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Newly defined liver disorder associated with COVID mortality
People with metabolic dysfunction–associated fatty liver disease (MAFLD) – a newly defined condition – may be more likely to die from COVID-19, researchers say.
A cohort of people hospitalized for COVID-19 in Central Military Hospital, Mexico City, who met the criteria for MAFLD died at a higher rate than a control group without fatty liver disease, said Martín Uriel Vázquez-Medina, MSc, a researcher in the National Polytechnic Institute in Mexico City.
Patients who met only the criteria for the traditional classification, nonalcoholic fatty liver disease (NAFLD), also died of COVID-19 at a higher rate than the control group, but the difference was not statistically significant.
“It is important to screen for MAFLD,” Mr. Vázquez-Medina told this news organization. “It’s a new definition, but it has really helped us to identify which patients are going to get worse by COVID-19.”
The study was published in Hepatology Communications.
More evidence for clinical relevance of MAFLD
The finding lends support to an initiative to use MAFLD instead of NAFLD to identify patients whose liver steatosis poses a threat to their health, Mr. Vázquez-Medina said.
NAFLD affects as much as a quarter of the world’s population. No drugs have been approved to treat it. Some researchers have reasoned that the imprecision of the definition of NAFLD could be one reason for the lack of progress in treatment.
“NAFLD is something that doesn’t have positive criteria to be diagnosed,” said Mr. Vázquez-Medina. “You only say NAFLD when you don’t find hepatitis or another disease.”
In an article published in Gastroenterology, an international consensus panel proposed MAFLD as an alternative, arguing that a focus on metabolic dysfunction could more accurately reflect the pathogenesis of the disease and help stratify patients.
Previous research has suggested that patients with MAFLD have a higher risk of atherosclerotic cardiovascular disease and that the prevalence of colorectal adenomas is a higher in these patients, compared with patients with NAFLD.
The high prevalence of MAFLD in Mexico – about 30% – could help explain the country’s high rate of mortality from COVID-19, Mr. Vázquez-Medina said. Almost 6% of people diagnosed with COVID in Mexico have died from it, according to the Johns Hopkins University and Medical Center Coronavirus Resource Center.
Sorting COVID outcomes by liver steatosis
To understand the interaction of MAFLD, NAFLD, liver fibrosis, and COVID-19, Mr. Vázquez-Medina and his colleagues analyzed the records of all patients admitted to the Central Military Hospital with COVID-19 from April 4, 2020, to June 24, 2020.
They excluded patients for whom complete data were lacking or for whom a liver function test was not conducted in the first 24 hours of hospitalization. Also excluded were patients with significant consumption of alcohol (> 30 g/day for men and > 20 g/day for women) and those with a history of autoimmune liver disease, liver cancer, decompensated cirrhosis, platelet disorders, or myopathies.
The remaining patients were divided into three groups – 220 who met the criteria for MAFLD, 79 who met the criteria for NAFLD but not MAFLD, and 60 other patients as a control group.
The researchers defined MAFLD as the presence of liver steatosis detected with a noninvasive method and one of the following: overweight (body mass index, 25-29.9 kg/m2), type 2 diabetes, or the presence of two metabolic abnormalities (blood pressure > 140/90 mm Hg, plasma triglycerides > 150 mg/dL, plasma high-density lipoprotein cholesterol < 40 mg/dL in men and < 50 mg/dL in women, and prediabetes).
They defined NAFLD as the presence of liver steatosis without the other criteria for MAFLD.
The patients with MAFLD were the most likely to be intubated and were the most likely to die (intubation, 44.09%; mortality, 55%), followed by those with NAFLD (intubation, 40.51%; mortality, 51.9%) and those in the control group (intubation, 20%; mortality, 38.33%).
The difference in mortality between the MAFLD group and the control group was statistically significant (P = .02). The mortality difference between the NAFLD and the control group fell just short of statistical significance (P = .07).
For intubation, the difference between the MAFLD and the control group was highly statistically significant (P = .001), and the difference between the NAFLD and the control group was also statistically significant (P = .01)
Patients with advanced fibrosis and either MAFLD or NAFLD were also more likely to die than patients in the control group with advanced fibrosis.
That’s why screening for MAFLD is important, Mr. Vázquez-Medina said.
Next steps and new questions
Future research should examine whether patients with MAFLD have elevated levels of biomarkers for inflammation, such as interleukin 6, Mr. Vázquez-Medina said. A “chronic low proinflammatory state” may be the key to understanding the vulnerability of patients to MAFLD to COVID-19, he speculated.
The metabolic traits associated with MAFLD could explain the higher mortality and intubation rates with COVID, said Rohit Loomba, MD, MHSc, a professor of medicine in the division of gastroenterology at the University of California, San Diego, who was not involved in the study.
“Hypertension, diabetes, and obesity increase the risk of complications from COVID in all patients, whether they have been diagnosed with NAFLD or not,” he told this news organization in an email.
Mr. Vasquez-Medina pointed out that the patients with MAFLD had a higher risk of mortality even after adjusting for age, sex, type 2 diabetes, hypertension, overweight, and obesity (BMI ≥ 30 kg/m2). MAFLD also was more strongly associated with a poor outcome than either hypertension alone or obesity alone. Only age emerged as a significant independent covariate in the study.
Dr. Loomba also questioned whether the regression model used in this study for liver steatosis was “fully reflective of NAFLD.”
The researchers identified liver steatosis with a diagnostic formula that used noninvasive clinical BMI and laboratory tests (alanine aminotransferase), citing a study that found the regression formula was better at diagnosing NAFLD than FibroScan.
Mr. Vázquez-Medina reported no relevant financial relationships. Dr. Loomba serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse Bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89bio, Terns Pharmaceuticals, and Viking Therapeutics. He is co-founder of LipoNexus.
A version of this article first appeared on Medscape.com.
People with metabolic dysfunction–associated fatty liver disease (MAFLD) – a newly defined condition – may be more likely to die from COVID-19, researchers say.
A cohort of people hospitalized for COVID-19 in Central Military Hospital, Mexico City, who met the criteria for MAFLD died at a higher rate than a control group without fatty liver disease, said Martín Uriel Vázquez-Medina, MSc, a researcher in the National Polytechnic Institute in Mexico City.
Patients who met only the criteria for the traditional classification, nonalcoholic fatty liver disease (NAFLD), also died of COVID-19 at a higher rate than the control group, but the difference was not statistically significant.
“It is important to screen for MAFLD,” Mr. Vázquez-Medina told this news organization. “It’s a new definition, but it has really helped us to identify which patients are going to get worse by COVID-19.”
The study was published in Hepatology Communications.
More evidence for clinical relevance of MAFLD
The finding lends support to an initiative to use MAFLD instead of NAFLD to identify patients whose liver steatosis poses a threat to their health, Mr. Vázquez-Medina said.
NAFLD affects as much as a quarter of the world’s population. No drugs have been approved to treat it. Some researchers have reasoned that the imprecision of the definition of NAFLD could be one reason for the lack of progress in treatment.
“NAFLD is something that doesn’t have positive criteria to be diagnosed,” said Mr. Vázquez-Medina. “You only say NAFLD when you don’t find hepatitis or another disease.”
In an article published in Gastroenterology, an international consensus panel proposed MAFLD as an alternative, arguing that a focus on metabolic dysfunction could more accurately reflect the pathogenesis of the disease and help stratify patients.
Previous research has suggested that patients with MAFLD have a higher risk of atherosclerotic cardiovascular disease and that the prevalence of colorectal adenomas is a higher in these patients, compared with patients with NAFLD.
The high prevalence of MAFLD in Mexico – about 30% – could help explain the country’s high rate of mortality from COVID-19, Mr. Vázquez-Medina said. Almost 6% of people diagnosed with COVID in Mexico have died from it, according to the Johns Hopkins University and Medical Center Coronavirus Resource Center.
Sorting COVID outcomes by liver steatosis
To understand the interaction of MAFLD, NAFLD, liver fibrosis, and COVID-19, Mr. Vázquez-Medina and his colleagues analyzed the records of all patients admitted to the Central Military Hospital with COVID-19 from April 4, 2020, to June 24, 2020.
They excluded patients for whom complete data were lacking or for whom a liver function test was not conducted in the first 24 hours of hospitalization. Also excluded were patients with significant consumption of alcohol (> 30 g/day for men and > 20 g/day for women) and those with a history of autoimmune liver disease, liver cancer, decompensated cirrhosis, platelet disorders, or myopathies.
The remaining patients were divided into three groups – 220 who met the criteria for MAFLD, 79 who met the criteria for NAFLD but not MAFLD, and 60 other patients as a control group.
The researchers defined MAFLD as the presence of liver steatosis detected with a noninvasive method and one of the following: overweight (body mass index, 25-29.9 kg/m2), type 2 diabetes, or the presence of two metabolic abnormalities (blood pressure > 140/90 mm Hg, plasma triglycerides > 150 mg/dL, plasma high-density lipoprotein cholesterol < 40 mg/dL in men and < 50 mg/dL in women, and prediabetes).
They defined NAFLD as the presence of liver steatosis without the other criteria for MAFLD.
The patients with MAFLD were the most likely to be intubated and were the most likely to die (intubation, 44.09%; mortality, 55%), followed by those with NAFLD (intubation, 40.51%; mortality, 51.9%) and those in the control group (intubation, 20%; mortality, 38.33%).
The difference in mortality between the MAFLD group and the control group was statistically significant (P = .02). The mortality difference between the NAFLD and the control group fell just short of statistical significance (P = .07).
For intubation, the difference between the MAFLD and the control group was highly statistically significant (P = .001), and the difference between the NAFLD and the control group was also statistically significant (P = .01)
Patients with advanced fibrosis and either MAFLD or NAFLD were also more likely to die than patients in the control group with advanced fibrosis.
That’s why screening for MAFLD is important, Mr. Vázquez-Medina said.
Next steps and new questions
Future research should examine whether patients with MAFLD have elevated levels of biomarkers for inflammation, such as interleukin 6, Mr. Vázquez-Medina said. A “chronic low proinflammatory state” may be the key to understanding the vulnerability of patients to MAFLD to COVID-19, he speculated.
The metabolic traits associated with MAFLD could explain the higher mortality and intubation rates with COVID, said Rohit Loomba, MD, MHSc, a professor of medicine in the division of gastroenterology at the University of California, San Diego, who was not involved in the study.
“Hypertension, diabetes, and obesity increase the risk of complications from COVID in all patients, whether they have been diagnosed with NAFLD or not,” he told this news organization in an email.
Mr. Vasquez-Medina pointed out that the patients with MAFLD had a higher risk of mortality even after adjusting for age, sex, type 2 diabetes, hypertension, overweight, and obesity (BMI ≥ 30 kg/m2). MAFLD also was more strongly associated with a poor outcome than either hypertension alone or obesity alone. Only age emerged as a significant independent covariate in the study.
Dr. Loomba also questioned whether the regression model used in this study for liver steatosis was “fully reflective of NAFLD.”
The researchers identified liver steatosis with a diagnostic formula that used noninvasive clinical BMI and laboratory tests (alanine aminotransferase), citing a study that found the regression formula was better at diagnosing NAFLD than FibroScan.
Mr. Vázquez-Medina reported no relevant financial relationships. Dr. Loomba serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse Bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89bio, Terns Pharmaceuticals, and Viking Therapeutics. He is co-founder of LipoNexus.
A version of this article first appeared on Medscape.com.
People with metabolic dysfunction–associated fatty liver disease (MAFLD) – a newly defined condition – may be more likely to die from COVID-19, researchers say.
A cohort of people hospitalized for COVID-19 in Central Military Hospital, Mexico City, who met the criteria for MAFLD died at a higher rate than a control group without fatty liver disease, said Martín Uriel Vázquez-Medina, MSc, a researcher in the National Polytechnic Institute in Mexico City.
Patients who met only the criteria for the traditional classification, nonalcoholic fatty liver disease (NAFLD), also died of COVID-19 at a higher rate than the control group, but the difference was not statistically significant.
“It is important to screen for MAFLD,” Mr. Vázquez-Medina told this news organization. “It’s a new definition, but it has really helped us to identify which patients are going to get worse by COVID-19.”
The study was published in Hepatology Communications.
More evidence for clinical relevance of MAFLD
The finding lends support to an initiative to use MAFLD instead of NAFLD to identify patients whose liver steatosis poses a threat to their health, Mr. Vázquez-Medina said.
NAFLD affects as much as a quarter of the world’s population. No drugs have been approved to treat it. Some researchers have reasoned that the imprecision of the definition of NAFLD could be one reason for the lack of progress in treatment.
“NAFLD is something that doesn’t have positive criteria to be diagnosed,” said Mr. Vázquez-Medina. “You only say NAFLD when you don’t find hepatitis or another disease.”
In an article published in Gastroenterology, an international consensus panel proposed MAFLD as an alternative, arguing that a focus on metabolic dysfunction could more accurately reflect the pathogenesis of the disease and help stratify patients.
Previous research has suggested that patients with MAFLD have a higher risk of atherosclerotic cardiovascular disease and that the prevalence of colorectal adenomas is a higher in these patients, compared with patients with NAFLD.
The high prevalence of MAFLD in Mexico – about 30% – could help explain the country’s high rate of mortality from COVID-19, Mr. Vázquez-Medina said. Almost 6% of people diagnosed with COVID in Mexico have died from it, according to the Johns Hopkins University and Medical Center Coronavirus Resource Center.
Sorting COVID outcomes by liver steatosis
To understand the interaction of MAFLD, NAFLD, liver fibrosis, and COVID-19, Mr. Vázquez-Medina and his colleagues analyzed the records of all patients admitted to the Central Military Hospital with COVID-19 from April 4, 2020, to June 24, 2020.
They excluded patients for whom complete data were lacking or for whom a liver function test was not conducted in the first 24 hours of hospitalization. Also excluded were patients with significant consumption of alcohol (> 30 g/day for men and > 20 g/day for women) and those with a history of autoimmune liver disease, liver cancer, decompensated cirrhosis, platelet disorders, or myopathies.
The remaining patients were divided into three groups – 220 who met the criteria for MAFLD, 79 who met the criteria for NAFLD but not MAFLD, and 60 other patients as a control group.
The researchers defined MAFLD as the presence of liver steatosis detected with a noninvasive method and one of the following: overweight (body mass index, 25-29.9 kg/m2), type 2 diabetes, or the presence of two metabolic abnormalities (blood pressure > 140/90 mm Hg, plasma triglycerides > 150 mg/dL, plasma high-density lipoprotein cholesterol < 40 mg/dL in men and < 50 mg/dL in women, and prediabetes).
They defined NAFLD as the presence of liver steatosis without the other criteria for MAFLD.
The patients with MAFLD were the most likely to be intubated and were the most likely to die (intubation, 44.09%; mortality, 55%), followed by those with NAFLD (intubation, 40.51%; mortality, 51.9%) and those in the control group (intubation, 20%; mortality, 38.33%).
The difference in mortality between the MAFLD group and the control group was statistically significant (P = .02). The mortality difference between the NAFLD and the control group fell just short of statistical significance (P = .07).
For intubation, the difference between the MAFLD and the control group was highly statistically significant (P = .001), and the difference between the NAFLD and the control group was also statistically significant (P = .01)
Patients with advanced fibrosis and either MAFLD or NAFLD were also more likely to die than patients in the control group with advanced fibrosis.
That’s why screening for MAFLD is important, Mr. Vázquez-Medina said.
Next steps and new questions
Future research should examine whether patients with MAFLD have elevated levels of biomarkers for inflammation, such as interleukin 6, Mr. Vázquez-Medina said. A “chronic low proinflammatory state” may be the key to understanding the vulnerability of patients to MAFLD to COVID-19, he speculated.
The metabolic traits associated with MAFLD could explain the higher mortality and intubation rates with COVID, said Rohit Loomba, MD, MHSc, a professor of medicine in the division of gastroenterology at the University of California, San Diego, who was not involved in the study.
“Hypertension, diabetes, and obesity increase the risk of complications from COVID in all patients, whether they have been diagnosed with NAFLD or not,” he told this news organization in an email.
Mr. Vasquez-Medina pointed out that the patients with MAFLD had a higher risk of mortality even after adjusting for age, sex, type 2 diabetes, hypertension, overweight, and obesity (BMI ≥ 30 kg/m2). MAFLD also was more strongly associated with a poor outcome than either hypertension alone or obesity alone. Only age emerged as a significant independent covariate in the study.
Dr. Loomba also questioned whether the regression model used in this study for liver steatosis was “fully reflective of NAFLD.”
The researchers identified liver steatosis with a diagnostic formula that used noninvasive clinical BMI and laboratory tests (alanine aminotransferase), citing a study that found the regression formula was better at diagnosing NAFLD than FibroScan.
Mr. Vázquez-Medina reported no relevant financial relationships. Dr. Loomba serves as a consultant to Aardvark Therapeutics, Altimmune, Anylam/Regeneron, Amgen, Arrowhead Pharmaceuticals, AstraZeneca, Bristol-Myers Squibb, CohBar, Eli Lilly, Galmed, Gilead, Glympse Bio, Hightide, Inipharma, Intercept, Inventiva, Ionis, Janssen, Madrigal, Metacrine, NGM Biopharmaceuticals, Novartis, Novo Nordisk, Merck, Pfizer, Sagimet, Theratechnologies, 89bio, Terns Pharmaceuticals, and Viking Therapeutics. He is co-founder of LipoNexus.
A version of this article first appeared on Medscape.com.
FROM HEPATOLOGY COMMUNICATIONS
To engage injection drug users in HCV care, go to where they are
For injection drug users with hepatitis C virus (HCV) infection, providing treatment opportunities within a local needle exchange program can provide care to more patients and eventually cure more patients, a new study suggests.
The study’s findings help “counteract the implicit belief within the medical community that people who inject drugs can’t or don’t want to engage in health care,” lead author Benjamin Eckhardt, MD, with NYU Grossman School of Medicine, told this news organization.
“By simply focusing on patient accompaniment, limiting stigma, and removing the punitive response for missed appointments, we can effectively engage people who inject drugs in health care and more specifically cure their infection, making significant inroads to HCV elimination,” Dr. Eckhardt said.
The study was published online in JAMA Internal Medicine.
Nonjudgmental, patient-centered approach
Researchers included 165 injection drug users with HCV (mean age, 42 years; 78% men); 82 were randomly allocated to the accessible care intervention and 83 to a usual care control group.
The accessible care model provides HCV treatment within a community-based needle exchange program in a comfortable, nonjudgmental atmosphere, “without fear of shame or stigma that people who inject drugs often experience in mainstream institutions,” the investigators explain.
Control participants were connected to a patient navigator who facilitated referrals to community direct antigen antiviral therapy programs that were not at a syringe service program.
In an intent-to-treat analysis, those enrolled in the accessible care group achieved sustained viral eradication at 12 months at significantly higher rates than those in the control group (67% vs. 23%; P < .001).
Once patients initiated treatment, cure rates were the same in both groups (86%), indicating that the major benefit of the accessible care program was in facilitating treatment, rather than increasing adherence to or response to treatment, the researchers noted.
This is reflected in the fact that the percentage of participants who advanced along the care cascade was significantly higher at each step for the accessible care group than the control group, from referral to an HCV clinician (93% vs. 45%), attendance of the initial HCV clinical visit (87% vs. 37%), completion of baseline laboratory testing (87% vs. 31%), and treatment initiation (78% vs. 27%).
Getting to the population in need
“The most surprising aspect of the study was how successful we were at recruiting, engaging, and treating people who inject drugs who lived outside the immediate community where the syringe exchange program was located and had no prior connection to the program,” Dr. Eckhardt said.
“We had numerous individuals travel 45-plus minutes on the subway from the South Bronx, passing four major medical centers with robust hepatitis C treatment programs, to seek care for hepatitis C in a small, dark office – but also an office they’d heard can be trusted – without fear of stigma or preconditions,” Dr. Eckhardt said.
Commenting on the study’s findings, Nancy Reau, MD, section chief of hepatology at Rush Medical College, Chicago, said, “This is another successful example of making therapy accessible to the population who is in need versus trying to move them into a tertiary care model.”
Dr. Reau noted that similar care models exist in the United States but are not always accessible to the population in need.
“The safety and efficacy of current therapy and the simplified care cascade make HCV an appropriate disease for this delivery,” she said, adding that this study “highlights not just the importance of these programs but also the necessity of engaging the medical community, changing policy, and using patient navigators and monetary support/prioritization to provide appropriate HCV management to those who are at high risk for the disease and for transmission.”
Accessible care beyond HCV
The coauthors of an accompanying editor’s note point out that the treatment for HCV has improved substantially, but it can be a real challenge to provide treatment to injection drug users because the U.S. health care system is not oriented toward the needs of this population.
“It is not surprising that the accessible care arm achieved a higher rate of viral eradication, as it created a patient-focused experience,” write Asha Choudhury, MD, MPH, with the University of California, San Francisco, and Mitchell Katz, MD, with NYC Health and Hospitals. “Creating inviting and engaging environments is particularly important when caring for patients from stigmatized groups. Having more sites that are accessible and inclusive like this for treating patients will likely increase treatment of hepatitis C.”
In their view, the study raises “two dueling questions: Is this model replicable across the U.S.? And, conversely, why isn’t all medical care offered in friendly, nonjudgmental settings with the intention of meeting patient goals?”
They conclude that the study’s lessons extend beyond this particular population and have implications for the field at large.
“The model is replicable to the extent that health care systems are prepared to provide nonjudgmental supportive care for persons who inject drugs,” they write. “However, all patients would benefit from a health care system that provided more patient-centered environments.”
The study was funded by the National Institute on Drug Abuse. Dr. Eckhardt reports receiving grants from the National Institutes of Health and Gilead during the conduct of the study. Dr. Choudhury, Dr. Katz, and Dr. Reau report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
For injection drug users with hepatitis C virus (HCV) infection, providing treatment opportunities within a local needle exchange program can provide care to more patients and eventually cure more patients, a new study suggests.
The study’s findings help “counteract the implicit belief within the medical community that people who inject drugs can’t or don’t want to engage in health care,” lead author Benjamin Eckhardt, MD, with NYU Grossman School of Medicine, told this news organization.
“By simply focusing on patient accompaniment, limiting stigma, and removing the punitive response for missed appointments, we can effectively engage people who inject drugs in health care and more specifically cure their infection, making significant inroads to HCV elimination,” Dr. Eckhardt said.
The study was published online in JAMA Internal Medicine.
Nonjudgmental, patient-centered approach
Researchers included 165 injection drug users with HCV (mean age, 42 years; 78% men); 82 were randomly allocated to the accessible care intervention and 83 to a usual care control group.
The accessible care model provides HCV treatment within a community-based needle exchange program in a comfortable, nonjudgmental atmosphere, “without fear of shame or stigma that people who inject drugs often experience in mainstream institutions,” the investigators explain.
Control participants were connected to a patient navigator who facilitated referrals to community direct antigen antiviral therapy programs that were not at a syringe service program.
In an intent-to-treat analysis, those enrolled in the accessible care group achieved sustained viral eradication at 12 months at significantly higher rates than those in the control group (67% vs. 23%; P < .001).
Once patients initiated treatment, cure rates were the same in both groups (86%), indicating that the major benefit of the accessible care program was in facilitating treatment, rather than increasing adherence to or response to treatment, the researchers noted.
This is reflected in the fact that the percentage of participants who advanced along the care cascade was significantly higher at each step for the accessible care group than the control group, from referral to an HCV clinician (93% vs. 45%), attendance of the initial HCV clinical visit (87% vs. 37%), completion of baseline laboratory testing (87% vs. 31%), and treatment initiation (78% vs. 27%).
Getting to the population in need
“The most surprising aspect of the study was how successful we were at recruiting, engaging, and treating people who inject drugs who lived outside the immediate community where the syringe exchange program was located and had no prior connection to the program,” Dr. Eckhardt said.
“We had numerous individuals travel 45-plus minutes on the subway from the South Bronx, passing four major medical centers with robust hepatitis C treatment programs, to seek care for hepatitis C in a small, dark office – but also an office they’d heard can be trusted – without fear of stigma or preconditions,” Dr. Eckhardt said.
Commenting on the study’s findings, Nancy Reau, MD, section chief of hepatology at Rush Medical College, Chicago, said, “This is another successful example of making therapy accessible to the population who is in need versus trying to move them into a tertiary care model.”
Dr. Reau noted that similar care models exist in the United States but are not always accessible to the population in need.
“The safety and efficacy of current therapy and the simplified care cascade make HCV an appropriate disease for this delivery,” she said, adding that this study “highlights not just the importance of these programs but also the necessity of engaging the medical community, changing policy, and using patient navigators and monetary support/prioritization to provide appropriate HCV management to those who are at high risk for the disease and for transmission.”
Accessible care beyond HCV
The coauthors of an accompanying editor’s note point out that the treatment for HCV has improved substantially, but it can be a real challenge to provide treatment to injection drug users because the U.S. health care system is not oriented toward the needs of this population.
“It is not surprising that the accessible care arm achieved a higher rate of viral eradication, as it created a patient-focused experience,” write Asha Choudhury, MD, MPH, with the University of California, San Francisco, and Mitchell Katz, MD, with NYC Health and Hospitals. “Creating inviting and engaging environments is particularly important when caring for patients from stigmatized groups. Having more sites that are accessible and inclusive like this for treating patients will likely increase treatment of hepatitis C.”
In their view, the study raises “two dueling questions: Is this model replicable across the U.S.? And, conversely, why isn’t all medical care offered in friendly, nonjudgmental settings with the intention of meeting patient goals?”
They conclude that the study’s lessons extend beyond this particular population and have implications for the field at large.
“The model is replicable to the extent that health care systems are prepared to provide nonjudgmental supportive care for persons who inject drugs,” they write. “However, all patients would benefit from a health care system that provided more patient-centered environments.”
The study was funded by the National Institute on Drug Abuse. Dr. Eckhardt reports receiving grants from the National Institutes of Health and Gilead during the conduct of the study. Dr. Choudhury, Dr. Katz, and Dr. Reau report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
For injection drug users with hepatitis C virus (HCV) infection, providing treatment opportunities within a local needle exchange program can provide care to more patients and eventually cure more patients, a new study suggests.
The study’s findings help “counteract the implicit belief within the medical community that people who inject drugs can’t or don’t want to engage in health care,” lead author Benjamin Eckhardt, MD, with NYU Grossman School of Medicine, told this news organization.
“By simply focusing on patient accompaniment, limiting stigma, and removing the punitive response for missed appointments, we can effectively engage people who inject drugs in health care and more specifically cure their infection, making significant inroads to HCV elimination,” Dr. Eckhardt said.
The study was published online in JAMA Internal Medicine.
Nonjudgmental, patient-centered approach
Researchers included 165 injection drug users with HCV (mean age, 42 years; 78% men); 82 were randomly allocated to the accessible care intervention and 83 to a usual care control group.
The accessible care model provides HCV treatment within a community-based needle exchange program in a comfortable, nonjudgmental atmosphere, “without fear of shame or stigma that people who inject drugs often experience in mainstream institutions,” the investigators explain.
Control participants were connected to a patient navigator who facilitated referrals to community direct antigen antiviral therapy programs that were not at a syringe service program.
In an intent-to-treat analysis, those enrolled in the accessible care group achieved sustained viral eradication at 12 months at significantly higher rates than those in the control group (67% vs. 23%; P < .001).
Once patients initiated treatment, cure rates were the same in both groups (86%), indicating that the major benefit of the accessible care program was in facilitating treatment, rather than increasing adherence to or response to treatment, the researchers noted.
This is reflected in the fact that the percentage of participants who advanced along the care cascade was significantly higher at each step for the accessible care group than the control group, from referral to an HCV clinician (93% vs. 45%), attendance of the initial HCV clinical visit (87% vs. 37%), completion of baseline laboratory testing (87% vs. 31%), and treatment initiation (78% vs. 27%).
Getting to the population in need
“The most surprising aspect of the study was how successful we were at recruiting, engaging, and treating people who inject drugs who lived outside the immediate community where the syringe exchange program was located and had no prior connection to the program,” Dr. Eckhardt said.
“We had numerous individuals travel 45-plus minutes on the subway from the South Bronx, passing four major medical centers with robust hepatitis C treatment programs, to seek care for hepatitis C in a small, dark office – but also an office they’d heard can be trusted – without fear of stigma or preconditions,” Dr. Eckhardt said.
Commenting on the study’s findings, Nancy Reau, MD, section chief of hepatology at Rush Medical College, Chicago, said, “This is another successful example of making therapy accessible to the population who is in need versus trying to move them into a tertiary care model.”
Dr. Reau noted that similar care models exist in the United States but are not always accessible to the population in need.
“The safety and efficacy of current therapy and the simplified care cascade make HCV an appropriate disease for this delivery,” she said, adding that this study “highlights not just the importance of these programs but also the necessity of engaging the medical community, changing policy, and using patient navigators and monetary support/prioritization to provide appropriate HCV management to those who are at high risk for the disease and for transmission.”
Accessible care beyond HCV
The coauthors of an accompanying editor’s note point out that the treatment for HCV has improved substantially, but it can be a real challenge to provide treatment to injection drug users because the U.S. health care system is not oriented toward the needs of this population.
“It is not surprising that the accessible care arm achieved a higher rate of viral eradication, as it created a patient-focused experience,” write Asha Choudhury, MD, MPH, with the University of California, San Francisco, and Mitchell Katz, MD, with NYC Health and Hospitals. “Creating inviting and engaging environments is particularly important when caring for patients from stigmatized groups. Having more sites that are accessible and inclusive like this for treating patients will likely increase treatment of hepatitis C.”
In their view, the study raises “two dueling questions: Is this model replicable across the U.S.? And, conversely, why isn’t all medical care offered in friendly, nonjudgmental settings with the intention of meeting patient goals?”
They conclude that the study’s lessons extend beyond this particular population and have implications for the field at large.
“The model is replicable to the extent that health care systems are prepared to provide nonjudgmental supportive care for persons who inject drugs,” they write. “However, all patients would benefit from a health care system that provided more patient-centered environments.”
The study was funded by the National Institute on Drug Abuse. Dr. Eckhardt reports receiving grants from the National Institutes of Health and Gilead during the conduct of the study. Dr. Choudhury, Dr. Katz, and Dr. Reau report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Less cirrhosis but worse outcomes for Black patients with NASH
Compared with White people, Black people are less likely to develop cirrhosis from nonalcoholic steatohepatitis (NASH) but are more likely to die when hospitalized with this condition, researchers say.
The finding highlights the importance of addressing hepatic complications and nonhepatic comorbidities with a comprehensive and interdisciplinary approach that includes social determinants of health, said Emad Qayed, MD, MPH, an associate professor of medicine at Emory University School of Medicine, Atlanta.
“Clinicians should realize that in Black patients with NASH and NASH cirrhosis, mortality can be high despite a low rate of hepatic complications,” he told this news organization.
The study by Dr. Qayed and colleagues was published in the Journal of Clinical Gastroenterology.
A nationwide analysis
Previous studies have indicated that Black people are less likely than White people to develop nonalcoholic fatty liver disease (NAFLD), despite the fact that prevalence is increasing. Furthermore, when Black people do develop NAFLD, the disease is less likely to progress to NASH. In cases in which NASH does develop, the evidence has been mixed as to the effect of race on hospital outcomes.
To shed new light on that question, Dr. Qayed and colleagues analyzed data from 2016 to 2018 from the National Inpatient Sample, which is produced by the Healthcare Cost and Utilization Project and is sponsored by the Agency of Healthcare Research and Quality.
They identified 43,409 hospitalizations for NASH, with 41,143 White patients and 2,266 Black patients. The mean age of the Black patients was less than that of the White patients (56.4 years vs. 63.0 years), and Black patients were more likely to be women (69.9% vs. 61.6%).
More of the Black patients had hypertension, obesity, chronic kidney disease, and congestive heart failure, while more of the White patients had diabetes, dyslipidemia, and ischemic heart disease.
Among the Black patients, 33.6% had cirrhosis, compared with 56.4% of the White patients. Likewise, among the Black patients, there were fewer manifestations of decompensated cirrhosis, compared with the White patients. Black patients were also less likely to have had to undergo upper endoscopy and paracentesis.
The Black patients died in the hospital at a rate of 3.9%, which was not significantly higher than the 3.7% rate for the White patients (unadjusted odds ratio = 1.06; 95% confidence interval: 0.84-1.32; P = .6). But, when the researchers adjusted for age, sex, cirrhosis, risk of mortality (based on the overall number and severity of diseases), and insurance status, there were significantly higher odds of mortality among the Black patients (adjusted OR, 1.34; 95% CI: 1.05-1.71; P = .018).
They did not find any association between hospital size, location, or region with mortality.
They also found no difference in mortality between Black patients and White patients among those those with and those without cirrhosis. However, they found that Black patients were more likely to have acute kidney injury, chronic kidney disease, and congestive heart failure.
Regarding the reasons for hospitalization, the researchers found liver-related illnesses, such as hepatic failure and noninfectious hepatitis, to be most common among the White patients. Circulatory disorders, such as heart failure, and endocrine disorders, such as diabetes mellitus with complications, were found to be most common among the Black patients.
The length of time in the hospital was longer for the Black patients than the White patients (6.3 days vs. 5.6 days; P < .0001). The cost of hospitalization was higher for Black patients as well ($18,603 vs. $17,467). This suggests that Black patients were sicker overall, despite their lower rates of liver complications.
“Some of these differences are likely related to socioeconomic factors and clinical comorbidities, such as cardiac and renal disease,” Dr. Qayed said. “However, the underlying etiologies for such disparities in NASH and cirrhosis remain unclear. Further research is warranted to clarify these etiologies.”
NASH as part of the metabolic syndrome
“Clinicians should consider NASH as part of the metabolic syndrome,” Paul Martin, MD, chief of digestive health and liver diseases at the University of Miami, told this news organization. He was not involved in the study.
“Typically, these patients have a number of risk factors for fatty liver, including obesity and often hyperlipidemia, hypertension, and sleep apnea,” he said. “Clinicians should screen their patients for such comorbidities and then treat them.”
Genetic factors could also play a role in the difference in susceptibility to fatty liver disease found between Black and White patients, he added.
Dr. Martin noted a prevalence of fatty liver in many Hispanic populations and that it is found in Asia but sometimes in the absence of the risk factors associated with it in the United States.
Dr. Qayed and Dr. Martin reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Compared with White people, Black people are less likely to develop cirrhosis from nonalcoholic steatohepatitis (NASH) but are more likely to die when hospitalized with this condition, researchers say.
The finding highlights the importance of addressing hepatic complications and nonhepatic comorbidities with a comprehensive and interdisciplinary approach that includes social determinants of health, said Emad Qayed, MD, MPH, an associate professor of medicine at Emory University School of Medicine, Atlanta.
“Clinicians should realize that in Black patients with NASH and NASH cirrhosis, mortality can be high despite a low rate of hepatic complications,” he told this news organization.
The study by Dr. Qayed and colleagues was published in the Journal of Clinical Gastroenterology.
A nationwide analysis
Previous studies have indicated that Black people are less likely than White people to develop nonalcoholic fatty liver disease (NAFLD), despite the fact that prevalence is increasing. Furthermore, when Black people do develop NAFLD, the disease is less likely to progress to NASH. In cases in which NASH does develop, the evidence has been mixed as to the effect of race on hospital outcomes.
To shed new light on that question, Dr. Qayed and colleagues analyzed data from 2016 to 2018 from the National Inpatient Sample, which is produced by the Healthcare Cost and Utilization Project and is sponsored by the Agency of Healthcare Research and Quality.
They identified 43,409 hospitalizations for NASH, with 41,143 White patients and 2,266 Black patients. The mean age of the Black patients was less than that of the White patients (56.4 years vs. 63.0 years), and Black patients were more likely to be women (69.9% vs. 61.6%).
More of the Black patients had hypertension, obesity, chronic kidney disease, and congestive heart failure, while more of the White patients had diabetes, dyslipidemia, and ischemic heart disease.
Among the Black patients, 33.6% had cirrhosis, compared with 56.4% of the White patients. Likewise, among the Black patients, there were fewer manifestations of decompensated cirrhosis, compared with the White patients. Black patients were also less likely to have had to undergo upper endoscopy and paracentesis.
The Black patients died in the hospital at a rate of 3.9%, which was not significantly higher than the 3.7% rate for the White patients (unadjusted odds ratio = 1.06; 95% confidence interval: 0.84-1.32; P = .6). But, when the researchers adjusted for age, sex, cirrhosis, risk of mortality (based on the overall number and severity of diseases), and insurance status, there were significantly higher odds of mortality among the Black patients (adjusted OR, 1.34; 95% CI: 1.05-1.71; P = .018).
They did not find any association between hospital size, location, or region with mortality.
They also found no difference in mortality between Black patients and White patients among those those with and those without cirrhosis. However, they found that Black patients were more likely to have acute kidney injury, chronic kidney disease, and congestive heart failure.
Regarding the reasons for hospitalization, the researchers found liver-related illnesses, such as hepatic failure and noninfectious hepatitis, to be most common among the White patients. Circulatory disorders, such as heart failure, and endocrine disorders, such as diabetes mellitus with complications, were found to be most common among the Black patients.
The length of time in the hospital was longer for the Black patients than the White patients (6.3 days vs. 5.6 days; P < .0001). The cost of hospitalization was higher for Black patients as well ($18,603 vs. $17,467). This suggests that Black patients were sicker overall, despite their lower rates of liver complications.
“Some of these differences are likely related to socioeconomic factors and clinical comorbidities, such as cardiac and renal disease,” Dr. Qayed said. “However, the underlying etiologies for such disparities in NASH and cirrhosis remain unclear. Further research is warranted to clarify these etiologies.”
NASH as part of the metabolic syndrome
“Clinicians should consider NASH as part of the metabolic syndrome,” Paul Martin, MD, chief of digestive health and liver diseases at the University of Miami, told this news organization. He was not involved in the study.
“Typically, these patients have a number of risk factors for fatty liver, including obesity and often hyperlipidemia, hypertension, and sleep apnea,” he said. “Clinicians should screen their patients for such comorbidities and then treat them.”
Genetic factors could also play a role in the difference in susceptibility to fatty liver disease found between Black and White patients, he added.
Dr. Martin noted a prevalence of fatty liver in many Hispanic populations and that it is found in Asia but sometimes in the absence of the risk factors associated with it in the United States.
Dr. Qayed and Dr. Martin reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Compared with White people, Black people are less likely to develop cirrhosis from nonalcoholic steatohepatitis (NASH) but are more likely to die when hospitalized with this condition, researchers say.
The finding highlights the importance of addressing hepatic complications and nonhepatic comorbidities with a comprehensive and interdisciplinary approach that includes social determinants of health, said Emad Qayed, MD, MPH, an associate professor of medicine at Emory University School of Medicine, Atlanta.
“Clinicians should realize that in Black patients with NASH and NASH cirrhosis, mortality can be high despite a low rate of hepatic complications,” he told this news organization.
The study by Dr. Qayed and colleagues was published in the Journal of Clinical Gastroenterology.
A nationwide analysis
Previous studies have indicated that Black people are less likely than White people to develop nonalcoholic fatty liver disease (NAFLD), despite the fact that prevalence is increasing. Furthermore, when Black people do develop NAFLD, the disease is less likely to progress to NASH. In cases in which NASH does develop, the evidence has been mixed as to the effect of race on hospital outcomes.
To shed new light on that question, Dr. Qayed and colleagues analyzed data from 2016 to 2018 from the National Inpatient Sample, which is produced by the Healthcare Cost and Utilization Project and is sponsored by the Agency of Healthcare Research and Quality.
They identified 43,409 hospitalizations for NASH, with 41,143 White patients and 2,266 Black patients. The mean age of the Black patients was less than that of the White patients (56.4 years vs. 63.0 years), and Black patients were more likely to be women (69.9% vs. 61.6%).
More of the Black patients had hypertension, obesity, chronic kidney disease, and congestive heart failure, while more of the White patients had diabetes, dyslipidemia, and ischemic heart disease.
Among the Black patients, 33.6% had cirrhosis, compared with 56.4% of the White patients. Likewise, among the Black patients, there were fewer manifestations of decompensated cirrhosis, compared with the White patients. Black patients were also less likely to have had to undergo upper endoscopy and paracentesis.
The Black patients died in the hospital at a rate of 3.9%, which was not significantly higher than the 3.7% rate for the White patients (unadjusted odds ratio = 1.06; 95% confidence interval: 0.84-1.32; P = .6). But, when the researchers adjusted for age, sex, cirrhosis, risk of mortality (based on the overall number and severity of diseases), and insurance status, there were significantly higher odds of mortality among the Black patients (adjusted OR, 1.34; 95% CI: 1.05-1.71; P = .018).
They did not find any association between hospital size, location, or region with mortality.
They also found no difference in mortality between Black patients and White patients among those those with and those without cirrhosis. However, they found that Black patients were more likely to have acute kidney injury, chronic kidney disease, and congestive heart failure.
Regarding the reasons for hospitalization, the researchers found liver-related illnesses, such as hepatic failure and noninfectious hepatitis, to be most common among the White patients. Circulatory disorders, such as heart failure, and endocrine disorders, such as diabetes mellitus with complications, were found to be most common among the Black patients.
The length of time in the hospital was longer for the Black patients than the White patients (6.3 days vs. 5.6 days; P < .0001). The cost of hospitalization was higher for Black patients as well ($18,603 vs. $17,467). This suggests that Black patients were sicker overall, despite their lower rates of liver complications.
“Some of these differences are likely related to socioeconomic factors and clinical comorbidities, such as cardiac and renal disease,” Dr. Qayed said. “However, the underlying etiologies for such disparities in NASH and cirrhosis remain unclear. Further research is warranted to clarify these etiologies.”
NASH as part of the metabolic syndrome
“Clinicians should consider NASH as part of the metabolic syndrome,” Paul Martin, MD, chief of digestive health and liver diseases at the University of Miami, told this news organization. He was not involved in the study.
“Typically, these patients have a number of risk factors for fatty liver, including obesity and often hyperlipidemia, hypertension, and sleep apnea,” he said. “Clinicians should screen their patients for such comorbidities and then treat them.”
Genetic factors could also play a role in the difference in susceptibility to fatty liver disease found between Black and White patients, he added.
Dr. Martin noted a prevalence of fatty liver in many Hispanic populations and that it is found in Asia but sometimes in the absence of the risk factors associated with it in the United States.
Dr. Qayed and Dr. Martin reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Locoregional therapy lowers wait-list dropout in HCC
The use of bridging locoregional therapy (LRT) before liver transplantation in patients with hepatocellular carcinoma (HCC) has significantly increased in the United States within the past 15 years, a recent analysis suggests. Data show that liver transplant candidates with HCC who have elevated tumor burden and patients with more compensated liver disease have received a greater number of treatments while awaiting transplant.
According to the researchers, led by Allison Kwong, MD, of Stanford (Calif.) University, liver transplant remains a curative option for individuals with unresectable HCC who meet prespecified size criteria. In the United States, a mandated waiting period of 6 months prior “to gaining exception points has been implemented” in an effort “to allow for consideration of tumor biology and reduce the disparities in wait-list dropout between HCC and non-HCC patients,” the researchers wrote.
Several forms of LRT are now available for HCC, including chemoembolization, external beam radiation, radioembolization, and radiofrequency or microwave ablation. In the liver transplant setting, these LRT options enable management of intrahepatic disease in patients who are waiting for liver transplant, Dr. Kwong and colleagues explained.
The researchers, who published their study findings in the May issue of Clinical Gastroenterology and Hepatology, sought to examine the national temporal trends and wait-list outcomes of LRT in 31,609 patients eligible for liver transplant with greater than or equal to one approved HCC exception application in the United States.
Patient data were obtained from the Organ Procurement and Transplantation Network database and comprised primary adult LT candidates who were listed from the years 2003 to 2018. The investigators assessed explant histology and performed multivariable competing risk analysis to examine the relationship between the type of first LRT and time to wait-list dropout.
The wait-list dropout variable was defined by list removal because of death or excessive illness. The researchers noted that list removal likely represents disease progression “beyond transplantable criteria and beyond which patients were unlikely to benefit from or be eligible for further LRT.”
In the study population, the median age was 59 years, and approximately 77% of patients were male. More than half (53.1%) of the cohort had hepatitis C as the predominant liver disease etiology. Patients had a median follow-up period of 214 days on the waiting list.
Most patients (79%) received deceased or living-donor transplants, and 18.6% of patients were removed from the waiting list. Between the 2003 and 2006 period, the median wait-list time was 123 days, but this median wait-list duration increased to 257 days for patients listed between 2015 and 2018.
A total of 34,610 LRTs were performed among 24,145 liver transplant candidates during the study period. From 2003 to 2018, the proportion of patients with greater than or equal to 1 LRT recorded in the database rose from 42.3% to 92.4%, respectively. Most patients (67.8%) who received liver-directed therapy had a single LRT, while 23.8% of patients had two LRTs, 6.2% had three LRTs, and 2.2% had greater than or equal to four LRTs.
The most frequent type of LRT performed was chemoembolization, followed by thermal ablation. Radioembolization increased from less than 5% in 2013 to 19% in 2018. Moreover, in 2018, chemoembolization accounted for 50% of LRTs, while thermal ablation accounted for 22% of LRTs.
The incidence rates of LRT per 100 wait-list days was above average in patients who had an initial tumor burden beyond the Milan criteria (0.188), an alpha-fetoprotein level of 21-40 (0.171) or 41-500 ng/mL (0.179), Child-Pugh class A (0.160), patients in short (0.151) and medium (0.154) wait-time regions, as well as patients who were listed following implementation of cap-and-delay in October 2015 (0.192).
In the multivariable competing-risk analysis for wait-list dropout, adjusting for initial tumor burden and AFP, Child-Pugh class, wait region, and listing era, no locoregional therapy was associated with an increased risk of wait-list dropout versus chemoembolization as the first LRT in a multivariable competing-risk analysis (subhazard ratio, 1.37; 95% CI, 1.28-1.47). The inverse probability of treatment weighting–adjusted analysis found an association between radioembolization, when compared with chemoembolization, and a reduced risk of wait-list dropout (sHR, 0.85; 95% CI, 0.81-0.89). Thermal ablation was also associated with a reduced risk of wait-list dropout, compared with chemoembolization (sHR, 0.95; 95% CI, 0.91-0.99). “Radioembolization and thermal ablation may be superior to chemoembolization and prove to be more cost-effective options, depending on the clinical context,” the researchers wrote.
The researchers noted that they were unable to distinguish patients who were removed from the waiting list between those with disease progression versus liver failure.
The researchers reported no conflicts of interest with the pharmaceutical industry. The study received no industry funding.
In 1996, Mazzaferro and colleagues reported the results of a cohort of 48 patients with cirrhosis who had small, unresectable hepatocellular carcinoma (HCC). The actuarial survival rate was 75% at 4 years, and 83% of these patients had no recurrence, so, orthotopic liver transplantation became one of the standard options with curative intent for the treatment HCC. Because of HCC biology, some of these tumors grow or, worst-case scenario, are outside the Milan criteria. Locoregional therapies (LRT) were applied to arrest or downsize the tumor(s) to be within the liver transplantation criteria.
Kwong and colleagues, using the data of the Organ Procurement and Transplantation Network database, showed an exponential increase of LRT over 15 years: from 32.5% in 2003 to 92.4% in 2018. The Barcelona Clinic Liver Cancer staging system classifies chemoembolization, the most common LRT modality used in this cohort, as a palliative treatment rather than curative. Not surprisingly, the authors found that radioembolization was independently associated with a 15% reduction in the wait-list dropout rate, compared with chemoembolization. Further, listing in longer wait-time regions and more recent years was independently associated with a higher likelihood of wait-list dropout.
These data may be worrisome for patients listed for HCC. The median Model for End-Stage Liver Disease at Transplant Minus 3 National Policy, introduced in May 2019, decreases the transplantation rates in patients with HCC. Consequently, longer wait-list time leads to increase utilization of LRT to keep these patients within criteria. Radioembolization could become the preferred LRT therapy to stop tumor growth than chemoembolization and, probably, will be more cost effective. Future work should address explant outcomes and outcome on downstaging with external radiation therapy and adjuvant use of immunotherapy.
Ruben Hernaez, MD, MPH, PhD, is an assistant professor at the Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, both in Houston. He has no relevant conflicts to disclose.
In 1996, Mazzaferro and colleagues reported the results of a cohort of 48 patients with cirrhosis who had small, unresectable hepatocellular carcinoma (HCC). The actuarial survival rate was 75% at 4 years, and 83% of these patients had no recurrence, so, orthotopic liver transplantation became one of the standard options with curative intent for the treatment HCC. Because of HCC biology, some of these tumors grow or, worst-case scenario, are outside the Milan criteria. Locoregional therapies (LRT) were applied to arrest or downsize the tumor(s) to be within the liver transplantation criteria.
Kwong and colleagues, using the data of the Organ Procurement and Transplantation Network database, showed an exponential increase of LRT over 15 years: from 32.5% in 2003 to 92.4% in 2018. The Barcelona Clinic Liver Cancer staging system classifies chemoembolization, the most common LRT modality used in this cohort, as a palliative treatment rather than curative. Not surprisingly, the authors found that radioembolization was independently associated with a 15% reduction in the wait-list dropout rate, compared with chemoembolization. Further, listing in longer wait-time regions and more recent years was independently associated with a higher likelihood of wait-list dropout.
These data may be worrisome for patients listed for HCC. The median Model for End-Stage Liver Disease at Transplant Minus 3 National Policy, introduced in May 2019, decreases the transplantation rates in patients with HCC. Consequently, longer wait-list time leads to increase utilization of LRT to keep these patients within criteria. Radioembolization could become the preferred LRT therapy to stop tumor growth than chemoembolization and, probably, will be more cost effective. Future work should address explant outcomes and outcome on downstaging with external radiation therapy and adjuvant use of immunotherapy.
Ruben Hernaez, MD, MPH, PhD, is an assistant professor at the Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, both in Houston. He has no relevant conflicts to disclose.
In 1996, Mazzaferro and colleagues reported the results of a cohort of 48 patients with cirrhosis who had small, unresectable hepatocellular carcinoma (HCC). The actuarial survival rate was 75% at 4 years, and 83% of these patients had no recurrence, so, orthotopic liver transplantation became one of the standard options with curative intent for the treatment HCC. Because of HCC biology, some of these tumors grow or, worst-case scenario, are outside the Milan criteria. Locoregional therapies (LRT) were applied to arrest or downsize the tumor(s) to be within the liver transplantation criteria.
Kwong and colleagues, using the data of the Organ Procurement and Transplantation Network database, showed an exponential increase of LRT over 15 years: from 32.5% in 2003 to 92.4% in 2018. The Barcelona Clinic Liver Cancer staging system classifies chemoembolization, the most common LRT modality used in this cohort, as a palliative treatment rather than curative. Not surprisingly, the authors found that radioembolization was independently associated with a 15% reduction in the wait-list dropout rate, compared with chemoembolization. Further, listing in longer wait-time regions and more recent years was independently associated with a higher likelihood of wait-list dropout.
These data may be worrisome for patients listed for HCC. The median Model for End-Stage Liver Disease at Transplant Minus 3 National Policy, introduced in May 2019, decreases the transplantation rates in patients with HCC. Consequently, longer wait-list time leads to increase utilization of LRT to keep these patients within criteria. Radioembolization could become the preferred LRT therapy to stop tumor growth than chemoembolization and, probably, will be more cost effective. Future work should address explant outcomes and outcome on downstaging with external radiation therapy and adjuvant use of immunotherapy.
Ruben Hernaez, MD, MPH, PhD, is an assistant professor at the Michael E. DeBakey Veterans Affairs Medical Center and Baylor College of Medicine, both in Houston. He has no relevant conflicts to disclose.
The use of bridging locoregional therapy (LRT) before liver transplantation in patients with hepatocellular carcinoma (HCC) has significantly increased in the United States within the past 15 years, a recent analysis suggests. Data show that liver transplant candidates with HCC who have elevated tumor burden and patients with more compensated liver disease have received a greater number of treatments while awaiting transplant.
According to the researchers, led by Allison Kwong, MD, of Stanford (Calif.) University, liver transplant remains a curative option for individuals with unresectable HCC who meet prespecified size criteria. In the United States, a mandated waiting period of 6 months prior “to gaining exception points has been implemented” in an effort “to allow for consideration of tumor biology and reduce the disparities in wait-list dropout between HCC and non-HCC patients,” the researchers wrote.
Several forms of LRT are now available for HCC, including chemoembolization, external beam radiation, radioembolization, and radiofrequency or microwave ablation. In the liver transplant setting, these LRT options enable management of intrahepatic disease in patients who are waiting for liver transplant, Dr. Kwong and colleagues explained.
The researchers, who published their study findings in the May issue of Clinical Gastroenterology and Hepatology, sought to examine the national temporal trends and wait-list outcomes of LRT in 31,609 patients eligible for liver transplant with greater than or equal to one approved HCC exception application in the United States.
Patient data were obtained from the Organ Procurement and Transplantation Network database and comprised primary adult LT candidates who were listed from the years 2003 to 2018. The investigators assessed explant histology and performed multivariable competing risk analysis to examine the relationship between the type of first LRT and time to wait-list dropout.
The wait-list dropout variable was defined by list removal because of death or excessive illness. The researchers noted that list removal likely represents disease progression “beyond transplantable criteria and beyond which patients were unlikely to benefit from or be eligible for further LRT.”
In the study population, the median age was 59 years, and approximately 77% of patients were male. More than half (53.1%) of the cohort had hepatitis C as the predominant liver disease etiology. Patients had a median follow-up period of 214 days on the waiting list.
Most patients (79%) received deceased or living-donor transplants, and 18.6% of patients were removed from the waiting list. Between the 2003 and 2006 period, the median wait-list time was 123 days, but this median wait-list duration increased to 257 days for patients listed between 2015 and 2018.
A total of 34,610 LRTs were performed among 24,145 liver transplant candidates during the study period. From 2003 to 2018, the proportion of patients with greater than or equal to 1 LRT recorded in the database rose from 42.3% to 92.4%, respectively. Most patients (67.8%) who received liver-directed therapy had a single LRT, while 23.8% of patients had two LRTs, 6.2% had three LRTs, and 2.2% had greater than or equal to four LRTs.
The most frequent type of LRT performed was chemoembolization, followed by thermal ablation. Radioembolization increased from less than 5% in 2013 to 19% in 2018. Moreover, in 2018, chemoembolization accounted for 50% of LRTs, while thermal ablation accounted for 22% of LRTs.
The incidence rates of LRT per 100 wait-list days was above average in patients who had an initial tumor burden beyond the Milan criteria (0.188), an alpha-fetoprotein level of 21-40 (0.171) or 41-500 ng/mL (0.179), Child-Pugh class A (0.160), patients in short (0.151) and medium (0.154) wait-time regions, as well as patients who were listed following implementation of cap-and-delay in October 2015 (0.192).
In the multivariable competing-risk analysis for wait-list dropout, adjusting for initial tumor burden and AFP, Child-Pugh class, wait region, and listing era, no locoregional therapy was associated with an increased risk of wait-list dropout versus chemoembolization as the first LRT in a multivariable competing-risk analysis (subhazard ratio, 1.37; 95% CI, 1.28-1.47). The inverse probability of treatment weighting–adjusted analysis found an association between radioembolization, when compared with chemoembolization, and a reduced risk of wait-list dropout (sHR, 0.85; 95% CI, 0.81-0.89). Thermal ablation was also associated with a reduced risk of wait-list dropout, compared with chemoembolization (sHR, 0.95; 95% CI, 0.91-0.99). “Radioembolization and thermal ablation may be superior to chemoembolization and prove to be more cost-effective options, depending on the clinical context,” the researchers wrote.
The researchers noted that they were unable to distinguish patients who were removed from the waiting list between those with disease progression versus liver failure.
The researchers reported no conflicts of interest with the pharmaceutical industry. The study received no industry funding.
The use of bridging locoregional therapy (LRT) before liver transplantation in patients with hepatocellular carcinoma (HCC) has significantly increased in the United States within the past 15 years, a recent analysis suggests. Data show that liver transplant candidates with HCC who have elevated tumor burden and patients with more compensated liver disease have received a greater number of treatments while awaiting transplant.
According to the researchers, led by Allison Kwong, MD, of Stanford (Calif.) University, liver transplant remains a curative option for individuals with unresectable HCC who meet prespecified size criteria. In the United States, a mandated waiting period of 6 months prior “to gaining exception points has been implemented” in an effort “to allow for consideration of tumor biology and reduce the disparities in wait-list dropout between HCC and non-HCC patients,” the researchers wrote.
Several forms of LRT are now available for HCC, including chemoembolization, external beam radiation, radioembolization, and radiofrequency or microwave ablation. In the liver transplant setting, these LRT options enable management of intrahepatic disease in patients who are waiting for liver transplant, Dr. Kwong and colleagues explained.
The researchers, who published their study findings in the May issue of Clinical Gastroenterology and Hepatology, sought to examine the national temporal trends and wait-list outcomes of LRT in 31,609 patients eligible for liver transplant with greater than or equal to one approved HCC exception application in the United States.
Patient data were obtained from the Organ Procurement and Transplantation Network database and comprised primary adult LT candidates who were listed from the years 2003 to 2018. The investigators assessed explant histology and performed multivariable competing risk analysis to examine the relationship between the type of first LRT and time to wait-list dropout.
The wait-list dropout variable was defined by list removal because of death or excessive illness. The researchers noted that list removal likely represents disease progression “beyond transplantable criteria and beyond which patients were unlikely to benefit from or be eligible for further LRT.”
In the study population, the median age was 59 years, and approximately 77% of patients were male. More than half (53.1%) of the cohort had hepatitis C as the predominant liver disease etiology. Patients had a median follow-up period of 214 days on the waiting list.
Most patients (79%) received deceased or living-donor transplants, and 18.6% of patients were removed from the waiting list. Between the 2003 and 2006 period, the median wait-list time was 123 days, but this median wait-list duration increased to 257 days for patients listed between 2015 and 2018.
A total of 34,610 LRTs were performed among 24,145 liver transplant candidates during the study period. From 2003 to 2018, the proportion of patients with greater than or equal to 1 LRT recorded in the database rose from 42.3% to 92.4%, respectively. Most patients (67.8%) who received liver-directed therapy had a single LRT, while 23.8% of patients had two LRTs, 6.2% had three LRTs, and 2.2% had greater than or equal to four LRTs.
The most frequent type of LRT performed was chemoembolization, followed by thermal ablation. Radioembolization increased from less than 5% in 2013 to 19% in 2018. Moreover, in 2018, chemoembolization accounted for 50% of LRTs, while thermal ablation accounted for 22% of LRTs.
The incidence rates of LRT per 100 wait-list days was above average in patients who had an initial tumor burden beyond the Milan criteria (0.188), an alpha-fetoprotein level of 21-40 (0.171) or 41-500 ng/mL (0.179), Child-Pugh class A (0.160), patients in short (0.151) and medium (0.154) wait-time regions, as well as patients who were listed following implementation of cap-and-delay in October 2015 (0.192).
In the multivariable competing-risk analysis for wait-list dropout, adjusting for initial tumor burden and AFP, Child-Pugh class, wait region, and listing era, no locoregional therapy was associated with an increased risk of wait-list dropout versus chemoembolization as the first LRT in a multivariable competing-risk analysis (subhazard ratio, 1.37; 95% CI, 1.28-1.47). The inverse probability of treatment weighting–adjusted analysis found an association between radioembolization, when compared with chemoembolization, and a reduced risk of wait-list dropout (sHR, 0.85; 95% CI, 0.81-0.89). Thermal ablation was also associated with a reduced risk of wait-list dropout, compared with chemoembolization (sHR, 0.95; 95% CI, 0.91-0.99). “Radioembolization and thermal ablation may be superior to chemoembolization and prove to be more cost-effective options, depending on the clinical context,” the researchers wrote.
The researchers noted that they were unable to distinguish patients who were removed from the waiting list between those with disease progression versus liver failure.
The researchers reported no conflicts of interest with the pharmaceutical industry. The study received no industry funding.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
CDC recommends hep B vaccination for most adults
It also added that adults aged 60 years or older without known risk factors for hepatitis B may get vaccinated.
The agency earlier recommended the vaccination for all infants and children under the age of 19 years and for adults aged 60 years or older with known risk factors.
The CDC said it wants to expand vaccinations because, after decades of progress, the number of new hepatitis B infections is increasing among adults. Acute hepatitis B infections among adults lead to chronic hepatitis B disease in an estimated 2%-6% of cases, and can result in cirrhosis, liver cancer, and death.
Among adults aged 40-49 years, the rate of cases increased from 1.9 per 100,000 people in 2011 to 2.7 per 100,000 in 2019. Among adults aged 50-59 years, the rate increased during this period from 1.1 to 1.6 per 100,000.
Most adults aren’t vaccinated. Among adults aged 19 years or older, only 30.0% reported that they’d received at least the three recommended doses of the vaccine. The rate was 40.3% for adults aged 19-49 years, and 19.1% for adults aged 50 years or older.
Hepatitis B infection rates are particularly elevated among African Americans.
Even among adults with chronic liver disease, the vaccination rate is only 33.0%. And, among travelers to countries where the virus has been endemic since 1995, only 38.9% were vaccinated.
In a 2018 survey of internal medicine and family physicians, 68% said their patients had not told them about risk factors, making it difficult to assess whether the patients needed the vaccine according to the recommendations at the time. These risk factors include injection drug use, incarceration, and multiple sex partners, experiences the patients may not have been willing to discuss.
CDC researchers calculated that universal adult hepatitis B vaccination would cost $153,000 for every quality-adjusted life-year (QALY) gained. For adults aged 19-59 years, a QALY would cost $117,000 because infections are more prevalent in that age group.
The CDC specified that it intends its new guidelines to prompt physicians to offer the vaccine to adults aged 60 years or older rather than wait for them to request it.
The Food and Drug Administration has approved both three-dose and two-dose hepatitis B vaccines, with evidence showing similar seroprotection and adverse events.
People who have already completed their vaccination or have a history of hepatitis B infection should only receive additional vaccinations in specific cases, as detailed in the CDC’s 2018 recommendations.
A version of this article first appeared on Medscape.com.
It also added that adults aged 60 years or older without known risk factors for hepatitis B may get vaccinated.
The agency earlier recommended the vaccination for all infants and children under the age of 19 years and for adults aged 60 years or older with known risk factors.
The CDC said it wants to expand vaccinations because, after decades of progress, the number of new hepatitis B infections is increasing among adults. Acute hepatitis B infections among adults lead to chronic hepatitis B disease in an estimated 2%-6% of cases, and can result in cirrhosis, liver cancer, and death.
Among adults aged 40-49 years, the rate of cases increased from 1.9 per 100,000 people in 2011 to 2.7 per 100,000 in 2019. Among adults aged 50-59 years, the rate increased during this period from 1.1 to 1.6 per 100,000.
Most adults aren’t vaccinated. Among adults aged 19 years or older, only 30.0% reported that they’d received at least the three recommended doses of the vaccine. The rate was 40.3% for adults aged 19-49 years, and 19.1% for adults aged 50 years or older.
Hepatitis B infection rates are particularly elevated among African Americans.
Even among adults with chronic liver disease, the vaccination rate is only 33.0%. And, among travelers to countries where the virus has been endemic since 1995, only 38.9% were vaccinated.
In a 2018 survey of internal medicine and family physicians, 68% said their patients had not told them about risk factors, making it difficult to assess whether the patients needed the vaccine according to the recommendations at the time. These risk factors include injection drug use, incarceration, and multiple sex partners, experiences the patients may not have been willing to discuss.
CDC researchers calculated that universal adult hepatitis B vaccination would cost $153,000 for every quality-adjusted life-year (QALY) gained. For adults aged 19-59 years, a QALY would cost $117,000 because infections are more prevalent in that age group.
The CDC specified that it intends its new guidelines to prompt physicians to offer the vaccine to adults aged 60 years or older rather than wait for them to request it.
The Food and Drug Administration has approved both three-dose and two-dose hepatitis B vaccines, with evidence showing similar seroprotection and adverse events.
People who have already completed their vaccination or have a history of hepatitis B infection should only receive additional vaccinations in specific cases, as detailed in the CDC’s 2018 recommendations.
A version of this article first appeared on Medscape.com.
It also added that adults aged 60 years or older without known risk factors for hepatitis B may get vaccinated.
The agency earlier recommended the vaccination for all infants and children under the age of 19 years and for adults aged 60 years or older with known risk factors.
The CDC said it wants to expand vaccinations because, after decades of progress, the number of new hepatitis B infections is increasing among adults. Acute hepatitis B infections among adults lead to chronic hepatitis B disease in an estimated 2%-6% of cases, and can result in cirrhosis, liver cancer, and death.
Among adults aged 40-49 years, the rate of cases increased from 1.9 per 100,000 people in 2011 to 2.7 per 100,000 in 2019. Among adults aged 50-59 years, the rate increased during this period from 1.1 to 1.6 per 100,000.
Most adults aren’t vaccinated. Among adults aged 19 years or older, only 30.0% reported that they’d received at least the three recommended doses of the vaccine. The rate was 40.3% for adults aged 19-49 years, and 19.1% for adults aged 50 years or older.
Hepatitis B infection rates are particularly elevated among African Americans.
Even among adults with chronic liver disease, the vaccination rate is only 33.0%. And, among travelers to countries where the virus has been endemic since 1995, only 38.9% were vaccinated.
In a 2018 survey of internal medicine and family physicians, 68% said their patients had not told them about risk factors, making it difficult to assess whether the patients needed the vaccine according to the recommendations at the time. These risk factors include injection drug use, incarceration, and multiple sex partners, experiences the patients may not have been willing to discuss.
CDC researchers calculated that universal adult hepatitis B vaccination would cost $153,000 for every quality-adjusted life-year (QALY) gained. For adults aged 19-59 years, a QALY would cost $117,000 because infections are more prevalent in that age group.
The CDC specified that it intends its new guidelines to prompt physicians to offer the vaccine to adults aged 60 years or older rather than wait for them to request it.
The Food and Drug Administration has approved both three-dose and two-dose hepatitis B vaccines, with evidence showing similar seroprotection and adverse events.
People who have already completed their vaccination or have a history of hepatitis B infection should only receive additional vaccinations in specific cases, as detailed in the CDC’s 2018 recommendations.
A version of this article first appeared on Medscape.com.
FROM THE MMWR
New HBV model may open door to more effective antivirals
A new mouse model that better represents chronic infection with hepatitis B virus (HBV) in humans may lead to more effective antiviral therapies for HBV, according to investigators.
During human infection, HBV genomes take the form of covalently closed circular DNA (cccDNA), a structure that has thwarted effective antiviral therapy and, until now, creation of an accurate mouse model, reported lead author Zaichao Xu, PhD, of Wuhan (China) University and colleagues.
“As the viral persistence reservoir plays a central role in HBV infection, HBV cccDNA is the key obstacle for a cure,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology.
Although several previous mouse models have approximated this phenomenon with recombinant cccDNA-like molecules (rcccDNA), the present model is the first to achieve genuine cccDNA, which does not naturally occur in mice.
“Although rcccDNA supports persistent viral replication and antigen expression, the nature of rcccDNA may differ from authentic cccDNA, as additional sequences, like LoxP or attR, were inserted into the HBV genome,” the investigators noted.
The new model was created by first constructing an adeno-associated virus vector carrying a replication-deficient HBV1.04-fold genome (AAV-HBV1.04). When injected into mice, the vector led to cccDNA formation via ataxia-telangiectasia and Rad3-related protein (ATR)–mediated DNA damage response, a finding that was confirmed by blocking the same process with ATR inhibitors.
Immediately after injection, mice tested positive for both hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg), with peak concentrations after either 4 or 8 weeks depending on dose. HBV DNA was also detected in serum after injection, and 50% of hepatocytes exhibited HBsAg and hepatitis B core protein (HBc) after 1 week. At week 66, HBsAg, HBeAg, and HBc were still detectable in the liver.
“The expression of HBc could only be observed in the liver, but not in other organs or tissues, suggesting that the AAV-HBV1.04 only targeted the mouse liver,” the investigators wrote.
Further experimentation involving known cccDNA-binding proteins supported the similarity between cccDNA in the mouse model and natural infection.
“These results suggested that the chromatinization and transcriptional activation of cccDNA formed in this model dose not differ from wild-type cccDNA formed through infection.”
Next, Dr. Xu and colleagues demonstrated that the infected mice could serve as a reliable model for antiviral research. One week after injection with the vector, mice were treated with entecavir, polyinosinic-polycytidylic acid (poly[I:C]), or phosphate-buffered saline (PBS; control). As anticipated, entecavir suppressed circulating HBV DNA, but not HBsAg, HBeAg, or HBV cccDNA, whereas treatment with poly(I:C) reduced all HBV markers.
“This novel mouse model will provide a unique platform for studying HBV cccDNA and developing novel antivirals to achieve HBV cure,” the investigators concluded.
The study was supported by the National Natural Science Foundation of China, the Fundamental Research Funds for the Central Universities, Hubei Province’s Outstanding Medical Academic Leader Program, and others. The investigators reported no conflicts of interest.
On the heels of the wondrous development of curative antiviral agents for hepatitis C virus (HCV), renewed attention has been directed to efforts to bring about the cure of HBV. However, this task will hinge on successful elimination of covalently closed circular DNA (cccDNA), a highly stable form of viral DNA that is exceedingly difficult to eliminate. Efforts to develop successful curative strategies will in turn rely on development of small animal models that support HBV cccDNA formation and virus production, which has until recently proved elusive. In the past several years, several mouse HBV models supporting cccDNA formation have been constructed using adeno-associated vector (AAV)–mediated transduction of a linearized HBV genome. Both the AAV-HBV linear episome and cccDNA have been consistently replicated and detected in these models. While they recapitulate the key steps of the viral life cycle, these models do not, however, lend themselves to direct assessment of cccDNA, which have traditionally required detection of cccDNA in the liver.
Raymond T. Chung, MD, is a professor of medicine at Harvard Medical School and director of the Hepatology and Liver Center at Massachusetts General Hospital, both in Boston. He has no conflicts to disclose.
On the heels of the wondrous development of curative antiviral agents for hepatitis C virus (HCV), renewed attention has been directed to efforts to bring about the cure of HBV. However, this task will hinge on successful elimination of covalently closed circular DNA (cccDNA), a highly stable form of viral DNA that is exceedingly difficult to eliminate. Efforts to develop successful curative strategies will in turn rely on development of small animal models that support HBV cccDNA formation and virus production, which has until recently proved elusive. In the past several years, several mouse HBV models supporting cccDNA formation have been constructed using adeno-associated vector (AAV)–mediated transduction of a linearized HBV genome. Both the AAV-HBV linear episome and cccDNA have been consistently replicated and detected in these models. While they recapitulate the key steps of the viral life cycle, these models do not, however, lend themselves to direct assessment of cccDNA, which have traditionally required detection of cccDNA in the liver.
Raymond T. Chung, MD, is a professor of medicine at Harvard Medical School and director of the Hepatology and Liver Center at Massachusetts General Hospital, both in Boston. He has no conflicts to disclose.
On the heels of the wondrous development of curative antiviral agents for hepatitis C virus (HCV), renewed attention has been directed to efforts to bring about the cure of HBV. However, this task will hinge on successful elimination of covalently closed circular DNA (cccDNA), a highly stable form of viral DNA that is exceedingly difficult to eliminate. Efforts to develop successful curative strategies will in turn rely on development of small animal models that support HBV cccDNA formation and virus production, which has until recently proved elusive. In the past several years, several mouse HBV models supporting cccDNA formation have been constructed using adeno-associated vector (AAV)–mediated transduction of a linearized HBV genome. Both the AAV-HBV linear episome and cccDNA have been consistently replicated and detected in these models. While they recapitulate the key steps of the viral life cycle, these models do not, however, lend themselves to direct assessment of cccDNA, which have traditionally required detection of cccDNA in the liver.
Raymond T. Chung, MD, is a professor of medicine at Harvard Medical School and director of the Hepatology and Liver Center at Massachusetts General Hospital, both in Boston. He has no conflicts to disclose.
A new mouse model that better represents chronic infection with hepatitis B virus (HBV) in humans may lead to more effective antiviral therapies for HBV, according to investigators.
During human infection, HBV genomes take the form of covalently closed circular DNA (cccDNA), a structure that has thwarted effective antiviral therapy and, until now, creation of an accurate mouse model, reported lead author Zaichao Xu, PhD, of Wuhan (China) University and colleagues.
“As the viral persistence reservoir plays a central role in HBV infection, HBV cccDNA is the key obstacle for a cure,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology.
Although several previous mouse models have approximated this phenomenon with recombinant cccDNA-like molecules (rcccDNA), the present model is the first to achieve genuine cccDNA, which does not naturally occur in mice.
“Although rcccDNA supports persistent viral replication and antigen expression, the nature of rcccDNA may differ from authentic cccDNA, as additional sequences, like LoxP or attR, were inserted into the HBV genome,” the investigators noted.
The new model was created by first constructing an adeno-associated virus vector carrying a replication-deficient HBV1.04-fold genome (AAV-HBV1.04). When injected into mice, the vector led to cccDNA formation via ataxia-telangiectasia and Rad3-related protein (ATR)–mediated DNA damage response, a finding that was confirmed by blocking the same process with ATR inhibitors.
Immediately after injection, mice tested positive for both hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg), with peak concentrations after either 4 or 8 weeks depending on dose. HBV DNA was also detected in serum after injection, and 50% of hepatocytes exhibited HBsAg and hepatitis B core protein (HBc) after 1 week. At week 66, HBsAg, HBeAg, and HBc were still detectable in the liver.
“The expression of HBc could only be observed in the liver, but not in other organs or tissues, suggesting that the AAV-HBV1.04 only targeted the mouse liver,” the investigators wrote.
Further experimentation involving known cccDNA-binding proteins supported the similarity between cccDNA in the mouse model and natural infection.
“These results suggested that the chromatinization and transcriptional activation of cccDNA formed in this model dose not differ from wild-type cccDNA formed through infection.”
Next, Dr. Xu and colleagues demonstrated that the infected mice could serve as a reliable model for antiviral research. One week after injection with the vector, mice were treated with entecavir, polyinosinic-polycytidylic acid (poly[I:C]), or phosphate-buffered saline (PBS; control). As anticipated, entecavir suppressed circulating HBV DNA, but not HBsAg, HBeAg, or HBV cccDNA, whereas treatment with poly(I:C) reduced all HBV markers.
“This novel mouse model will provide a unique platform for studying HBV cccDNA and developing novel antivirals to achieve HBV cure,” the investigators concluded.
The study was supported by the National Natural Science Foundation of China, the Fundamental Research Funds for the Central Universities, Hubei Province’s Outstanding Medical Academic Leader Program, and others. The investigators reported no conflicts of interest.
A new mouse model that better represents chronic infection with hepatitis B virus (HBV) in humans may lead to more effective antiviral therapies for HBV, according to investigators.
During human infection, HBV genomes take the form of covalently closed circular DNA (cccDNA), a structure that has thwarted effective antiviral therapy and, until now, creation of an accurate mouse model, reported lead author Zaichao Xu, PhD, of Wuhan (China) University and colleagues.
“As the viral persistence reservoir plays a central role in HBV infection, HBV cccDNA is the key obstacle for a cure,” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology.
Although several previous mouse models have approximated this phenomenon with recombinant cccDNA-like molecules (rcccDNA), the present model is the first to achieve genuine cccDNA, which does not naturally occur in mice.
“Although rcccDNA supports persistent viral replication and antigen expression, the nature of rcccDNA may differ from authentic cccDNA, as additional sequences, like LoxP or attR, were inserted into the HBV genome,” the investigators noted.
The new model was created by first constructing an adeno-associated virus vector carrying a replication-deficient HBV1.04-fold genome (AAV-HBV1.04). When injected into mice, the vector led to cccDNA formation via ataxia-telangiectasia and Rad3-related protein (ATR)–mediated DNA damage response, a finding that was confirmed by blocking the same process with ATR inhibitors.
Immediately after injection, mice tested positive for both hepatitis B e antigen (HBeAg) and hepatitis B surface antigen (HBsAg), with peak concentrations after either 4 or 8 weeks depending on dose. HBV DNA was also detected in serum after injection, and 50% of hepatocytes exhibited HBsAg and hepatitis B core protein (HBc) after 1 week. At week 66, HBsAg, HBeAg, and HBc were still detectable in the liver.
“The expression of HBc could only be observed in the liver, but not in other organs or tissues, suggesting that the AAV-HBV1.04 only targeted the mouse liver,” the investigators wrote.
Further experimentation involving known cccDNA-binding proteins supported the similarity between cccDNA in the mouse model and natural infection.
“These results suggested that the chromatinization and transcriptional activation of cccDNA formed in this model dose not differ from wild-type cccDNA formed through infection.”
Next, Dr. Xu and colleagues demonstrated that the infected mice could serve as a reliable model for antiviral research. One week after injection with the vector, mice were treated with entecavir, polyinosinic-polycytidylic acid (poly[I:C]), or phosphate-buffered saline (PBS; control). As anticipated, entecavir suppressed circulating HBV DNA, but not HBsAg, HBeAg, or HBV cccDNA, whereas treatment with poly(I:C) reduced all HBV markers.
“This novel mouse model will provide a unique platform for studying HBV cccDNA and developing novel antivirals to achieve HBV cure,” the investigators concluded.
The study was supported by the National Natural Science Foundation of China, the Fundamental Research Funds for the Central Universities, Hubei Province’s Outstanding Medical Academic Leader Program, and others. The investigators reported no conflicts of interest.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Weekend catch-up sleep may help fatty liver
People who don’t get enough sleep during the week may be able to reduce their risk for nonalcoholic fatty liver disease (NAFLD) by catching up on the weekends, researchers say.
“Our study revealed that people who get enough sleep have a lower risk of developing NAFLD than those who get insufficient sleep,” Sangheun Lee, MD, PhD, from Catholic Kwandong University, Incheon, South Korea, and colleagues wrote in Annals of Hepatology.
However, they cautioned that further research is needed to verify their finding.
Previous studies have associated insufficient sleep with obesity, hypertension, diabetes mellitus, and cardiovascular disease, as well as liver fibrosis.
A busy weekday schedule can make it harder to get enough sleep, and some people try to compensate by sleeping longer on weekends. Studies so far have produced mixed findings on this strategy, with some showing that more sleep on the weekend reduces the risk for obesity, hypertension, and metabolic syndrome, and others showing no effect on metabolic dysregulation or energy balance.
Accessing a nation’s sleep data
To explore the relationship between sleep patterns and NAFLD, Dr. Lee and colleagues analyzed data from Korea National Health and Nutrition Examination Surveys collected from 2008 to 2019. They excluded people aged less than 20 years, those with hepatitis B or C infections, liver cirrhosis or liver cancer, shift workers and others who “slept irregularly,” and those who consumed alcohol excessively, leaving a cohort of 101,138 participants.
The survey didn’t distinguish between sleep on weekdays and weekends until 2016, so the researchers divided their findings into two: 68,759 people surveyed from 2008 to 2015 (set 1) and 32,379 surveyed from 2016 to 2019 (set 2).
Set 1 was further divided into those who averaged more than 7 hours of sleep per day and those who slept less than that. Set 2 was divided into three groups: one that averaged less than 7 hours of sleep per day and did not catch up on weekends, one that averaged less than 7 hours of sleep per day and did catch up on weekends, and one that averaged more than 7 hours of sleep throughout the week.
The researchers used the hepatic steatosis index (HSI) to determine the presence of a fatty liver, calculated as 8 x (ratio of serum ALT to serum AST) + body mass index (+ 2 for female, + 2 in case of diabetes). An HSI of at least36 was considered an indicator of fatty liver.
Less sleep, more risk
Participants in set 1 slept for a mean of 6.8 hours, with 58.6% sleeping more than 7 hours a day. Those in set 2 slept a mean of 6.9 hours during weekdays, with 59.9% sleeping more than 7 hours. They also slept a mean of 7.7 hours on weekends.
In set 1, sleeping at least7 hours was associated with a 16% lower risk for NAFLD (odds ratio, 0.84; 95% confidence interval, 0.79-0.89).
In set 2, sleeping at least 7 hours on weekdays was associated with a 19% reduced risk for NAFLD (OR, 0.81; 95% CI, 0.74-0.89). Sleeping at least 7 hours on the weekend was associated with a 22% reduced risk for NAFLD (OR, 0.78; 95% CI, 0.70-0.87). Compared with those who slept less than 7 hours throughout the week, those who slept less than 7 hours on weekdays and more than 7 hours on weekends had a 20% lower rate of NAFLD (OR, 0.80; 95% CI, 0.70-0.92).
All these associations held true for both men and women.
Why getting your Z’s may have hepatic advantages
One explanation for the link between sleep patterns and NAFLD is that dysregulation of cortisol, inflammatory cytokines, and norepinephrine are associated with both variations in sleep and NAFLD onset, Dr. Lee and colleagues wrote.
They also pointed out that a lack of sleep can reduce the secretion of two hormones that promote satiety: leptin and glucagonlike peptide–1. As a result, people who sleep less may eat more and gain weight, which increases the risk for NAFLD.
Ashwani K. Singal, MD, MS, a professor of medicine at the University of South Dakota, Vermillion, who was not involved in the study, noted that it was based on comparing a cross section of a population instead of following the participants over time.
“So, I think it’s an association rather than a cause and effect,” he said in an interview.
The authors don’t report a multivariate analysis to determine whether comorbidities or other characteristics of the patients could explain the association, he pointed out, noting that obesity, for example, can increase the risk for both NAFLD and sleep apnea.
Still, Dr. Singal said, the paper will influence him to mention sleep in the context of lifestyle factors that can affect fatty liver disease. “I’m going to tell my patients, and tell the community physicians to tell their patients, to follow a good sleep hygiene and make sure that they sleep at least 5-7 hours.”
Dr. Singal and the study authors all reported no relevant financial relationships. The study was supported by the National Research Foundation of Korea.
A version of this article first appeared on Medscape.com.
People who don’t get enough sleep during the week may be able to reduce their risk for nonalcoholic fatty liver disease (NAFLD) by catching up on the weekends, researchers say.
“Our study revealed that people who get enough sleep have a lower risk of developing NAFLD than those who get insufficient sleep,” Sangheun Lee, MD, PhD, from Catholic Kwandong University, Incheon, South Korea, and colleagues wrote in Annals of Hepatology.
However, they cautioned that further research is needed to verify their finding.
Previous studies have associated insufficient sleep with obesity, hypertension, diabetes mellitus, and cardiovascular disease, as well as liver fibrosis.
A busy weekday schedule can make it harder to get enough sleep, and some people try to compensate by sleeping longer on weekends. Studies so far have produced mixed findings on this strategy, with some showing that more sleep on the weekend reduces the risk for obesity, hypertension, and metabolic syndrome, and others showing no effect on metabolic dysregulation or energy balance.
Accessing a nation’s sleep data
To explore the relationship between sleep patterns and NAFLD, Dr. Lee and colleagues analyzed data from Korea National Health and Nutrition Examination Surveys collected from 2008 to 2019. They excluded people aged less than 20 years, those with hepatitis B or C infections, liver cirrhosis or liver cancer, shift workers and others who “slept irregularly,” and those who consumed alcohol excessively, leaving a cohort of 101,138 participants.
The survey didn’t distinguish between sleep on weekdays and weekends until 2016, so the researchers divided their findings into two: 68,759 people surveyed from 2008 to 2015 (set 1) and 32,379 surveyed from 2016 to 2019 (set 2).
Set 1 was further divided into those who averaged more than 7 hours of sleep per day and those who slept less than that. Set 2 was divided into three groups: one that averaged less than 7 hours of sleep per day and did not catch up on weekends, one that averaged less than 7 hours of sleep per day and did catch up on weekends, and one that averaged more than 7 hours of sleep throughout the week.
The researchers used the hepatic steatosis index (HSI) to determine the presence of a fatty liver, calculated as 8 x (ratio of serum ALT to serum AST) + body mass index (+ 2 for female, + 2 in case of diabetes). An HSI of at least36 was considered an indicator of fatty liver.
Less sleep, more risk
Participants in set 1 slept for a mean of 6.8 hours, with 58.6% sleeping more than 7 hours a day. Those in set 2 slept a mean of 6.9 hours during weekdays, with 59.9% sleeping more than 7 hours. They also slept a mean of 7.7 hours on weekends.
In set 1, sleeping at least7 hours was associated with a 16% lower risk for NAFLD (odds ratio, 0.84; 95% confidence interval, 0.79-0.89).
In set 2, sleeping at least 7 hours on weekdays was associated with a 19% reduced risk for NAFLD (OR, 0.81; 95% CI, 0.74-0.89). Sleeping at least 7 hours on the weekend was associated with a 22% reduced risk for NAFLD (OR, 0.78; 95% CI, 0.70-0.87). Compared with those who slept less than 7 hours throughout the week, those who slept less than 7 hours on weekdays and more than 7 hours on weekends had a 20% lower rate of NAFLD (OR, 0.80; 95% CI, 0.70-0.92).
All these associations held true for both men and women.
Why getting your Z’s may have hepatic advantages
One explanation for the link between sleep patterns and NAFLD is that dysregulation of cortisol, inflammatory cytokines, and norepinephrine are associated with both variations in sleep and NAFLD onset, Dr. Lee and colleagues wrote.
They also pointed out that a lack of sleep can reduce the secretion of two hormones that promote satiety: leptin and glucagonlike peptide–1. As a result, people who sleep less may eat more and gain weight, which increases the risk for NAFLD.
Ashwani K. Singal, MD, MS, a professor of medicine at the University of South Dakota, Vermillion, who was not involved in the study, noted that it was based on comparing a cross section of a population instead of following the participants over time.
“So, I think it’s an association rather than a cause and effect,” he said in an interview.
The authors don’t report a multivariate analysis to determine whether comorbidities or other characteristics of the patients could explain the association, he pointed out, noting that obesity, for example, can increase the risk for both NAFLD and sleep apnea.
Still, Dr. Singal said, the paper will influence him to mention sleep in the context of lifestyle factors that can affect fatty liver disease. “I’m going to tell my patients, and tell the community physicians to tell their patients, to follow a good sleep hygiene and make sure that they sleep at least 5-7 hours.”
Dr. Singal and the study authors all reported no relevant financial relationships. The study was supported by the National Research Foundation of Korea.
A version of this article first appeared on Medscape.com.
People who don’t get enough sleep during the week may be able to reduce their risk for nonalcoholic fatty liver disease (NAFLD) by catching up on the weekends, researchers say.
“Our study revealed that people who get enough sleep have a lower risk of developing NAFLD than those who get insufficient sleep,” Sangheun Lee, MD, PhD, from Catholic Kwandong University, Incheon, South Korea, and colleagues wrote in Annals of Hepatology.
However, they cautioned that further research is needed to verify their finding.
Previous studies have associated insufficient sleep with obesity, hypertension, diabetes mellitus, and cardiovascular disease, as well as liver fibrosis.
A busy weekday schedule can make it harder to get enough sleep, and some people try to compensate by sleeping longer on weekends. Studies so far have produced mixed findings on this strategy, with some showing that more sleep on the weekend reduces the risk for obesity, hypertension, and metabolic syndrome, and others showing no effect on metabolic dysregulation or energy balance.
Accessing a nation’s sleep data
To explore the relationship between sleep patterns and NAFLD, Dr. Lee and colleagues analyzed data from Korea National Health and Nutrition Examination Surveys collected from 2008 to 2019. They excluded people aged less than 20 years, those with hepatitis B or C infections, liver cirrhosis or liver cancer, shift workers and others who “slept irregularly,” and those who consumed alcohol excessively, leaving a cohort of 101,138 participants.
The survey didn’t distinguish between sleep on weekdays and weekends until 2016, so the researchers divided their findings into two: 68,759 people surveyed from 2008 to 2015 (set 1) and 32,379 surveyed from 2016 to 2019 (set 2).
Set 1 was further divided into those who averaged more than 7 hours of sleep per day and those who slept less than that. Set 2 was divided into three groups: one that averaged less than 7 hours of sleep per day and did not catch up on weekends, one that averaged less than 7 hours of sleep per day and did catch up on weekends, and one that averaged more than 7 hours of sleep throughout the week.
The researchers used the hepatic steatosis index (HSI) to determine the presence of a fatty liver, calculated as 8 x (ratio of serum ALT to serum AST) + body mass index (+ 2 for female, + 2 in case of diabetes). An HSI of at least36 was considered an indicator of fatty liver.
Less sleep, more risk
Participants in set 1 slept for a mean of 6.8 hours, with 58.6% sleeping more than 7 hours a day. Those in set 2 slept a mean of 6.9 hours during weekdays, with 59.9% sleeping more than 7 hours. They also slept a mean of 7.7 hours on weekends.
In set 1, sleeping at least7 hours was associated with a 16% lower risk for NAFLD (odds ratio, 0.84; 95% confidence interval, 0.79-0.89).
In set 2, sleeping at least 7 hours on weekdays was associated with a 19% reduced risk for NAFLD (OR, 0.81; 95% CI, 0.74-0.89). Sleeping at least 7 hours on the weekend was associated with a 22% reduced risk for NAFLD (OR, 0.78; 95% CI, 0.70-0.87). Compared with those who slept less than 7 hours throughout the week, those who slept less than 7 hours on weekdays and more than 7 hours on weekends had a 20% lower rate of NAFLD (OR, 0.80; 95% CI, 0.70-0.92).
All these associations held true for both men and women.
Why getting your Z’s may have hepatic advantages
One explanation for the link between sleep patterns and NAFLD is that dysregulation of cortisol, inflammatory cytokines, and norepinephrine are associated with both variations in sleep and NAFLD onset, Dr. Lee and colleagues wrote.
They also pointed out that a lack of sleep can reduce the secretion of two hormones that promote satiety: leptin and glucagonlike peptide–1. As a result, people who sleep less may eat more and gain weight, which increases the risk for NAFLD.
Ashwani K. Singal, MD, MS, a professor of medicine at the University of South Dakota, Vermillion, who was not involved in the study, noted that it was based on comparing a cross section of a population instead of following the participants over time.
“So, I think it’s an association rather than a cause and effect,” he said in an interview.
The authors don’t report a multivariate analysis to determine whether comorbidities or other characteristics of the patients could explain the association, he pointed out, noting that obesity, for example, can increase the risk for both NAFLD and sleep apnea.
Still, Dr. Singal said, the paper will influence him to mention sleep in the context of lifestyle factors that can affect fatty liver disease. “I’m going to tell my patients, and tell the community physicians to tell their patients, to follow a good sleep hygiene and make sure that they sleep at least 5-7 hours.”
Dr. Singal and the study authors all reported no relevant financial relationships. The study was supported by the National Research Foundation of Korea.
A version of this article first appeared on Medscape.com.
FROM ANNALS OF HEPATOLOGY
Freiburg index accurately predicts survival in liver procedure
A new prognostic score is more accurate than the commonly used Model for End-Stage Liver Disease (MELD) in predicting post–transjugular intrahepatic portosystemic shunt (TIPS) survival, researchers say.
The Freiburg Index of Post-TIPS Survival (FIPS) could help patients and doctors weigh the benefits and risks of the procedure, said Chongtu Yang, MD, a postgraduate fellow at the Huazhong University of Science and Technology, Wuhan, China.
“For patients defined as high risk, the TIPS procedure may not be the optimal choice, and transplantation may be better,” Dr. Yang told this news organization. He cautioned that FIPS needs further validation before being applied in clinical practice.
The study by Dr. Yang and his colleagues was published online Feb. 9 in the American Journal of Roentgenology. To their knowledge, this is the first study to validate FIPS in a cohort of Asian patients.
Decompensated cirrhosis can cause variceal bleeding and refractory ascites and may be life threatening. TIPS can manage these complications but comes with its own risks.
To determine which patients can best benefit from the procedure, researchers have proposed a variety of prognostic scoring systems. Some were developed for other purposes, such as predicting survival following hospitalization, rather than specifically for TIPS. Additionally, few studies have compared these approaches to each other.
A four-way comparison
To fill that gap, Dr. Yang and his colleagues compared four predictive models: the MELD, the sodium MELD (MELD-Na), the Chronic Liver Failure–Consortium Acute Decompensation (CLIF-CAD), and FIPS.
The MELD score uses serum bilirubin, serum creatinine, and the international normalized ratio (INR) of prothrombin time. MELD-Na adds sodium to this algorithm. The CLIF-CAD score is calculated using age, serum creatinine, INR, white blood count, and sodium level. FIPS, which was recently devised to predict results with TIPS, uses age, bilirubin, albumin, and creatinine.
To see which yielded more accurate predictions, Dr. Yang and his colleagues followed 383 patients with cirrhosis (mean age, 55 years; 341 with variceal bleeding and 42 with refractory ascites) who underwent TIPS placement at Wuhan Union Hospital between January 2016 and August 2021.
The most common cause of cirrhosis was hepatitis B infection (58.2% of patients), followed by hepatitis C infection (11.7%) and alcohol use (13.6%).
The researchers followed the patients for a median of 23.4 months. They lost track of 31 patients over that time, and another 72 died. The survival rate after TIPS placement was 92.3% at 6 months, 87.8% at 12 months, and 81.2% at 24 months. Thirty-seven patients received a TIPS revision.
In their first measure of the models’ accuracy, the researchers used a concordance index, which compares actual results with predicted results. The number of concordant pairs are divided by the total number of possible evaluation pairs. A score of 1 represents 100% accuracy.
By this measure, the prediction of survival at 6 months was highest for FIPS followed by CLIF-CAD, MELD, and MELD-Na. However, the confidence intervals overlapped.
FIPS also scored highest in the concordance index at 12 and 24 months.
In a second measure of the models’ accuracy, the researchers used Brier scores, which calculate the mean squared error between predicted probabilities and actual values. Like the concordance index, Brier scores range from 0.0 to 1.0 but differ in that the lowest Brier score number represents the highest accuracy.
At 6 months, the CLIF-CAD score was the best, at 0.074. MELD and FIPS were equivalent at 0.075, with MELD-Na coming in at 0.077. However, FIPS attained slightly better scores than the other systems at 12 and 24 months.
Is FIPS worth implementing?
With scores this close, it may not be worth changing the predictive model clinicians use for choosing TIPS candidates, said Nancy Reau, MD, chief of hepatology at Rush University Medical Center, Chicago, who was not involved in the study.
MELD scores are already programmed into many electronic medical record systems in the United States, and clinicians are familiar with using that system to aid in further decisions, such as decisions regarding other kinds of surgery, she told this news organization.
“If you’re going to try to advocate for a new system, you really have to show that the performance of the predictive score is monumentally better than the tried and true,” she said.
Dr. Yang and Dr. Reau report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A new prognostic score is more accurate than the commonly used Model for End-Stage Liver Disease (MELD) in predicting post–transjugular intrahepatic portosystemic shunt (TIPS) survival, researchers say.
The Freiburg Index of Post-TIPS Survival (FIPS) could help patients and doctors weigh the benefits and risks of the procedure, said Chongtu Yang, MD, a postgraduate fellow at the Huazhong University of Science and Technology, Wuhan, China.
“For patients defined as high risk, the TIPS procedure may not be the optimal choice, and transplantation may be better,” Dr. Yang told this news organization. He cautioned that FIPS needs further validation before being applied in clinical practice.
The study by Dr. Yang and his colleagues was published online Feb. 9 in the American Journal of Roentgenology. To their knowledge, this is the first study to validate FIPS in a cohort of Asian patients.
Decompensated cirrhosis can cause variceal bleeding and refractory ascites and may be life threatening. TIPS can manage these complications but comes with its own risks.
To determine which patients can best benefit from the procedure, researchers have proposed a variety of prognostic scoring systems. Some were developed for other purposes, such as predicting survival following hospitalization, rather than specifically for TIPS. Additionally, few studies have compared these approaches to each other.
A four-way comparison
To fill that gap, Dr. Yang and his colleagues compared four predictive models: the MELD, the sodium MELD (MELD-Na), the Chronic Liver Failure–Consortium Acute Decompensation (CLIF-CAD), and FIPS.
The MELD score uses serum bilirubin, serum creatinine, and the international normalized ratio (INR) of prothrombin time. MELD-Na adds sodium to this algorithm. The CLIF-CAD score is calculated using age, serum creatinine, INR, white blood count, and sodium level. FIPS, which was recently devised to predict results with TIPS, uses age, bilirubin, albumin, and creatinine.
To see which yielded more accurate predictions, Dr. Yang and his colleagues followed 383 patients with cirrhosis (mean age, 55 years; 341 with variceal bleeding and 42 with refractory ascites) who underwent TIPS placement at Wuhan Union Hospital between January 2016 and August 2021.
The most common cause of cirrhosis was hepatitis B infection (58.2% of patients), followed by hepatitis C infection (11.7%) and alcohol use (13.6%).
The researchers followed the patients for a median of 23.4 months. They lost track of 31 patients over that time, and another 72 died. The survival rate after TIPS placement was 92.3% at 6 months, 87.8% at 12 months, and 81.2% at 24 months. Thirty-seven patients received a TIPS revision.
In their first measure of the models’ accuracy, the researchers used a concordance index, which compares actual results with predicted results. The number of concordant pairs are divided by the total number of possible evaluation pairs. A score of 1 represents 100% accuracy.
By this measure, the prediction of survival at 6 months was highest for FIPS followed by CLIF-CAD, MELD, and MELD-Na. However, the confidence intervals overlapped.
FIPS also scored highest in the concordance index at 12 and 24 months.
In a second measure of the models’ accuracy, the researchers used Brier scores, which calculate the mean squared error between predicted probabilities and actual values. Like the concordance index, Brier scores range from 0.0 to 1.0 but differ in that the lowest Brier score number represents the highest accuracy.
At 6 months, the CLIF-CAD score was the best, at 0.074. MELD and FIPS were equivalent at 0.075, with MELD-Na coming in at 0.077. However, FIPS attained slightly better scores than the other systems at 12 and 24 months.
Is FIPS worth implementing?
With scores this close, it may not be worth changing the predictive model clinicians use for choosing TIPS candidates, said Nancy Reau, MD, chief of hepatology at Rush University Medical Center, Chicago, who was not involved in the study.
MELD scores are already programmed into many electronic medical record systems in the United States, and clinicians are familiar with using that system to aid in further decisions, such as decisions regarding other kinds of surgery, she told this news organization.
“If you’re going to try to advocate for a new system, you really have to show that the performance of the predictive score is monumentally better than the tried and true,” she said.
Dr. Yang and Dr. Reau report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A new prognostic score is more accurate than the commonly used Model for End-Stage Liver Disease (MELD) in predicting post–transjugular intrahepatic portosystemic shunt (TIPS) survival, researchers say.
The Freiburg Index of Post-TIPS Survival (FIPS) could help patients and doctors weigh the benefits and risks of the procedure, said Chongtu Yang, MD, a postgraduate fellow at the Huazhong University of Science and Technology, Wuhan, China.
“For patients defined as high risk, the TIPS procedure may not be the optimal choice, and transplantation may be better,” Dr. Yang told this news organization. He cautioned that FIPS needs further validation before being applied in clinical practice.
The study by Dr. Yang and his colleagues was published online Feb. 9 in the American Journal of Roentgenology. To their knowledge, this is the first study to validate FIPS in a cohort of Asian patients.
Decompensated cirrhosis can cause variceal bleeding and refractory ascites and may be life threatening. TIPS can manage these complications but comes with its own risks.
To determine which patients can best benefit from the procedure, researchers have proposed a variety of prognostic scoring systems. Some were developed for other purposes, such as predicting survival following hospitalization, rather than specifically for TIPS. Additionally, few studies have compared these approaches to each other.
A four-way comparison
To fill that gap, Dr. Yang and his colleagues compared four predictive models: the MELD, the sodium MELD (MELD-Na), the Chronic Liver Failure–Consortium Acute Decompensation (CLIF-CAD), and FIPS.
The MELD score uses serum bilirubin, serum creatinine, and the international normalized ratio (INR) of prothrombin time. MELD-Na adds sodium to this algorithm. The CLIF-CAD score is calculated using age, serum creatinine, INR, white blood count, and sodium level. FIPS, which was recently devised to predict results with TIPS, uses age, bilirubin, albumin, and creatinine.
To see which yielded more accurate predictions, Dr. Yang and his colleagues followed 383 patients with cirrhosis (mean age, 55 years; 341 with variceal bleeding and 42 with refractory ascites) who underwent TIPS placement at Wuhan Union Hospital between January 2016 and August 2021.
The most common cause of cirrhosis was hepatitis B infection (58.2% of patients), followed by hepatitis C infection (11.7%) and alcohol use (13.6%).
The researchers followed the patients for a median of 23.4 months. They lost track of 31 patients over that time, and another 72 died. The survival rate after TIPS placement was 92.3% at 6 months, 87.8% at 12 months, and 81.2% at 24 months. Thirty-seven patients received a TIPS revision.
In their first measure of the models’ accuracy, the researchers used a concordance index, which compares actual results with predicted results. The number of concordant pairs are divided by the total number of possible evaluation pairs. A score of 1 represents 100% accuracy.
By this measure, the prediction of survival at 6 months was highest for FIPS followed by CLIF-CAD, MELD, and MELD-Na. However, the confidence intervals overlapped.
FIPS also scored highest in the concordance index at 12 and 24 months.
In a second measure of the models’ accuracy, the researchers used Brier scores, which calculate the mean squared error between predicted probabilities and actual values. Like the concordance index, Brier scores range from 0.0 to 1.0 but differ in that the lowest Brier score number represents the highest accuracy.
At 6 months, the CLIF-CAD score was the best, at 0.074. MELD and FIPS were equivalent at 0.075, with MELD-Na coming in at 0.077. However, FIPS attained slightly better scores than the other systems at 12 and 24 months.
Is FIPS worth implementing?
With scores this close, it may not be worth changing the predictive model clinicians use for choosing TIPS candidates, said Nancy Reau, MD, chief of hepatology at Rush University Medical Center, Chicago, who was not involved in the study.
MELD scores are already programmed into many electronic medical record systems in the United States, and clinicians are familiar with using that system to aid in further decisions, such as decisions regarding other kinds of surgery, she told this news organization.
“If you’re going to try to advocate for a new system, you really have to show that the performance of the predictive score is monumentally better than the tried and true,” she said.
Dr. Yang and Dr. Reau report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE AMERICAN JOURNAL OF ROENTGENOLOGY
Novel scoring system emerges for alcoholic hepatitis mortality
A new scoring system proved more accurate than several other available models at predicting the 30-day mortality risk for patients with alcohol-associated hepatitis (AH), according to new data.
The system, called the Mortality Index for Alcohol-Associated Hepatitis (MIAAH), was created by a team of Mayo Clinic researchers, who published their results in Mayo Clinic Proceedings.
Among the currently available prognostic models for assessing AH severity are the Model for End-Stage Liver Disease (MELD); the Age, serum Bilirubin, International normalized ratio, and serum Creatinine (ABIC) score; the Maddrey Discriminant Function (MDF); and the Glasgow Alcoholic Hepatitis Score (GAHS). However, these models have poor accuracy, with the area under the curve between 0.71 and 0.77.
By comparison, the new model has an accuracy of 86% in predicting 30-day mortality for AH, said coauthor Ashwani K. Singal, MD, MS, professor of medicine at the University of South Dakota Sanford School of Medicine, Sioux Falls.
“It’s a better predictor of the outcome, and that’s what sets it apart,” he told this news organization. “I think providers and patients will benefit.”
He said accuracy in determining the likelihood of death can help clinicians better determine treatment options and prepare patients and their families.
Camille Kezer, MD, a Mayo Clinic resident internist and first author of the paper, said in a statement, “MIAAH also has the advantage of performing well in patients, regardless of whether they’ve been treated with steroids, which makes it generalizable.”
Creating and validating the MIAAH
Researchers analyzed the health records of 266 eligible patients diagnosed with AH between 1998 and 2018 at the Mayo Clinic, Rochester, Minn. The patients collectively had a 30-day mortality rate of 19.2%.
They then studied the effect of several variables, of which the following were found to be significantly associated with mortality: age (P = .002), blood urea nitrogen (P = .003), albumin (P = .01), bilirubin (P = .02), and international normalized ratio (P = .001).
Mayo researchers built the MIAAH model using these variables and found that it was able to achieve a C statistic of 0.86, which translates into its being able to accurately predict mortality more than 86% of the time. When tested in the initial cohort of 266 patients, MIAAH had a significantly superior C statistic compared with several other available models, such as the MELD, MDF, and GAHS, although not for the ABIC.
The researchers then tested the MIAAH model in a validation cohort of 249 patients from health care centers at the University of South Dakota, Sioux Falls, and the University of Kansas, Lawrence. In this cohort, the MIAAH’s C statistic decreased to 0.73, which remained significantly more accurate than the MDF but was comparable to that found with the MELD.
Helping with transplant decisions
There are no pharmacologic treatments that can reduce 90-day mortality in severe cases of AH, and only a small survival benefit at 30 days has been reported with prednisolone use.
With a shortage of liver donors, many centers still require 6 months of alcohol abstinence for transplant consideration, although exceptions are sometimes made for cases of early transplant.
A model that more accurately predicts who is at the highest risk of dying within a month can help clinicians decide how best to proceed, Dr. Singal said.
Paul Martin, MD, chief of the division of digestive health and liver diseases, Mandel Chair in gastroenterology, and professor of medicine at the University of Miami, told this news organization that the model is potentially important in light of the rising prevalence of AH.
“The numbers of patients with AH are unequivocally increasing and often in young patients,” he noted, presenting difficult choices of who to treat with steroids and who to refer for a transplant.
“This model is certainly timely,” he said. “We need more accuracy in predicting which patients will recover with medical therapy and which patients won’t in the absence of a liver transplant.”
He noted, however, that the study’s retrospective design requires that it’s validated prospectively: “not only looking at the outcome in terms of mortality of patients, but its potential utility in identifying candidates for liver transplantation who are not going to recover on their own.”
He said it was unlikely that the model would replace others, particularly MELD, which is ingrained in practices in the United States and other countries, but may instead have a complementary role.
Dr. Singal, Dr. Kezer, and Dr. Martin report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A new scoring system proved more accurate than several other available models at predicting the 30-day mortality risk for patients with alcohol-associated hepatitis (AH), according to new data.
The system, called the Mortality Index for Alcohol-Associated Hepatitis (MIAAH), was created by a team of Mayo Clinic researchers, who published their results in Mayo Clinic Proceedings.
Among the currently available prognostic models for assessing AH severity are the Model for End-Stage Liver Disease (MELD); the Age, serum Bilirubin, International normalized ratio, and serum Creatinine (ABIC) score; the Maddrey Discriminant Function (MDF); and the Glasgow Alcoholic Hepatitis Score (GAHS). However, these models have poor accuracy, with the area under the curve between 0.71 and 0.77.
By comparison, the new model has an accuracy of 86% in predicting 30-day mortality for AH, said coauthor Ashwani K. Singal, MD, MS, professor of medicine at the University of South Dakota Sanford School of Medicine, Sioux Falls.
“It’s a better predictor of the outcome, and that’s what sets it apart,” he told this news organization. “I think providers and patients will benefit.”
He said accuracy in determining the likelihood of death can help clinicians better determine treatment options and prepare patients and their families.
Camille Kezer, MD, a Mayo Clinic resident internist and first author of the paper, said in a statement, “MIAAH also has the advantage of performing well in patients, regardless of whether they’ve been treated with steroids, which makes it generalizable.”
Creating and validating the MIAAH
Researchers analyzed the health records of 266 eligible patients diagnosed with AH between 1998 and 2018 at the Mayo Clinic, Rochester, Minn. The patients collectively had a 30-day mortality rate of 19.2%.
They then studied the effect of several variables, of which the following were found to be significantly associated with mortality: age (P = .002), blood urea nitrogen (P = .003), albumin (P = .01), bilirubin (P = .02), and international normalized ratio (P = .001).
Mayo researchers built the MIAAH model using these variables and found that it was able to achieve a C statistic of 0.86, which translates into its being able to accurately predict mortality more than 86% of the time. When tested in the initial cohort of 266 patients, MIAAH had a significantly superior C statistic compared with several other available models, such as the MELD, MDF, and GAHS, although not for the ABIC.
The researchers then tested the MIAAH model in a validation cohort of 249 patients from health care centers at the University of South Dakota, Sioux Falls, and the University of Kansas, Lawrence. In this cohort, the MIAAH’s C statistic decreased to 0.73, which remained significantly more accurate than the MDF but was comparable to that found with the MELD.
Helping with transplant decisions
There are no pharmacologic treatments that can reduce 90-day mortality in severe cases of AH, and only a small survival benefit at 30 days has been reported with prednisolone use.
With a shortage of liver donors, many centers still require 6 months of alcohol abstinence for transplant consideration, although exceptions are sometimes made for cases of early transplant.
A model that more accurately predicts who is at the highest risk of dying within a month can help clinicians decide how best to proceed, Dr. Singal said.
Paul Martin, MD, chief of the division of digestive health and liver diseases, Mandel Chair in gastroenterology, and professor of medicine at the University of Miami, told this news organization that the model is potentially important in light of the rising prevalence of AH.
“The numbers of patients with AH are unequivocally increasing and often in young patients,” he noted, presenting difficult choices of who to treat with steroids and who to refer for a transplant.
“This model is certainly timely,” he said. “We need more accuracy in predicting which patients will recover with medical therapy and which patients won’t in the absence of a liver transplant.”
He noted, however, that the study’s retrospective design requires that it’s validated prospectively: “not only looking at the outcome in terms of mortality of patients, but its potential utility in identifying candidates for liver transplantation who are not going to recover on their own.”
He said it was unlikely that the model would replace others, particularly MELD, which is ingrained in practices in the United States and other countries, but may instead have a complementary role.
Dr. Singal, Dr. Kezer, and Dr. Martin report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
A new scoring system proved more accurate than several other available models at predicting the 30-day mortality risk for patients with alcohol-associated hepatitis (AH), according to new data.
The system, called the Mortality Index for Alcohol-Associated Hepatitis (MIAAH), was created by a team of Mayo Clinic researchers, who published their results in Mayo Clinic Proceedings.
Among the currently available prognostic models for assessing AH severity are the Model for End-Stage Liver Disease (MELD); the Age, serum Bilirubin, International normalized ratio, and serum Creatinine (ABIC) score; the Maddrey Discriminant Function (MDF); and the Glasgow Alcoholic Hepatitis Score (GAHS). However, these models have poor accuracy, with the area under the curve between 0.71 and 0.77.
By comparison, the new model has an accuracy of 86% in predicting 30-day mortality for AH, said coauthor Ashwani K. Singal, MD, MS, professor of medicine at the University of South Dakota Sanford School of Medicine, Sioux Falls.
“It’s a better predictor of the outcome, and that’s what sets it apart,” he told this news organization. “I think providers and patients will benefit.”
He said accuracy in determining the likelihood of death can help clinicians better determine treatment options and prepare patients and their families.
Camille Kezer, MD, a Mayo Clinic resident internist and first author of the paper, said in a statement, “MIAAH also has the advantage of performing well in patients, regardless of whether they’ve been treated with steroids, which makes it generalizable.”
Creating and validating the MIAAH
Researchers analyzed the health records of 266 eligible patients diagnosed with AH between 1998 and 2018 at the Mayo Clinic, Rochester, Minn. The patients collectively had a 30-day mortality rate of 19.2%.
They then studied the effect of several variables, of which the following were found to be significantly associated with mortality: age (P = .002), blood urea nitrogen (P = .003), albumin (P = .01), bilirubin (P = .02), and international normalized ratio (P = .001).
Mayo researchers built the MIAAH model using these variables and found that it was able to achieve a C statistic of 0.86, which translates into its being able to accurately predict mortality more than 86% of the time. When tested in the initial cohort of 266 patients, MIAAH had a significantly superior C statistic compared with several other available models, such as the MELD, MDF, and GAHS, although not for the ABIC.
The researchers then tested the MIAAH model in a validation cohort of 249 patients from health care centers at the University of South Dakota, Sioux Falls, and the University of Kansas, Lawrence. In this cohort, the MIAAH’s C statistic decreased to 0.73, which remained significantly more accurate than the MDF but was comparable to that found with the MELD.
Helping with transplant decisions
There are no pharmacologic treatments that can reduce 90-day mortality in severe cases of AH, and only a small survival benefit at 30 days has been reported with prednisolone use.
With a shortage of liver donors, many centers still require 6 months of alcohol abstinence for transplant consideration, although exceptions are sometimes made for cases of early transplant.
A model that more accurately predicts who is at the highest risk of dying within a month can help clinicians decide how best to proceed, Dr. Singal said.
Paul Martin, MD, chief of the division of digestive health and liver diseases, Mandel Chair in gastroenterology, and professor of medicine at the University of Miami, told this news organization that the model is potentially important in light of the rising prevalence of AH.
“The numbers of patients with AH are unequivocally increasing and often in young patients,” he noted, presenting difficult choices of who to treat with steroids and who to refer for a transplant.
“This model is certainly timely,” he said. “We need more accuracy in predicting which patients will recover with medical therapy and which patients won’t in the absence of a liver transplant.”
He noted, however, that the study’s retrospective design requires that it’s validated prospectively: “not only looking at the outcome in terms of mortality of patients, but its potential utility in identifying candidates for liver transplantation who are not going to recover on their own.”
He said it was unlikely that the model would replace others, particularly MELD, which is ingrained in practices in the United States and other countries, but may instead have a complementary role.
Dr. Singal, Dr. Kezer, and Dr. Martin report no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM MAYO CLINIC PROCEEDINGS
RECAM vs. RUCAM: Finding a better way to diagnose DILI
Researchers looking for a better way to diagnose drug-induced liver injury (DILI) have found evidence to support the use of the Revised Electronic Causality Assessment Method (RECAM).
The broadly used Roussel Uclaf Causality Assessment Method (RUCAM), introduced in 1993, “has been a valuable clinical framework for DILI diagnosis,” but it has been clouded by subjectivity and poor reliability, wrote the authors, led by Paul H. Hayashi, MD, MPH, with the Food and Drug Administration, in Hepatology. Citing a review from the Journal of Hepatology, Dr. Hayashi and colleagues noted three major problems: “(1) unclear operating instructions and subjectivity leading to poor reliability and usability, (2) unclear validity due to lack of an accepted gold standard and (3) domain criteria that are not evidence-based.”
Currently, a diagnosis of DILI is primarily based on clinicians’ judgment and ruling out alternative diagnoses, the authors of this study wrote. The lack of an evidence-based and reliable diagnostic tool is a significant obstacle in clinical care and research .
Reaching a new method
The researchers used classification tree analysis to set diagnostic cut-offs for RECAM and then compared RECAM with RUCAM for correlation with expert opinion diagnostic categories in 194 DILI cases (98 from the Drug-Induced Liver Injury Network, 96 from the Spanish DILI Registry).
The area under receiver operator curves for identifying at least probable DILI were the same at 0.89 for both RECAM and RUCAM.
The authors wrote, “However, RECAM diagnostic categories have better observed overall agreement with expert opinion (0.62 vs. 0.56 weighted kappa, P = .14), and had better sensitivity to detect extreme diagnostic categories (73 vs. 54 for highly likely or high probable, P = .02; 65 vs. 48 for unlikely/excluded, P = .08) than RUCAM diagnostic categories.”
They concluded that RECAM “is at least as capable as RUCAM in diagnosing DILI compared to expert opinion but is better than RUCAM at the diagnostic extremes.”
RECAM appears to add objectivity and clarity that can improve precision and reliability when diagnosing DILI and improve diagnostic standardization, according to authors. It has automated scoring, which reduces subjective input and should lead to better reliability among raters, something that has limited RUCAM’s adaptation in clinical practice and research.
RECAM has automatic warnings for data inconsistencies, which DILI and RUCAM do not. In RUCAM, a different diagnosis or other data could rule out DILI, but the case would still gain points in other criteria.
The authors explained, “Even when data clearly diagnose acute viral hepatitis or autoimmune hepatitis by simplified autoimmune hepatitis score, points are still given for latency, dechallenge, or underlying hepatotoxicity risk of the drug. In these situations of highly implausible DILI, RECAM gives warnings to stop with an imputed total score of –6. One can over-ride these warnings, if one believes DILI may be concurrent with the non-DILI diagnosis. However, –6 points are still assessed.”
Diagnosis of exclusion
Paul Martin, MD, chief, division of digestive health and liver diseases, Mandel Chair in Gastroenterology and professor of medicine at the University of Miami, said in an interview that he hopes RECAM will become widely used and better address a condition that sometimes doesn’t get enough attention. DILI remains underappreciated, he said, despite it being a major cause of morbidity and mortality in some patients.
“Any algorithm or criteria that can improve diagnostic accuracy is useful because typically it is a diagnosis of exclusion,” Dr. Martin said. “This new system seems to be as good as any other prior algorithms to diagnose drug-induced liver injury.”
He added, “This should help clinicians with individual patients with unexplained liver disease.”
The authors noted some limitations. RECAM was developed in U.S. and Spanish cohorts, so its performance in other regions is unclear. Both registries have minimum enrollment requirements for liver enzyme and bilirubin elevation, so it is not known how effective RECAM is in less severe cases. It also needs to be tested by other clinicians, including nonhepatologists.
The authors also added, “It is currently limited to single-agent medication cases leaving the user to score each medication individually in multidrug cases. However, any competing medication causing loss of points in the RUCAM, probably deserves its own RECAM score.”
The DILIN is structured as a cooperative agreement with funds provided by the National Institute of Diabetes and Digestive and Kidney Diseases.
Dr. Hayashi is employed by the FDA, but the conclusions of this paper do not reflect any opinion of the FDA. One coauthor has advised Pfizer, GSK, and NuCANA through Nottingham University Consultants, and another has received support from Gilead and AbbVie and consulted for Sanofi. The remaining authors have no conflicts. Dr. Martin reports no relevant financial relationships.
Researchers looking for a better way to diagnose drug-induced liver injury (DILI) have found evidence to support the use of the Revised Electronic Causality Assessment Method (RECAM).
The broadly used Roussel Uclaf Causality Assessment Method (RUCAM), introduced in 1993, “has been a valuable clinical framework for DILI diagnosis,” but it has been clouded by subjectivity and poor reliability, wrote the authors, led by Paul H. Hayashi, MD, MPH, with the Food and Drug Administration, in Hepatology. Citing a review from the Journal of Hepatology, Dr. Hayashi and colleagues noted three major problems: “(1) unclear operating instructions and subjectivity leading to poor reliability and usability, (2) unclear validity due to lack of an accepted gold standard and (3) domain criteria that are not evidence-based.”
Currently, a diagnosis of DILI is primarily based on clinicians’ judgment and ruling out alternative diagnoses, the authors of this study wrote. The lack of an evidence-based and reliable diagnostic tool is a significant obstacle in clinical care and research .
Reaching a new method
The researchers used classification tree analysis to set diagnostic cut-offs for RECAM and then compared RECAM with RUCAM for correlation with expert opinion diagnostic categories in 194 DILI cases (98 from the Drug-Induced Liver Injury Network, 96 from the Spanish DILI Registry).
The area under receiver operator curves for identifying at least probable DILI were the same at 0.89 for both RECAM and RUCAM.
The authors wrote, “However, RECAM diagnostic categories have better observed overall agreement with expert opinion (0.62 vs. 0.56 weighted kappa, P = .14), and had better sensitivity to detect extreme diagnostic categories (73 vs. 54 for highly likely or high probable, P = .02; 65 vs. 48 for unlikely/excluded, P = .08) than RUCAM diagnostic categories.”
They concluded that RECAM “is at least as capable as RUCAM in diagnosing DILI compared to expert opinion but is better than RUCAM at the diagnostic extremes.”
RECAM appears to add objectivity and clarity that can improve precision and reliability when diagnosing DILI and improve diagnostic standardization, according to authors. It has automated scoring, which reduces subjective input and should lead to better reliability among raters, something that has limited RUCAM’s adaptation in clinical practice and research.
RECAM has automatic warnings for data inconsistencies, which DILI and RUCAM do not. In RUCAM, a different diagnosis or other data could rule out DILI, but the case would still gain points in other criteria.
The authors explained, “Even when data clearly diagnose acute viral hepatitis or autoimmune hepatitis by simplified autoimmune hepatitis score, points are still given for latency, dechallenge, or underlying hepatotoxicity risk of the drug. In these situations of highly implausible DILI, RECAM gives warnings to stop with an imputed total score of –6. One can over-ride these warnings, if one believes DILI may be concurrent with the non-DILI diagnosis. However, –6 points are still assessed.”
Diagnosis of exclusion
Paul Martin, MD, chief, division of digestive health and liver diseases, Mandel Chair in Gastroenterology and professor of medicine at the University of Miami, said in an interview that he hopes RECAM will become widely used and better address a condition that sometimes doesn’t get enough attention. DILI remains underappreciated, he said, despite it being a major cause of morbidity and mortality in some patients.
“Any algorithm or criteria that can improve diagnostic accuracy is useful because typically it is a diagnosis of exclusion,” Dr. Martin said. “This new system seems to be as good as any other prior algorithms to diagnose drug-induced liver injury.”
He added, “This should help clinicians with individual patients with unexplained liver disease.”
The authors noted some limitations. RECAM was developed in U.S. and Spanish cohorts, so its performance in other regions is unclear. Both registries have minimum enrollment requirements for liver enzyme and bilirubin elevation, so it is not known how effective RECAM is in less severe cases. It also needs to be tested by other clinicians, including nonhepatologists.
The authors also added, “It is currently limited to single-agent medication cases leaving the user to score each medication individually in multidrug cases. However, any competing medication causing loss of points in the RUCAM, probably deserves its own RECAM score.”
The DILIN is structured as a cooperative agreement with funds provided by the National Institute of Diabetes and Digestive and Kidney Diseases.
Dr. Hayashi is employed by the FDA, but the conclusions of this paper do not reflect any opinion of the FDA. One coauthor has advised Pfizer, GSK, and NuCANA through Nottingham University Consultants, and another has received support from Gilead and AbbVie and consulted for Sanofi. The remaining authors have no conflicts. Dr. Martin reports no relevant financial relationships.
Researchers looking for a better way to diagnose drug-induced liver injury (DILI) have found evidence to support the use of the Revised Electronic Causality Assessment Method (RECAM).
The broadly used Roussel Uclaf Causality Assessment Method (RUCAM), introduced in 1993, “has been a valuable clinical framework for DILI diagnosis,” but it has been clouded by subjectivity and poor reliability, wrote the authors, led by Paul H. Hayashi, MD, MPH, with the Food and Drug Administration, in Hepatology. Citing a review from the Journal of Hepatology, Dr. Hayashi and colleagues noted three major problems: “(1) unclear operating instructions and subjectivity leading to poor reliability and usability, (2) unclear validity due to lack of an accepted gold standard and (3) domain criteria that are not evidence-based.”
Currently, a diagnosis of DILI is primarily based on clinicians’ judgment and ruling out alternative diagnoses, the authors of this study wrote. The lack of an evidence-based and reliable diagnostic tool is a significant obstacle in clinical care and research .
Reaching a new method
The researchers used classification tree analysis to set diagnostic cut-offs for RECAM and then compared RECAM with RUCAM for correlation with expert opinion diagnostic categories in 194 DILI cases (98 from the Drug-Induced Liver Injury Network, 96 from the Spanish DILI Registry).
The area under receiver operator curves for identifying at least probable DILI were the same at 0.89 for both RECAM and RUCAM.
The authors wrote, “However, RECAM diagnostic categories have better observed overall agreement with expert opinion (0.62 vs. 0.56 weighted kappa, P = .14), and had better sensitivity to detect extreme diagnostic categories (73 vs. 54 for highly likely or high probable, P = .02; 65 vs. 48 for unlikely/excluded, P = .08) than RUCAM diagnostic categories.”
They concluded that RECAM “is at least as capable as RUCAM in diagnosing DILI compared to expert opinion but is better than RUCAM at the diagnostic extremes.”
RECAM appears to add objectivity and clarity that can improve precision and reliability when diagnosing DILI and improve diagnostic standardization, according to authors. It has automated scoring, which reduces subjective input and should lead to better reliability among raters, something that has limited RUCAM’s adaptation in clinical practice and research.
RECAM has automatic warnings for data inconsistencies, which DILI and RUCAM do not. In RUCAM, a different diagnosis or other data could rule out DILI, but the case would still gain points in other criteria.
The authors explained, “Even when data clearly diagnose acute viral hepatitis or autoimmune hepatitis by simplified autoimmune hepatitis score, points are still given for latency, dechallenge, or underlying hepatotoxicity risk of the drug. In these situations of highly implausible DILI, RECAM gives warnings to stop with an imputed total score of –6. One can over-ride these warnings, if one believes DILI may be concurrent with the non-DILI diagnosis. However, –6 points are still assessed.”
Diagnosis of exclusion
Paul Martin, MD, chief, division of digestive health and liver diseases, Mandel Chair in Gastroenterology and professor of medicine at the University of Miami, said in an interview that he hopes RECAM will become widely used and better address a condition that sometimes doesn’t get enough attention. DILI remains underappreciated, he said, despite it being a major cause of morbidity and mortality in some patients.
“Any algorithm or criteria that can improve diagnostic accuracy is useful because typically it is a diagnosis of exclusion,” Dr. Martin said. “This new system seems to be as good as any other prior algorithms to diagnose drug-induced liver injury.”
He added, “This should help clinicians with individual patients with unexplained liver disease.”
The authors noted some limitations. RECAM was developed in U.S. and Spanish cohorts, so its performance in other regions is unclear. Both registries have minimum enrollment requirements for liver enzyme and bilirubin elevation, so it is not known how effective RECAM is in less severe cases. It also needs to be tested by other clinicians, including nonhepatologists.
The authors also added, “It is currently limited to single-agent medication cases leaving the user to score each medication individually in multidrug cases. However, any competing medication causing loss of points in the RUCAM, probably deserves its own RECAM score.”
The DILIN is structured as a cooperative agreement with funds provided by the National Institute of Diabetes and Digestive and Kidney Diseases.
Dr. Hayashi is employed by the FDA, but the conclusions of this paper do not reflect any opinion of the FDA. One coauthor has advised Pfizer, GSK, and NuCANA through Nottingham University Consultants, and another has received support from Gilead and AbbVie and consulted for Sanofi. The remaining authors have no conflicts. Dr. Martin reports no relevant financial relationships.
FROM HEPATOLOGY