.

With the same calorie restrictions, an 8-hour time-restricted eating (TRE) pattern was no more effective in lowering intrahepatic triglyceride content or achieving resolution of NAFLD than daily calorie restriction (DCR) without time constraints (habitual meal timing).

TRE also did not provide additional benefits over DCR for reducing body fat or metabolic risk factors.

Calorie intake restriction seems to explain most of the beneficial effects of TRE and supports the importance of calorie restriction in a TRE regimen in adults with obesity and NAFLD, say the investigators, led by Xueyun Wei, MD, with Southern Medical University, Guangzhou (China).

The study “supports some other recent data that kind of disproves that intermittent fasting actually works that well and that it basically comes down to calorie restriction,” said Lisa Ganjhu, DO, who wasn’t involved in the research.

“It doesn’t matter when you are calorie restricting; it’s just that you are restricting calories to a certain amount. We know that works,” Dr. Ganjhu, a clinical associate professor in the division of gastroenterology and hepatology at NYU Grossman School of Medicine, told this news organization.

Results of the TREATY-FLD study were published online  in JAMA Network Open.
 

Calorie reduction is key

NAFLD has become a major worldwide public health challenge, affecting roughly 20%-30% of adults in the general population and more than 70% of adults with obesity and diabetes.

Weight loss through lifestyle modifications has been shown to improve liver fat and metabolic disorders. TRE, a type of intermittent fasting, has garnered attention as a potential alternative to DCR for weight loss. “However, most of the reported benefits of TRE are either ‘untested or under tested’ and can’t isolate the effects of TRE itself,” Dr. Wei and colleagues note.

In the TREATY-FLD study, 88 adults (mean age, 32 years; 56% male) with obesity and NAFLD and similar baseline characteristics were randomly allocated to a TRE or DCR group.

All participants were instructed to maintain a diet of 1,500-1,800 kcal per day for men and 1,200-1,500 kcal per day for women for 12 months. The diets consisted of 40%-55% carbohydrate, 15%-20% protein, and 20%-30% fat. Participants were also given one protein shake per day for the first 6 months and received dietary counseling throughout the study.

Participants in the TRE group were told to eat only between 8 AM and 4 PM each day. Only noncaloric beverages were permitted outside of the daily eating window. Participants in the DCR group had no restrictions on when they could eat.

Investigators found no significant between-group differences in change in MRI-measured IHTG content from baseline to 6 or 12 months (the primary outcome).

At 6 months, IHTG content was reduced by 8.3% in the TRE group and by 8.1% in the DRC group. At 12 months, IHTG content was reduced by 6.9% and 7.9%, respectively. The net change in IHTG content was not significantly different between the groups at 6 months (percentage point difference: −0.2; P = .86) or 12 months (percentage point difference: 1; P = .45)

Liver stiffness was reduced by 2.1 kPa in the TRE group and 1.7 kPa in the DCR group at 12 months, with no significant difference between the groups (P = .33). A percentage of participants in the TRE and DCR groups had resolution of NAFLD (defined as IHTG content less than 5%) at 12 months (33% vs. 49%; P = .31).

During the 12-month intervention, body weight was significantly reduced by 8.4 kg in the TRE group and 7.8 kg in the DCR group, with no significant between-group differences (P = .69).

In addition, waist circumference, body fat percentage, fat mass, lean mass, total abdominal fat, subcutaneous fat, visceral fat, and visceral to subcutaneous fat ratio were all significantly and comparably reduced in the two groups.

Both groups also saw significant and comparable improvement over 12 months in metabolic risk factors, including systolic and diastolic blood pressure, pulse rate, and total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol levels.

However, TRE might be more effective in improving insulin sensitivity than DCR. Both diets significantly reduced fasting plasma glucose level, hemoglobin A1c, and homeostasis model assessment of insulin resistance (HOMA-IR) at 6 months. TRE significantly reduced HOMA-IR, compared with DCR at 12 months.

Both diets significantly reduced levels of liver enzymes, including serum alanine aminotransferase, aspartate aminotransferase, and gamma-glutamyl transferase, with no significant between-group differences.
 

Eat less, exercise more

Although the study found no additional benefit from TRE, it’s still good advice to skip snacking in the evening, Dr. Ganjhu said in an interview. “No one snacks on anything healthy at night. I mean, who’s chewing on celery?” she added.

Eating late at night can trigger reflux, so “not eating anything for several hours before bed or better yet going for a walk after dinner to kickstart your metabolism is good advice,” Dr. Ganjhu said.

For obesity and fatty liver disease, it really comes down to diet and exercise, she noted.

“For all the money that is going into pharmaceuticals, the long and the short of it is you just have to eat less and work out more and manage all the other factors like diabetes, high blood pressure, and metabolic syndrome. But getting people to follow that is tough,” Dr. Ganjhu said.

The study was supported by grants from the National Key Research and Development Project, Joint Funds of the National Natural Science Foundation of China, and Key-Area Clinical Research Program of Southern Medical University. Dr. Wei and Dr. Ganjhu report no relevant financial relationships.

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

Semaglutide didn’t significantly improve liver fibrosis or achieve resolution of nonalcoholic steatohepatitis (NASH)–related compensated cirrhosis, compared with placebo, according to a phase 2 trial.

However, the glucagonlike peptide–1 (GLP-1) receptor agonist led to improvements in liver enzymes, liver steatosis, weight, triglycerides, and very low-density lipoprotein (VLDL) cholesterol. Similar proportions of patients in each group reported adverse events, such as nausea, diarrhea, and vomiting.

“Previous studies in patients with NASH and stage 2 or 3 fibrosis have shown that semaglutide can improve NASH resolution over 72 weeks. However, there are limited data on whether any therapy is effective in patients with NASH cirrhosis,” lead author Rohit Loomba, MD, founding director of the NAFLD Research Center at the University of California, San Diego, said in an interview.

“Although semaglutide did not succeed in improving histological fibrosis, it had success in improving other clinically important parameters, such as cardiometabolic risk factors, liver enzymes, liver fat, and noninvasive biomarkers of fibrosis,” he said.

The study was published online  in The Lancet Gastroenterology & Hepatology.
 

Analyzing safety and efficacy

Dr. Loomba and colleagues conducted a double-blind, placebo-controlled phase 2 trial that enrolled 71 patients at 38 centers in the United States and Europe between June 2019 and April 2021. Adults with biopsy-confirmed NASH-related cirrhosis and a body mass index (BMI) of at least 27 kg/m² were randomly assigned 2:1 to receive either once-weekly subcutaneous semaglutide at 2.4 mg or a visually matching placebo.

Patients were randomly allocated through an interactive web system, which stratified participants on the basis of the presence or absence of type 2 diabetes. Patients, investigators, and outcomes analysts were masked to the treatment assignment.

The primary endpoint was the proportion of patients with an improvement in liver fibrosis of one stage or more without a worsening of NASH after 48 weeks, which was measured through biopsy in the intention-to-treat population. Safety was also assessed in all patients who received at least one dose of semaglutide.

Among the 71 patients, 47 were randomly assigned to the semaglutide group and 24 to the placebo group. About 90% completed treatment, and 63 had evaluable paired biopsies for primary endpoint assessment.

Between the groups, 49 participants (69%) were women and 22 were men. The average age was 59.5 years, and the average BMI was 34.9. About 75% of patients had diabetes at baseline, with an average hemoglobin A1c of 7.1%.

After 48 weeks, researchers found no statistically significant difference between the groups in the proportion of patients with an improvement in liver fibrosis of one stage or more without worsening of NASH. In the semaglutide group, five patients (11%) had an improvement, compared with seven patients (29%) in the placebo group (odds ratio, 0.28; 95% confidence interval, 0.06-1.24, P = .087).

There also wasn’t a significant difference between groups in the proportion of patients who achieved NASH resolution. In the semaglutide group, 16 patients (34%) had resolution, compared with 5 patients (21%) in the placebo group (OR, 1.97; 95% CI, 0.56-7.91; P = .29).

In addition, a lower proportion of patients achieved both NASH resolution and improvement in liver fibrosis with semaglutide versus placebo, although the difference wasn’t significant. In the semaglutide group, three patients (6%) achieved both, compared with three patients (13%) in the placebo group (OR, 0.48; 95% CI, 0.06-3.91; P = .4). A lower proportion of patients had an improvement in liver fibrosis stage with semaglutide versus placebo.
 

Some improvements seen

However, the semaglutide group had significantly greater improvements in liver steatosis (but not stiffness), liver fat volume, procollagen 3 peptide, and liver enzymes such as ALT, AST, and gamma-glutamyltransferase.

Body weight decreased by 8.83% in the semaglutide group, compared with 0.09% in the placebo group, which was a significant difference. BMI, waist circumference, triglycerides, and VLDL cholesterol were also significantly lower in the semaglutide group, but total cholesterol and blood pressure measurements weren’t significantly different. Among those with type 2 diabetes, A1c also decreased in the semaglutide group but did not in the placebo group.

Similar proportions of patients in each group reported adverse events. In the semaglutide group, 42 patients (89%) had an adverse event, compared with 19 patients (79%) in the placebo group. In addition, six patients (13%) in the semaglutide group and two patients (8%) in the placebo group reported serious adverse events.

The most common adverse events in the semaglutide and placebo groups were nausea (45% and 17%), diarrhea (19% and 8%), and vomiting (17% and none), which mainly occurred during treatment initiation or dose escalation. No patients withdrew from the trial because of adverse events, although five had a dose reduction. Hepatic and renal function remained stable after semaglutide treatment, and there were no decompensating events or deaths.

“GLP-1 analogue exposure – among patients with compensated cirrhosis who suffer from morbid obesity and type 2 diabetes – for the treatment of diabetes appears to be well-tolerated and may be safe,” Dr. Loomba said. “Further studies are needed in this study population.”
 

Considering next steps

Dr. Loomba and colleagues are continuing research around risk factors linked to advanced fibrosis, such as type 2 diabetes, a family history of cirrhosis, and the presence of key genetic risk alleles. Gut dysbiosis also appears to increase the risk for advanced fatty liver disease, he said.

Future clinical trials could focus on therapeutic options for patients with advanced fibrosis, particularly those with cirrhosis who face increased risks for liver-related complications and mortality.

“As these patients are oftentimes excluded from initial randomized controlled trials, we have significantly less information on how to address obesity, type 2 diabetes, and NASH in these patients,” Fernando Bril, MD, a physician-scientist focused on NASH-related research at the University of Alabama at Birmingham, said in an interview.

Dr. Bril, who wasn’t involved with this study, wrote an accompanying editorial in The Lancet Gastroenterology & Hepatology.

Patients with NASH-related cirrhosis may have progressed to a point of the disease where fibrosis regression may be more difficult to achieve, he said.

“This emphasizes that early diagnosis of patients with NASH is crucial,” he said.

“Therefore, primary care providers, endocrinologists, and diabetologists need to have a low threshold to suspect liver disease in patients with overweight, obesity, and/or type 2 diabetes. Only this will allow for early initiation of therapy, which may delay the progression of liver disease.”

In further research, investigators may want to consider the lack of NASH resolution, a result that could be caused by this study being underpowered, Dr. Bril noted. The trend in resolution in this study appeared similar to improvements seen in NASH patients without cirrhosis in other studies, he said. The weight reduction and improved diabetes control in this group also shows promise.

“While a purist may be adamant that this was a negative study for histological outcomes, it is essential to take note of the positive results in many secondary outcomes,” he said. “Improving cardiometabolic risk in these patients is essential because many still die of cardiovascular disease and not liver-related complications.”

At the same time, it’s important to note that NASH can’t be oversimplified as “a matter of weight,” Dr. Bril said. Significant weight loss in the study didn’t result in histologic improvement, which means other strategies are needed to treat the disease.

“Negative results from this study emphasize that monotherapy may not be enough to improve NASH and liver fibrosis,” he said. “In a similar way we treat type 2 diabetes and hypertension with combination therapy, we need to consider a similar approach for patients with NASH.”

The study was sponsored by Novo Nordisk, which manufactures semaglutide. The authors declared grant funding, speaker fees, and consultant roles with numerous pharmaceutical companies. Dr. Bril had no relevant disclosures.

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

Semaglutide didn’t significantly improve liver fibrosis or achieve resolution of nonalcoholic steatohepatitis (NASH)–related compensated cirrhosis, compared with placebo, according to a phase 2 trial.

However, the glucagonlike peptide–1 (GLP-1) receptor agonist led to improvements in liver enzymes, liver steatosis, weight, triglycerides, and very low-density lipoprotein (VLDL) cholesterol. Similar proportions of patients in each group reported adverse events, such as nausea, diarrhea, and vomiting.

“Previous studies in patients with NASH and stage 2 or 3 fibrosis have shown that semaglutide can improve NASH resolution over 72 weeks. However, there are limited data on whether any therapy is effective in patients with NASH cirrhosis,” lead author Rohit Loomba, MD, founding director of the NAFLD Research Center at the University of California, San Diego, said in an interview.

“Although semaglutide did not succeed in improving histological fibrosis, it had success in improving other clinically important parameters, such as cardiometabolic risk factors, liver enzymes, liver fat, and noninvasive biomarkers of fibrosis,” he said.

The study was published online  in The Lancet Gastroenterology & Hepatology.
 

Analyzing safety and efficacy

Dr. Loomba and colleagues conducted a double-blind, placebo-controlled phase 2 trial that enrolled 71 patients at 38 centers in the United States and Europe between June 2019 and April 2021. Adults with biopsy-confirmed NASH-related cirrhosis and a body mass index (BMI) of at least 27 kg/m² were randomly assigned 2:1 to receive either once-weekly subcutaneous semaglutide at 2.4 mg or a visually matching placebo.

Patients were randomly allocated through an interactive web system, which stratified participants on the basis of the presence or absence of type 2 diabetes. Patients, investigators, and outcomes analysts were masked to the treatment assignment.

The primary endpoint was the proportion of patients with an improvement in liver fibrosis of one stage or more without a worsening of NASH after 48 weeks, which was measured through biopsy in the intention-to-treat population. Safety was also assessed in all patients who received at least one dose of semaglutide.

Among the 71 patients, 47 were randomly assigned to the semaglutide group and 24 to the placebo group. About 90% completed treatment, and 63 had evaluable paired biopsies for primary endpoint assessment.

Between the groups, 49 participants (69%) were women and 22 were men. The average age was 59.5 years, and the average BMI was 34.9. About 75% of patients had diabetes at baseline, with an average hemoglobin A1c of 7.1%.

After 48 weeks, researchers found no statistically significant difference between the groups in the proportion of patients with an improvement in liver fibrosis of one stage or more without worsening of NASH. In the semaglutide group, five patients (11%) had an improvement, compared with seven patients (29%) in the placebo group (odds ratio, 0.28; 95% confidence interval, 0.06-1.24, P = .087).

There also wasn’t a significant difference between groups in the proportion of patients who achieved NASH resolution. In the semaglutide group, 16 patients (34%) had resolution, compared with 5 patients (21%) in the placebo group (OR, 1.97; 95% CI, 0.56-7.91; P = .29).

In addition, a lower proportion of patients achieved both NASH resolution and improvement in liver fibrosis with semaglutide versus placebo, although the difference wasn’t significant. In the semaglutide group, three patients (6%) achieved both, compared with three patients (13%) in the placebo group (OR, 0.48; 95% CI, 0.06-3.91; P = .4). A lower proportion of patients had an improvement in liver fibrosis stage with semaglutide versus placebo.
 

Some improvements seen

However, the semaglutide group had significantly greater improvements in liver steatosis (but not stiffness), liver fat volume, procollagen 3 peptide, and liver enzymes such as ALT, AST, and gamma-glutamyltransferase.

Body weight decreased by 8.83% in the semaglutide group, compared with 0.09% in the placebo group, which was a significant difference. BMI, waist circumference, triglycerides, and VLDL cholesterol were also significantly lower in the semaglutide group, but total cholesterol and blood pressure measurements weren’t significantly different. Among those with type 2 diabetes, A1c also decreased in the semaglutide group but did not in the placebo group.

Similar proportions of patients in each group reported adverse events. In the semaglutide group, 42 patients (89%) had an adverse event, compared with 19 patients (79%) in the placebo group. In addition, six patients (13%) in the semaglutide group and two patients (8%) in the placebo group reported serious adverse events.

The most common adverse events in the semaglutide and placebo groups were nausea (45% and 17%), diarrhea (19% and 8%), and vomiting (17% and none), which mainly occurred during treatment initiation or dose escalation. No patients withdrew from the trial because of adverse events, although five had a dose reduction. Hepatic and renal function remained stable after semaglutide treatment, and there were no decompensating events or deaths.

“GLP-1 analogue exposure – among patients with compensated cirrhosis who suffer from morbid obesity and type 2 diabetes – for the treatment of diabetes appears to be well-tolerated and may be safe,” Dr. Loomba said. “Further studies are needed in this study population.”
 

Considering next steps

Dr. Loomba and colleagues are continuing research around risk factors linked to advanced fibrosis, such as type 2 diabetes, a family history of cirrhosis, and the presence of key genetic risk alleles. Gut dysbiosis also appears to increase the risk for advanced fatty liver disease, he said.

Future clinical trials could focus on therapeutic options for patients with advanced fibrosis, particularly those with cirrhosis who face increased risks for liver-related complications and mortality.

“As these patients are oftentimes excluded from initial randomized controlled trials, we have significantly less information on how to address obesity, type 2 diabetes, and NASH in these patients,” Fernando Bril, MD, a physician-scientist focused on NASH-related research at the University of Alabama at Birmingham, said in an interview.

Dr. Bril, who wasn’t involved with this study, wrote an accompanying editorial in The Lancet Gastroenterology & Hepatology.

Patients with NASH-related cirrhosis may have progressed to a point of the disease where fibrosis regression may be more difficult to achieve, he said.

“This emphasizes that early diagnosis of patients with NASH is crucial,” he said.

“Therefore, primary care providers, endocrinologists, and diabetologists need to have a low threshold to suspect liver disease in patients with overweight, obesity, and/or type 2 diabetes. Only this will allow for early initiation of therapy, which may delay the progression of liver disease.”

In further research, investigators may want to consider the lack of NASH resolution, a result that could be caused by this study being underpowered, Dr. Bril noted. The trend in resolution in this study appeared similar to improvements seen in NASH patients without cirrhosis in other studies, he said. The weight reduction and improved diabetes control in this group also shows promise.

“While a purist may be adamant that this was a negative study for histological outcomes, it is essential to take note of the positive results in many secondary outcomes,” he said. “Improving cardiometabolic risk in these patients is essential because many still die of cardiovascular disease and not liver-related complications.”

At the same time, it’s important to note that NASH can’t be oversimplified as “a matter of weight,” Dr. Bril said. Significant weight loss in the study didn’t result in histologic improvement, which means other strategies are needed to treat the disease.

“Negative results from this study emphasize that monotherapy may not be enough to improve NASH and liver fibrosis,” he said. “In a similar way we treat type 2 diabetes and hypertension with combination therapy, we need to consider a similar approach for patients with NASH.”

The study was sponsored by Novo Nordisk, which manufactures semaglutide. The authors declared grant funding, speaker fees, and consultant roles with numerous pharmaceutical companies. Dr. Bril had no relevant disclosures.

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

Semaglutide didn’t significantly improve liver fibrosis or achieve resolution of nonalcoholic steatohepatitis (NASH)–related compensated cirrhosis, compared with placebo, according to a phase 2 trial.

However, the glucagonlike peptide–1 (GLP-1) receptor agonist led to improvements in liver enzymes, liver steatosis, weight, triglycerides, and very low-density lipoprotein (VLDL) cholesterol. Similar proportions of patients in each group reported adverse events, such as nausea, diarrhea, and vomiting.

“Previous studies in patients with NASH and stage 2 or 3 fibrosis have shown that semaglutide can improve NASH resolution over 72 weeks. However, there are limited data on whether any therapy is effective in patients with NASH cirrhosis,” lead author Rohit Loomba, MD, founding director of the NAFLD Research Center at the University of California, San Diego, said in an interview.

“Although semaglutide did not succeed in improving histological fibrosis, it had success in improving other clinically important parameters, such as cardiometabolic risk factors, liver enzymes, liver fat, and noninvasive biomarkers of fibrosis,” he said.

The study was published online  in The Lancet Gastroenterology & Hepatology.
 

Analyzing safety and efficacy

Dr. Loomba and colleagues conducted a double-blind, placebo-controlled phase 2 trial that enrolled 71 patients at 38 centers in the United States and Europe between June 2019 and April 2021. Adults with biopsy-confirmed NASH-related cirrhosis and a body mass index (BMI) of at least 27 kg/m² were randomly assigned 2:1 to receive either once-weekly subcutaneous semaglutide at 2.4 mg or a visually matching placebo.

Patients were randomly allocated through an interactive web system, which stratified participants on the basis of the presence or absence of type 2 diabetes. Patients, investigators, and outcomes analysts were masked to the treatment assignment.

The primary endpoint was the proportion of patients with an improvement in liver fibrosis of one stage or more without a worsening of NASH after 48 weeks, which was measured through biopsy in the intention-to-treat population. Safety was also assessed in all patients who received at least one dose of semaglutide.

Among the 71 patients, 47 were randomly assigned to the semaglutide group and 24 to the placebo group. About 90% completed treatment, and 63 had evaluable paired biopsies for primary endpoint assessment.

Between the groups, 49 participants (69%) were women and 22 were men. The average age was 59.5 years, and the average BMI was 34.9. About 75% of patients had diabetes at baseline, with an average hemoglobin A1c of 7.1%.

After 48 weeks, researchers found no statistically significant difference between the groups in the proportion of patients with an improvement in liver fibrosis of one stage or more without worsening of NASH. In the semaglutide group, five patients (11%) had an improvement, compared with seven patients (29%) in the placebo group (odds ratio, 0.28; 95% confidence interval, 0.06-1.24, P = .087).

There also wasn’t a significant difference between groups in the proportion of patients who achieved NASH resolution. In the semaglutide group, 16 patients (34%) had resolution, compared with 5 patients (21%) in the placebo group (OR, 1.97; 95% CI, 0.56-7.91; P = .29).

In addition, a lower proportion of patients achieved both NASH resolution and improvement in liver fibrosis with semaglutide versus placebo, although the difference wasn’t significant. In the semaglutide group, three patients (6%) achieved both, compared with three patients (13%) in the placebo group (OR, 0.48; 95% CI, 0.06-3.91; P = .4). A lower proportion of patients had an improvement in liver fibrosis stage with semaglutide versus placebo.
 

Some improvements seen

However, the semaglutide group had significantly greater improvements in liver steatosis (but not stiffness), liver fat volume, procollagen 3 peptide, and liver enzymes such as ALT, AST, and gamma-glutamyltransferase.

Body weight decreased by 8.83% in the semaglutide group, compared with 0.09% in the placebo group, which was a significant difference. BMI, waist circumference, triglycerides, and VLDL cholesterol were also significantly lower in the semaglutide group, but total cholesterol and blood pressure measurements weren’t significantly different. Among those with type 2 diabetes, A1c also decreased in the semaglutide group but did not in the placebo group.

Similar proportions of patients in each group reported adverse events. In the semaglutide group, 42 patients (89%) had an adverse event, compared with 19 patients (79%) in the placebo group. In addition, six patients (13%) in the semaglutide group and two patients (8%) in the placebo group reported serious adverse events.

The most common adverse events in the semaglutide and placebo groups were nausea (45% and 17%), diarrhea (19% and 8%), and vomiting (17% and none), which mainly occurred during treatment initiation or dose escalation. No patients withdrew from the trial because of adverse events, although five had a dose reduction. Hepatic and renal function remained stable after semaglutide treatment, and there were no decompensating events or deaths.

“GLP-1 analogue exposure – among patients with compensated cirrhosis who suffer from morbid obesity and type 2 diabetes – for the treatment of diabetes appears to be well-tolerated and may be safe,” Dr. Loomba said. “Further studies are needed in this study population.”
 

Considering next steps

Dr. Loomba and colleagues are continuing research around risk factors linked to advanced fibrosis, such as type 2 diabetes, a family history of cirrhosis, and the presence of key genetic risk alleles. Gut dysbiosis also appears to increase the risk for advanced fatty liver disease, he said.

Future clinical trials could focus on therapeutic options for patients with advanced fibrosis, particularly those with cirrhosis who face increased risks for liver-related complications and mortality.

“As these patients are oftentimes excluded from initial randomized controlled trials, we have significantly less information on how to address obesity, type 2 diabetes, and NASH in these patients,” Fernando Bril, MD, a physician-scientist focused on NASH-related research at the University of Alabama at Birmingham, said in an interview.

Dr. Bril, who wasn’t involved with this study, wrote an accompanying editorial in The Lancet Gastroenterology & Hepatology.

Patients with NASH-related cirrhosis may have progressed to a point of the disease where fibrosis regression may be more difficult to achieve, he said.

“This emphasizes that early diagnosis of patients with NASH is crucial,” he said.

“Therefore, primary care providers, endocrinologists, and diabetologists need to have a low threshold to suspect liver disease in patients with overweight, obesity, and/or type 2 diabetes. Only this will allow for early initiation of therapy, which may delay the progression of liver disease.”

In further research, investigators may want to consider the lack of NASH resolution, a result that could be caused by this study being underpowered, Dr. Bril noted. The trend in resolution in this study appeared similar to improvements seen in NASH patients without cirrhosis in other studies, he said. The weight reduction and improved diabetes control in this group also shows promise.

“While a purist may be adamant that this was a negative study for histological outcomes, it is essential to take note of the positive results in many secondary outcomes,” he said. “Improving cardiometabolic risk in these patients is essential because many still die of cardiovascular disease and not liver-related complications.”

At the same time, it’s important to note that NASH can’t be oversimplified as “a matter of weight,” Dr. Bril said. Significant weight loss in the study didn’t result in histologic improvement, which means other strategies are needed to treat the disease.

“Negative results from this study emphasize that monotherapy may not be enough to improve NASH and liver fibrosis,” he said. “In a similar way we treat type 2 diabetes and hypertension with combination therapy, we need to consider a similar approach for patients with NASH.”

The study was sponsored by Novo Nordisk, which manufactures semaglutide. The authors declared grant funding, speaker fees, and consultant roles with numerous pharmaceutical companies. Dr. Bril 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.

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.