User login
Fatty liver disease drives rise in liver cancer deaths
LONDON – Around the world, nonalcoholic fatty liver disease (NAFLD) has driven an increase in deaths from liver cancer over the past decade, overtaking alcoholic liver disease, hepatitis B, and hepatitis C, according to an analysis of the Global Burden of Disease Study 2019.
A global rise in liver cancer deaths and chronic liver disease reflects changes in underlying health patterns, said Zobair Younossi, MD, MPH, professor and chair, department of medicine, Inova Fairfax Medical Campus, Falls Church, Va., who presented the analysis at the meeting sponsored by the European Association for the Study of the Liver.
Dr. Younossi told this news organization. “We have known about the increasing prevalence for some time, but now the outcomes in terms of mortality are catching up,” he said.
“The bottom line of this study is that the burden of this disease [NAFLD] is going up, and it will be the most important disease of the next decade or so,” he said, adding that “the largest annual percentage increase in rates of mortality from liver cancer or chronic liver disease cirrhosis is related to NAFLD.”
Specifically, during the decade of 2009–2019, the annual percent change of +1.33% in the global liver cancer death rate was driven by the fact that the APC for NAFLD was +2.47%. By comparison, the APC for alcoholic liver disease was +1.91%; for hepatitis B, the APC was +0.21%; and for hepatitis C, the APC was +1.12%.
Aleksander Krag, MD, PhD, professor and senior consultant of hepatology and director of Odense (Denmark) Liver Research Centre at SDU and Odense University Hospital, who chaired the session in which this presentation was a part, acknowledged the importance of recognizing the contribution of NAFLD to liver cancer mortality.
“Liver diseases are on the rise. They are the fastest rising cause of death in the United Kingdom, faster than heart disease and other cancers. NAFLD in particular is the fastest growing cause of liver cancer, and the leading cause in France and the United States,” he remarked.
Dr. Krag also highlighted the costs of disease management.
“Managing fatty liver disease in Europe is estimated at €35 billion in direct health care, so we need to do something now,” he stressed.
“The global burden of NAFLD is so high that we need both prevention and treatment tools,” Dr. Krag said. “Change to lifestyle is a ‘no-brainer’ and costs governments very little. For the sake of our young people, we need to take this very seriously. At a political level, we can easily implement this, for example, by banning junk food advertisements, but also educating young people and their families. Good drugs will also help.”
NAFLD: The liver manifestation of type 2 diabetes
About 25%-30% of the global population have NAFLD, and 3%-5% have NASH. Dr. Younossi highlighted that the U.S. transplant database shows that NAFLD was the second indication for all liver transplants in the country. NAFLD also was a leading cause of liver transplants for patients with hepatocellular carcinoma.
There are around 2 billion cases of chronic liver disease globally, he said. He noted that, over time, there has been an increase in all kinds of liver diseases, as reflected in the annual percent change.
“The global epidemic of obesity and type 2 diabetes is driving the rise in NAFLD, but even among lean people, the prevalence of NAFLD is around 9%,” Dr. Younossi said. “Alongside the eye and kidney complications of diabetes, this is the liver manifestation of type 2 diabetes.”
To assess global liver disease and death, Dr. Younossi and his colleagues turned to the Global Burden of Disease Study, which gathered data from around 7,000 investigators located across 22 different regions of the world, comprising 156 countries.
They calculated the incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) in relation to liver cancer and chronic liver disease, including the APC. They linked the data to changes in four liver diseases: NAFLD, alcoholic liver disease, hepatitis B infection, and hepatitis C infection.
The cases of NAFLD reported in the study had been diagnosed by ultrasound or other imaging. Importantly, the prevalence of NAFLD was adjusted for alcohol use in the various national populations, explained Dr. Younossi.
In 2019, they reported that the overall global prevalence of liver disease reached 1.69 billion (liver cancer, 0.04%; chronic liver disease, 99.96%), with an incidence of 2.59 million (liver cancer, 20.7%; chronic liver disease, 79.3%), mortality of 1.95 million (liver cancer, 24.8%; chronic liver disease, 75.3%), and DALYs of 58.7 million (liver cancer, 21.3%; chronic liver disease, 78.7%).
Between 2009 and 2019, deaths from liver cancer rose by 27.2%, and deaths from chronic liver disease rose by 10.6%. DALYs from liver cancer rose by 21.9%, and DALYs from chronic liver disease were up by 5.1%.
In contrast to the increase in liver cancer deaths, deaths from chronic liver disease decreased (APC, –0.18%). The decrease was driven by a decrease in hepatitis B (APC, –1.83%). APCs for hepatitis C (+0.37%), alcoholic liver disease (+0.45%), and NAFLD (+1.33%) increased.
“The burden of hepatitis B–related mortality has decreased because we have been so good at vaccinating people,” Dr. Younossi remarked.
NAFLD ‘exploding’ in Middle East, North Africa, and East Asia
The increase in NAFLD has been seen in all regions of the world, but a breakdown by region shows that NAFLD is primarily “exploding” with highest prevalence and mortality in the Middle East (mostly Egypt, Iran, and Turkey), North Africa, and East Asia, said Dr. Younossi. In addition, there are large increases in the West and South America.
“We knew that the prevalence was high in the Middle East, but we now know that mortality is also high, so we are connecting these data,” said Dr. Younossi.
Awareness lacking
Dr. Younossi pressed the fact that awareness among the general population, primary care providers, and policy makers is very low. “From my perspective, raising awareness of NAFLD is the No. 1 priority, and that is the value of this study.”
He added that more people will become aware as testing becomes more manageable.
“There are some noninvasive tests being developed, so in the future, we won’t have to do liver biopsies to diagnose these patients,” he said. “Currently, there are some excellent treatments being developed.”
“The [World Health Organization] does not mention NAFLD as an important noncommunicable disease, and this too has to change,” Dr. Younossi added.
Dr. Younossi has received research funds and/or has consulted for Abbott, Allergan, Bristol-Myers Squibb, Echosens, Genfit, Gilead Sciences, Intercept, Madrigal, Merck, and Novo Nordisk. Dr. Karg disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
LONDON – Around the world, nonalcoholic fatty liver disease (NAFLD) has driven an increase in deaths from liver cancer over the past decade, overtaking alcoholic liver disease, hepatitis B, and hepatitis C, according to an analysis of the Global Burden of Disease Study 2019.
A global rise in liver cancer deaths and chronic liver disease reflects changes in underlying health patterns, said Zobair Younossi, MD, MPH, professor and chair, department of medicine, Inova Fairfax Medical Campus, Falls Church, Va., who presented the analysis at the meeting sponsored by the European Association for the Study of the Liver.
Dr. Younossi told this news organization. “We have known about the increasing prevalence for some time, but now the outcomes in terms of mortality are catching up,” he said.
“The bottom line of this study is that the burden of this disease [NAFLD] is going up, and it will be the most important disease of the next decade or so,” he said, adding that “the largest annual percentage increase in rates of mortality from liver cancer or chronic liver disease cirrhosis is related to NAFLD.”
Specifically, during the decade of 2009–2019, the annual percent change of +1.33% in the global liver cancer death rate was driven by the fact that the APC for NAFLD was +2.47%. By comparison, the APC for alcoholic liver disease was +1.91%; for hepatitis B, the APC was +0.21%; and for hepatitis C, the APC was +1.12%.
Aleksander Krag, MD, PhD, professor and senior consultant of hepatology and director of Odense (Denmark) Liver Research Centre at SDU and Odense University Hospital, who chaired the session in which this presentation was a part, acknowledged the importance of recognizing the contribution of NAFLD to liver cancer mortality.
“Liver diseases are on the rise. They are the fastest rising cause of death in the United Kingdom, faster than heart disease and other cancers. NAFLD in particular is the fastest growing cause of liver cancer, and the leading cause in France and the United States,” he remarked.
Dr. Krag also highlighted the costs of disease management.
“Managing fatty liver disease in Europe is estimated at €35 billion in direct health care, so we need to do something now,” he stressed.
“The global burden of NAFLD is so high that we need both prevention and treatment tools,” Dr. Krag said. “Change to lifestyle is a ‘no-brainer’ and costs governments very little. For the sake of our young people, we need to take this very seriously. At a political level, we can easily implement this, for example, by banning junk food advertisements, but also educating young people and their families. Good drugs will also help.”
NAFLD: The liver manifestation of type 2 diabetes
About 25%-30% of the global population have NAFLD, and 3%-5% have NASH. Dr. Younossi highlighted that the U.S. transplant database shows that NAFLD was the second indication for all liver transplants in the country. NAFLD also was a leading cause of liver transplants for patients with hepatocellular carcinoma.
There are around 2 billion cases of chronic liver disease globally, he said. He noted that, over time, there has been an increase in all kinds of liver diseases, as reflected in the annual percent change.
“The global epidemic of obesity and type 2 diabetes is driving the rise in NAFLD, but even among lean people, the prevalence of NAFLD is around 9%,” Dr. Younossi said. “Alongside the eye and kidney complications of diabetes, this is the liver manifestation of type 2 diabetes.”
To assess global liver disease and death, Dr. Younossi and his colleagues turned to the Global Burden of Disease Study, which gathered data from around 7,000 investigators located across 22 different regions of the world, comprising 156 countries.
They calculated the incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) in relation to liver cancer and chronic liver disease, including the APC. They linked the data to changes in four liver diseases: NAFLD, alcoholic liver disease, hepatitis B infection, and hepatitis C infection.
The cases of NAFLD reported in the study had been diagnosed by ultrasound or other imaging. Importantly, the prevalence of NAFLD was adjusted for alcohol use in the various national populations, explained Dr. Younossi.
In 2019, they reported that the overall global prevalence of liver disease reached 1.69 billion (liver cancer, 0.04%; chronic liver disease, 99.96%), with an incidence of 2.59 million (liver cancer, 20.7%; chronic liver disease, 79.3%), mortality of 1.95 million (liver cancer, 24.8%; chronic liver disease, 75.3%), and DALYs of 58.7 million (liver cancer, 21.3%; chronic liver disease, 78.7%).
Between 2009 and 2019, deaths from liver cancer rose by 27.2%, and deaths from chronic liver disease rose by 10.6%. DALYs from liver cancer rose by 21.9%, and DALYs from chronic liver disease were up by 5.1%.
In contrast to the increase in liver cancer deaths, deaths from chronic liver disease decreased (APC, –0.18%). The decrease was driven by a decrease in hepatitis B (APC, –1.83%). APCs for hepatitis C (+0.37%), alcoholic liver disease (+0.45%), and NAFLD (+1.33%) increased.
“The burden of hepatitis B–related mortality has decreased because we have been so good at vaccinating people,” Dr. Younossi remarked.
NAFLD ‘exploding’ in Middle East, North Africa, and East Asia
The increase in NAFLD has been seen in all regions of the world, but a breakdown by region shows that NAFLD is primarily “exploding” with highest prevalence and mortality in the Middle East (mostly Egypt, Iran, and Turkey), North Africa, and East Asia, said Dr. Younossi. In addition, there are large increases in the West and South America.
“We knew that the prevalence was high in the Middle East, but we now know that mortality is also high, so we are connecting these data,” said Dr. Younossi.
Awareness lacking
Dr. Younossi pressed the fact that awareness among the general population, primary care providers, and policy makers is very low. “From my perspective, raising awareness of NAFLD is the No. 1 priority, and that is the value of this study.”
He added that more people will become aware as testing becomes more manageable.
“There are some noninvasive tests being developed, so in the future, we won’t have to do liver biopsies to diagnose these patients,” he said. “Currently, there are some excellent treatments being developed.”
“The [World Health Organization] does not mention NAFLD as an important noncommunicable disease, and this too has to change,” Dr. Younossi added.
Dr. Younossi has received research funds and/or has consulted for Abbott, Allergan, Bristol-Myers Squibb, Echosens, Genfit, Gilead Sciences, Intercept, Madrigal, Merck, and Novo Nordisk. Dr. Karg disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
LONDON – Around the world, nonalcoholic fatty liver disease (NAFLD) has driven an increase in deaths from liver cancer over the past decade, overtaking alcoholic liver disease, hepatitis B, and hepatitis C, according to an analysis of the Global Burden of Disease Study 2019.
A global rise in liver cancer deaths and chronic liver disease reflects changes in underlying health patterns, said Zobair Younossi, MD, MPH, professor and chair, department of medicine, Inova Fairfax Medical Campus, Falls Church, Va., who presented the analysis at the meeting sponsored by the European Association for the Study of the Liver.
Dr. Younossi told this news organization. “We have known about the increasing prevalence for some time, but now the outcomes in terms of mortality are catching up,” he said.
“The bottom line of this study is that the burden of this disease [NAFLD] is going up, and it will be the most important disease of the next decade or so,” he said, adding that “the largest annual percentage increase in rates of mortality from liver cancer or chronic liver disease cirrhosis is related to NAFLD.”
Specifically, during the decade of 2009–2019, the annual percent change of +1.33% in the global liver cancer death rate was driven by the fact that the APC for NAFLD was +2.47%. By comparison, the APC for alcoholic liver disease was +1.91%; for hepatitis B, the APC was +0.21%; and for hepatitis C, the APC was +1.12%.
Aleksander Krag, MD, PhD, professor and senior consultant of hepatology and director of Odense (Denmark) Liver Research Centre at SDU and Odense University Hospital, who chaired the session in which this presentation was a part, acknowledged the importance of recognizing the contribution of NAFLD to liver cancer mortality.
“Liver diseases are on the rise. They are the fastest rising cause of death in the United Kingdom, faster than heart disease and other cancers. NAFLD in particular is the fastest growing cause of liver cancer, and the leading cause in France and the United States,” he remarked.
Dr. Krag also highlighted the costs of disease management.
“Managing fatty liver disease in Europe is estimated at €35 billion in direct health care, so we need to do something now,” he stressed.
“The global burden of NAFLD is so high that we need both prevention and treatment tools,” Dr. Krag said. “Change to lifestyle is a ‘no-brainer’ and costs governments very little. For the sake of our young people, we need to take this very seriously. At a political level, we can easily implement this, for example, by banning junk food advertisements, but also educating young people and their families. Good drugs will also help.”
NAFLD: The liver manifestation of type 2 diabetes
About 25%-30% of the global population have NAFLD, and 3%-5% have NASH. Dr. Younossi highlighted that the U.S. transplant database shows that NAFLD was the second indication for all liver transplants in the country. NAFLD also was a leading cause of liver transplants for patients with hepatocellular carcinoma.
There are around 2 billion cases of chronic liver disease globally, he said. He noted that, over time, there has been an increase in all kinds of liver diseases, as reflected in the annual percent change.
“The global epidemic of obesity and type 2 diabetes is driving the rise in NAFLD, but even among lean people, the prevalence of NAFLD is around 9%,” Dr. Younossi said. “Alongside the eye and kidney complications of diabetes, this is the liver manifestation of type 2 diabetes.”
To assess global liver disease and death, Dr. Younossi and his colleagues turned to the Global Burden of Disease Study, which gathered data from around 7,000 investigators located across 22 different regions of the world, comprising 156 countries.
They calculated the incidence, prevalence, mortality, and disability-adjusted life-years (DALYs) in relation to liver cancer and chronic liver disease, including the APC. They linked the data to changes in four liver diseases: NAFLD, alcoholic liver disease, hepatitis B infection, and hepatitis C infection.
The cases of NAFLD reported in the study had been diagnosed by ultrasound or other imaging. Importantly, the prevalence of NAFLD was adjusted for alcohol use in the various national populations, explained Dr. Younossi.
In 2019, they reported that the overall global prevalence of liver disease reached 1.69 billion (liver cancer, 0.04%; chronic liver disease, 99.96%), with an incidence of 2.59 million (liver cancer, 20.7%; chronic liver disease, 79.3%), mortality of 1.95 million (liver cancer, 24.8%; chronic liver disease, 75.3%), and DALYs of 58.7 million (liver cancer, 21.3%; chronic liver disease, 78.7%).
Between 2009 and 2019, deaths from liver cancer rose by 27.2%, and deaths from chronic liver disease rose by 10.6%. DALYs from liver cancer rose by 21.9%, and DALYs from chronic liver disease were up by 5.1%.
In contrast to the increase in liver cancer deaths, deaths from chronic liver disease decreased (APC, –0.18%). The decrease was driven by a decrease in hepatitis B (APC, –1.83%). APCs for hepatitis C (+0.37%), alcoholic liver disease (+0.45%), and NAFLD (+1.33%) increased.
“The burden of hepatitis B–related mortality has decreased because we have been so good at vaccinating people,” Dr. Younossi remarked.
NAFLD ‘exploding’ in Middle East, North Africa, and East Asia
The increase in NAFLD has been seen in all regions of the world, but a breakdown by region shows that NAFLD is primarily “exploding” with highest prevalence and mortality in the Middle East (mostly Egypt, Iran, and Turkey), North Africa, and East Asia, said Dr. Younossi. In addition, there are large increases in the West and South America.
“We knew that the prevalence was high in the Middle East, but we now know that mortality is also high, so we are connecting these data,” said Dr. Younossi.
Awareness lacking
Dr. Younossi pressed the fact that awareness among the general population, primary care providers, and policy makers is very low. “From my perspective, raising awareness of NAFLD is the No. 1 priority, and that is the value of this study.”
He added that more people will become aware as testing becomes more manageable.
“There are some noninvasive tests being developed, so in the future, we won’t have to do liver biopsies to diagnose these patients,” he said. “Currently, there are some excellent treatments being developed.”
“The [World Health Organization] does not mention NAFLD as an important noncommunicable disease, and this too has to change,” Dr. Younossi added.
Dr. Younossi has received research funds and/or has consulted for Abbott, Allergan, Bristol-Myers Squibb, Echosens, Genfit, Gilead Sciences, Intercept, Madrigal, Merck, and Novo Nordisk. Dr. Karg disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
AT ILC 2022
CDC releases new details on mysterious hepatitis in children
A new analysis from the Centers for Disease Control and Prevention provides further details on mysterious cases of pediatric hepatitis identified across the United States. While 45% of patients have tested positive for adenovirus infection, it is likely that these children “represent a heterogenous group of hepatitis etiologies,” the CDC authors wrote.
Of the 296 children diagnosed between Oct. 1, 2021, and June 15, 2022, in the United States, 18 have required liver transplants and 11 have died.
On April 21, 2022, the CDC issued an alert to providers to report pediatric hepatitis cases of unknown etiology in children under 10 after similar cases had been identified in Europe and the United States. While the United Kingdom has found an uptick in cases over the past year, researchers from the CDC published data on June 14 that suggested pediatric hepatitis cases had not increased from 2017 to 2021.
This newest analysis, published Morbidity and Mortality Weekly Report, provides additional demographic data on affected patients and explores possible causes, including previous infection with COVID-19. Investigators had earlier ruled out COVID-19 vaccination as a potential factor in these cases, as most children were unvaccinated or not yet eligible to receive the vaccine. According to the analysis, only five patients had received at least one dose of a COVID-19 vaccine.
The 296 cases included in the analysis occurred in 42 U.S. states and territories, and the median age for patients was 2 years and 2 months. Nearly 60% of patients were male (58.1%) and 40.9% were female. The largest percentage of cases occurred in Hispanic or Latino children (37.8%), followed by non-Hispanic White (32.4%) children. Black patients made up 9.8% of all cases, and 3.7% of affected children were of Asian descent. Vomiting, fatigue, and jaundice were all common symptoms, and about 90% (89.9%) of children required hospitalization..
Of 224 children tested for adenovirus, 44.6% were positive. The analysis also included information on 123 of these hepatitis patients tested for other various pathogens. Nearly 80% (98/123) received a COVID-19 test and just 10.2% were positive. About 26% of patients had previously had COVID-19, and hepatitis onset occurred, on average, 133 days after the reported SARS-CoV-2 infection.
Other viruses detected included rhinovirus/enterovirus (24.5%), rotavirus (14.0%), and acute Epstein-Barr virus (11.4%)
Simultaneous infection with SARS-CoV-2 and adenovirus occurred in three patients.
There was no evidence of viral inclusions in the 36 patients who had pathological evaluation liver biopsies, explants, or autopsied tissue.
The findings suggest that there may be many different causes behind these severe hepatitis cases, and it is estimated that about one-third of hepatitis cases in children do not have a known cause. However, the identification of adenovirus infection in many cases “raises the question whether a new pattern of disease is emerging in this population or if adenovirus might be an underrecognized cause or cofactor in previously indeterminate cases of pediatric hepatitis,” the authors wrote. As the investigation continues, “further clinical data are needed to understand the cause of these cases and to assess the potential association with adenovirus.”
A version of this article first appeared on Medscape.com.
A new analysis from the Centers for Disease Control and Prevention provides further details on mysterious cases of pediatric hepatitis identified across the United States. While 45% of patients have tested positive for adenovirus infection, it is likely that these children “represent a heterogenous group of hepatitis etiologies,” the CDC authors wrote.
Of the 296 children diagnosed between Oct. 1, 2021, and June 15, 2022, in the United States, 18 have required liver transplants and 11 have died.
On April 21, 2022, the CDC issued an alert to providers to report pediatric hepatitis cases of unknown etiology in children under 10 after similar cases had been identified in Europe and the United States. While the United Kingdom has found an uptick in cases over the past year, researchers from the CDC published data on June 14 that suggested pediatric hepatitis cases had not increased from 2017 to 2021.
This newest analysis, published Morbidity and Mortality Weekly Report, provides additional demographic data on affected patients and explores possible causes, including previous infection with COVID-19. Investigators had earlier ruled out COVID-19 vaccination as a potential factor in these cases, as most children were unvaccinated or not yet eligible to receive the vaccine. According to the analysis, only five patients had received at least one dose of a COVID-19 vaccine.
The 296 cases included in the analysis occurred in 42 U.S. states and territories, and the median age for patients was 2 years and 2 months. Nearly 60% of patients were male (58.1%) and 40.9% were female. The largest percentage of cases occurred in Hispanic or Latino children (37.8%), followed by non-Hispanic White (32.4%) children. Black patients made up 9.8% of all cases, and 3.7% of affected children were of Asian descent. Vomiting, fatigue, and jaundice were all common symptoms, and about 90% (89.9%) of children required hospitalization..
Of 224 children tested for adenovirus, 44.6% were positive. The analysis also included information on 123 of these hepatitis patients tested for other various pathogens. Nearly 80% (98/123) received a COVID-19 test and just 10.2% were positive. About 26% of patients had previously had COVID-19, and hepatitis onset occurred, on average, 133 days after the reported SARS-CoV-2 infection.
Other viruses detected included rhinovirus/enterovirus (24.5%), rotavirus (14.0%), and acute Epstein-Barr virus (11.4%)
Simultaneous infection with SARS-CoV-2 and adenovirus occurred in three patients.
There was no evidence of viral inclusions in the 36 patients who had pathological evaluation liver biopsies, explants, or autopsied tissue.
The findings suggest that there may be many different causes behind these severe hepatitis cases, and it is estimated that about one-third of hepatitis cases in children do not have a known cause. However, the identification of adenovirus infection in many cases “raises the question whether a new pattern of disease is emerging in this population or if adenovirus might be an underrecognized cause or cofactor in previously indeterminate cases of pediatric hepatitis,” the authors wrote. As the investigation continues, “further clinical data are needed to understand the cause of these cases and to assess the potential association with adenovirus.”
A version of this article first appeared on Medscape.com.
A new analysis from the Centers for Disease Control and Prevention provides further details on mysterious cases of pediatric hepatitis identified across the United States. While 45% of patients have tested positive for adenovirus infection, it is likely that these children “represent a heterogenous group of hepatitis etiologies,” the CDC authors wrote.
Of the 296 children diagnosed between Oct. 1, 2021, and June 15, 2022, in the United States, 18 have required liver transplants and 11 have died.
On April 21, 2022, the CDC issued an alert to providers to report pediatric hepatitis cases of unknown etiology in children under 10 after similar cases had been identified in Europe and the United States. While the United Kingdom has found an uptick in cases over the past year, researchers from the CDC published data on June 14 that suggested pediatric hepatitis cases had not increased from 2017 to 2021.
This newest analysis, published Morbidity and Mortality Weekly Report, provides additional demographic data on affected patients and explores possible causes, including previous infection with COVID-19. Investigators had earlier ruled out COVID-19 vaccination as a potential factor in these cases, as most children were unvaccinated or not yet eligible to receive the vaccine. According to the analysis, only five patients had received at least one dose of a COVID-19 vaccine.
The 296 cases included in the analysis occurred in 42 U.S. states and territories, and the median age for patients was 2 years and 2 months. Nearly 60% of patients were male (58.1%) and 40.9% were female. The largest percentage of cases occurred in Hispanic or Latino children (37.8%), followed by non-Hispanic White (32.4%) children. Black patients made up 9.8% of all cases, and 3.7% of affected children were of Asian descent. Vomiting, fatigue, and jaundice were all common symptoms, and about 90% (89.9%) of children required hospitalization..
Of 224 children tested for adenovirus, 44.6% were positive. The analysis also included information on 123 of these hepatitis patients tested for other various pathogens. Nearly 80% (98/123) received a COVID-19 test and just 10.2% were positive. About 26% of patients had previously had COVID-19, and hepatitis onset occurred, on average, 133 days after the reported SARS-CoV-2 infection.
Other viruses detected included rhinovirus/enterovirus (24.5%), rotavirus (14.0%), and acute Epstein-Barr virus (11.4%)
Simultaneous infection with SARS-CoV-2 and adenovirus occurred in three patients.
There was no evidence of viral inclusions in the 36 patients who had pathological evaluation liver biopsies, explants, or autopsied tissue.
The findings suggest that there may be many different causes behind these severe hepatitis cases, and it is estimated that about one-third of hepatitis cases in children do not have a known cause. However, the identification of adenovirus infection in many cases “raises the question whether a new pattern of disease is emerging in this population or if adenovirus might be an underrecognized cause or cofactor in previously indeterminate cases of pediatric hepatitis,” the authors wrote. As the investigation continues, “further clinical data are needed to understand the cause of these cases and to assess the potential association with adenovirus.”
A version of this article first appeared on Medscape.com.
FROM THE MMWR
Novel liver-targeting drug offers hope for AAT deficiency
LONDON – The novel liver-targeting agent fazirsiran has fared well in a small, but significant, study looking at its ability to improve liver histology in adults with alpha-1 antitrypsin (AAT) deficiency.
Not only were serum and liver levels of the aberrant Z-AAT protein decreased, but also reductions in key liver enzymes were observed.
AAT is “a greatly understudied disease,” said study investigator Pavel Strnad, MD, who presented the results of the phase 2 AROAAT-2002 study at a meeting sponsored by the European Association for the Study of the Liver. The results were published simultaneously in the New England Journal of Medicine.
“We have a great candidate drug, but we will only be able to bring this drug into the clinic when we understand the disease much better, and for this I would like to ask all of you for your support,” he said to delegates at the meeting.
There is currently no pharmacological treatment for AAT, observed Emmanuel Tsochatzis, MD, who chaired the late-breaker session during which the study findings were presented.
“It is a rare disease, but it really does affect the patients who have it. So it would be great to have a therapeutic solution for these patients,” said Dr. Tsochatzis in an interview.
Dr. Tsochatzis, who is professor of hepatology and Consultant Hepatologist at the UCL Institute for Liver and Digestive Health, Royal Free Hospital in London, noted that AAT was associated with liver impairment, fibrosis and cirrhosis, and ultimately end-stage liver disease in which the only option for some patients would be a liver transplant.
“It depends on the stage; many patients are not at the stage that they require a liver transplant,” he said. “For those with significant liver disease, not yet at the cirrhosis stage, you might be able to intervene early and prevent them from progressing to needing a liver transplant.”
Dr. Tsochatzis speculated: “If this becomes an approved treatment, it is a breakthrough for patients.”
New hope for AAT deficiency
There is still a long way to go before fazirsiran is anywhere near ready for clinical use, but the early data presented by Dr. Strnad offer a glimpse that a treatment could be on the horizon.
Naturally occurring AAT is produced in the liver and is thought to play a role in protecting against lung damage via its antiprotease activity. However, mutations in the SERPINA1 gene coding for the AAT protein leads to loss-of-function pulmonary disease and gain-of-function liver disease.
“The PI ZZ [proteinase inhibitor ZZ] genotype occurs in about one in 2,500 to 3,500 Caucasians, so actually is pretty common, and a third of them may actually have a clinically significant liver fibrosis,” said Dr. Strnad.
As levels of Z-AAT accumulate in the liver this “presumably causes the liver toxicity,” he observed. So, the thinking is that stopping the production of this mutant protein might help to reduce liver damage and allow the liver to regenerate and repair itself.
Study details
To test out this theory, a phase 2, open-label study was performed in 16 patients with confirmed AAT deficiency, all of whom had the PI ZZ genotype.
Eight patients were treated with fazirsiran, also known as ARO-AAT, for 24 weeks (cohorts 1 and 1b), while the other eight were treated for 48 weeks (cohort 2); cohort 1 (n = 4) and cohort 2 (n = 8) received 200 mg, while cohort 1b (n = 4), which was added during the trial to evaluate dose response, received 100 mg. In all cases, fazirsiran was given as a subcutaneous injection on day 1, day 4, and then every 12 weeks. All patients had biopsies at baseline, then at either 24 weeks (cohorts 1/1b) or 48 weeks (cohort 2).
“We saw a dramatic reduction in Z-AAT both in serum and in liver biopsies,” Dr. Strnad reported. Indeed, reductions in Z-AAT were around 80%-88%, he said, with a median reduction of 83% at week 24 or 48 according to the published paper.
To illustrate the clear results, Dr. Strand showed a sample biopsy slide where globules of Z-AAT present at the initial assessment were “virtually gone after 48 weeks of treatment.”
“The change in the serum and hepatic Z-AAT levels translated into improvement in liver function tests,” said Dr. Strnad.
Alanine aminotransferase levels were normalized in all patients and there was “marked improvement” in gamma glutamyl transferase (GGT) with the 200-mg dose of fazirsiran. Substantial changes in liver stiffness were recorded with the higher dose, –18% at 24 weeks and –15% at 48 weeks. There were also reductions in serum Pro-C3 of –36% and –17% at 52 weeks.
“Histological changes showed an improvement in liver inflammation and hepatocyte cell death in most of the patients,” Dr. Strnad said. He also noted that there were multiple cases where there was no change and a few where there was a deterioration.
Liver fibrosis was improved in seven of 12 patients given the highest dose of fazirsiran; however, there was no change in three patients and a worsening of 1 point or more in two patients. None of the three patients with evaluable biopsies who received 100 mg showed regression of fibrosis.
Stopping or rolling back fibrosis will be the final goal of proving clinical benefit in liver disease associated with AAT, Dr. Strnad and coinvestigators observe in their published paper, and while the changes seen so far with fazirsiran may not be uniform, they appear to be in the right direction.
Safety findings
”We didn’t see any drug discontinuation, dose interruption, or premature study withdrawals,” said Dr. Strnad.
“We had four different SAE [serious adverse events] which were kind of all over the place and did not seem to be related to treatment.” Those SAEs included viral myocarditis associated with Epstein-Barr virus infection, diverticulitis, dyspnea in a subject with a history of lung disease, and vestibular neuronitis after COVID-19 vaccination.
No significant safety signals were seen regarding lung function. Time will of course tell, he said in response to a question, but “our hope, our hypothesis, is that this will not change lung function dramatically.
“I would not expect any major things over a few years. Of course, whether this can lead to something over 20 years it is difficult to say.”
The current experience with fazirsiran looks good so far, but placebo-controlled, larger and longer studies are needed.
The study was funded by Arrowhead Pharmaceuticals. Dr. Strnad was an investigator in the study and acknowledged receipt of research funding via his institution from the company. Dr. Strnad also acknowledged paid and unpaid relationships with Alnylam Pharmaceuticals, Alpha1 Deutschland, Alpha1 Global, CSL Behring, Grifols Biologicals, Ono Pharmaceuticals, and Takeda California. Dr. Tsochatzis, chaired the late-breaker session at ILC 2022 during which the study findings were presented, was not connected to the study, and reported no relevant conflicts of interest.
LONDON – The novel liver-targeting agent fazirsiran has fared well in a small, but significant, study looking at its ability to improve liver histology in adults with alpha-1 antitrypsin (AAT) deficiency.
Not only were serum and liver levels of the aberrant Z-AAT protein decreased, but also reductions in key liver enzymes were observed.
AAT is “a greatly understudied disease,” said study investigator Pavel Strnad, MD, who presented the results of the phase 2 AROAAT-2002 study at a meeting sponsored by the European Association for the Study of the Liver. The results were published simultaneously in the New England Journal of Medicine.
“We have a great candidate drug, but we will only be able to bring this drug into the clinic when we understand the disease much better, and for this I would like to ask all of you for your support,” he said to delegates at the meeting.
There is currently no pharmacological treatment for AAT, observed Emmanuel Tsochatzis, MD, who chaired the late-breaker session during which the study findings were presented.
“It is a rare disease, but it really does affect the patients who have it. So it would be great to have a therapeutic solution for these patients,” said Dr. Tsochatzis in an interview.
Dr. Tsochatzis, who is professor of hepatology and Consultant Hepatologist at the UCL Institute for Liver and Digestive Health, Royal Free Hospital in London, noted that AAT was associated with liver impairment, fibrosis and cirrhosis, and ultimately end-stage liver disease in which the only option for some patients would be a liver transplant.
“It depends on the stage; many patients are not at the stage that they require a liver transplant,” he said. “For those with significant liver disease, not yet at the cirrhosis stage, you might be able to intervene early and prevent them from progressing to needing a liver transplant.”
Dr. Tsochatzis speculated: “If this becomes an approved treatment, it is a breakthrough for patients.”
New hope for AAT deficiency
There is still a long way to go before fazirsiran is anywhere near ready for clinical use, but the early data presented by Dr. Strnad offer a glimpse that a treatment could be on the horizon.
Naturally occurring AAT is produced in the liver and is thought to play a role in protecting against lung damage via its antiprotease activity. However, mutations in the SERPINA1 gene coding for the AAT protein leads to loss-of-function pulmonary disease and gain-of-function liver disease.
“The PI ZZ [proteinase inhibitor ZZ] genotype occurs in about one in 2,500 to 3,500 Caucasians, so actually is pretty common, and a third of them may actually have a clinically significant liver fibrosis,” said Dr. Strnad.
As levels of Z-AAT accumulate in the liver this “presumably causes the liver toxicity,” he observed. So, the thinking is that stopping the production of this mutant protein might help to reduce liver damage and allow the liver to regenerate and repair itself.
Study details
To test out this theory, a phase 2, open-label study was performed in 16 patients with confirmed AAT deficiency, all of whom had the PI ZZ genotype.
Eight patients were treated with fazirsiran, also known as ARO-AAT, for 24 weeks (cohorts 1 and 1b), while the other eight were treated for 48 weeks (cohort 2); cohort 1 (n = 4) and cohort 2 (n = 8) received 200 mg, while cohort 1b (n = 4), which was added during the trial to evaluate dose response, received 100 mg. In all cases, fazirsiran was given as a subcutaneous injection on day 1, day 4, and then every 12 weeks. All patients had biopsies at baseline, then at either 24 weeks (cohorts 1/1b) or 48 weeks (cohort 2).
“We saw a dramatic reduction in Z-AAT both in serum and in liver biopsies,” Dr. Strnad reported. Indeed, reductions in Z-AAT were around 80%-88%, he said, with a median reduction of 83% at week 24 or 48 according to the published paper.
To illustrate the clear results, Dr. Strand showed a sample biopsy slide where globules of Z-AAT present at the initial assessment were “virtually gone after 48 weeks of treatment.”
“The change in the serum and hepatic Z-AAT levels translated into improvement in liver function tests,” said Dr. Strnad.
Alanine aminotransferase levels were normalized in all patients and there was “marked improvement” in gamma glutamyl transferase (GGT) with the 200-mg dose of fazirsiran. Substantial changes in liver stiffness were recorded with the higher dose, –18% at 24 weeks and –15% at 48 weeks. There were also reductions in serum Pro-C3 of –36% and –17% at 52 weeks.
“Histological changes showed an improvement in liver inflammation and hepatocyte cell death in most of the patients,” Dr. Strnad said. He also noted that there were multiple cases where there was no change and a few where there was a deterioration.
Liver fibrosis was improved in seven of 12 patients given the highest dose of fazirsiran; however, there was no change in three patients and a worsening of 1 point or more in two patients. None of the three patients with evaluable biopsies who received 100 mg showed regression of fibrosis.
Stopping or rolling back fibrosis will be the final goal of proving clinical benefit in liver disease associated with AAT, Dr. Strnad and coinvestigators observe in their published paper, and while the changes seen so far with fazirsiran may not be uniform, they appear to be in the right direction.
Safety findings
”We didn’t see any drug discontinuation, dose interruption, or premature study withdrawals,” said Dr. Strnad.
“We had four different SAE [serious adverse events] which were kind of all over the place and did not seem to be related to treatment.” Those SAEs included viral myocarditis associated with Epstein-Barr virus infection, diverticulitis, dyspnea in a subject with a history of lung disease, and vestibular neuronitis after COVID-19 vaccination.
No significant safety signals were seen regarding lung function. Time will of course tell, he said in response to a question, but “our hope, our hypothesis, is that this will not change lung function dramatically.
“I would not expect any major things over a few years. Of course, whether this can lead to something over 20 years it is difficult to say.”
The current experience with fazirsiran looks good so far, but placebo-controlled, larger and longer studies are needed.
The study was funded by Arrowhead Pharmaceuticals. Dr. Strnad was an investigator in the study and acknowledged receipt of research funding via his institution from the company. Dr. Strnad also acknowledged paid and unpaid relationships with Alnylam Pharmaceuticals, Alpha1 Deutschland, Alpha1 Global, CSL Behring, Grifols Biologicals, Ono Pharmaceuticals, and Takeda California. Dr. Tsochatzis, chaired the late-breaker session at ILC 2022 during which the study findings were presented, was not connected to the study, and reported no relevant conflicts of interest.
LONDON – The novel liver-targeting agent fazirsiran has fared well in a small, but significant, study looking at its ability to improve liver histology in adults with alpha-1 antitrypsin (AAT) deficiency.
Not only were serum and liver levels of the aberrant Z-AAT protein decreased, but also reductions in key liver enzymes were observed.
AAT is “a greatly understudied disease,” said study investigator Pavel Strnad, MD, who presented the results of the phase 2 AROAAT-2002 study at a meeting sponsored by the European Association for the Study of the Liver. The results were published simultaneously in the New England Journal of Medicine.
“We have a great candidate drug, but we will only be able to bring this drug into the clinic when we understand the disease much better, and for this I would like to ask all of you for your support,” he said to delegates at the meeting.
There is currently no pharmacological treatment for AAT, observed Emmanuel Tsochatzis, MD, who chaired the late-breaker session during which the study findings were presented.
“It is a rare disease, but it really does affect the patients who have it. So it would be great to have a therapeutic solution for these patients,” said Dr. Tsochatzis in an interview.
Dr. Tsochatzis, who is professor of hepatology and Consultant Hepatologist at the UCL Institute for Liver and Digestive Health, Royal Free Hospital in London, noted that AAT was associated with liver impairment, fibrosis and cirrhosis, and ultimately end-stage liver disease in which the only option for some patients would be a liver transplant.
“It depends on the stage; many patients are not at the stage that they require a liver transplant,” he said. “For those with significant liver disease, not yet at the cirrhosis stage, you might be able to intervene early and prevent them from progressing to needing a liver transplant.”
Dr. Tsochatzis speculated: “If this becomes an approved treatment, it is a breakthrough for patients.”
New hope for AAT deficiency
There is still a long way to go before fazirsiran is anywhere near ready for clinical use, but the early data presented by Dr. Strnad offer a glimpse that a treatment could be on the horizon.
Naturally occurring AAT is produced in the liver and is thought to play a role in protecting against lung damage via its antiprotease activity. However, mutations in the SERPINA1 gene coding for the AAT protein leads to loss-of-function pulmonary disease and gain-of-function liver disease.
“The PI ZZ [proteinase inhibitor ZZ] genotype occurs in about one in 2,500 to 3,500 Caucasians, so actually is pretty common, and a third of them may actually have a clinically significant liver fibrosis,” said Dr. Strnad.
As levels of Z-AAT accumulate in the liver this “presumably causes the liver toxicity,” he observed. So, the thinking is that stopping the production of this mutant protein might help to reduce liver damage and allow the liver to regenerate and repair itself.
Study details
To test out this theory, a phase 2, open-label study was performed in 16 patients with confirmed AAT deficiency, all of whom had the PI ZZ genotype.
Eight patients were treated with fazirsiran, also known as ARO-AAT, for 24 weeks (cohorts 1 and 1b), while the other eight were treated for 48 weeks (cohort 2); cohort 1 (n = 4) and cohort 2 (n = 8) received 200 mg, while cohort 1b (n = 4), which was added during the trial to evaluate dose response, received 100 mg. In all cases, fazirsiran was given as a subcutaneous injection on day 1, day 4, and then every 12 weeks. All patients had biopsies at baseline, then at either 24 weeks (cohorts 1/1b) or 48 weeks (cohort 2).
“We saw a dramatic reduction in Z-AAT both in serum and in liver biopsies,” Dr. Strnad reported. Indeed, reductions in Z-AAT were around 80%-88%, he said, with a median reduction of 83% at week 24 or 48 according to the published paper.
To illustrate the clear results, Dr. Strand showed a sample biopsy slide where globules of Z-AAT present at the initial assessment were “virtually gone after 48 weeks of treatment.”
“The change in the serum and hepatic Z-AAT levels translated into improvement in liver function tests,” said Dr. Strnad.
Alanine aminotransferase levels were normalized in all patients and there was “marked improvement” in gamma glutamyl transferase (GGT) with the 200-mg dose of fazirsiran. Substantial changes in liver stiffness were recorded with the higher dose, –18% at 24 weeks and –15% at 48 weeks. There were also reductions in serum Pro-C3 of –36% and –17% at 52 weeks.
“Histological changes showed an improvement in liver inflammation and hepatocyte cell death in most of the patients,” Dr. Strnad said. He also noted that there were multiple cases where there was no change and a few where there was a deterioration.
Liver fibrosis was improved in seven of 12 patients given the highest dose of fazirsiran; however, there was no change in three patients and a worsening of 1 point or more in two patients. None of the three patients with evaluable biopsies who received 100 mg showed regression of fibrosis.
Stopping or rolling back fibrosis will be the final goal of proving clinical benefit in liver disease associated with AAT, Dr. Strnad and coinvestigators observe in their published paper, and while the changes seen so far with fazirsiran may not be uniform, they appear to be in the right direction.
Safety findings
”We didn’t see any drug discontinuation, dose interruption, or premature study withdrawals,” said Dr. Strnad.
“We had four different SAE [serious adverse events] which were kind of all over the place and did not seem to be related to treatment.” Those SAEs included viral myocarditis associated with Epstein-Barr virus infection, diverticulitis, dyspnea in a subject with a history of lung disease, and vestibular neuronitis after COVID-19 vaccination.
No significant safety signals were seen regarding lung function. Time will of course tell, he said in response to a question, but “our hope, our hypothesis, is that this will not change lung function dramatically.
“I would not expect any major things over a few years. Of course, whether this can lead to something over 20 years it is difficult to say.”
The current experience with fazirsiran looks good so far, but placebo-controlled, larger and longer studies are needed.
The study was funded by Arrowhead Pharmaceuticals. Dr. Strnad was an investigator in the study and acknowledged receipt of research funding via his institution from the company. Dr. Strnad also acknowledged paid and unpaid relationships with Alnylam Pharmaceuticals, Alpha1 Deutschland, Alpha1 Global, CSL Behring, Grifols Biologicals, Ono Pharmaceuticals, and Takeda California. Dr. Tsochatzis, chaired the late-breaker session at ILC 2022 during which the study findings were presented, was not connected to the study, and reported no relevant conflicts of interest.
AT ILC 2022
Are pain meds the only option for chronic pain in cirrhosis?
Pain is common in patients with cirrhosis, and its management presents significant challenges to health care providers, such as worries about GI bleeding, renal injury, falls, and hepatic encephalopathy.
To address those issues, researchers at the University of Michigan, Ann Arbor, authored a review, published in Hepatology, that describes the pain syndromes experienced by patients, as well as pharmaceutical and nonpharmaceutical treatment options.
“I think it’s a very pragmatic approach to a very common problem. Health care providers are concerned about prescribing analgesia for people with cirrhosis for a number of different reasons. One of them is acetaminophen can be toxic to the liver, but generally only in pretty large doses. It’s actually a pretty good option in a dose of less than about 2 g/day because it doesn’t have some of the side effects that other painkillers such as the NSAIDs have. It doesn’t irritate the stomach, and it doesn’t affect kidney function,” said Paul Martin, MD, who was asked to comment on the review. He is chief of digestive health and liver diseases at the University of Miami.
He appreciated the discussion of both pharmacologic and nonpharmacologic interventions, including diet and psychological interventions. “And I think it provides a useful overview of the pharmacological agents we can use in patients with cirrhosis, so I think it’s a very useful contribution to the literature,” said Dr. Martin.
An estimated 40%-79% of cirrhosis patients experience chronic pain, and it can be a key factor in worsening functional status and quality of life. The authors noted that, although recent practice guidance had recommended involving palliative care providers, psychiatry, and physical therapy in for patients with decompensated cirrhosis, this is not always feasible. The authors also pointed out that there are different pain phenotypes in cirrhosis, and these require different management strategies.
They described three mechanistic categories of chronic pain: Nociceptive pain involves tissue damage and inflammation; neuropathic pain results from nerve damage; and nociplastic pain describes situations in which there is no evidence of tissue or nerve damage, but clinical or psychophysical signs suggest changes to nociception.
The different pain types are best assessed using different tools: The 2016 Fibromyalgia Survey Criteria is useful for nociplastic pain, the Neuropathic Pain Questionnaire and painDETECT can be useful for neuropathic pain, and a physical examination can pinpoint nociceptive pain.
When managing chronic pain, the initial patient workup should include a complete evaluation of the location, quality, and severity of pain, along with any functional interference or associated symptoms like fatigue, mood disturbance, or sensory sensitivity. One option is to use a body map to assess how widespread the pain is. Multisite pain is often a signal that it could be nociplastic. Any comorbid psychiatric disorders should be identified and treated.
The first treatment option for any pain should be self-directed, nonpharmacologic interventions. This is because most analgesics are only modestly effective in the treatment of chronic pain, leading to improvement in only about one in three cases, the authors noted. Opioids have poor efficacy against chronic pain, particularly nociplastic pain, which may even be worsened by opioid use.
Although there is evidence that patients are motivated to seek out nonpharmacologic pain treatment, they have reported frustration by a dearth of simple, evidence-based therapies. The authors noted that digital self-management tools for pain have been developed, including their own PainGuide, which focuses on exercise and behavioral interventions for chronic pain. Other nonpharmacologic approaches include diet modification and sleep hygiene. Patients should be allowed to choose the approach that interests them most, with the physician emphasizing the importance of self-directed management.
Pharmacologic therapy may be added to these approaches, but they have limited utility and are associated with adverse effects. For nociceptive pain, topical NSAIDs like diclofenac gel can be used, as can acetaminophen (500 mg every 6 hours, maximum dose of 2 g/day). Opioids can be employed for short-term treatment of acute pain (for example: hydromorphone 1 mg every 6 hours as needed, oxycodone 2.5 mg by mouth every 6-8 hours as needed, or fentanyl patch in select patients). Tricyclic antidepressants may be used for multiple symptoms or neuropathic pain, but with caution. Neuropathic pain, as well as associated depression or fatigue, can be treated with low-dose serotonin and norepinephrine reuptake inhibitors, though there is a small risk of hepatotoxicity. Neuropathic pain, sleep difficulties, or anxiety can be treated with gabapentin at low starting doses (for example, 300 mg/day) or pregabalin (for example, 50 mg twice a day). Lidocaine patches are an option for peripheral neuropathic pain or postherpetic neuralgia, and topical capsaicin may be used for peripheral neuropathic pain.
“Since all pain types can co-occur, interventions to address nociplastic pain may be broadly therapeutic,” the authors concluded. “The treatment of nociplastic pain emphasizes nonpharmacologic management, including self-management techniques addressing mood, cognitions, behaviors, sleep, and environment. Future research should continue to explore methods of pain phenotyping, as well as self-management therapies, including implementation tools.”
The authors and Dr. Martin reported no relevant conflicts of interest.
Pain is common in patients with cirrhosis, and its management presents significant challenges to health care providers, such as worries about GI bleeding, renal injury, falls, and hepatic encephalopathy.
To address those issues, researchers at the University of Michigan, Ann Arbor, authored a review, published in Hepatology, that describes the pain syndromes experienced by patients, as well as pharmaceutical and nonpharmaceutical treatment options.
“I think it’s a very pragmatic approach to a very common problem. Health care providers are concerned about prescribing analgesia for people with cirrhosis for a number of different reasons. One of them is acetaminophen can be toxic to the liver, but generally only in pretty large doses. It’s actually a pretty good option in a dose of less than about 2 g/day because it doesn’t have some of the side effects that other painkillers such as the NSAIDs have. It doesn’t irritate the stomach, and it doesn’t affect kidney function,” said Paul Martin, MD, who was asked to comment on the review. He is chief of digestive health and liver diseases at the University of Miami.
He appreciated the discussion of both pharmacologic and nonpharmacologic interventions, including diet and psychological interventions. “And I think it provides a useful overview of the pharmacological agents we can use in patients with cirrhosis, so I think it’s a very useful contribution to the literature,” said Dr. Martin.
An estimated 40%-79% of cirrhosis patients experience chronic pain, and it can be a key factor in worsening functional status and quality of life. The authors noted that, although recent practice guidance had recommended involving palliative care providers, psychiatry, and physical therapy in for patients with decompensated cirrhosis, this is not always feasible. The authors also pointed out that there are different pain phenotypes in cirrhosis, and these require different management strategies.
They described three mechanistic categories of chronic pain: Nociceptive pain involves tissue damage and inflammation; neuropathic pain results from nerve damage; and nociplastic pain describes situations in which there is no evidence of tissue or nerve damage, but clinical or psychophysical signs suggest changes to nociception.
The different pain types are best assessed using different tools: The 2016 Fibromyalgia Survey Criteria is useful for nociplastic pain, the Neuropathic Pain Questionnaire and painDETECT can be useful for neuropathic pain, and a physical examination can pinpoint nociceptive pain.
When managing chronic pain, the initial patient workup should include a complete evaluation of the location, quality, and severity of pain, along with any functional interference or associated symptoms like fatigue, mood disturbance, or sensory sensitivity. One option is to use a body map to assess how widespread the pain is. Multisite pain is often a signal that it could be nociplastic. Any comorbid psychiatric disorders should be identified and treated.
The first treatment option for any pain should be self-directed, nonpharmacologic interventions. This is because most analgesics are only modestly effective in the treatment of chronic pain, leading to improvement in only about one in three cases, the authors noted. Opioids have poor efficacy against chronic pain, particularly nociplastic pain, which may even be worsened by opioid use.
Although there is evidence that patients are motivated to seek out nonpharmacologic pain treatment, they have reported frustration by a dearth of simple, evidence-based therapies. The authors noted that digital self-management tools for pain have been developed, including their own PainGuide, which focuses on exercise and behavioral interventions for chronic pain. Other nonpharmacologic approaches include diet modification and sleep hygiene. Patients should be allowed to choose the approach that interests them most, with the physician emphasizing the importance of self-directed management.
Pharmacologic therapy may be added to these approaches, but they have limited utility and are associated with adverse effects. For nociceptive pain, topical NSAIDs like diclofenac gel can be used, as can acetaminophen (500 mg every 6 hours, maximum dose of 2 g/day). Opioids can be employed for short-term treatment of acute pain (for example: hydromorphone 1 mg every 6 hours as needed, oxycodone 2.5 mg by mouth every 6-8 hours as needed, or fentanyl patch in select patients). Tricyclic antidepressants may be used for multiple symptoms or neuropathic pain, but with caution. Neuropathic pain, as well as associated depression or fatigue, can be treated with low-dose serotonin and norepinephrine reuptake inhibitors, though there is a small risk of hepatotoxicity. Neuropathic pain, sleep difficulties, or anxiety can be treated with gabapentin at low starting doses (for example, 300 mg/day) or pregabalin (for example, 50 mg twice a day). Lidocaine patches are an option for peripheral neuropathic pain or postherpetic neuralgia, and topical capsaicin may be used for peripheral neuropathic pain.
“Since all pain types can co-occur, interventions to address nociplastic pain may be broadly therapeutic,” the authors concluded. “The treatment of nociplastic pain emphasizes nonpharmacologic management, including self-management techniques addressing mood, cognitions, behaviors, sleep, and environment. Future research should continue to explore methods of pain phenotyping, as well as self-management therapies, including implementation tools.”
The authors and Dr. Martin reported no relevant conflicts of interest.
Pain is common in patients with cirrhosis, and its management presents significant challenges to health care providers, such as worries about GI bleeding, renal injury, falls, and hepatic encephalopathy.
To address those issues, researchers at the University of Michigan, Ann Arbor, authored a review, published in Hepatology, that describes the pain syndromes experienced by patients, as well as pharmaceutical and nonpharmaceutical treatment options.
“I think it’s a very pragmatic approach to a very common problem. Health care providers are concerned about prescribing analgesia for people with cirrhosis for a number of different reasons. One of them is acetaminophen can be toxic to the liver, but generally only in pretty large doses. It’s actually a pretty good option in a dose of less than about 2 g/day because it doesn’t have some of the side effects that other painkillers such as the NSAIDs have. It doesn’t irritate the stomach, and it doesn’t affect kidney function,” said Paul Martin, MD, who was asked to comment on the review. He is chief of digestive health and liver diseases at the University of Miami.
He appreciated the discussion of both pharmacologic and nonpharmacologic interventions, including diet and psychological interventions. “And I think it provides a useful overview of the pharmacological agents we can use in patients with cirrhosis, so I think it’s a very useful contribution to the literature,” said Dr. Martin.
An estimated 40%-79% of cirrhosis patients experience chronic pain, and it can be a key factor in worsening functional status and quality of life. The authors noted that, although recent practice guidance had recommended involving palliative care providers, psychiatry, and physical therapy in for patients with decompensated cirrhosis, this is not always feasible. The authors also pointed out that there are different pain phenotypes in cirrhosis, and these require different management strategies.
They described three mechanistic categories of chronic pain: Nociceptive pain involves tissue damage and inflammation; neuropathic pain results from nerve damage; and nociplastic pain describes situations in which there is no evidence of tissue or nerve damage, but clinical or psychophysical signs suggest changes to nociception.
The different pain types are best assessed using different tools: The 2016 Fibromyalgia Survey Criteria is useful for nociplastic pain, the Neuropathic Pain Questionnaire and painDETECT can be useful for neuropathic pain, and a physical examination can pinpoint nociceptive pain.
When managing chronic pain, the initial patient workup should include a complete evaluation of the location, quality, and severity of pain, along with any functional interference or associated symptoms like fatigue, mood disturbance, or sensory sensitivity. One option is to use a body map to assess how widespread the pain is. Multisite pain is often a signal that it could be nociplastic. Any comorbid psychiatric disorders should be identified and treated.
The first treatment option for any pain should be self-directed, nonpharmacologic interventions. This is because most analgesics are only modestly effective in the treatment of chronic pain, leading to improvement in only about one in three cases, the authors noted. Opioids have poor efficacy against chronic pain, particularly nociplastic pain, which may even be worsened by opioid use.
Although there is evidence that patients are motivated to seek out nonpharmacologic pain treatment, they have reported frustration by a dearth of simple, evidence-based therapies. The authors noted that digital self-management tools for pain have been developed, including their own PainGuide, which focuses on exercise and behavioral interventions for chronic pain. Other nonpharmacologic approaches include diet modification and sleep hygiene. Patients should be allowed to choose the approach that interests them most, with the physician emphasizing the importance of self-directed management.
Pharmacologic therapy may be added to these approaches, but they have limited utility and are associated with adverse effects. For nociceptive pain, topical NSAIDs like diclofenac gel can be used, as can acetaminophen (500 mg every 6 hours, maximum dose of 2 g/day). Opioids can be employed for short-term treatment of acute pain (for example: hydromorphone 1 mg every 6 hours as needed, oxycodone 2.5 mg by mouth every 6-8 hours as needed, or fentanyl patch in select patients). Tricyclic antidepressants may be used for multiple symptoms or neuropathic pain, but with caution. Neuropathic pain, as well as associated depression or fatigue, can be treated with low-dose serotonin and norepinephrine reuptake inhibitors, though there is a small risk of hepatotoxicity. Neuropathic pain, sleep difficulties, or anxiety can be treated with gabapentin at low starting doses (for example, 300 mg/day) or pregabalin (for example, 50 mg twice a day). Lidocaine patches are an option for peripheral neuropathic pain or postherpetic neuralgia, and topical capsaicin may be used for peripheral neuropathic pain.
“Since all pain types can co-occur, interventions to address nociplastic pain may be broadly therapeutic,” the authors concluded. “The treatment of nociplastic pain emphasizes nonpharmacologic management, including self-management techniques addressing mood, cognitions, behaviors, sleep, and environment. Future research should continue to explore methods of pain phenotyping, as well as self-management therapies, including implementation tools.”
The authors and Dr. Martin reported no relevant conflicts of interest.
FROM HEPATOLOGY
Pediatric hepatitis has not increased during pandemic: CDC
The number of pediatric hepatitis cases has remained steady since 2017, new research from the Centers for Disease Control and Prevention suggests, despite the recent investigation into children with hepatitis of unknown cause. The study also found that there was no indication of elevated rates of adenovirus type 40/41 infection in children.
But Rohit Kohli, MBBS, MS, chief of the Division of Gastroenterology, Hepatology, and Nutrition at the Children’s Hospital Los Angeles, California, says that although the study is “well-designed and robust,” that does not mean that these hepatitis cases of unknown origin are no longer a concern. He was not involved with the CDC research. “As a clinician, I’m still worried,” he said. “Why I feel like this is not conclusive is that there are other data from entities like the United Kingdom Health Security Agency that are incongruent with [these findings],” he said.
The research was published in the CDC’s Morbidity and Mortality Weekly Report.
In November 2021, the Alabama Department of Public Health began an investigation with the CDC after a cluster of children were admitted to a children’s hospital in the state with severe hepatitis, who all tested positive for adenovirus. When the United Kingdom’s Health Security Agency announced an investigation into similar cases in early April 2022, the CDC decided to expand their search nationally.
Now, as of June 15, the agency is investigating 290 cases in 41 states and U.S. territories. Worldwide, 650 cases in 33 countries have been reported, according to the most recent update by the World Health Organization on May 27, 2022. At least 38 patients have needed liver transplants, and nine deaths have been reported to WHO.
In its most recent press call on the topic, the CDC announced that it’s aware of six deaths in the United States through May 20, 2022. The COVID-19 vaccine has been ruled out as a potential cause because the majority of affected children are unvaccinated or are too young to receive the vaccine. Adenovirus infection remains a leading suspect in these sick children because the virus has been detected in 60.8% of tested cases, WHO reports.
Investigators have detected an increase in reported pediatric hepatitis cases, compared with prior years in the United Kingdom, but it was not clear whether that same pattern would be found in the United States. Neither pediatric hepatitis nor adenovirus type 40/41 are reportable conditions in the United States. In the May 20 CDC press call, Umesh Parashar, MD, chief of the CDC’s Viral Gastroenteritis Branch, said that an estimated 1,500-2,000 children aged younger than 10 are hospitalized in the United States for hepatitis every year. “That’s a fairly large number,” he said, and it might make it difficult to detect a small increase in cases.
To better estimate trends in pediatric hepatitis and adenovirus infection in the United States, investigators collected available data on emergency department (ED) visits, hospitalizations, and liver transplants associated with hepatitis in children as well as adenovirus stool testing results. Researchers used four large databases: the National Syndromic Surveillance Program; the Premier Healthcare Database Special Release; the Organ Procurement and Transplant Network; and Labcorp, which is a large commercial lab network.
To account for changes in health care utilization in the first year of the COVID-19 pandemic, the team compared hepatitis-associated ED visits, hospitalizations, and liver transplants from October 2021 to March 2022 versus the same months (January to March and October to December) in 2017, 2018, and 2019. For adenovirus stool testing, results from October 2021 to March 2022 were compared with the same calendar months (October to March) from 2017-2018, 2018-2019, and 2019-2020, to help control for seasonality.
Investigators found no statistically significant increases in the outcomes during October 2021 to March 2022 versus pre-pandemic years:
- Weekly ED visits with hepatitis-associated discharge codes
- Hepatitis-associated monthly hospitalizations in children aged 0-4 years (22 vs. 19.5; P = .26)
- Hepatitis-associated monthly hospitalization in children aged 5-11 years (12 vs. 10.5; P = .42)
- Monthly liver transplants (5 vs. 4; P = .19)
- Percentage of stool specimens positive for adenovirus types 40/41, though the number of specimens tested was highest in March 2022
The authors acknowledged that pediatric hepatitis is rare, so it may be difficult tease out small changes in the number of cases. Also, data on hospitalizations and liver transplants have a 2- to 3-month reporting delay, so the case counts for March 2022 “might be underreported,” they wrote. Mr. Kohli noted that because hepatitis and adenovirus are not reportable conditions, the analysis relied on retrospective data from insurance companies and electronic medical records. Retrospective data are inherently limited, compared with prospective analyses, he said, and it’s possible that certain cases could be included in more than one database and thus be double-counted, whereas other cases could be missed entirely.
These findings also conflict with data from the United Kingdom, which in May reported that the average number of hepatitis cases had increased, compared with previous years, he said. More data are needed, he said, and he is involved with a study with the North American Society for Pediatric Gastroenterology and the American Association for the Study of Liver Diseases that is also collecting data to try to understand whether there has been an uptick in pediatric hepatitis cases. The study will collect patient data directly from hospitals as well as include additional pathology data, such as biopsy results.
“We should not be inhibited to look further academically – and public health–wise – while we take into cognizance this very good, robust attempt from the CDC,” he said.
A version of this article first appeared on Medscape.com.
The number of pediatric hepatitis cases has remained steady since 2017, new research from the Centers for Disease Control and Prevention suggests, despite the recent investigation into children with hepatitis of unknown cause. The study also found that there was no indication of elevated rates of adenovirus type 40/41 infection in children.
But Rohit Kohli, MBBS, MS, chief of the Division of Gastroenterology, Hepatology, and Nutrition at the Children’s Hospital Los Angeles, California, says that although the study is “well-designed and robust,” that does not mean that these hepatitis cases of unknown origin are no longer a concern. He was not involved with the CDC research. “As a clinician, I’m still worried,” he said. “Why I feel like this is not conclusive is that there are other data from entities like the United Kingdom Health Security Agency that are incongruent with [these findings],” he said.
The research was published in the CDC’s Morbidity and Mortality Weekly Report.
In November 2021, the Alabama Department of Public Health began an investigation with the CDC after a cluster of children were admitted to a children’s hospital in the state with severe hepatitis, who all tested positive for adenovirus. When the United Kingdom’s Health Security Agency announced an investigation into similar cases in early April 2022, the CDC decided to expand their search nationally.
Now, as of June 15, the agency is investigating 290 cases in 41 states and U.S. territories. Worldwide, 650 cases in 33 countries have been reported, according to the most recent update by the World Health Organization on May 27, 2022. At least 38 patients have needed liver transplants, and nine deaths have been reported to WHO.
In its most recent press call on the topic, the CDC announced that it’s aware of six deaths in the United States through May 20, 2022. The COVID-19 vaccine has been ruled out as a potential cause because the majority of affected children are unvaccinated or are too young to receive the vaccine. Adenovirus infection remains a leading suspect in these sick children because the virus has been detected in 60.8% of tested cases, WHO reports.
Investigators have detected an increase in reported pediatric hepatitis cases, compared with prior years in the United Kingdom, but it was not clear whether that same pattern would be found in the United States. Neither pediatric hepatitis nor adenovirus type 40/41 are reportable conditions in the United States. In the May 20 CDC press call, Umesh Parashar, MD, chief of the CDC’s Viral Gastroenteritis Branch, said that an estimated 1,500-2,000 children aged younger than 10 are hospitalized in the United States for hepatitis every year. “That’s a fairly large number,” he said, and it might make it difficult to detect a small increase in cases.
To better estimate trends in pediatric hepatitis and adenovirus infection in the United States, investigators collected available data on emergency department (ED) visits, hospitalizations, and liver transplants associated with hepatitis in children as well as adenovirus stool testing results. Researchers used four large databases: the National Syndromic Surveillance Program; the Premier Healthcare Database Special Release; the Organ Procurement and Transplant Network; and Labcorp, which is a large commercial lab network.
To account for changes in health care utilization in the first year of the COVID-19 pandemic, the team compared hepatitis-associated ED visits, hospitalizations, and liver transplants from October 2021 to March 2022 versus the same months (January to March and October to December) in 2017, 2018, and 2019. For adenovirus stool testing, results from October 2021 to March 2022 were compared with the same calendar months (October to March) from 2017-2018, 2018-2019, and 2019-2020, to help control for seasonality.
Investigators found no statistically significant increases in the outcomes during October 2021 to March 2022 versus pre-pandemic years:
- Weekly ED visits with hepatitis-associated discharge codes
- Hepatitis-associated monthly hospitalizations in children aged 0-4 years (22 vs. 19.5; P = .26)
- Hepatitis-associated monthly hospitalization in children aged 5-11 years (12 vs. 10.5; P = .42)
- Monthly liver transplants (5 vs. 4; P = .19)
- Percentage of stool specimens positive for adenovirus types 40/41, though the number of specimens tested was highest in March 2022
The authors acknowledged that pediatric hepatitis is rare, so it may be difficult tease out small changes in the number of cases. Also, data on hospitalizations and liver transplants have a 2- to 3-month reporting delay, so the case counts for March 2022 “might be underreported,” they wrote. Mr. Kohli noted that because hepatitis and adenovirus are not reportable conditions, the analysis relied on retrospective data from insurance companies and electronic medical records. Retrospective data are inherently limited, compared with prospective analyses, he said, and it’s possible that certain cases could be included in more than one database and thus be double-counted, whereas other cases could be missed entirely.
These findings also conflict with data from the United Kingdom, which in May reported that the average number of hepatitis cases had increased, compared with previous years, he said. More data are needed, he said, and he is involved with a study with the North American Society for Pediatric Gastroenterology and the American Association for the Study of Liver Diseases that is also collecting data to try to understand whether there has been an uptick in pediatric hepatitis cases. The study will collect patient data directly from hospitals as well as include additional pathology data, such as biopsy results.
“We should not be inhibited to look further academically – and public health–wise – while we take into cognizance this very good, robust attempt from the CDC,” he said.
A version of this article first appeared on Medscape.com.
The number of pediatric hepatitis cases has remained steady since 2017, new research from the Centers for Disease Control and Prevention suggests, despite the recent investigation into children with hepatitis of unknown cause. The study also found that there was no indication of elevated rates of adenovirus type 40/41 infection in children.
But Rohit Kohli, MBBS, MS, chief of the Division of Gastroenterology, Hepatology, and Nutrition at the Children’s Hospital Los Angeles, California, says that although the study is “well-designed and robust,” that does not mean that these hepatitis cases of unknown origin are no longer a concern. He was not involved with the CDC research. “As a clinician, I’m still worried,” he said. “Why I feel like this is not conclusive is that there are other data from entities like the United Kingdom Health Security Agency that are incongruent with [these findings],” he said.
The research was published in the CDC’s Morbidity and Mortality Weekly Report.
In November 2021, the Alabama Department of Public Health began an investigation with the CDC after a cluster of children were admitted to a children’s hospital in the state with severe hepatitis, who all tested positive for adenovirus. When the United Kingdom’s Health Security Agency announced an investigation into similar cases in early April 2022, the CDC decided to expand their search nationally.
Now, as of June 15, the agency is investigating 290 cases in 41 states and U.S. territories. Worldwide, 650 cases in 33 countries have been reported, according to the most recent update by the World Health Organization on May 27, 2022. At least 38 patients have needed liver transplants, and nine deaths have been reported to WHO.
In its most recent press call on the topic, the CDC announced that it’s aware of six deaths in the United States through May 20, 2022. The COVID-19 vaccine has been ruled out as a potential cause because the majority of affected children are unvaccinated or are too young to receive the vaccine. Adenovirus infection remains a leading suspect in these sick children because the virus has been detected in 60.8% of tested cases, WHO reports.
Investigators have detected an increase in reported pediatric hepatitis cases, compared with prior years in the United Kingdom, but it was not clear whether that same pattern would be found in the United States. Neither pediatric hepatitis nor adenovirus type 40/41 are reportable conditions in the United States. In the May 20 CDC press call, Umesh Parashar, MD, chief of the CDC’s Viral Gastroenteritis Branch, said that an estimated 1,500-2,000 children aged younger than 10 are hospitalized in the United States for hepatitis every year. “That’s a fairly large number,” he said, and it might make it difficult to detect a small increase in cases.
To better estimate trends in pediatric hepatitis and adenovirus infection in the United States, investigators collected available data on emergency department (ED) visits, hospitalizations, and liver transplants associated with hepatitis in children as well as adenovirus stool testing results. Researchers used four large databases: the National Syndromic Surveillance Program; the Premier Healthcare Database Special Release; the Organ Procurement and Transplant Network; and Labcorp, which is a large commercial lab network.
To account for changes in health care utilization in the first year of the COVID-19 pandemic, the team compared hepatitis-associated ED visits, hospitalizations, and liver transplants from October 2021 to March 2022 versus the same months (January to March and October to December) in 2017, 2018, and 2019. For adenovirus stool testing, results from October 2021 to March 2022 were compared with the same calendar months (October to March) from 2017-2018, 2018-2019, and 2019-2020, to help control for seasonality.
Investigators found no statistically significant increases in the outcomes during October 2021 to March 2022 versus pre-pandemic years:
- Weekly ED visits with hepatitis-associated discharge codes
- Hepatitis-associated monthly hospitalizations in children aged 0-4 years (22 vs. 19.5; P = .26)
- Hepatitis-associated monthly hospitalization in children aged 5-11 years (12 vs. 10.5; P = .42)
- Monthly liver transplants (5 vs. 4; P = .19)
- Percentage of stool specimens positive for adenovirus types 40/41, though the number of specimens tested was highest in March 2022
The authors acknowledged that pediatric hepatitis is rare, so it may be difficult tease out small changes in the number of cases. Also, data on hospitalizations and liver transplants have a 2- to 3-month reporting delay, so the case counts for March 2022 “might be underreported,” they wrote. Mr. Kohli noted that because hepatitis and adenovirus are not reportable conditions, the analysis relied on retrospective data from insurance companies and electronic medical records. Retrospective data are inherently limited, compared with prospective analyses, he said, and it’s possible that certain cases could be included in more than one database and thus be double-counted, whereas other cases could be missed entirely.
These findings also conflict with data from the United Kingdom, which in May reported that the average number of hepatitis cases had increased, compared with previous years, he said. More data are needed, he said, and he is involved with a study with the North American Society for Pediatric Gastroenterology and the American Association for the Study of Liver Diseases that is also collecting data to try to understand whether there has been an uptick in pediatric hepatitis cases. The study will collect patient data directly from hospitals as well as include additional pathology data, such as biopsy results.
“We should not be inhibited to look further academically – and public health–wise – while we take into cognizance this very good, robust attempt from the CDC,” he said.
A version of this article first appeared on Medscape.com.
FROM MMWR
Liver transplanted after 3 days outside body
A poor-quality human liver, rejected by all transplant centers, was treated outside the body for 3 days using a perfusion machine that simulated some functions of the human body and has been successfully transplanted into a patient with advanced cirrhosis.
The 62-year-old patient rapidly returned to normal quality of life and at the 1-year follow-up had no signs of liver damage, such as rejection or bile duct injury, according to the report published in Nature Biotechnology.
The study team was led by Pierre-Alain Clavien, MD, PhD, with the department of surgery and transplantation, Swiss Hepato-Pancreato-Biliary and Transplant Center, University Hospital Zürich, and the Wyss Zürich Translational Center, ETH Zürich and University of Zürich.
Expanding the viability window
Livers for transplant are routinely preserved in a static cold solution and implanted within a few hours. Most centers limit the time in the cold solution to 12 hours as the organ’s viability drops quickly after that time.
“This inaugural clinical success opens new horizons in clinical research and promises an extended time window of up to 10 days for assessment of viability of donor organs as well as converting an urgent and highly demanding surgery into an elective procedure,” the authors wrote.
The Liver4Life team, made up of physicians, engineers, and biochemists, developed the complex perfusion machine. Features of the machine, which mimics human body functions, include automated remote control of all key parameters. A pump mimics the heart, an oxygenator replaces the lungs, and a dialysis unit performs as kidneys would. Hormone and nutrient infusions take over the work of the intestines and pancreas. The machine also moves the liver to the rhythm of simulated breathing.
The team had to solve factors that limit viability for any solid organ outside the body over a few hours including hemolysis, hemodynamic stability, glucose control, pathologic glycogen deposition and perfusate quality and dilution.
Additionally, because the organ would be under machine perfusion for several days, the scientists also had to address pressure necrosis.
History behind the procedure
The process started in 2015 with the support of the Wyss Zürich Translational Center, with the goal of long-term ex situ machine perfusion of injured liver grafts.
As part of the agreement from the Swiss regulatory authority (the Federal Office of Public Health) the process would be used only if the organ was rejected by all transplant centers, the recipient had no other options for a donor liver, and if the organ met a rigorous bar for viability.
On May 19, 2021, the team was offered a liver graft from a 29-year-old female donor who had an invasive abdominal desmoid fibromatosis associated with chronic intra-abdominal abscesses and recurrent sepsis episodes from multiresistant bacteria. The donor needed long-term multiple medications and parenteral nutrition. Additionally, there was a 4-cm tumor in segment 1 of the liver.
The liver was refused by all other centers, “primarily because it required diagnostic workup of the liver lesion, which was not immediately possible, and because of the ongoing sepsis in the donor with multiresistant microorganisms,” the authors wrote.
The team removed the liver, and the graft was connected to the Wyss perfusion device for normothermic (37 °C) ex situ perfusion after 4 hours of cold preservation.
A 62-year-old male potential recipient on the official national transplant list, had earlier agreed to be considered for receiving a graft preserved ex situ in the Wyss machine.
The patient was fully informed about the process and the presence of a benign lesion in the graft and accepted the transplantation procedure. The patient had advanced cirrhosis, severe portal hypertension, and multiple and recurrent hepatocellular carcinoma (HCC).
Recipient had ‘near-zero’ chance to get a liver in time
The authors wrote that the patient had “a near-zero chance to receive a graft in time.”
For patients with HCC in Switzerland, the wait for liver transplant is longer than a year and no living-donor options were available.
The transplant operation took 5 hours and 26 minutes and blood loss was limited (600 mL). No transfusion was required. The patient was extubated in the operating room, transferred to the ICU, and discharged 12 days later.
Because a biopsy showed no detectable liver injury or rejection, and based on previous evidence of lower immunogenicity in perfused livers and kidneys, the researchers chose a reduced immunosuppressive regimen with quickly tapering steroids. The steroids were completely discontinued 6 weeks after surgery.
The authors wrote: “In our experience, the absence or very low degree of reperfusion injury seen in our transplant is observed only in living donation, where ‘close-to-perfect’ livers from healthy young donors are transplanted immediately as both donors and recipient are operated in parallel.”
In a press release, the team said the next step is to assess the procedure in other patients in a multicenter study.
Dr. Clavien and several coauthors affiliated with ETH (the Swiss Federal Institute of Technology in Zürich) and the University of Zürich have applied for patents on this new perfusion technology. No other authors have any competing interest.
A poor-quality human liver, rejected by all transplant centers, was treated outside the body for 3 days using a perfusion machine that simulated some functions of the human body and has been successfully transplanted into a patient with advanced cirrhosis.
The 62-year-old patient rapidly returned to normal quality of life and at the 1-year follow-up had no signs of liver damage, such as rejection or bile duct injury, according to the report published in Nature Biotechnology.
The study team was led by Pierre-Alain Clavien, MD, PhD, with the department of surgery and transplantation, Swiss Hepato-Pancreato-Biliary and Transplant Center, University Hospital Zürich, and the Wyss Zürich Translational Center, ETH Zürich and University of Zürich.
Expanding the viability window
Livers for transplant are routinely preserved in a static cold solution and implanted within a few hours. Most centers limit the time in the cold solution to 12 hours as the organ’s viability drops quickly after that time.
“This inaugural clinical success opens new horizons in clinical research and promises an extended time window of up to 10 days for assessment of viability of donor organs as well as converting an urgent and highly demanding surgery into an elective procedure,” the authors wrote.
The Liver4Life team, made up of physicians, engineers, and biochemists, developed the complex perfusion machine. Features of the machine, which mimics human body functions, include automated remote control of all key parameters. A pump mimics the heart, an oxygenator replaces the lungs, and a dialysis unit performs as kidneys would. Hormone and nutrient infusions take over the work of the intestines and pancreas. The machine also moves the liver to the rhythm of simulated breathing.
The team had to solve factors that limit viability for any solid organ outside the body over a few hours including hemolysis, hemodynamic stability, glucose control, pathologic glycogen deposition and perfusate quality and dilution.
Additionally, because the organ would be under machine perfusion for several days, the scientists also had to address pressure necrosis.
History behind the procedure
The process started in 2015 with the support of the Wyss Zürich Translational Center, with the goal of long-term ex situ machine perfusion of injured liver grafts.
As part of the agreement from the Swiss regulatory authority (the Federal Office of Public Health) the process would be used only if the organ was rejected by all transplant centers, the recipient had no other options for a donor liver, and if the organ met a rigorous bar for viability.
On May 19, 2021, the team was offered a liver graft from a 29-year-old female donor who had an invasive abdominal desmoid fibromatosis associated with chronic intra-abdominal abscesses and recurrent sepsis episodes from multiresistant bacteria. The donor needed long-term multiple medications and parenteral nutrition. Additionally, there was a 4-cm tumor in segment 1 of the liver.
The liver was refused by all other centers, “primarily because it required diagnostic workup of the liver lesion, which was not immediately possible, and because of the ongoing sepsis in the donor with multiresistant microorganisms,” the authors wrote.
The team removed the liver, and the graft was connected to the Wyss perfusion device for normothermic (37 °C) ex situ perfusion after 4 hours of cold preservation.
A 62-year-old male potential recipient on the official national transplant list, had earlier agreed to be considered for receiving a graft preserved ex situ in the Wyss machine.
The patient was fully informed about the process and the presence of a benign lesion in the graft and accepted the transplantation procedure. The patient had advanced cirrhosis, severe portal hypertension, and multiple and recurrent hepatocellular carcinoma (HCC).
Recipient had ‘near-zero’ chance to get a liver in time
The authors wrote that the patient had “a near-zero chance to receive a graft in time.”
For patients with HCC in Switzerland, the wait for liver transplant is longer than a year and no living-donor options were available.
The transplant operation took 5 hours and 26 minutes and blood loss was limited (600 mL). No transfusion was required. The patient was extubated in the operating room, transferred to the ICU, and discharged 12 days later.
Because a biopsy showed no detectable liver injury or rejection, and based on previous evidence of lower immunogenicity in perfused livers and kidneys, the researchers chose a reduced immunosuppressive regimen with quickly tapering steroids. The steroids were completely discontinued 6 weeks after surgery.
The authors wrote: “In our experience, the absence or very low degree of reperfusion injury seen in our transplant is observed only in living donation, where ‘close-to-perfect’ livers from healthy young donors are transplanted immediately as both donors and recipient are operated in parallel.”
In a press release, the team said the next step is to assess the procedure in other patients in a multicenter study.
Dr. Clavien and several coauthors affiliated with ETH (the Swiss Federal Institute of Technology in Zürich) and the University of Zürich have applied for patents on this new perfusion technology. No other authors have any competing interest.
A poor-quality human liver, rejected by all transplant centers, was treated outside the body for 3 days using a perfusion machine that simulated some functions of the human body and has been successfully transplanted into a patient with advanced cirrhosis.
The 62-year-old patient rapidly returned to normal quality of life and at the 1-year follow-up had no signs of liver damage, such as rejection or bile duct injury, according to the report published in Nature Biotechnology.
The study team was led by Pierre-Alain Clavien, MD, PhD, with the department of surgery and transplantation, Swiss Hepato-Pancreato-Biliary and Transplant Center, University Hospital Zürich, and the Wyss Zürich Translational Center, ETH Zürich and University of Zürich.
Expanding the viability window
Livers for transplant are routinely preserved in a static cold solution and implanted within a few hours. Most centers limit the time in the cold solution to 12 hours as the organ’s viability drops quickly after that time.
“This inaugural clinical success opens new horizons in clinical research and promises an extended time window of up to 10 days for assessment of viability of donor organs as well as converting an urgent and highly demanding surgery into an elective procedure,” the authors wrote.
The Liver4Life team, made up of physicians, engineers, and biochemists, developed the complex perfusion machine. Features of the machine, which mimics human body functions, include automated remote control of all key parameters. A pump mimics the heart, an oxygenator replaces the lungs, and a dialysis unit performs as kidneys would. Hormone and nutrient infusions take over the work of the intestines and pancreas. The machine also moves the liver to the rhythm of simulated breathing.
The team had to solve factors that limit viability for any solid organ outside the body over a few hours including hemolysis, hemodynamic stability, glucose control, pathologic glycogen deposition and perfusate quality and dilution.
Additionally, because the organ would be under machine perfusion for several days, the scientists also had to address pressure necrosis.
History behind the procedure
The process started in 2015 with the support of the Wyss Zürich Translational Center, with the goal of long-term ex situ machine perfusion of injured liver grafts.
As part of the agreement from the Swiss regulatory authority (the Federal Office of Public Health) the process would be used only if the organ was rejected by all transplant centers, the recipient had no other options for a donor liver, and if the organ met a rigorous bar for viability.
On May 19, 2021, the team was offered a liver graft from a 29-year-old female donor who had an invasive abdominal desmoid fibromatosis associated with chronic intra-abdominal abscesses and recurrent sepsis episodes from multiresistant bacteria. The donor needed long-term multiple medications and parenteral nutrition. Additionally, there was a 4-cm tumor in segment 1 of the liver.
The liver was refused by all other centers, “primarily because it required diagnostic workup of the liver lesion, which was not immediately possible, and because of the ongoing sepsis in the donor with multiresistant microorganisms,” the authors wrote.
The team removed the liver, and the graft was connected to the Wyss perfusion device for normothermic (37 °C) ex situ perfusion after 4 hours of cold preservation.
A 62-year-old male potential recipient on the official national transplant list, had earlier agreed to be considered for receiving a graft preserved ex situ in the Wyss machine.
The patient was fully informed about the process and the presence of a benign lesion in the graft and accepted the transplantation procedure. The patient had advanced cirrhosis, severe portal hypertension, and multiple and recurrent hepatocellular carcinoma (HCC).
Recipient had ‘near-zero’ chance to get a liver in time
The authors wrote that the patient had “a near-zero chance to receive a graft in time.”
For patients with HCC in Switzerland, the wait for liver transplant is longer than a year and no living-donor options were available.
The transplant operation took 5 hours and 26 minutes and blood loss was limited (600 mL). No transfusion was required. The patient was extubated in the operating room, transferred to the ICU, and discharged 12 days later.
Because a biopsy showed no detectable liver injury or rejection, and based on previous evidence of lower immunogenicity in perfused livers and kidneys, the researchers chose a reduced immunosuppressive regimen with quickly tapering steroids. The steroids were completely discontinued 6 weeks after surgery.
The authors wrote: “In our experience, the absence or very low degree of reperfusion injury seen in our transplant is observed only in living donation, where ‘close-to-perfect’ livers from healthy young donors are transplanted immediately as both donors and recipient are operated in parallel.”
In a press release, the team said the next step is to assess the procedure in other patients in a multicenter study.
Dr. Clavien and several coauthors affiliated with ETH (the Swiss Federal Institute of Technology in Zürich) and the University of Zürich have applied for patents on this new perfusion technology. No other authors have any competing interest.
FROM NATURE BIOTECHNOLOGY
Race-, ethnicity-based clinical guidelines miss the mark: Study
SAN DIEGO – Race-based recommendations and clinical algorithms may be doing more harm than good, according to a systematic review of databases and guidelines.
The study found examples of screening recommendations based on race or ethnicity that were likely misleading since these are social constructs that don’t reflect a patient’s individual risk, said Shazia Siddique, MD, who presented the study at the annual Digestive Disease Week® (DDW). “Historically, we’ve made so many clinical decisions based on somebody’s race and ethnicity. We walk into a room, we don’t even ask people which racial or ethnic category they identify with. We just look at them and we say, ‘Their skin color looks black, and therefore we’re going to apply a different equation to them.’ ”
However, a patient’s risks and unique health circumstances are much more complicated than that. They may be related to genetics, or environmental exposures, or level of access to quality health care. Race can often be inappropriately used as a stand-in for these and other factors, she explained.
“These [racial] categories are truly a social construct. It’s becoming very problematic that people are literally making decisions based on somebody’s skin color. That’s just not what the science supports. If there are specific genes or environmental factors, or differences in access to health care that then impact outcomes for certain racial or ethnic groups, we need to figure out what those are,” said Dr. Siddique, who is an assistant professor of medicine at the University of Pennsylvania, Philadelphia.
Those messages are still entrenched in medical education. “I graduated medical school in 2012, and it was taught to me to use race and ethnicity in clinical decision-making. We need to start in medical education to shift the way that we’re thinking. On the research side, we really need to think about how we can replace or remove race and ethnicity and understand the consequences of that, so that over time we can make a shift,” said Dr. Siddique.
For example, Dr. Siddique discussed recommendations that suggest Asian heritage as a risk factor for hepatitis B screening, but that’s not a good factor to consider: “People were saying that Asians should be screened at an earlier age, but it’s really people that were born and raised in Asian countries where it’s endemic or they may have gotten it from their mothers at birth. It’s a marker for how long you have had the disease and how much virus is in your bloodstream. It’s not because you’re Asian. If you’re born and raised in the United States, and you don’t have any of those risk factors, you shouldn’t be treated differently based on your identified racial and ethnic group,” said Dr. Siddique.
These questions have become even more important in recent years because of patients with multiracial identifies and other considerations. “Now the proxy for which race was being used is even messier,” said Dr. Siddique.
So, how should physicians think about assessing a patient’s personalized risks? The key, said Dr. Siddique, is to look at each patient’s individual factors, such as health care access, environmental exposures from jobs or living conditions, or the country they emigrated from if they weren’t born in the United States. “Disease prevalences are different in different areas, and that changes your index of suspicion,” she said.
And when considering current guidelines that incorporate race or ethnicity, she recommends viewing them skeptically: “If there is a current algorithm in your health system or in a guideline that you’re reading that says you should be making a change based on race and ethnicity, you should look at that with a close eye and say, “What do I think it’s being used as a proxy for, and how can I elicit that from my patient?’ ”
The issues raised by Dr. Siddique’s study are important, but there also could be concerns in taking them too far, according to Gary Falk, MD, a professor of medicine at the University of Pennsylvania who comoderated the session where Dr. Siddique presented. He was not involved in the study, but was listed on Dr. Siddique’s acknowledgement slide.
Dr. Falk coauthored Barrett’s esophagus guidelines in 2016 that incorporated White race as a risk factor.
“There are certain clear ethnic factors or country of origin factors that impact one’s risk for cancer, and there are certain diseases that are more common in certain ethnic groups. I think that if we homogenize everybody, we may potentially hurt some people in the effort to be inclusive. That’s my only concern. I think it’s totally correct that we have to get out of our comfort zone, but I hate to see us reach too far on the other end, and homogenize things to the point that people who have increased risk are not being recognized for that reason,” said Dr. Falk.
He acknowledged that White race as a risk for Barrett’s is not easy to define given the uncertainty of the genetic risk, for example, in patients with mixed heritage. “This is all very provocative. We have to think about it carefully,” said Dr. Falk.
Dr. Siddique and Dr. Falk have no relevant financial disclosures.
SAN DIEGO – Race-based recommendations and clinical algorithms may be doing more harm than good, according to a systematic review of databases and guidelines.
The study found examples of screening recommendations based on race or ethnicity that were likely misleading since these are social constructs that don’t reflect a patient’s individual risk, said Shazia Siddique, MD, who presented the study at the annual Digestive Disease Week® (DDW). “Historically, we’ve made so many clinical decisions based on somebody’s race and ethnicity. We walk into a room, we don’t even ask people which racial or ethnic category they identify with. We just look at them and we say, ‘Their skin color looks black, and therefore we’re going to apply a different equation to them.’ ”
However, a patient’s risks and unique health circumstances are much more complicated than that. They may be related to genetics, or environmental exposures, or level of access to quality health care. Race can often be inappropriately used as a stand-in for these and other factors, she explained.
“These [racial] categories are truly a social construct. It’s becoming very problematic that people are literally making decisions based on somebody’s skin color. That’s just not what the science supports. If there are specific genes or environmental factors, or differences in access to health care that then impact outcomes for certain racial or ethnic groups, we need to figure out what those are,” said Dr. Siddique, who is an assistant professor of medicine at the University of Pennsylvania, Philadelphia.
Those messages are still entrenched in medical education. “I graduated medical school in 2012, and it was taught to me to use race and ethnicity in clinical decision-making. We need to start in medical education to shift the way that we’re thinking. On the research side, we really need to think about how we can replace or remove race and ethnicity and understand the consequences of that, so that over time we can make a shift,” said Dr. Siddique.
For example, Dr. Siddique discussed recommendations that suggest Asian heritage as a risk factor for hepatitis B screening, but that’s not a good factor to consider: “People were saying that Asians should be screened at an earlier age, but it’s really people that were born and raised in Asian countries where it’s endemic or they may have gotten it from their mothers at birth. It’s a marker for how long you have had the disease and how much virus is in your bloodstream. It’s not because you’re Asian. If you’re born and raised in the United States, and you don’t have any of those risk factors, you shouldn’t be treated differently based on your identified racial and ethnic group,” said Dr. Siddique.
These questions have become even more important in recent years because of patients with multiracial identifies and other considerations. “Now the proxy for which race was being used is even messier,” said Dr. Siddique.
So, how should physicians think about assessing a patient’s personalized risks? The key, said Dr. Siddique, is to look at each patient’s individual factors, such as health care access, environmental exposures from jobs or living conditions, or the country they emigrated from if they weren’t born in the United States. “Disease prevalences are different in different areas, and that changes your index of suspicion,” she said.
And when considering current guidelines that incorporate race or ethnicity, she recommends viewing them skeptically: “If there is a current algorithm in your health system or in a guideline that you’re reading that says you should be making a change based on race and ethnicity, you should look at that with a close eye and say, “What do I think it’s being used as a proxy for, and how can I elicit that from my patient?’ ”
The issues raised by Dr. Siddique’s study are important, but there also could be concerns in taking them too far, according to Gary Falk, MD, a professor of medicine at the University of Pennsylvania who comoderated the session where Dr. Siddique presented. He was not involved in the study, but was listed on Dr. Siddique’s acknowledgement slide.
Dr. Falk coauthored Barrett’s esophagus guidelines in 2016 that incorporated White race as a risk factor.
“There are certain clear ethnic factors or country of origin factors that impact one’s risk for cancer, and there are certain diseases that are more common in certain ethnic groups. I think that if we homogenize everybody, we may potentially hurt some people in the effort to be inclusive. That’s my only concern. I think it’s totally correct that we have to get out of our comfort zone, but I hate to see us reach too far on the other end, and homogenize things to the point that people who have increased risk are not being recognized for that reason,” said Dr. Falk.
He acknowledged that White race as a risk for Barrett’s is not easy to define given the uncertainty of the genetic risk, for example, in patients with mixed heritage. “This is all very provocative. We have to think about it carefully,” said Dr. Falk.
Dr. Siddique and Dr. Falk have no relevant financial disclosures.
SAN DIEGO – Race-based recommendations and clinical algorithms may be doing more harm than good, according to a systematic review of databases and guidelines.
The study found examples of screening recommendations based on race or ethnicity that were likely misleading since these are social constructs that don’t reflect a patient’s individual risk, said Shazia Siddique, MD, who presented the study at the annual Digestive Disease Week® (DDW). “Historically, we’ve made so many clinical decisions based on somebody’s race and ethnicity. We walk into a room, we don’t even ask people which racial or ethnic category they identify with. We just look at them and we say, ‘Their skin color looks black, and therefore we’re going to apply a different equation to them.’ ”
However, a patient’s risks and unique health circumstances are much more complicated than that. They may be related to genetics, or environmental exposures, or level of access to quality health care. Race can often be inappropriately used as a stand-in for these and other factors, she explained.
“These [racial] categories are truly a social construct. It’s becoming very problematic that people are literally making decisions based on somebody’s skin color. That’s just not what the science supports. If there are specific genes or environmental factors, or differences in access to health care that then impact outcomes for certain racial or ethnic groups, we need to figure out what those are,” said Dr. Siddique, who is an assistant professor of medicine at the University of Pennsylvania, Philadelphia.
Those messages are still entrenched in medical education. “I graduated medical school in 2012, and it was taught to me to use race and ethnicity in clinical decision-making. We need to start in medical education to shift the way that we’re thinking. On the research side, we really need to think about how we can replace or remove race and ethnicity and understand the consequences of that, so that over time we can make a shift,” said Dr. Siddique.
For example, Dr. Siddique discussed recommendations that suggest Asian heritage as a risk factor for hepatitis B screening, but that’s not a good factor to consider: “People were saying that Asians should be screened at an earlier age, but it’s really people that were born and raised in Asian countries where it’s endemic or they may have gotten it from their mothers at birth. It’s a marker for how long you have had the disease and how much virus is in your bloodstream. It’s not because you’re Asian. If you’re born and raised in the United States, and you don’t have any of those risk factors, you shouldn’t be treated differently based on your identified racial and ethnic group,” said Dr. Siddique.
These questions have become even more important in recent years because of patients with multiracial identifies and other considerations. “Now the proxy for which race was being used is even messier,” said Dr. Siddique.
So, how should physicians think about assessing a patient’s personalized risks? The key, said Dr. Siddique, is to look at each patient’s individual factors, such as health care access, environmental exposures from jobs or living conditions, or the country they emigrated from if they weren’t born in the United States. “Disease prevalences are different in different areas, and that changes your index of suspicion,” she said.
And when considering current guidelines that incorporate race or ethnicity, she recommends viewing them skeptically: “If there is a current algorithm in your health system or in a guideline that you’re reading that says you should be making a change based on race and ethnicity, you should look at that with a close eye and say, “What do I think it’s being used as a proxy for, and how can I elicit that from my patient?’ ”
The issues raised by Dr. Siddique’s study are important, but there also could be concerns in taking them too far, according to Gary Falk, MD, a professor of medicine at the University of Pennsylvania who comoderated the session where Dr. Siddique presented. He was not involved in the study, but was listed on Dr. Siddique’s acknowledgement slide.
Dr. Falk coauthored Barrett’s esophagus guidelines in 2016 that incorporated White race as a risk factor.
“There are certain clear ethnic factors or country of origin factors that impact one’s risk for cancer, and there are certain diseases that are more common in certain ethnic groups. I think that if we homogenize everybody, we may potentially hurt some people in the effort to be inclusive. That’s my only concern. I think it’s totally correct that we have to get out of our comfort zone, but I hate to see us reach too far on the other end, and homogenize things to the point that people who have increased risk are not being recognized for that reason,” said Dr. Falk.
He acknowledged that White race as a risk for Barrett’s is not easy to define given the uncertainty of the genetic risk, for example, in patients with mixed heritage. “This is all very provocative. We have to think about it carefully,” said Dr. Falk.
Dr. Siddique and Dr. Falk have no relevant financial disclosures.
AT DDW 2022
PI-based DAAs appear safe in decompensated patients
SAN DIEGO – An analysis of a large, international cohort suggests that treatment with protease-inhibitor (PI)–based direct-acting antivirals (DAAs) may be safe for patients with hepatitis C virus (HCV) with cirrhosis and early-stage liver decompensation.
The study relied on data from the REAL-C registry, including 935 patients treated with oral DAAs at 27 centers in the U.S., Europe, and Asia Pacific countries. The researchers compared efficacy and tolerability outcomes from PI-based and non PI-based DAA regimens in patients deemed to have decompensated HCV cirrhosis.
The findings were encouraging. “It is something important because currently we are short of treatments for decompensated HCV patients. If the tolerability is similar, we perhaps should not withhold [PI] treatment for these patients that sometimes need them the most,” said Yu Jun Wong, MD, who presented the study at the annual Digestive Disease Week® (DDW). Dr. Wong is a second-year consultant at Changchi General Hospital in Singapore.
“I think it was a very interesting study and something that needed to be done. It was encouraging that patients who did have some level of decompensated cirrhosis did not worsen compared to those who were on a non PI-based therapy,” said Meena Bansal, MD, who comoderated the session where the research was presented.
However, the study was limited by some uncertainty around the definition of decompensation among the study participants. During the Q&A session, audience members questioned whether patients categorized as decompensated were truly decompensated at the time of treatment initiation. Dr. Bansal noted, for example, that a patient might experience a variceal bleed in the context of heavy alcohol consumption, and therefore be considered decompensated, but might stop drinking afterward with a reduction in portal hypertension and recovery of liver function. “So it would be important to know if they were still decompensated at the time they initiated therapy. If that was the case, then these results are more promising,” said Dr. Bansal.
Despite these limitations, the study is good news. “If you do not have access to non-PI based therapy, you might feel a little bit more secure starting a PI-based therapy, particularly the second generation PI-based therapies, if they’re at least on the earlier side of that decompensation scale. But it’s still unclear in true decompensated Child’s B or C whether or not PI-based therapy would have the same results,” said Dr. Bansal.
Dr. Wong acknowledged the limitation that the study doesn’t apply to more severely decompensated patients. “Whether it remains safe in patients with higher Child-Pugh scores is hard to extrapolate at this point of time. We still need to look further into the data,” said Dr. Wong.
Still, the results offer hope to physicians and patients who might find themselves in difficult circumstances. “If you’re resource limited, and you don’t even have access to transplant, these findings suggest that early decompensated patients may benefit from PI-based therapy. If I say to the patient, there’s a chance this could make you worse, but there’s a chance this could make you better, [this is an option] as long as the patient is aware of the possible outcomes,” said Dr. Bansal.
The study included patients with a history of ascites, variceal bleeding, jaundice, or hepatic encephalopathy 6 months before treatment with DAA, or baseline measures of Child-Turcotte-Pugh (CTP) score ≥7 or Model of End-Stage Liver Disease (MELD) score >10. The analysis included data between 2014 and 2021.
The mean age was 64, and 59.6% of participants were male. Overall, 70.8% had genotype 1, and 32% were treatment experienced. In total, 45.2% were treated with PI-based DAAs.
The PI cohort was older (64.6 versus 62.7; P = .01), and more likely to have genotype 1 (87.2% versus 56.3%; P < .001) and chronic renal disease (64.0% vs. 53.9%; P = .001).
The two groups had similar rates of sustained virologic response at 12 and 24 weeks, as well as similar rates of significant improvement or significant worsening, suggesting similar tolerability. There was a lower frequency of liver decompensation in the PI group at 12 weeks (4.4% vs. 7.9%; P = .04) and a trend at 24 weeks (8.8% versus 12.6%; P = .08).
Another limitation of the study is the potential for bias due to its retrospective nature.
Dr. Wong has been an invited speaker for AbbVie and Gilead. Dr. Bansal has no relevant financial disclosures.
SAN DIEGO – An analysis of a large, international cohort suggests that treatment with protease-inhibitor (PI)–based direct-acting antivirals (DAAs) may be safe for patients with hepatitis C virus (HCV) with cirrhosis and early-stage liver decompensation.
The study relied on data from the REAL-C registry, including 935 patients treated with oral DAAs at 27 centers in the U.S., Europe, and Asia Pacific countries. The researchers compared efficacy and tolerability outcomes from PI-based and non PI-based DAA regimens in patients deemed to have decompensated HCV cirrhosis.
The findings were encouraging. “It is something important because currently we are short of treatments for decompensated HCV patients. If the tolerability is similar, we perhaps should not withhold [PI] treatment for these patients that sometimes need them the most,” said Yu Jun Wong, MD, who presented the study at the annual Digestive Disease Week® (DDW). Dr. Wong is a second-year consultant at Changchi General Hospital in Singapore.
“I think it was a very interesting study and something that needed to be done. It was encouraging that patients who did have some level of decompensated cirrhosis did not worsen compared to those who were on a non PI-based therapy,” said Meena Bansal, MD, who comoderated the session where the research was presented.
However, the study was limited by some uncertainty around the definition of decompensation among the study participants. During the Q&A session, audience members questioned whether patients categorized as decompensated were truly decompensated at the time of treatment initiation. Dr. Bansal noted, for example, that a patient might experience a variceal bleed in the context of heavy alcohol consumption, and therefore be considered decompensated, but might stop drinking afterward with a reduction in portal hypertension and recovery of liver function. “So it would be important to know if they were still decompensated at the time they initiated therapy. If that was the case, then these results are more promising,” said Dr. Bansal.
Despite these limitations, the study is good news. “If you do not have access to non-PI based therapy, you might feel a little bit more secure starting a PI-based therapy, particularly the second generation PI-based therapies, if they’re at least on the earlier side of that decompensation scale. But it’s still unclear in true decompensated Child’s B or C whether or not PI-based therapy would have the same results,” said Dr. Bansal.
Dr. Wong acknowledged the limitation that the study doesn’t apply to more severely decompensated patients. “Whether it remains safe in patients with higher Child-Pugh scores is hard to extrapolate at this point of time. We still need to look further into the data,” said Dr. Wong.
Still, the results offer hope to physicians and patients who might find themselves in difficult circumstances. “If you’re resource limited, and you don’t even have access to transplant, these findings suggest that early decompensated patients may benefit from PI-based therapy. If I say to the patient, there’s a chance this could make you worse, but there’s a chance this could make you better, [this is an option] as long as the patient is aware of the possible outcomes,” said Dr. Bansal.
The study included patients with a history of ascites, variceal bleeding, jaundice, or hepatic encephalopathy 6 months before treatment with DAA, or baseline measures of Child-Turcotte-Pugh (CTP) score ≥7 or Model of End-Stage Liver Disease (MELD) score >10. The analysis included data between 2014 and 2021.
The mean age was 64, and 59.6% of participants were male. Overall, 70.8% had genotype 1, and 32% were treatment experienced. In total, 45.2% were treated with PI-based DAAs.
The PI cohort was older (64.6 versus 62.7; P = .01), and more likely to have genotype 1 (87.2% versus 56.3%; P < .001) and chronic renal disease (64.0% vs. 53.9%; P = .001).
The two groups had similar rates of sustained virologic response at 12 and 24 weeks, as well as similar rates of significant improvement or significant worsening, suggesting similar tolerability. There was a lower frequency of liver decompensation in the PI group at 12 weeks (4.4% vs. 7.9%; P = .04) and a trend at 24 weeks (8.8% versus 12.6%; P = .08).
Another limitation of the study is the potential for bias due to its retrospective nature.
Dr. Wong has been an invited speaker for AbbVie and Gilead. Dr. Bansal has no relevant financial disclosures.
SAN DIEGO – An analysis of a large, international cohort suggests that treatment with protease-inhibitor (PI)–based direct-acting antivirals (DAAs) may be safe for patients with hepatitis C virus (HCV) with cirrhosis and early-stage liver decompensation.
The study relied on data from the REAL-C registry, including 935 patients treated with oral DAAs at 27 centers in the U.S., Europe, and Asia Pacific countries. The researchers compared efficacy and tolerability outcomes from PI-based and non PI-based DAA regimens in patients deemed to have decompensated HCV cirrhosis.
The findings were encouraging. “It is something important because currently we are short of treatments for decompensated HCV patients. If the tolerability is similar, we perhaps should not withhold [PI] treatment for these patients that sometimes need them the most,” said Yu Jun Wong, MD, who presented the study at the annual Digestive Disease Week® (DDW). Dr. Wong is a second-year consultant at Changchi General Hospital in Singapore.
“I think it was a very interesting study and something that needed to be done. It was encouraging that patients who did have some level of decompensated cirrhosis did not worsen compared to those who were on a non PI-based therapy,” said Meena Bansal, MD, who comoderated the session where the research was presented.
However, the study was limited by some uncertainty around the definition of decompensation among the study participants. During the Q&A session, audience members questioned whether patients categorized as decompensated were truly decompensated at the time of treatment initiation. Dr. Bansal noted, for example, that a patient might experience a variceal bleed in the context of heavy alcohol consumption, and therefore be considered decompensated, but might stop drinking afterward with a reduction in portal hypertension and recovery of liver function. “So it would be important to know if they were still decompensated at the time they initiated therapy. If that was the case, then these results are more promising,” said Dr. Bansal.
Despite these limitations, the study is good news. “If you do not have access to non-PI based therapy, you might feel a little bit more secure starting a PI-based therapy, particularly the second generation PI-based therapies, if they’re at least on the earlier side of that decompensation scale. But it’s still unclear in true decompensated Child’s B or C whether or not PI-based therapy would have the same results,” said Dr. Bansal.
Dr. Wong acknowledged the limitation that the study doesn’t apply to more severely decompensated patients. “Whether it remains safe in patients with higher Child-Pugh scores is hard to extrapolate at this point of time. We still need to look further into the data,” said Dr. Wong.
Still, the results offer hope to physicians and patients who might find themselves in difficult circumstances. “If you’re resource limited, and you don’t even have access to transplant, these findings suggest that early decompensated patients may benefit from PI-based therapy. If I say to the patient, there’s a chance this could make you worse, but there’s a chance this could make you better, [this is an option] as long as the patient is aware of the possible outcomes,” said Dr. Bansal.
The study included patients with a history of ascites, variceal bleeding, jaundice, or hepatic encephalopathy 6 months before treatment with DAA, or baseline measures of Child-Turcotte-Pugh (CTP) score ≥7 or Model of End-Stage Liver Disease (MELD) score >10. The analysis included data between 2014 and 2021.
The mean age was 64, and 59.6% of participants were male. Overall, 70.8% had genotype 1, and 32% were treatment experienced. In total, 45.2% were treated with PI-based DAAs.
The PI cohort was older (64.6 versus 62.7; P = .01), and more likely to have genotype 1 (87.2% versus 56.3%; P < .001) and chronic renal disease (64.0% vs. 53.9%; P = .001).
The two groups had similar rates of sustained virologic response at 12 and 24 weeks, as well as similar rates of significant improvement or significant worsening, suggesting similar tolerability. There was a lower frequency of liver decompensation in the PI group at 12 weeks (4.4% vs. 7.9%; P = .04) and a trend at 24 weeks (8.8% versus 12.6%; P = .08).
Another limitation of the study is the potential for bias due to its retrospective nature.
Dr. Wong has been an invited speaker for AbbVie and Gilead. Dr. Bansal has no relevant financial disclosures.
AT DDW 2022
Treatment for alcohol abuse reduces hepatitis readmission
SAN DIEGO – Treating people with alcoholic hepatitis for alcohol abuse may reduce their risk of hospital readmission, researchers reported.
In a retrospective analysis of nationwide data, 7.83% of those patients who received psychotherapy, counseling, or drug treatment for alcohol abuse were readmitted within 30 days, versus 11.67% of those who did not receive these kinds of treatment.
The finding lends support to the argument that hospitals should invest more in the treatments, despite the complexities involved.
“It takes a multidisciplinary approach, starting from the physician or the health care provider along with the pharmacists, the behavioral health specialists, or a psychiatrist or psychologist, along with case management as well,” said Harleen Chela, MD, a third-year resident at the University of Missouri in Columbia. She presented the findings at the annual Digestive Disease Week® (DDW).
The researchers started with the premise that patients with alcoholic hepatitis can prevent the condition from worsening by abstaining from alcohol. To see whether interventions aimed at encouraging that abstention could prevent readmissions, Dr. Chela and colleagues analyzed data on readmissions for the first 11 months of the year 2018.
They included patients who were at least 18 years of age and who had a nonelective admission with a principal diagnosis of alcohol abuse.
Using procedure codes, they compared those patients given psychotherapy (including cognitive behavioral therapy), formal inpatient counseling, and drug treatment for alcohol abuse to those who didn’t. Then they counted how many patients were readmitted within 30 days.
They found records of 45,617 patients admitted for alcoholic hepatitis of whom 1,552 received treatment for alcohol abuse and 44,065 did not.
They did not find any significant difference between the two groups in demographics, income, or insurance status.
Adjusting for such factors, the researchers found that people who received alcohol abuse treatment were 64% as likely to be readmitted as were those who did not (hazard ratio, 0.64; 95% confidence interval, 0.46-0.91; P = 0.01).
If alcohol abuse treatment is so effective, why isn’t it routine? “It’s not always feasible to implement this, on the inpatient side, because it takes more than a day or two just to get some of these things put in place,” Dr. Chela told this news organization.
They did find that people were more likely to get treatment for alcohol abuse if they were admitted to a hospital in a big city rather than a small town and if their hospital was owned by private investors rather than by a not-for-profit organization or the government.
“Larger hospitals and private sector institutions have more access to resources and money to have those kinds of systems in place for the patients,” said Dr. Chela.
She became interested in the issue at her hospital when she noticed that patients with alcoholic hepatitis were not getting behavioral counseling. “The inpatient load in the behavioral health side is so much that they don’t have time for these kinds of consults,” she said. “That’s one of the challenges: A shortage of behavioral specialists like psychiatrists.”
And hospitals tend to focus on treating conditions that threaten their patients’ lives in the short term. “Someone who has a heart attack or a gastrointestinal bleed – there’s more focus on resources for those kinds of patients,” she said.
Virginia Commonwealth University in Richmond provides alcohol abuse treatment to patients with alcoholic hepatitis partly using telehealth, said Richard Sterling, MD, MSc, chief of hepatology, who was not involved in the study. “For people who live too far away, don’t have transportation, or have other health disparities, we now have technology and mechanisms to keep them engaged in care,” he told this news organization. “We’re doing a lot of Zoom visits.”
Dr. Chela and colleagues also found that those who got alcohol abuse treatment were less likely to be discharged to a skilled nursing facility or to home health. The data couldn’t give the researchers a definitive reason for this, but Dr. Chela speculated that the patients who received treatment for alcohol abuse stayed longer in the hospital and may have been in better shape when they were discharged.
The U.S. health care system doesn’t necessarily provide incentives to keep patients healthy, Dr. Sterling said. “Hospital systems make money off of filling beds, and providing a lot of inpatient care and hospital days,” he said. “That may be not necessarily congruent with a health system that is supposed to provide health for these covered lives.”
Neither Dr. Chela nor Dr. Sterling reported any relevant financial relationships.
SAN DIEGO – Treating people with alcoholic hepatitis for alcohol abuse may reduce their risk of hospital readmission, researchers reported.
In a retrospective analysis of nationwide data, 7.83% of those patients who received psychotherapy, counseling, or drug treatment for alcohol abuse were readmitted within 30 days, versus 11.67% of those who did not receive these kinds of treatment.
The finding lends support to the argument that hospitals should invest more in the treatments, despite the complexities involved.
“It takes a multidisciplinary approach, starting from the physician or the health care provider along with the pharmacists, the behavioral health specialists, or a psychiatrist or psychologist, along with case management as well,” said Harleen Chela, MD, a third-year resident at the University of Missouri in Columbia. She presented the findings at the annual Digestive Disease Week® (DDW).
The researchers started with the premise that patients with alcoholic hepatitis can prevent the condition from worsening by abstaining from alcohol. To see whether interventions aimed at encouraging that abstention could prevent readmissions, Dr. Chela and colleagues analyzed data on readmissions for the first 11 months of the year 2018.
They included patients who were at least 18 years of age and who had a nonelective admission with a principal diagnosis of alcohol abuse.
Using procedure codes, they compared those patients given psychotherapy (including cognitive behavioral therapy), formal inpatient counseling, and drug treatment for alcohol abuse to those who didn’t. Then they counted how many patients were readmitted within 30 days.
They found records of 45,617 patients admitted for alcoholic hepatitis of whom 1,552 received treatment for alcohol abuse and 44,065 did not.
They did not find any significant difference between the two groups in demographics, income, or insurance status.
Adjusting for such factors, the researchers found that people who received alcohol abuse treatment were 64% as likely to be readmitted as were those who did not (hazard ratio, 0.64; 95% confidence interval, 0.46-0.91; P = 0.01).
If alcohol abuse treatment is so effective, why isn’t it routine? “It’s not always feasible to implement this, on the inpatient side, because it takes more than a day or two just to get some of these things put in place,” Dr. Chela told this news organization.
They did find that people were more likely to get treatment for alcohol abuse if they were admitted to a hospital in a big city rather than a small town and if their hospital was owned by private investors rather than by a not-for-profit organization or the government.
“Larger hospitals and private sector institutions have more access to resources and money to have those kinds of systems in place for the patients,” said Dr. Chela.
She became interested in the issue at her hospital when she noticed that patients with alcoholic hepatitis were not getting behavioral counseling. “The inpatient load in the behavioral health side is so much that they don’t have time for these kinds of consults,” she said. “That’s one of the challenges: A shortage of behavioral specialists like psychiatrists.”
And hospitals tend to focus on treating conditions that threaten their patients’ lives in the short term. “Someone who has a heart attack or a gastrointestinal bleed – there’s more focus on resources for those kinds of patients,” she said.
Virginia Commonwealth University in Richmond provides alcohol abuse treatment to patients with alcoholic hepatitis partly using telehealth, said Richard Sterling, MD, MSc, chief of hepatology, who was not involved in the study. “For people who live too far away, don’t have transportation, or have other health disparities, we now have technology and mechanisms to keep them engaged in care,” he told this news organization. “We’re doing a lot of Zoom visits.”
Dr. Chela and colleagues also found that those who got alcohol abuse treatment were less likely to be discharged to a skilled nursing facility or to home health. The data couldn’t give the researchers a definitive reason for this, but Dr. Chela speculated that the patients who received treatment for alcohol abuse stayed longer in the hospital and may have been in better shape when they were discharged.
The U.S. health care system doesn’t necessarily provide incentives to keep patients healthy, Dr. Sterling said. “Hospital systems make money off of filling beds, and providing a lot of inpatient care and hospital days,” he said. “That may be not necessarily congruent with a health system that is supposed to provide health for these covered lives.”
Neither Dr. Chela nor Dr. Sterling reported any relevant financial relationships.
SAN DIEGO – Treating people with alcoholic hepatitis for alcohol abuse may reduce their risk of hospital readmission, researchers reported.
In a retrospective analysis of nationwide data, 7.83% of those patients who received psychotherapy, counseling, or drug treatment for alcohol abuse were readmitted within 30 days, versus 11.67% of those who did not receive these kinds of treatment.
The finding lends support to the argument that hospitals should invest more in the treatments, despite the complexities involved.
“It takes a multidisciplinary approach, starting from the physician or the health care provider along with the pharmacists, the behavioral health specialists, or a psychiatrist or psychologist, along with case management as well,” said Harleen Chela, MD, a third-year resident at the University of Missouri in Columbia. She presented the findings at the annual Digestive Disease Week® (DDW).
The researchers started with the premise that patients with alcoholic hepatitis can prevent the condition from worsening by abstaining from alcohol. To see whether interventions aimed at encouraging that abstention could prevent readmissions, Dr. Chela and colleagues analyzed data on readmissions for the first 11 months of the year 2018.
They included patients who were at least 18 years of age and who had a nonelective admission with a principal diagnosis of alcohol abuse.
Using procedure codes, they compared those patients given psychotherapy (including cognitive behavioral therapy), formal inpatient counseling, and drug treatment for alcohol abuse to those who didn’t. Then they counted how many patients were readmitted within 30 days.
They found records of 45,617 patients admitted for alcoholic hepatitis of whom 1,552 received treatment for alcohol abuse and 44,065 did not.
They did not find any significant difference between the two groups in demographics, income, or insurance status.
Adjusting for such factors, the researchers found that people who received alcohol abuse treatment were 64% as likely to be readmitted as were those who did not (hazard ratio, 0.64; 95% confidence interval, 0.46-0.91; P = 0.01).
If alcohol abuse treatment is so effective, why isn’t it routine? “It’s not always feasible to implement this, on the inpatient side, because it takes more than a day or two just to get some of these things put in place,” Dr. Chela told this news organization.
They did find that people were more likely to get treatment for alcohol abuse if they were admitted to a hospital in a big city rather than a small town and if their hospital was owned by private investors rather than by a not-for-profit organization or the government.
“Larger hospitals and private sector institutions have more access to resources and money to have those kinds of systems in place for the patients,” said Dr. Chela.
She became interested in the issue at her hospital when she noticed that patients with alcoholic hepatitis were not getting behavioral counseling. “The inpatient load in the behavioral health side is so much that they don’t have time for these kinds of consults,” she said. “That’s one of the challenges: A shortage of behavioral specialists like psychiatrists.”
And hospitals tend to focus on treating conditions that threaten their patients’ lives in the short term. “Someone who has a heart attack or a gastrointestinal bleed – there’s more focus on resources for those kinds of patients,” she said.
Virginia Commonwealth University in Richmond provides alcohol abuse treatment to patients with alcoholic hepatitis partly using telehealth, said Richard Sterling, MD, MSc, chief of hepatology, who was not involved in the study. “For people who live too far away, don’t have transportation, or have other health disparities, we now have technology and mechanisms to keep them engaged in care,” he told this news organization. “We’re doing a lot of Zoom visits.”
Dr. Chela and colleagues also found that those who got alcohol abuse treatment were less likely to be discharged to a skilled nursing facility or to home health. The data couldn’t give the researchers a definitive reason for this, but Dr. Chela speculated that the patients who received treatment for alcohol abuse stayed longer in the hospital and may have been in better shape when they were discharged.
The U.S. health care system doesn’t necessarily provide incentives to keep patients healthy, Dr. Sterling said. “Hospital systems make money off of filling beds, and providing a lot of inpatient care and hospital days,” he said. “That may be not necessarily congruent with a health system that is supposed to provide health for these covered lives.”
Neither Dr. Chela nor Dr. Sterling reported any relevant financial relationships.
AT DDW 2022
Creatinine variability linked to liver transplant outcomes
Patients with greater changes in serum creatinine are more likely to have worse pre- and post–liver transplant outcomes. Moreover, underserved patients may be most frequently affected, according to a retrospective analysis of UNOS (United Network for Organ Sharing) data.
These results should drive further development of serum creatinine coefficient of variation (sCr CoV) as an independent predictor of renal-related mortality risk, according to lead author Giuseppe Cullaro, MD, of the University of California, San Francisco, and colleagues.
“Intra-individual clinical and laboratory parameter dynamics often provide additional prognostic information – added information that goes beyond what can be found with cross-sectional data,” the researchers wrote in Hepatology. “This finding has been seen in several scenarios in the general population – intra-individual variability in blood pressure, weight, hemoglobin, and kidney function, have all been associated with worse clinical outcomes. However, in cirrhosis patients, and more specifically in patients awaiting a liver transplant, kidney function dynamics as a predictor of clinical outcomes has yet to be investigated.”
To gauge the predictive power of shifting kidney values, Dr. Cullaro and colleagues analyzed UNOS/OPTN (Organ Procurement and Transplantation Network) registry data from 2011 through 2019. Exclusion criteria included patients who were aged younger than 18 years, were listed as status 1, received a living donor liver transplantation, were on hemodialysis, or had fewer than three updates. The final dataset included 25,204 patients.
After the researchers sorted patients into low, intermediate, and high sCr CoV tertiles, they used logistic regression to determine relationships between higher sCr and a variety of covariates, such as age, sex, diagnosis, presence of acute kidney injury, or chronic kidney disease. A competing risk regression was then done to look for associations between wait list mortality and the covariables, with liver transplant used as the competing risk.
The median sCr CoV was 17.4% (interquartile range [IQR], 10.8%-29.5%). Patients in the bottom sCr CoV tertile had a median value of 8.8% (IQR, 6.6%-10.8%), compared with 17.4% (IQR, 14.8%-20.4%) in the intermediate variability group and 36.8% (IQR, 29.5%-48.8%) in the high variability group. High variability was associated with female sex, Hispanic ethnicity, ascites, and hepatic encephalopathy as well as higher body mass index, MELDNa score, and serum creatinine.
Of note, each decreasing serum creatinine variability tertile was associated with a significantly lower rate of wait list mortality (34.7% vs. 19.6% vs. 11.7%; P < .001). The creatinine variability profiles were similarly associated with the likelihood of receiving a liver transplant (52.3% vs. 48.9% vs. 43.7%; P < .001) and posttransplant mortality (7.5% vs. 5.5% vs. 3.9%; P < .001).
A multivariate model showed that each 10% increase in sCr CoV predicted an 8% increased risk of a combined outcome comprising post–liver transplant death or post–liver transplant kidney transplant (KALT), independently of other variables (adjusted hazard ratio, 1.08; 95% confidence interval, 1.05-1.11).
“These data highlight that all fluctuations in sCr are associated with worse pre- and post–liver transplant outcomes,” the investigators concluded. “Moreover, the groups that are most underserved by sCr, specifically women, were most likely to have greater sCr CoVs. We believe our work lays the foundation for implementing the sCr CoV as an independent metric of renal-related mortality risk and may be most beneficial for those groups most underserved by sCr values alone.”
According to Brian P. Lee, MD, a hepatologist with Keck Medicine of USC and assistant professor of clinical medicine with the Keck School of Medicine of USC in Los Angeles, “this is a great study ... in an area of high need” that used “high quality data.”
Current liver allocation strategies depend on a snapshot of kidney function, but these new findings suggest that a more dynamic approach may be needed. “As a practicing liver specialist I see that creatinine numbers can fluctuate a lot. ... So which number do you use when you’re trying to calculate what a patient’s risk of death is on the wait list? This study gets toward that answer. If there is a lot of variability, these might be higher risk patients; these might be patients that we should put higher on the transplant waiting list,” said Dr. Lee.
He suggested that clinicians should account for creatinine fluctuations when considering mortality risk; however, the evidence is “not quite there yet ... in terms of changing transplant policy and allocation.” He pointed out three unanswered questions: Why are creatinine values fluctuating? How should fluctuations be scored for risk modeling? And, what impact would those risk scores have on transplant waitlist prioritization?
“I think that that’s the work that you would need to do before you could really change national transplant policy,” Dr. Lee concluded.
The study was supported by the National Institutes of Health and the UCSF Liver Center. Dr. Cullaro and another author have disclosed relationships with Mallinckrodt Pharmaceuticals and Axcella Health, respectively. Dr. Lee reported no conflicts of interest.
Patients with greater changes in serum creatinine are more likely to have worse pre- and post–liver transplant outcomes. Moreover, underserved patients may be most frequently affected, according to a retrospective analysis of UNOS (United Network for Organ Sharing) data.
These results should drive further development of serum creatinine coefficient of variation (sCr CoV) as an independent predictor of renal-related mortality risk, according to lead author Giuseppe Cullaro, MD, of the University of California, San Francisco, and colleagues.
“Intra-individual clinical and laboratory parameter dynamics often provide additional prognostic information – added information that goes beyond what can be found with cross-sectional data,” the researchers wrote in Hepatology. “This finding has been seen in several scenarios in the general population – intra-individual variability in blood pressure, weight, hemoglobin, and kidney function, have all been associated with worse clinical outcomes. However, in cirrhosis patients, and more specifically in patients awaiting a liver transplant, kidney function dynamics as a predictor of clinical outcomes has yet to be investigated.”
To gauge the predictive power of shifting kidney values, Dr. Cullaro and colleagues analyzed UNOS/OPTN (Organ Procurement and Transplantation Network) registry data from 2011 through 2019. Exclusion criteria included patients who were aged younger than 18 years, were listed as status 1, received a living donor liver transplantation, were on hemodialysis, or had fewer than three updates. The final dataset included 25,204 patients.
After the researchers sorted patients into low, intermediate, and high sCr CoV tertiles, they used logistic regression to determine relationships between higher sCr and a variety of covariates, such as age, sex, diagnosis, presence of acute kidney injury, or chronic kidney disease. A competing risk regression was then done to look for associations between wait list mortality and the covariables, with liver transplant used as the competing risk.
The median sCr CoV was 17.4% (interquartile range [IQR], 10.8%-29.5%). Patients in the bottom sCr CoV tertile had a median value of 8.8% (IQR, 6.6%-10.8%), compared with 17.4% (IQR, 14.8%-20.4%) in the intermediate variability group and 36.8% (IQR, 29.5%-48.8%) in the high variability group. High variability was associated with female sex, Hispanic ethnicity, ascites, and hepatic encephalopathy as well as higher body mass index, MELDNa score, and serum creatinine.
Of note, each decreasing serum creatinine variability tertile was associated with a significantly lower rate of wait list mortality (34.7% vs. 19.6% vs. 11.7%; P < .001). The creatinine variability profiles were similarly associated with the likelihood of receiving a liver transplant (52.3% vs. 48.9% vs. 43.7%; P < .001) and posttransplant mortality (7.5% vs. 5.5% vs. 3.9%; P < .001).
A multivariate model showed that each 10% increase in sCr CoV predicted an 8% increased risk of a combined outcome comprising post–liver transplant death or post–liver transplant kidney transplant (KALT), independently of other variables (adjusted hazard ratio, 1.08; 95% confidence interval, 1.05-1.11).
“These data highlight that all fluctuations in sCr are associated with worse pre- and post–liver transplant outcomes,” the investigators concluded. “Moreover, the groups that are most underserved by sCr, specifically women, were most likely to have greater sCr CoVs. We believe our work lays the foundation for implementing the sCr CoV as an independent metric of renal-related mortality risk and may be most beneficial for those groups most underserved by sCr values alone.”
According to Brian P. Lee, MD, a hepatologist with Keck Medicine of USC and assistant professor of clinical medicine with the Keck School of Medicine of USC in Los Angeles, “this is a great study ... in an area of high need” that used “high quality data.”
Current liver allocation strategies depend on a snapshot of kidney function, but these new findings suggest that a more dynamic approach may be needed. “As a practicing liver specialist I see that creatinine numbers can fluctuate a lot. ... So which number do you use when you’re trying to calculate what a patient’s risk of death is on the wait list? This study gets toward that answer. If there is a lot of variability, these might be higher risk patients; these might be patients that we should put higher on the transplant waiting list,” said Dr. Lee.
He suggested that clinicians should account for creatinine fluctuations when considering mortality risk; however, the evidence is “not quite there yet ... in terms of changing transplant policy and allocation.” He pointed out three unanswered questions: Why are creatinine values fluctuating? How should fluctuations be scored for risk modeling? And, what impact would those risk scores have on transplant waitlist prioritization?
“I think that that’s the work that you would need to do before you could really change national transplant policy,” Dr. Lee concluded.
The study was supported by the National Institutes of Health and the UCSF Liver Center. Dr. Cullaro and another author have disclosed relationships with Mallinckrodt Pharmaceuticals and Axcella Health, respectively. Dr. Lee reported no conflicts of interest.
Patients with greater changes in serum creatinine are more likely to have worse pre- and post–liver transplant outcomes. Moreover, underserved patients may be most frequently affected, according to a retrospective analysis of UNOS (United Network for Organ Sharing) data.
These results should drive further development of serum creatinine coefficient of variation (sCr CoV) as an independent predictor of renal-related mortality risk, according to lead author Giuseppe Cullaro, MD, of the University of California, San Francisco, and colleagues.
“Intra-individual clinical and laboratory parameter dynamics often provide additional prognostic information – added information that goes beyond what can be found with cross-sectional data,” the researchers wrote in Hepatology. “This finding has been seen in several scenarios in the general population – intra-individual variability in blood pressure, weight, hemoglobin, and kidney function, have all been associated with worse clinical outcomes. However, in cirrhosis patients, and more specifically in patients awaiting a liver transplant, kidney function dynamics as a predictor of clinical outcomes has yet to be investigated.”
To gauge the predictive power of shifting kidney values, Dr. Cullaro and colleagues analyzed UNOS/OPTN (Organ Procurement and Transplantation Network) registry data from 2011 through 2019. Exclusion criteria included patients who were aged younger than 18 years, were listed as status 1, received a living donor liver transplantation, were on hemodialysis, or had fewer than three updates. The final dataset included 25,204 patients.
After the researchers sorted patients into low, intermediate, and high sCr CoV tertiles, they used logistic regression to determine relationships between higher sCr and a variety of covariates, such as age, sex, diagnosis, presence of acute kidney injury, or chronic kidney disease. A competing risk regression was then done to look for associations between wait list mortality and the covariables, with liver transplant used as the competing risk.
The median sCr CoV was 17.4% (interquartile range [IQR], 10.8%-29.5%). Patients in the bottom sCr CoV tertile had a median value of 8.8% (IQR, 6.6%-10.8%), compared with 17.4% (IQR, 14.8%-20.4%) in the intermediate variability group and 36.8% (IQR, 29.5%-48.8%) in the high variability group. High variability was associated with female sex, Hispanic ethnicity, ascites, and hepatic encephalopathy as well as higher body mass index, MELDNa score, and serum creatinine.
Of note, each decreasing serum creatinine variability tertile was associated with a significantly lower rate of wait list mortality (34.7% vs. 19.6% vs. 11.7%; P < .001). The creatinine variability profiles were similarly associated with the likelihood of receiving a liver transplant (52.3% vs. 48.9% vs. 43.7%; P < .001) and posttransplant mortality (7.5% vs. 5.5% vs. 3.9%; P < .001).
A multivariate model showed that each 10% increase in sCr CoV predicted an 8% increased risk of a combined outcome comprising post–liver transplant death or post–liver transplant kidney transplant (KALT), independently of other variables (adjusted hazard ratio, 1.08; 95% confidence interval, 1.05-1.11).
“These data highlight that all fluctuations in sCr are associated with worse pre- and post–liver transplant outcomes,” the investigators concluded. “Moreover, the groups that are most underserved by sCr, specifically women, were most likely to have greater sCr CoVs. We believe our work lays the foundation for implementing the sCr CoV as an independent metric of renal-related mortality risk and may be most beneficial for those groups most underserved by sCr values alone.”
According to Brian P. Lee, MD, a hepatologist with Keck Medicine of USC and assistant professor of clinical medicine with the Keck School of Medicine of USC in Los Angeles, “this is a great study ... in an area of high need” that used “high quality data.”
Current liver allocation strategies depend on a snapshot of kidney function, but these new findings suggest that a more dynamic approach may be needed. “As a practicing liver specialist I see that creatinine numbers can fluctuate a lot. ... So which number do you use when you’re trying to calculate what a patient’s risk of death is on the wait list? This study gets toward that answer. If there is a lot of variability, these might be higher risk patients; these might be patients that we should put higher on the transplant waiting list,” said Dr. Lee.
He suggested that clinicians should account for creatinine fluctuations when considering mortality risk; however, the evidence is “not quite there yet ... in terms of changing transplant policy and allocation.” He pointed out three unanswered questions: Why are creatinine values fluctuating? How should fluctuations be scored for risk modeling? And, what impact would those risk scores have on transplant waitlist prioritization?
“I think that that’s the work that you would need to do before you could really change national transplant policy,” Dr. Lee concluded.
The study was supported by the National Institutes of Health and the UCSF Liver Center. Dr. Cullaro and another author have disclosed relationships with Mallinckrodt Pharmaceuticals and Axcella Health, respectively. Dr. Lee reported no conflicts of interest.
FROM HEPATOLOGY