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Long COVID associated with risk of metabolic liver disease
Postacute COVID syndrome (PACS), an ongoing inflammatory state following infection with SARS-CoV-2, is associated with greater risk of metabolic-associated fatty liver disease (MAFLD), according to an analysis of patients at a single clinic in Canada published in Open Forum Infectious Diseases.
MAFLD, also known as nonalcoholic fatty liver disease (NAFLD), is considered an indicator of general health and is in turn linked to greater risk of cardiovascular complications and mortality. It may be a multisystem disorder with various underlying causes.
PACS includes symptoms that affect various organ systems, with neurocognitive, autonomic, gastrointestinal, respiratory, musculoskeletal, psychological, sensory, and dermatologic clusters. An estimated 50%-80% of COVID-19 patients experience one or more clusters of symptoms 3 months after leaving the hospital.
But liver problems also appear in the acute phase, said Paul Martin, MD, who was asked to comment on the study. “Up to about half the patients during the acute illness may have elevated liver tests, but there seems to be a subset of patients in whom the abnormality persists. And then there are some reports in the literature of patients developing injury to their bile ducts in the liver over the long term, apparently as a consequence of COVID infection. What this paper suggests is that there may be some metabolic derangements associated with COVID infection, which in turn can accentuate or possibly cause fatty liver,” said Dr. Martin in an interview. He is chief of digestive health and liver diseases and a professor of medicine at the University of Miami.
“It highlights the need to get vaccinated against COVID and to take appropriate precautions because contracting the infection may lead to all sorts of consequences quite apart from having a respiratory illness,” said Dr. Martin.
The researchers retrospectively identified 235 patients hospitalized with COVID-19 between July 2020 and April 2021. Overall, 69% were men, and the median age was 61 years; 19.2% underwent mechanical ventilation and the mean duration of hospitalization was 11.7 days. They were seen for PACS symptoms a median 143 days after COVID-19 symptoms began, with 77.5% having symptoms of at least one PACS cluster. Of these clusters, 34.9% were neurocognitive, 53.2% were respiratory, 26.4% were musculoskeletal, 29.4% were psychological, 25.1% were dermatologic, and 17.5% were sensory.
At the later clinical visit for PACS symptoms, all patients underwent screening for MAFLD, which was defined as the presence of liver steatosis plus overweight/obesity or type 2 diabetes. Hepatic steatosis was determined from controlled attenuation parameter using transient elastrography. The analysis excluded patients with significant alcohol intake or hepatitis B or C. All patients with liver steatosis also had MAFLD, and this included 55.3% of the study population.
The hospital was able to obtain hepatic steatosis index (HSI) scores for 103 of 235 patients. Of these, 50% had MAFLD on admission for acute COVID-19, and 48.1% had MAFLD upon discharge based on this criterion. At the PACS follow-up visit, 71.3% were diagnosed with MAFLD. There was no statistically significant difference in the use of glucocorticoids or tocilizumab during hospitalization between those with and without MAFLD, and remdesivir use was insignificant in the patient population.
Given that the prevalence of MAFLD among the study population is more than double that in the general population, the authors suggest that MAFLD may be a new PACS cluster phenotype that could lead to long-term metabolic and cardiovascular complications. A potential explanation is loss of lean body mass during COVID-19 hospitalization followed by liver fat accumulation during recovery.
Other infections have also shown an association with increased MAFLD incidence, including HIV, Heliobacter pylori, and viral hepatitis. The authors worry that COVID-19 infection could exacerbate underlying conditions to a more severe MAFLD disease state.
The study is limited by a small sample size, limited follow-up, and the lack of a control group. Its retrospective nature leaves it vulnerable to biases.
“The natural history of MAFLD in the context of PACS is unknown at this time, and careful follow-up of these patients is needed to understand the clinical implications of this syndrome in the context of long COVID,” the authors wrote. “We speculate that [MAFLD] may be considered as an independent PACS-cluster phenotype, potentially affecting the metabolic and cardiovascular health of patients with PACS.”
One author has relationships with several pharmaceutical companies, but the remaining authors reported no conflicts of interest. Dr. Martin has no relevant financial disclosures.
Postacute COVID syndrome (PACS), an ongoing inflammatory state following infection with SARS-CoV-2, is associated with greater risk of metabolic-associated fatty liver disease (MAFLD), according to an analysis of patients at a single clinic in Canada published in Open Forum Infectious Diseases.
MAFLD, also known as nonalcoholic fatty liver disease (NAFLD), is considered an indicator of general health and is in turn linked to greater risk of cardiovascular complications and mortality. It may be a multisystem disorder with various underlying causes.
PACS includes symptoms that affect various organ systems, with neurocognitive, autonomic, gastrointestinal, respiratory, musculoskeletal, psychological, sensory, and dermatologic clusters. An estimated 50%-80% of COVID-19 patients experience one or more clusters of symptoms 3 months after leaving the hospital.
But liver problems also appear in the acute phase, said Paul Martin, MD, who was asked to comment on the study. “Up to about half the patients during the acute illness may have elevated liver tests, but there seems to be a subset of patients in whom the abnormality persists. And then there are some reports in the literature of patients developing injury to their bile ducts in the liver over the long term, apparently as a consequence of COVID infection. What this paper suggests is that there may be some metabolic derangements associated with COVID infection, which in turn can accentuate or possibly cause fatty liver,” said Dr. Martin in an interview. He is chief of digestive health and liver diseases and a professor of medicine at the University of Miami.
“It highlights the need to get vaccinated against COVID and to take appropriate precautions because contracting the infection may lead to all sorts of consequences quite apart from having a respiratory illness,” said Dr. Martin.
The researchers retrospectively identified 235 patients hospitalized with COVID-19 between July 2020 and April 2021. Overall, 69% were men, and the median age was 61 years; 19.2% underwent mechanical ventilation and the mean duration of hospitalization was 11.7 days. They were seen for PACS symptoms a median 143 days after COVID-19 symptoms began, with 77.5% having symptoms of at least one PACS cluster. Of these clusters, 34.9% were neurocognitive, 53.2% were respiratory, 26.4% were musculoskeletal, 29.4% were psychological, 25.1% were dermatologic, and 17.5% were sensory.
At the later clinical visit for PACS symptoms, all patients underwent screening for MAFLD, which was defined as the presence of liver steatosis plus overweight/obesity or type 2 diabetes. Hepatic steatosis was determined from controlled attenuation parameter using transient elastrography. The analysis excluded patients with significant alcohol intake or hepatitis B or C. All patients with liver steatosis also had MAFLD, and this included 55.3% of the study population.
The hospital was able to obtain hepatic steatosis index (HSI) scores for 103 of 235 patients. Of these, 50% had MAFLD on admission for acute COVID-19, and 48.1% had MAFLD upon discharge based on this criterion. At the PACS follow-up visit, 71.3% were diagnosed with MAFLD. There was no statistically significant difference in the use of glucocorticoids or tocilizumab during hospitalization between those with and without MAFLD, and remdesivir use was insignificant in the patient population.
Given that the prevalence of MAFLD among the study population is more than double that in the general population, the authors suggest that MAFLD may be a new PACS cluster phenotype that could lead to long-term metabolic and cardiovascular complications. A potential explanation is loss of lean body mass during COVID-19 hospitalization followed by liver fat accumulation during recovery.
Other infections have also shown an association with increased MAFLD incidence, including HIV, Heliobacter pylori, and viral hepatitis. The authors worry that COVID-19 infection could exacerbate underlying conditions to a more severe MAFLD disease state.
The study is limited by a small sample size, limited follow-up, and the lack of a control group. Its retrospective nature leaves it vulnerable to biases.
“The natural history of MAFLD in the context of PACS is unknown at this time, and careful follow-up of these patients is needed to understand the clinical implications of this syndrome in the context of long COVID,” the authors wrote. “We speculate that [MAFLD] may be considered as an independent PACS-cluster phenotype, potentially affecting the metabolic and cardiovascular health of patients with PACS.”
One author has relationships with several pharmaceutical companies, but the remaining authors reported no conflicts of interest. Dr. Martin has no relevant financial disclosures.
Postacute COVID syndrome (PACS), an ongoing inflammatory state following infection with SARS-CoV-2, is associated with greater risk of metabolic-associated fatty liver disease (MAFLD), according to an analysis of patients at a single clinic in Canada published in Open Forum Infectious Diseases.
MAFLD, also known as nonalcoholic fatty liver disease (NAFLD), is considered an indicator of general health and is in turn linked to greater risk of cardiovascular complications and mortality. It may be a multisystem disorder with various underlying causes.
PACS includes symptoms that affect various organ systems, with neurocognitive, autonomic, gastrointestinal, respiratory, musculoskeletal, psychological, sensory, and dermatologic clusters. An estimated 50%-80% of COVID-19 patients experience one or more clusters of symptoms 3 months after leaving the hospital.
But liver problems also appear in the acute phase, said Paul Martin, MD, who was asked to comment on the study. “Up to about half the patients during the acute illness may have elevated liver tests, but there seems to be a subset of patients in whom the abnormality persists. And then there are some reports in the literature of patients developing injury to their bile ducts in the liver over the long term, apparently as a consequence of COVID infection. What this paper suggests is that there may be some metabolic derangements associated with COVID infection, which in turn can accentuate or possibly cause fatty liver,” said Dr. Martin in an interview. He is chief of digestive health and liver diseases and a professor of medicine at the University of Miami.
“It highlights the need to get vaccinated against COVID and to take appropriate precautions because contracting the infection may lead to all sorts of consequences quite apart from having a respiratory illness,” said Dr. Martin.
The researchers retrospectively identified 235 patients hospitalized with COVID-19 between July 2020 and April 2021. Overall, 69% were men, and the median age was 61 years; 19.2% underwent mechanical ventilation and the mean duration of hospitalization was 11.7 days. They were seen for PACS symptoms a median 143 days after COVID-19 symptoms began, with 77.5% having symptoms of at least one PACS cluster. Of these clusters, 34.9% were neurocognitive, 53.2% were respiratory, 26.4% were musculoskeletal, 29.4% were psychological, 25.1% were dermatologic, and 17.5% were sensory.
At the later clinical visit for PACS symptoms, all patients underwent screening for MAFLD, which was defined as the presence of liver steatosis plus overweight/obesity or type 2 diabetes. Hepatic steatosis was determined from controlled attenuation parameter using transient elastrography. The analysis excluded patients with significant alcohol intake or hepatitis B or C. All patients with liver steatosis also had MAFLD, and this included 55.3% of the study population.
The hospital was able to obtain hepatic steatosis index (HSI) scores for 103 of 235 patients. Of these, 50% had MAFLD on admission for acute COVID-19, and 48.1% had MAFLD upon discharge based on this criterion. At the PACS follow-up visit, 71.3% were diagnosed with MAFLD. There was no statistically significant difference in the use of glucocorticoids or tocilizumab during hospitalization between those with and without MAFLD, and remdesivir use was insignificant in the patient population.
Given that the prevalence of MAFLD among the study population is more than double that in the general population, the authors suggest that MAFLD may be a new PACS cluster phenotype that could lead to long-term metabolic and cardiovascular complications. A potential explanation is loss of lean body mass during COVID-19 hospitalization followed by liver fat accumulation during recovery.
Other infections have also shown an association with increased MAFLD incidence, including HIV, Heliobacter pylori, and viral hepatitis. The authors worry that COVID-19 infection could exacerbate underlying conditions to a more severe MAFLD disease state.
The study is limited by a small sample size, limited follow-up, and the lack of a control group. Its retrospective nature leaves it vulnerable to biases.
“The natural history of MAFLD in the context of PACS is unknown at this time, and careful follow-up of these patients is needed to understand the clinical implications of this syndrome in the context of long COVID,” the authors wrote. “We speculate that [MAFLD] may be considered as an independent PACS-cluster phenotype, potentially affecting the metabolic and cardiovascular health of patients with PACS.”
One author has relationships with several pharmaceutical companies, but the remaining authors reported no conflicts of interest. Dr. Martin has no relevant financial disclosures.
FROM OPEN FORUM INFECTIOUS DISEASES
Sleeve, RYGB reduce liver fat in type 2 diabetes
Both Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are effective at improving hepatic steatosis in type 2 diabetes patients, according to a new analysis of a randomized, controlled trial.
Both procedures resulted in near elimination of liver fat 1 year after the surgery, but the effect on liver fibrosis was less clear. The authors called for more research to examine longer-term effects on fibrosis.
“Both gastric bypass and the sleeve had complete resolution of the liver fat based on their MRI findings. That’s impressive,” said Ali Aminian, MD, who was asked to comment on the study. Dr. Aminian is a professor of surgery and director of the Bariatric & Metabolic Institute at the Cleveland Clinic.
About 25% of the general population, and about 90% of people with type 2 diabetes and obesity have nonalcoholic fatty liver disease (NAFLD), which can lead to liver failure or hepatocellular carcinoma. Hepatic steatosis can combine with obesity, insulin resistance, and inflammation to heighten the risk of cardiovascular disease.
Moderate weight loss can clear liver fat and lead to histologic improvement of hepatic steatosis, and retrospective studies have suggested that RYGB may be more effective than SG and gastric banding in countering hepatic steatosis and steatohepatitis.
In fact, Dr. Aminian recently coauthored a paper describing results from the SPLENDOR study, which looked at 650 adults with obesity and nonalcoholic steatohepatitis (NASH) who underwent bariatric surgery at U.S. hospitals between 2004 and 2016, and compared liver biopsy outcomes to 508 patients who went through nonsurgical weight loss protocols.
After a median follow-up of 7 years, 2.3% In the bariatric surgery group had major adverse liver outcomes, compared with 9.6% in the nonsurgical group (adjusted hazard ratio, 0.12; P = .01). The cumulative incidence of major adverse cardiovascular events (MACE) was 8.5% in the bariatric surgery group and 15.7% in the nonsurgery group (aHR, 0.30; P = .007). 0.6% of the surgical group died within the first year after surgery from surgical complications.
Still, the question has not been tested in a randomized, controlled trial.
In the study published online in the Annals of Internal Medicine, researchers led by Kathrine Aglen Seeberg, MD, and Jens Kristoffer Hertel, PhD, of Vestfold Hospital Trust, Tønsberg, Norway, conducted a prespecified secondary analysis of data from 100 patients (65% female, mean age, 47.5 years) with type 2 diabetes who had been randomized to undergo RYGB or SG between January 2013 and February 2018 at their center.
Prior to surgery, the mean liver fat fraction (LFF) was 19% (stand deviation, 12%). In the SG and RYGB groups, 24% and 26% of patients had no or low-grade steatosis (LFF ≤ 10%). LFF declined by 13% in both groups at 5 weeks, and by 20% and 22% at 1 year, respectively, with no significant difference between the two groups.
At 1 year, 100% of the RYGB group had no or low-grade steatosis, as did 94% in the SG group (no significant difference). At 1 year, both groups had similar percentage decreases in the NAFLD liver fat score (between group difference, –0.05) and NAFLD liver fat percentage (between-group difference, –0.3; no significant difference for either).
At baseline, 6% of the RYGB group and 8% of the SG group had severe fibrosis as measured by the enhanced liver fibrosis (ELF) test. At 1 year, the respective frequencies were 9% and 15%, which were not statistically significant changes.
There was much variation in ELF score changes between Individuals, but 18% moved to a higher ELF category and only 5% improved to a lower ELF category at 1 year.
Limitations of the study include the fact that it was conducted at a single center and in a predominantly White population. The study also did not use liver biopsy, which is the standard for measuring fibrosis. Individuals with type 2 diabetes may have more severe NAFLD, which could limit the applicability to individuals without type 2 diabetes.
Together, the studies produce a clear clinical message, according to Dr. Aminian. “It provides compelling evidence for patients and medical providers that, if we can help patients lose weight, we can reverse fatty liver disease,” he said.
The study was funded by the Southeastern Norway Regional Health Authority. Dr. Aminian has received research support from Medtronic.
Both Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are effective at improving hepatic steatosis in type 2 diabetes patients, according to a new analysis of a randomized, controlled trial.
Both procedures resulted in near elimination of liver fat 1 year after the surgery, but the effect on liver fibrosis was less clear. The authors called for more research to examine longer-term effects on fibrosis.
“Both gastric bypass and the sleeve had complete resolution of the liver fat based on their MRI findings. That’s impressive,” said Ali Aminian, MD, who was asked to comment on the study. Dr. Aminian is a professor of surgery and director of the Bariatric & Metabolic Institute at the Cleveland Clinic.
About 25% of the general population, and about 90% of people with type 2 diabetes and obesity have nonalcoholic fatty liver disease (NAFLD), which can lead to liver failure or hepatocellular carcinoma. Hepatic steatosis can combine with obesity, insulin resistance, and inflammation to heighten the risk of cardiovascular disease.
Moderate weight loss can clear liver fat and lead to histologic improvement of hepatic steatosis, and retrospective studies have suggested that RYGB may be more effective than SG and gastric banding in countering hepatic steatosis and steatohepatitis.
In fact, Dr. Aminian recently coauthored a paper describing results from the SPLENDOR study, which looked at 650 adults with obesity and nonalcoholic steatohepatitis (NASH) who underwent bariatric surgery at U.S. hospitals between 2004 and 2016, and compared liver biopsy outcomes to 508 patients who went through nonsurgical weight loss protocols.
After a median follow-up of 7 years, 2.3% In the bariatric surgery group had major adverse liver outcomes, compared with 9.6% in the nonsurgical group (adjusted hazard ratio, 0.12; P = .01). The cumulative incidence of major adverse cardiovascular events (MACE) was 8.5% in the bariatric surgery group and 15.7% in the nonsurgery group (aHR, 0.30; P = .007). 0.6% of the surgical group died within the first year after surgery from surgical complications.
Still, the question has not been tested in a randomized, controlled trial.
In the study published online in the Annals of Internal Medicine, researchers led by Kathrine Aglen Seeberg, MD, and Jens Kristoffer Hertel, PhD, of Vestfold Hospital Trust, Tønsberg, Norway, conducted a prespecified secondary analysis of data from 100 patients (65% female, mean age, 47.5 years) with type 2 diabetes who had been randomized to undergo RYGB or SG between January 2013 and February 2018 at their center.
Prior to surgery, the mean liver fat fraction (LFF) was 19% (stand deviation, 12%). In the SG and RYGB groups, 24% and 26% of patients had no or low-grade steatosis (LFF ≤ 10%). LFF declined by 13% in both groups at 5 weeks, and by 20% and 22% at 1 year, respectively, with no significant difference between the two groups.
At 1 year, 100% of the RYGB group had no or low-grade steatosis, as did 94% in the SG group (no significant difference). At 1 year, both groups had similar percentage decreases in the NAFLD liver fat score (between group difference, –0.05) and NAFLD liver fat percentage (between-group difference, –0.3; no significant difference for either).
At baseline, 6% of the RYGB group and 8% of the SG group had severe fibrosis as measured by the enhanced liver fibrosis (ELF) test. At 1 year, the respective frequencies were 9% and 15%, which were not statistically significant changes.
There was much variation in ELF score changes between Individuals, but 18% moved to a higher ELF category and only 5% improved to a lower ELF category at 1 year.
Limitations of the study include the fact that it was conducted at a single center and in a predominantly White population. The study also did not use liver biopsy, which is the standard for measuring fibrosis. Individuals with type 2 diabetes may have more severe NAFLD, which could limit the applicability to individuals without type 2 diabetes.
Together, the studies produce a clear clinical message, according to Dr. Aminian. “It provides compelling evidence for patients and medical providers that, if we can help patients lose weight, we can reverse fatty liver disease,” he said.
The study was funded by the Southeastern Norway Regional Health Authority. Dr. Aminian has received research support from Medtronic.
Both Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are effective at improving hepatic steatosis in type 2 diabetes patients, according to a new analysis of a randomized, controlled trial.
Both procedures resulted in near elimination of liver fat 1 year after the surgery, but the effect on liver fibrosis was less clear. The authors called for more research to examine longer-term effects on fibrosis.
“Both gastric bypass and the sleeve had complete resolution of the liver fat based on their MRI findings. That’s impressive,” said Ali Aminian, MD, who was asked to comment on the study. Dr. Aminian is a professor of surgery and director of the Bariatric & Metabolic Institute at the Cleveland Clinic.
About 25% of the general population, and about 90% of people with type 2 diabetes and obesity have nonalcoholic fatty liver disease (NAFLD), which can lead to liver failure or hepatocellular carcinoma. Hepatic steatosis can combine with obesity, insulin resistance, and inflammation to heighten the risk of cardiovascular disease.
Moderate weight loss can clear liver fat and lead to histologic improvement of hepatic steatosis, and retrospective studies have suggested that RYGB may be more effective than SG and gastric banding in countering hepatic steatosis and steatohepatitis.
In fact, Dr. Aminian recently coauthored a paper describing results from the SPLENDOR study, which looked at 650 adults with obesity and nonalcoholic steatohepatitis (NASH) who underwent bariatric surgery at U.S. hospitals between 2004 and 2016, and compared liver biopsy outcomes to 508 patients who went through nonsurgical weight loss protocols.
After a median follow-up of 7 years, 2.3% In the bariatric surgery group had major adverse liver outcomes, compared with 9.6% in the nonsurgical group (adjusted hazard ratio, 0.12; P = .01). The cumulative incidence of major adverse cardiovascular events (MACE) was 8.5% in the bariatric surgery group and 15.7% in the nonsurgery group (aHR, 0.30; P = .007). 0.6% of the surgical group died within the first year after surgery from surgical complications.
Still, the question has not been tested in a randomized, controlled trial.
In the study published online in the Annals of Internal Medicine, researchers led by Kathrine Aglen Seeberg, MD, and Jens Kristoffer Hertel, PhD, of Vestfold Hospital Trust, Tønsberg, Norway, conducted a prespecified secondary analysis of data from 100 patients (65% female, mean age, 47.5 years) with type 2 diabetes who had been randomized to undergo RYGB or SG between January 2013 and February 2018 at their center.
Prior to surgery, the mean liver fat fraction (LFF) was 19% (stand deviation, 12%). In the SG and RYGB groups, 24% and 26% of patients had no or low-grade steatosis (LFF ≤ 10%). LFF declined by 13% in both groups at 5 weeks, and by 20% and 22% at 1 year, respectively, with no significant difference between the two groups.
At 1 year, 100% of the RYGB group had no or low-grade steatosis, as did 94% in the SG group (no significant difference). At 1 year, both groups had similar percentage decreases in the NAFLD liver fat score (between group difference, –0.05) and NAFLD liver fat percentage (between-group difference, –0.3; no significant difference for either).
At baseline, 6% of the RYGB group and 8% of the SG group had severe fibrosis as measured by the enhanced liver fibrosis (ELF) test. At 1 year, the respective frequencies were 9% and 15%, which were not statistically significant changes.
There was much variation in ELF score changes between Individuals, but 18% moved to a higher ELF category and only 5% improved to a lower ELF category at 1 year.
Limitations of the study include the fact that it was conducted at a single center and in a predominantly White population. The study also did not use liver biopsy, which is the standard for measuring fibrosis. Individuals with type 2 diabetes may have more severe NAFLD, which could limit the applicability to individuals without type 2 diabetes.
Together, the studies produce a clear clinical message, according to Dr. Aminian. “It provides compelling evidence for patients and medical providers that, if we can help patients lose weight, we can reverse fatty liver disease,” he said.
The study was funded by the Southeastern Norway Regional Health Authority. Dr. Aminian has received research support from Medtronic.
FROM ANNALS OF INTERNAL MEDICINE
Home-based system relieves refractory ascites in cirrhosis
A home-based tunneled peritoneal catheter (PeCa) drainage system provided significant relief for patients with refractory ascites who were not candidates for transjugular intrahepatic portosystemic shunt (TIPS).
For these patients, the current standard of care is repeated large volume paracentesis, but this can require frequent hospital trips that can be costly and onerous.
The PeCa system consists of one part that lays in the peritoneal cavity, then a tunnel through subcutaneous tissue and an external port where the patient can connect drainage bags. It has been tested and found to provide relief for patients with malignant ascites, but there is little data available for patients with cirrhosis, according to Tammo Lambert Tergast, MD, who presented the study at the annual meeting of the American Association for the Study of Liver Diseases. Dr. Tergast is a resident in the department of gastroenterology, hepatology, and endocrinology at Hannover (Germany) Medical School.
“Patients with refractory ascites have a very high risk for rehospitalization, AKI [acute kidney injury], and death. Our data indicate that PeCa could be a valuable new treatment option for patients with refractory ascites and contraindication for TIPS. However, the risk for hyponatremia and AKI has to be considered and further explored,” said Dr. Tergast during his presentation.
The researchers retrospectively analyzed outcomes in 152 patients with refractory ascites who received a PeCa implant and 71 patients who received standard of care (SOC), which included repeated large volume paracentesis and albumin. The median explant-free survival was 74 days, and just under 50% were explant free at 90 days.
52 patients had the PeCa system removed: 54% because of an infection, 15% because of liver transplant, 12% because of dysfunction, and 10% because of accidental removal.
Factors associated with 90-day survival included PeCa (hazard ratio, 0.52; P = .05) and each point of Model for End-Stage Liver Disease (MELD) score (HR, 1.16; P = .001). There was a trend toward a higher incidence of hyponatremia in the PeCa group (P = .09).
Hospitalizations were more common in the PeCa group (P = .035), but there was no significant difference in mortality between the two groups. Reasons for hospitalization included spontaneous bacterial peritonitis (SBP; 18% in PeCa vs. 8% of SOC), hyponatremia (10% vs. 0%), and infections other than SBP (4% and 16%).
A propensity score–matched analysis that included age, history of SBP, platelet count, serum albumin levels, and MELD score found no significant differences between the two groups, but there were trends in the PeCa group towards higher 90-day survival (P = .16) and a higher frequency of acute kidney injury (P = .08).
Although the appropriate patient population for the system would be small, “once you get to refractory ascites, management of these individuals is really, really challenging, especially people that had contraindications to a TIPS procedure. Anything that you can do to improve their quality of life and help with management is definitely desired,” said Nancy Reau, MD, who was asked to comment on the study. Dr. Reau is chief of the section of hepatology at Rush University Medical Center, Chicago.
The study found little difference in infection risk between the PeCa and standard of care group, but there was a trend toward more hyponatremia in the PeCa group. That could be caused by reduced contact with the health system, according to Dr. Reau, since physicians may be keeping an eye on electrolytes, diuretics, and other factors during paracentesis visits. “But as long as you’re setting up home nursing or some other way to make sure that you’re managing them appropriately, that should be something that is overcome with awareness,” said Dr. Reau.
During the question-and-answer following the presentation, Dr. Tergast was asked about the heightened frequency of hospitalizations in the PeCa group. He posited that the observation may be caused by the retrospective nature of the study. His center is a tertiary care center, which accepts referrals from all over Germany. When a problem occurs with a PeCa, patients often get referred back to the tertiary center, leading to a higher number of hospitalizations observed in that group. “So this might be a bias in the analysis,” he said.
“I think if we can optimize the treatment after discharge, we can also minimize the rehospitalization in these patients. Rehospitalization rate because of ascites was quite low,” said Dr. Tergast.
Dr. Tergast and Dr. Reau have no relevant financial disclosures.
A home-based tunneled peritoneal catheter (PeCa) drainage system provided significant relief for patients with refractory ascites who were not candidates for transjugular intrahepatic portosystemic shunt (TIPS).
For these patients, the current standard of care is repeated large volume paracentesis, but this can require frequent hospital trips that can be costly and onerous.
The PeCa system consists of one part that lays in the peritoneal cavity, then a tunnel through subcutaneous tissue and an external port where the patient can connect drainage bags. It has been tested and found to provide relief for patients with malignant ascites, but there is little data available for patients with cirrhosis, according to Tammo Lambert Tergast, MD, who presented the study at the annual meeting of the American Association for the Study of Liver Diseases. Dr. Tergast is a resident in the department of gastroenterology, hepatology, and endocrinology at Hannover (Germany) Medical School.
“Patients with refractory ascites have a very high risk for rehospitalization, AKI [acute kidney injury], and death. Our data indicate that PeCa could be a valuable new treatment option for patients with refractory ascites and contraindication for TIPS. However, the risk for hyponatremia and AKI has to be considered and further explored,” said Dr. Tergast during his presentation.
The researchers retrospectively analyzed outcomes in 152 patients with refractory ascites who received a PeCa implant and 71 patients who received standard of care (SOC), which included repeated large volume paracentesis and albumin. The median explant-free survival was 74 days, and just under 50% were explant free at 90 days.
52 patients had the PeCa system removed: 54% because of an infection, 15% because of liver transplant, 12% because of dysfunction, and 10% because of accidental removal.
Factors associated with 90-day survival included PeCa (hazard ratio, 0.52; P = .05) and each point of Model for End-Stage Liver Disease (MELD) score (HR, 1.16; P = .001). There was a trend toward a higher incidence of hyponatremia in the PeCa group (P = .09).
Hospitalizations were more common in the PeCa group (P = .035), but there was no significant difference in mortality between the two groups. Reasons for hospitalization included spontaneous bacterial peritonitis (SBP; 18% in PeCa vs. 8% of SOC), hyponatremia (10% vs. 0%), and infections other than SBP (4% and 16%).
A propensity score–matched analysis that included age, history of SBP, platelet count, serum albumin levels, and MELD score found no significant differences between the two groups, but there were trends in the PeCa group towards higher 90-day survival (P = .16) and a higher frequency of acute kidney injury (P = .08).
Although the appropriate patient population for the system would be small, “once you get to refractory ascites, management of these individuals is really, really challenging, especially people that had contraindications to a TIPS procedure. Anything that you can do to improve their quality of life and help with management is definitely desired,” said Nancy Reau, MD, who was asked to comment on the study. Dr. Reau is chief of the section of hepatology at Rush University Medical Center, Chicago.
The study found little difference in infection risk between the PeCa and standard of care group, but there was a trend toward more hyponatremia in the PeCa group. That could be caused by reduced contact with the health system, according to Dr. Reau, since physicians may be keeping an eye on electrolytes, diuretics, and other factors during paracentesis visits. “But as long as you’re setting up home nursing or some other way to make sure that you’re managing them appropriately, that should be something that is overcome with awareness,” said Dr. Reau.
During the question-and-answer following the presentation, Dr. Tergast was asked about the heightened frequency of hospitalizations in the PeCa group. He posited that the observation may be caused by the retrospective nature of the study. His center is a tertiary care center, which accepts referrals from all over Germany. When a problem occurs with a PeCa, patients often get referred back to the tertiary center, leading to a higher number of hospitalizations observed in that group. “So this might be a bias in the analysis,” he said.
“I think if we can optimize the treatment after discharge, we can also minimize the rehospitalization in these patients. Rehospitalization rate because of ascites was quite low,” said Dr. Tergast.
Dr. Tergast and Dr. Reau have no relevant financial disclosures.
A home-based tunneled peritoneal catheter (PeCa) drainage system provided significant relief for patients with refractory ascites who were not candidates for transjugular intrahepatic portosystemic shunt (TIPS).
For these patients, the current standard of care is repeated large volume paracentesis, but this can require frequent hospital trips that can be costly and onerous.
The PeCa system consists of one part that lays in the peritoneal cavity, then a tunnel through subcutaneous tissue and an external port where the patient can connect drainage bags. It has been tested and found to provide relief for patients with malignant ascites, but there is little data available for patients with cirrhosis, according to Tammo Lambert Tergast, MD, who presented the study at the annual meeting of the American Association for the Study of Liver Diseases. Dr. Tergast is a resident in the department of gastroenterology, hepatology, and endocrinology at Hannover (Germany) Medical School.
“Patients with refractory ascites have a very high risk for rehospitalization, AKI [acute kidney injury], and death. Our data indicate that PeCa could be a valuable new treatment option for patients with refractory ascites and contraindication for TIPS. However, the risk for hyponatremia and AKI has to be considered and further explored,” said Dr. Tergast during his presentation.
The researchers retrospectively analyzed outcomes in 152 patients with refractory ascites who received a PeCa implant and 71 patients who received standard of care (SOC), which included repeated large volume paracentesis and albumin. The median explant-free survival was 74 days, and just under 50% were explant free at 90 days.
52 patients had the PeCa system removed: 54% because of an infection, 15% because of liver transplant, 12% because of dysfunction, and 10% because of accidental removal.
Factors associated with 90-day survival included PeCa (hazard ratio, 0.52; P = .05) and each point of Model for End-Stage Liver Disease (MELD) score (HR, 1.16; P = .001). There was a trend toward a higher incidence of hyponatremia in the PeCa group (P = .09).
Hospitalizations were more common in the PeCa group (P = .035), but there was no significant difference in mortality between the two groups. Reasons for hospitalization included spontaneous bacterial peritonitis (SBP; 18% in PeCa vs. 8% of SOC), hyponatremia (10% vs. 0%), and infections other than SBP (4% and 16%).
A propensity score–matched analysis that included age, history of SBP, platelet count, serum albumin levels, and MELD score found no significant differences between the two groups, but there were trends in the PeCa group towards higher 90-day survival (P = .16) and a higher frequency of acute kidney injury (P = .08).
Although the appropriate patient population for the system would be small, “once you get to refractory ascites, management of these individuals is really, really challenging, especially people that had contraindications to a TIPS procedure. Anything that you can do to improve their quality of life and help with management is definitely desired,” said Nancy Reau, MD, who was asked to comment on the study. Dr. Reau is chief of the section of hepatology at Rush University Medical Center, Chicago.
The study found little difference in infection risk between the PeCa and standard of care group, but there was a trend toward more hyponatremia in the PeCa group. That could be caused by reduced contact with the health system, according to Dr. Reau, since physicians may be keeping an eye on electrolytes, diuretics, and other factors during paracentesis visits. “But as long as you’re setting up home nursing or some other way to make sure that you’re managing them appropriately, that should be something that is overcome with awareness,” said Dr. Reau.
During the question-and-answer following the presentation, Dr. Tergast was asked about the heightened frequency of hospitalizations in the PeCa group. He posited that the observation may be caused by the retrospective nature of the study. His center is a tertiary care center, which accepts referrals from all over Germany. When a problem occurs with a PeCa, patients often get referred back to the tertiary center, leading to a higher number of hospitalizations observed in that group. “So this might be a bias in the analysis,” he said.
“I think if we can optimize the treatment after discharge, we can also minimize the rehospitalization in these patients. Rehospitalization rate because of ascites was quite low,” said Dr. Tergast.
Dr. Tergast and Dr. Reau have no relevant financial disclosures.
FROM THE LIVER MEETING
FIB-4 could ID liver risk in primary care
Fibrosis-4 index (FIB-4) scores are strongly associated with severe liver disease outcomes in a primary care population, both in patients with known chronic liver disease and those without known CLD. The result could help identify patients with CLD before their condition becomes severe.
FIB-4 has previously shown utility in predicting the risk of advanced fibrosis in patients with viral hepatitis B and C, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and alcohol-related liver disease.
“This is really important in primary care because FIB-4 is easy to calculate. Its inputs are accessible, and it is inexpensive, often taking advantage of labs that we’ve ordered anyway. And if we can use it to find advanced fibrosis, it will be critically important because we know that advanced fibrosis is associated with severe liver outcomes – these are going to be patients that we need to make sure are in touch with our hepatology colleagues,” said Andrew Schreiner, MD, during a presentation of the results at the annual meeting of the American Association for the Study of Liver Diseases. Dr. Schreiner is general internist at the Medical University of South Carolina, Charleston.
He also noted that FIB-4 is playing an important role in the assessment of NAFLD and NASH. Many newer algorithms to manage NAFLD in the primary care setting rely on FIB-4, but that application is limited because NAFLD is underdiagnosed according to administrative database studies, which found rates of about 2%-5% despite the fact that estimates put it at having a prevalence of 25%-30% in the U.S. population.
To determine if FIB-4 scores could assist in identifying primary care patients at risk of severe outcomes, including cirrhosis, hepatocellular carcinoma, and liver transplant, the researchers conducted a retrospective analysis of primary care electronic health care data from 20,556 patients between 2007 and 2018 who were seen at their institution. Participants had ALT and AST values less than 500 IU/L, as well as a platelet count within two months preceding or on the day of the liver enzyme tests. They excluded individuals with known chronic or severe liver disease.
65% of patients were female, 45% were Black, and the mean BMI was 29.8 kg/m2. 64% of participants were ranked as low risk (FIB-4 ≤1.3), 29% with undetermined risk (1.3-2.67), and 7% with high risk (>2.67).
The population had more liver risk than expected. “[It is] a distribution that certainly may have more high risk and indeterminant risks than we would have anticipated, but we have seen this in external studies,” said Dr. Schreiner.
Over a mean follow-up period of 8.2 years, 11% were diagnosed with CLD: 2.3% developed NAFLD, 8.2% another CLD, and 0.5% had NAFLD and another CLD. About 4% developed a severe CLD. A severe liver outcome occurred in 2.2% of those who had been classified as FIB-4 low risk, 4.2% classified as indeterminate risk, and 20.8% of those classified as high risk.
“Troublingly,” said Dr. Schreiner, 49% of those who went on to develop a severe liver outcome had no CLD diagnosis before it occurred. “This is a tremendous opportunity to improve diagnosis in this setting.”
After adjustment for race, gender, marital status, smoking history, BMI, and various comorbidities, the researchers found a higher risk of severe liver disease associated with indeterminate FIB-4 risk score (hazard ratio, 1.62; 95% confidence interval, 1.36-1.92) and a high FIB-4 risk score (HR, 6.64; 95% CI, 5.58-7.90), compared with those with a low FIB-4 risk score. The same was true for individual liver diseases, including NAFLD (indeterminate HR, 1.88; 95% CI, 0.99-3.60; high HR, 7.32; 95% CI, 3.44-15.58), other liver diagnosis (indeterminate HR, 2.65; 95% CI, 1.93-3.63; high HR, 11.39; 95% CI, 8.53-15.20), and NAFLD plus another liver disease (intermediate HR, 2.53; 95% CI, 0.79-8.12; high HR, 6.89; 95% CI, 1.82-26.14).
Dr. Schreiner conceded that the study may not be generalizable, since FIB-4 was not designed for use in general populations, and it was conducted at a single center.
During the question-and-answer session after the talk, Dr. Schreiner was asked if the majority of the 49% who had a severe liver outcome without previous liver disease had NAFLD. He said that was the team’s hypothesis, and they are in the process of examining that data, but a significant number appear to be alcohol related. “For us in the primary care setting, it’s just another opportunity to emphasize that we have to do a better job getting exposure histories, and alcohol histories in particular, and finding ways to document those in ways that we can make diagnoses for patients and for our hepatology colleagues,” said Dr. Schreiner.
Comoderator Kathleen Corey, MD, asked Dr. Schreiner if he had any concerns about false positives from FIB-4 screening, and whether that could lead to overtreatment. “We’ve seen other screening tests leading to patient distress and overutilization of resources. How do you think we might be able to mitigate that?” asked Dr. Corey, who is an assistant professor of medicine at Harvard Medical School and director of the Fatty Liver Clinic at Massachusetts General Hospital, both in Boston.
Dr. Schreiner underscored the need for more physician education about FIB-4, both its potential and its pitfalls, since many primary care providers don’t use it or even know about it. “FIB-4 is very popular in the hepatology literature, but in primary care, we don’t talk about it as often. So I think educational efforts about its possible utility, about some of the drawbacks, or some of the things that might lead to inappropriately positive results – like advanced age, for those of us who see patients 60 and older. Those are really important considerations both for the patient and the provider for management of expectations and concerns. I’m worried too about application in our younger cohorts. The explosion of NAFLD in adolescence, and the likelihood that we might get a false negative in maybe a 28-year-old who might have problematic disease, is a concern as well,” said Dr. Schreiner.
Dr. Schreiner has no relevant financial disclosures. Dr. Corey has been on an advisory committee or review panel for Bristol-Myers Squibb, Novo Nordisk, and Gilead. She has consulted for Novo Nordisk and received research support from BMS, Boehringer Ingelheim, Novartis, and Boehringer Ingelheim.
Fibrosis-4 index (FIB-4) scores are strongly associated with severe liver disease outcomes in a primary care population, both in patients with known chronic liver disease and those without known CLD. The result could help identify patients with CLD before their condition becomes severe.
FIB-4 has previously shown utility in predicting the risk of advanced fibrosis in patients with viral hepatitis B and C, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and alcohol-related liver disease.
“This is really important in primary care because FIB-4 is easy to calculate. Its inputs are accessible, and it is inexpensive, often taking advantage of labs that we’ve ordered anyway. And if we can use it to find advanced fibrosis, it will be critically important because we know that advanced fibrosis is associated with severe liver outcomes – these are going to be patients that we need to make sure are in touch with our hepatology colleagues,” said Andrew Schreiner, MD, during a presentation of the results at the annual meeting of the American Association for the Study of Liver Diseases. Dr. Schreiner is general internist at the Medical University of South Carolina, Charleston.
He also noted that FIB-4 is playing an important role in the assessment of NAFLD and NASH. Many newer algorithms to manage NAFLD in the primary care setting rely on FIB-4, but that application is limited because NAFLD is underdiagnosed according to administrative database studies, which found rates of about 2%-5% despite the fact that estimates put it at having a prevalence of 25%-30% in the U.S. population.
To determine if FIB-4 scores could assist in identifying primary care patients at risk of severe outcomes, including cirrhosis, hepatocellular carcinoma, and liver transplant, the researchers conducted a retrospective analysis of primary care electronic health care data from 20,556 patients between 2007 and 2018 who were seen at their institution. Participants had ALT and AST values less than 500 IU/L, as well as a platelet count within two months preceding or on the day of the liver enzyme tests. They excluded individuals with known chronic or severe liver disease.
65% of patients were female, 45% were Black, and the mean BMI was 29.8 kg/m2. 64% of participants were ranked as low risk (FIB-4 ≤1.3), 29% with undetermined risk (1.3-2.67), and 7% with high risk (>2.67).
The population had more liver risk than expected. “[It is] a distribution that certainly may have more high risk and indeterminant risks than we would have anticipated, but we have seen this in external studies,” said Dr. Schreiner.
Over a mean follow-up period of 8.2 years, 11% were diagnosed with CLD: 2.3% developed NAFLD, 8.2% another CLD, and 0.5% had NAFLD and another CLD. About 4% developed a severe CLD. A severe liver outcome occurred in 2.2% of those who had been classified as FIB-4 low risk, 4.2% classified as indeterminate risk, and 20.8% of those classified as high risk.
“Troublingly,” said Dr. Schreiner, 49% of those who went on to develop a severe liver outcome had no CLD diagnosis before it occurred. “This is a tremendous opportunity to improve diagnosis in this setting.”
After adjustment for race, gender, marital status, smoking history, BMI, and various comorbidities, the researchers found a higher risk of severe liver disease associated with indeterminate FIB-4 risk score (hazard ratio, 1.62; 95% confidence interval, 1.36-1.92) and a high FIB-4 risk score (HR, 6.64; 95% CI, 5.58-7.90), compared with those with a low FIB-4 risk score. The same was true for individual liver diseases, including NAFLD (indeterminate HR, 1.88; 95% CI, 0.99-3.60; high HR, 7.32; 95% CI, 3.44-15.58), other liver diagnosis (indeterminate HR, 2.65; 95% CI, 1.93-3.63; high HR, 11.39; 95% CI, 8.53-15.20), and NAFLD plus another liver disease (intermediate HR, 2.53; 95% CI, 0.79-8.12; high HR, 6.89; 95% CI, 1.82-26.14).
Dr. Schreiner conceded that the study may not be generalizable, since FIB-4 was not designed for use in general populations, and it was conducted at a single center.
During the question-and-answer session after the talk, Dr. Schreiner was asked if the majority of the 49% who had a severe liver outcome without previous liver disease had NAFLD. He said that was the team’s hypothesis, and they are in the process of examining that data, but a significant number appear to be alcohol related. “For us in the primary care setting, it’s just another opportunity to emphasize that we have to do a better job getting exposure histories, and alcohol histories in particular, and finding ways to document those in ways that we can make diagnoses for patients and for our hepatology colleagues,” said Dr. Schreiner.
Comoderator Kathleen Corey, MD, asked Dr. Schreiner if he had any concerns about false positives from FIB-4 screening, and whether that could lead to overtreatment. “We’ve seen other screening tests leading to patient distress and overutilization of resources. How do you think we might be able to mitigate that?” asked Dr. Corey, who is an assistant professor of medicine at Harvard Medical School and director of the Fatty Liver Clinic at Massachusetts General Hospital, both in Boston.
Dr. Schreiner underscored the need for more physician education about FIB-4, both its potential and its pitfalls, since many primary care providers don’t use it or even know about it. “FIB-4 is very popular in the hepatology literature, but in primary care, we don’t talk about it as often. So I think educational efforts about its possible utility, about some of the drawbacks, or some of the things that might lead to inappropriately positive results – like advanced age, for those of us who see patients 60 and older. Those are really important considerations both for the patient and the provider for management of expectations and concerns. I’m worried too about application in our younger cohorts. The explosion of NAFLD in adolescence, and the likelihood that we might get a false negative in maybe a 28-year-old who might have problematic disease, is a concern as well,” said Dr. Schreiner.
Dr. Schreiner has no relevant financial disclosures. Dr. Corey has been on an advisory committee or review panel for Bristol-Myers Squibb, Novo Nordisk, and Gilead. She has consulted for Novo Nordisk and received research support from BMS, Boehringer Ingelheim, Novartis, and Boehringer Ingelheim.
Fibrosis-4 index (FIB-4) scores are strongly associated with severe liver disease outcomes in a primary care population, both in patients with known chronic liver disease and those without known CLD. The result could help identify patients with CLD before their condition becomes severe.
FIB-4 has previously shown utility in predicting the risk of advanced fibrosis in patients with viral hepatitis B and C, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), and alcohol-related liver disease.
“This is really important in primary care because FIB-4 is easy to calculate. Its inputs are accessible, and it is inexpensive, often taking advantage of labs that we’ve ordered anyway. And if we can use it to find advanced fibrosis, it will be critically important because we know that advanced fibrosis is associated with severe liver outcomes – these are going to be patients that we need to make sure are in touch with our hepatology colleagues,” said Andrew Schreiner, MD, during a presentation of the results at the annual meeting of the American Association for the Study of Liver Diseases. Dr. Schreiner is general internist at the Medical University of South Carolina, Charleston.
He also noted that FIB-4 is playing an important role in the assessment of NAFLD and NASH. Many newer algorithms to manage NAFLD in the primary care setting rely on FIB-4, but that application is limited because NAFLD is underdiagnosed according to administrative database studies, which found rates of about 2%-5% despite the fact that estimates put it at having a prevalence of 25%-30% in the U.S. population.
To determine if FIB-4 scores could assist in identifying primary care patients at risk of severe outcomes, including cirrhosis, hepatocellular carcinoma, and liver transplant, the researchers conducted a retrospective analysis of primary care electronic health care data from 20,556 patients between 2007 and 2018 who were seen at their institution. Participants had ALT and AST values less than 500 IU/L, as well as a platelet count within two months preceding or on the day of the liver enzyme tests. They excluded individuals with known chronic or severe liver disease.
65% of patients were female, 45% were Black, and the mean BMI was 29.8 kg/m2. 64% of participants were ranked as low risk (FIB-4 ≤1.3), 29% with undetermined risk (1.3-2.67), and 7% with high risk (>2.67).
The population had more liver risk than expected. “[It is] a distribution that certainly may have more high risk and indeterminant risks than we would have anticipated, but we have seen this in external studies,” said Dr. Schreiner.
Over a mean follow-up period of 8.2 years, 11% were diagnosed with CLD: 2.3% developed NAFLD, 8.2% another CLD, and 0.5% had NAFLD and another CLD. About 4% developed a severe CLD. A severe liver outcome occurred in 2.2% of those who had been classified as FIB-4 low risk, 4.2% classified as indeterminate risk, and 20.8% of those classified as high risk.
“Troublingly,” said Dr. Schreiner, 49% of those who went on to develop a severe liver outcome had no CLD diagnosis before it occurred. “This is a tremendous opportunity to improve diagnosis in this setting.”
After adjustment for race, gender, marital status, smoking history, BMI, and various comorbidities, the researchers found a higher risk of severe liver disease associated with indeterminate FIB-4 risk score (hazard ratio, 1.62; 95% confidence interval, 1.36-1.92) and a high FIB-4 risk score (HR, 6.64; 95% CI, 5.58-7.90), compared with those with a low FIB-4 risk score. The same was true for individual liver diseases, including NAFLD (indeterminate HR, 1.88; 95% CI, 0.99-3.60; high HR, 7.32; 95% CI, 3.44-15.58), other liver diagnosis (indeterminate HR, 2.65; 95% CI, 1.93-3.63; high HR, 11.39; 95% CI, 8.53-15.20), and NAFLD plus another liver disease (intermediate HR, 2.53; 95% CI, 0.79-8.12; high HR, 6.89; 95% CI, 1.82-26.14).
Dr. Schreiner conceded that the study may not be generalizable, since FIB-4 was not designed for use in general populations, and it was conducted at a single center.
During the question-and-answer session after the talk, Dr. Schreiner was asked if the majority of the 49% who had a severe liver outcome without previous liver disease had NAFLD. He said that was the team’s hypothesis, and they are in the process of examining that data, but a significant number appear to be alcohol related. “For us in the primary care setting, it’s just another opportunity to emphasize that we have to do a better job getting exposure histories, and alcohol histories in particular, and finding ways to document those in ways that we can make diagnoses for patients and for our hepatology colleagues,” said Dr. Schreiner.
Comoderator Kathleen Corey, MD, asked Dr. Schreiner if he had any concerns about false positives from FIB-4 screening, and whether that could lead to overtreatment. “We’ve seen other screening tests leading to patient distress and overutilization of resources. How do you think we might be able to mitigate that?” asked Dr. Corey, who is an assistant professor of medicine at Harvard Medical School and director of the Fatty Liver Clinic at Massachusetts General Hospital, both in Boston.
Dr. Schreiner underscored the need for more physician education about FIB-4, both its potential and its pitfalls, since many primary care providers don’t use it or even know about it. “FIB-4 is very popular in the hepatology literature, but in primary care, we don’t talk about it as often. So I think educational efforts about its possible utility, about some of the drawbacks, or some of the things that might lead to inappropriately positive results – like advanced age, for those of us who see patients 60 and older. Those are really important considerations both for the patient and the provider for management of expectations and concerns. I’m worried too about application in our younger cohorts. The explosion of NAFLD in adolescence, and the likelihood that we might get a false negative in maybe a 28-year-old who might have problematic disease, is a concern as well,” said Dr. Schreiner.
Dr. Schreiner has no relevant financial disclosures. Dr. Corey has been on an advisory committee or review panel for Bristol-Myers Squibb, Novo Nordisk, and Gilead. She has consulted for Novo Nordisk and received research support from BMS, Boehringer Ingelheim, Novartis, and Boehringer Ingelheim.
FROM THE LIVER MEETING
Bulevirtide shows real-world efficacy versus HDV
A real-world analysis of bulevirtide found a safety and efficacy profile similar to what was seen in earlier clinical trials in the treatment of hepatitis delta virus (HDV) infection.
HDV can only infect patients already carrying hepatitis B virus (HBV), but it causes the most severe form of viral hepatitis as it can progress to cirrhosis within 5 years and to hepatocellular carcinoma within 10 years.
Bulevirtide is a first-in-class medication that mimics the hepatitis B surface antigen, binding to its receptor on hepatocytes and preventing HDV viral particles from binding to it. The drug received conditional marketing approval by the European Medicines Agency in 2020 and has received a breakthrough therapy designation from the U.S. Food and Drug Administration.
The study was presented at the annual meeting of the American Association for the Study of Liver Diseases by Victor De Ledinghen, PhD, who is a professor of hepatology and head of the hepatology and liver transplantation unit at Bordeaux (France) University Hospital.
The early-access program launched after the French National Agency for Medicines and Health Products approved bulevirtide in 2019. It was made available to patients with compensated cirrhosis or severe liver fibrosis (F3) or patients with F2 fibrosis and alanine amino transferase levels more than twice the upper limit of normal for 6 months or more. Patients received bulevirtide alone (n = 77) or in combination with peg-interferon (n = 68), as determined by their physician.
The researchers defined virologic efficacy as HDV RNA levels being undetectable, or decreased by at least 2 log10 from baseline. They defined biochemical efficacy as ALT levels below 40 IU/L.
A per-protocol analysis included all patients in the bulevirtide group, but excluded 12 from the combination group who discontinued peg-interferon (n = 56). Nineteen patients in bulevirtide group had a treatment modification, and seven discontinued treatment. Five in the combination group had a treatment modification, and 14 stopped treatment. At 12 months, there was a greater decline in median log10 IU/mL in the combination group (–5.65 versus –3.64), though the study was not powered to compare the two. At 12 months, the combination group had 93.9% virologic efficacy, compared with 68.3% in the bulevirtide group.
The two groups had similar mean ALT levels at 12 months (48.91 and 48.03 IU/mL, respectively), with more patients in the bulevirtide group having normal ALT levels (<40 IU/L; 48.8% versus 36.4%). At 12 months, 39.0% of the bulevirtide group and 30.3% of the combination group had a combined response, defined as either undetectable HDV RNA or ≥2 log10 from baseline plus normal ALT levels.
Twenty-nine patients in the bulevirtide group had an adverse event, compared with 43 in the combination group. The two groups were similar in the frequency of grade 3-4 adverse events (7 versus 6), discontinuation due to adverse events (2 versus 3), deaths (0 in both), injection-site reactions (2 in both), liver-related adverse events (4 versus 2), and elevated bile acid (76 versus 68).
During the Q&A period following the presentation, Dr. De Ledinghen was asked if he has a preferred regimen for HDV patients. “I think it depends on the tolerance of peg-interferon because of all the side effects with this drug. I think we need to have predictive factors of virological response with or without interferon. At this time, I don’t have a preference, but I think at this time we need to work on predictive factors associated with virologic response,” he said.
The EMA’s conditional bulevirtide approval hinged on results from phase 2 clinical trials, while the phase 3 clinical studies are ongoing. “This was a very unusual step for the EMA to provide what is similar to emergency use approval while the phase 3 clinical trials are still ongoing,” said Anna Lok, MD, who was asked to comment on the study. Dr. Lok is a professor of internal medicine, director of clinical hepatology, and assistant dean for clinical research at the University of Michigan, Ann Arbor.
She noted that the phase 2 studies indicated that the combination with peg-interferon seems to have an additive effect on HDV suppression, while monotherapy with bulevirtide has a greater effect on normalizing ALT levels. The real-world experience confirms these findings.
But the real-world data revealed some concerns. “What really worried me is the large number of patients who required dose modifications or discontinuations, and that seems to be the case in both treatment groups. They didn’t really go into a lot of details [about] why patients needed treatment modifications, but one has to assume that this is due to side effects,” said Dr. Lok.
She also noted that the per-protocol analysis, instead of an intention-to-treat analysis, is a weakness of the study. Additionally, over time, the number of patients analyzed decreased – as many as 40% of patients didn’t have test results at month 12. “It makes you wonder what happened to those patients. Many probably didn’t respond, in which case your overall response rate will be far lower,” said Dr. Lok.
The study was funded by Gilead. Dr. De Ledinghen has financial relationships with Gilead, AbbVie, Echosens, Hologic, Intercept Pharma, Tillotts, Orphalan, Alfasigma, Bristol Myers Squibb, and Siemens Healthineers. Dr. Lok has no relevant financial disclosures.
A real-world analysis of bulevirtide found a safety and efficacy profile similar to what was seen in earlier clinical trials in the treatment of hepatitis delta virus (HDV) infection.
HDV can only infect patients already carrying hepatitis B virus (HBV), but it causes the most severe form of viral hepatitis as it can progress to cirrhosis within 5 years and to hepatocellular carcinoma within 10 years.
Bulevirtide is a first-in-class medication that mimics the hepatitis B surface antigen, binding to its receptor on hepatocytes and preventing HDV viral particles from binding to it. The drug received conditional marketing approval by the European Medicines Agency in 2020 and has received a breakthrough therapy designation from the U.S. Food and Drug Administration.
The study was presented at the annual meeting of the American Association for the Study of Liver Diseases by Victor De Ledinghen, PhD, who is a professor of hepatology and head of the hepatology and liver transplantation unit at Bordeaux (France) University Hospital.
The early-access program launched after the French National Agency for Medicines and Health Products approved bulevirtide in 2019. It was made available to patients with compensated cirrhosis or severe liver fibrosis (F3) or patients with F2 fibrosis and alanine amino transferase levels more than twice the upper limit of normal for 6 months or more. Patients received bulevirtide alone (n = 77) or in combination with peg-interferon (n = 68), as determined by their physician.
The researchers defined virologic efficacy as HDV RNA levels being undetectable, or decreased by at least 2 log10 from baseline. They defined biochemical efficacy as ALT levels below 40 IU/L.
A per-protocol analysis included all patients in the bulevirtide group, but excluded 12 from the combination group who discontinued peg-interferon (n = 56). Nineteen patients in bulevirtide group had a treatment modification, and seven discontinued treatment. Five in the combination group had a treatment modification, and 14 stopped treatment. At 12 months, there was a greater decline in median log10 IU/mL in the combination group (–5.65 versus –3.64), though the study was not powered to compare the two. At 12 months, the combination group had 93.9% virologic efficacy, compared with 68.3% in the bulevirtide group.
The two groups had similar mean ALT levels at 12 months (48.91 and 48.03 IU/mL, respectively), with more patients in the bulevirtide group having normal ALT levels (<40 IU/L; 48.8% versus 36.4%). At 12 months, 39.0% of the bulevirtide group and 30.3% of the combination group had a combined response, defined as either undetectable HDV RNA or ≥2 log10 from baseline plus normal ALT levels.
Twenty-nine patients in the bulevirtide group had an adverse event, compared with 43 in the combination group. The two groups were similar in the frequency of grade 3-4 adverse events (7 versus 6), discontinuation due to adverse events (2 versus 3), deaths (0 in both), injection-site reactions (2 in both), liver-related adverse events (4 versus 2), and elevated bile acid (76 versus 68).
During the Q&A period following the presentation, Dr. De Ledinghen was asked if he has a preferred regimen for HDV patients. “I think it depends on the tolerance of peg-interferon because of all the side effects with this drug. I think we need to have predictive factors of virological response with or without interferon. At this time, I don’t have a preference, but I think at this time we need to work on predictive factors associated with virologic response,” he said.
The EMA’s conditional bulevirtide approval hinged on results from phase 2 clinical trials, while the phase 3 clinical studies are ongoing. “This was a very unusual step for the EMA to provide what is similar to emergency use approval while the phase 3 clinical trials are still ongoing,” said Anna Lok, MD, who was asked to comment on the study. Dr. Lok is a professor of internal medicine, director of clinical hepatology, and assistant dean for clinical research at the University of Michigan, Ann Arbor.
She noted that the phase 2 studies indicated that the combination with peg-interferon seems to have an additive effect on HDV suppression, while monotherapy with bulevirtide has a greater effect on normalizing ALT levels. The real-world experience confirms these findings.
But the real-world data revealed some concerns. “What really worried me is the large number of patients who required dose modifications or discontinuations, and that seems to be the case in both treatment groups. They didn’t really go into a lot of details [about] why patients needed treatment modifications, but one has to assume that this is due to side effects,” said Dr. Lok.
She also noted that the per-protocol analysis, instead of an intention-to-treat analysis, is a weakness of the study. Additionally, over time, the number of patients analyzed decreased – as many as 40% of patients didn’t have test results at month 12. “It makes you wonder what happened to those patients. Many probably didn’t respond, in which case your overall response rate will be far lower,” said Dr. Lok.
The study was funded by Gilead. Dr. De Ledinghen has financial relationships with Gilead, AbbVie, Echosens, Hologic, Intercept Pharma, Tillotts, Orphalan, Alfasigma, Bristol Myers Squibb, and Siemens Healthineers. Dr. Lok has no relevant financial disclosures.
A real-world analysis of bulevirtide found a safety and efficacy profile similar to what was seen in earlier clinical trials in the treatment of hepatitis delta virus (HDV) infection.
HDV can only infect patients already carrying hepatitis B virus (HBV), but it causes the most severe form of viral hepatitis as it can progress to cirrhosis within 5 years and to hepatocellular carcinoma within 10 years.
Bulevirtide is a first-in-class medication that mimics the hepatitis B surface antigen, binding to its receptor on hepatocytes and preventing HDV viral particles from binding to it. The drug received conditional marketing approval by the European Medicines Agency in 2020 and has received a breakthrough therapy designation from the U.S. Food and Drug Administration.
The study was presented at the annual meeting of the American Association for the Study of Liver Diseases by Victor De Ledinghen, PhD, who is a professor of hepatology and head of the hepatology and liver transplantation unit at Bordeaux (France) University Hospital.
The early-access program launched after the French National Agency for Medicines and Health Products approved bulevirtide in 2019. It was made available to patients with compensated cirrhosis or severe liver fibrosis (F3) or patients with F2 fibrosis and alanine amino transferase levels more than twice the upper limit of normal for 6 months or more. Patients received bulevirtide alone (n = 77) or in combination with peg-interferon (n = 68), as determined by their physician.
The researchers defined virologic efficacy as HDV RNA levels being undetectable, or decreased by at least 2 log10 from baseline. They defined biochemical efficacy as ALT levels below 40 IU/L.
A per-protocol analysis included all patients in the bulevirtide group, but excluded 12 from the combination group who discontinued peg-interferon (n = 56). Nineteen patients in bulevirtide group had a treatment modification, and seven discontinued treatment. Five in the combination group had a treatment modification, and 14 stopped treatment. At 12 months, there was a greater decline in median log10 IU/mL in the combination group (–5.65 versus –3.64), though the study was not powered to compare the two. At 12 months, the combination group had 93.9% virologic efficacy, compared with 68.3% in the bulevirtide group.
The two groups had similar mean ALT levels at 12 months (48.91 and 48.03 IU/mL, respectively), with more patients in the bulevirtide group having normal ALT levels (<40 IU/L; 48.8% versus 36.4%). At 12 months, 39.0% of the bulevirtide group and 30.3% of the combination group had a combined response, defined as either undetectable HDV RNA or ≥2 log10 from baseline plus normal ALT levels.
Twenty-nine patients in the bulevirtide group had an adverse event, compared with 43 in the combination group. The two groups were similar in the frequency of grade 3-4 adverse events (7 versus 6), discontinuation due to adverse events (2 versus 3), deaths (0 in both), injection-site reactions (2 in both), liver-related adverse events (4 versus 2), and elevated bile acid (76 versus 68).
During the Q&A period following the presentation, Dr. De Ledinghen was asked if he has a preferred regimen for HDV patients. “I think it depends on the tolerance of peg-interferon because of all the side effects with this drug. I think we need to have predictive factors of virological response with or without interferon. At this time, I don’t have a preference, but I think at this time we need to work on predictive factors associated with virologic response,” he said.
The EMA’s conditional bulevirtide approval hinged on results from phase 2 clinical trials, while the phase 3 clinical studies are ongoing. “This was a very unusual step for the EMA to provide what is similar to emergency use approval while the phase 3 clinical trials are still ongoing,” said Anna Lok, MD, who was asked to comment on the study. Dr. Lok is a professor of internal medicine, director of clinical hepatology, and assistant dean for clinical research at the University of Michigan, Ann Arbor.
She noted that the phase 2 studies indicated that the combination with peg-interferon seems to have an additive effect on HDV suppression, while monotherapy with bulevirtide has a greater effect on normalizing ALT levels. The real-world experience confirms these findings.
But the real-world data revealed some concerns. “What really worried me is the large number of patients who required dose modifications or discontinuations, and that seems to be the case in both treatment groups. They didn’t really go into a lot of details [about] why patients needed treatment modifications, but one has to assume that this is due to side effects,” said Dr. Lok.
She also noted that the per-protocol analysis, instead of an intention-to-treat analysis, is a weakness of the study. Additionally, over time, the number of patients analyzed decreased – as many as 40% of patients didn’t have test results at month 12. “It makes you wonder what happened to those patients. Many probably didn’t respond, in which case your overall response rate will be far lower,” said Dr. Lok.
The study was funded by Gilead. Dr. De Ledinghen has financial relationships with Gilead, AbbVie, Echosens, Hologic, Intercept Pharma, Tillotts, Orphalan, Alfasigma, Bristol Myers Squibb, and Siemens Healthineers. Dr. Lok has no relevant financial disclosures.
FROM THE LIVER MEETING
COVID-19 vaccines: Lower serologic response among IBD, rheumatic diseases
Patients with immune-mediated inflammatory diseases (IMIDs), such as inflammatory bowel disease and rheumatic conditions, have a reduced serologic response to a two-dose vaccination regimen with mRNA COVID-19 vaccines, according to the findings of a meta-analysis.
“These results suggest that IMID patients receiving mRNA vaccines should complete the vaccine series without delay and support the strategy of providing a third dose of the vaccine,” wrote study authors Atsushi Sakuraba, MD, of the University of Chicago Medicine, and colleagues in Gastroenterology.
During the COVID-19 pandemic, concerns were raised about the susceptibility of patients with pre-existing conditions to infection with the novel coronavirus, the authors noted. Likewise, ongoing concerns have centered on the risk of worse COVID-19–related outcomes among patients with IMIDs who are treated with immunosuppressive agents.
Since the onset of the pandemic, several registries have been established to gauge the incidence and prognosis of COVID-19 in patients with IMID, including the Surveillance Epidemiology of Coronavirus Under Research Exclusion (SECURE)–Inflammatory Bowel Disease (IBD) registry and the COVID-19 Global Rheumatology Alliance 75 (C19-GRA), which includes patients with rheumatic diseases.
Authorization of COVID-19 mRNA vaccines provided hope that the COVID-19 pandemic could soon come to an end given the overwhelming safety and efficacy data supporting the use of these vaccines for preventing hospitalization and death. Despite these data, little is known regarding the efficacy of mRNA COVID-19 vaccines in patients with IMIDs and/or patients treated with immunosuppressive therapies, as these patients were excluded from the regulatory vaccine studies.
The study by Dr. Sakuraba and colleagues was a meta-analysis of 25 observational studies that reported serologic response rates to COVID-19 vaccination in a pooled cohort of 5,360 patients with IMIDs. Data regarding the reference population, medications, vaccination, and proportion of patients who achieved a serologic response were extracted from the observational studies and included in the meta-analysis.
In the analyzed studies, serologic response was evaluated separately after one or two vaccine doses. The researchers also examined the post-vaccine serologic response rate in patients with IMIDs versus controls without IMIDs.
A total of 23 studies used the BNT162b2 or mRNA-1273 vaccines, while 3 studies reported that 50% to 75.9% of patients received the AZD1222 vaccine. Some studies also included patients who received other COVID-19 vaccines, including CoronaVac, BBV152, and Ad26.COV2.S.
While 6 studies assessed serologic response to COVID-19 after just 1 dose, 20 studies assessed the post-vaccination serologic response following 2 doses. In most cases, researchers evaluated serologic response at 2 to 3 weeks after the first dose. After the second vaccine dose, most studies examined serologic response at 1 to 3 weeks.
The serologic response after 1 dose of the mRNA vaccines was 73.2% (95% CI 65.7-79.5). In a multivariate meta-regression analysis, the researchers found that a significantly greater proportion of patients with IMIDs who took anti-tumor necrosis factor (anti-TNF) therapies had a lower serologic response rate (coefficient, –2.60; 95% CI –4.49 to –0.72; P =.0069). The investigators indicated this “likely contributed to the difference in serologic response rates and overall heterogeneity.”
Studies with patients with IBD reported a lower serologic response rate compared with studies that included patients with rheumatoid arthritis (49.2% vs. 65.0%, respectively), which the investigators explained was likely reflective of the increased use of anti-TNF agents in patients with IBD.
After 2 doses of the mRNA vaccines, the pooled serologic response was 83.4% (95% CI, 76.8%-88.4%). Multivariate meta-regression found that a significantly greater proportion of patients who took anti-CD20 treatments had a lower serologic response (coefficient, -6.08; 95% CI -9.40 to -2.76; P <.001). The investigators found that older age was significantly associated with lower serologic response after 2 doses (coefficient, -0.044; 95% CI -0.083 to -0.0050; P =.027).
For the non-mRNA COVID-19 vaccines, the rates of serologic response after 2 doses were 93.5% with AZD1222, 22.9% with CoronaVac, and 55.6% with BBV152.
Compared with controls without IMIDs, those with IMIDs were significantly less likely to achieve a serologic response following 2 mRNA vaccine doses (odds ratio, 0.086; 95% CI 0.036-0.206; P <.001). The investigators noted that there were not enough studies to examine and compare serologic response rates to adenoviral or inactivated vaccines between patients and controls.
In terms of limitations, the researchers wrote that additional studies examining humoral and cellular immunity to COVID-19 vaccines are needed to determine vaccine efficacy and durability in patients with IMIDs. Additionally, there is a need for studies with larger patient populations to determine serologic response to COVID-19 vaccines in the broader IMID population.
The researchers reported no funding for the study and no relevant conflicts of interest with the pharmaceutical industry.
Messenger RNA vaccines against COVID-19 play a certain role in controlling the pandemic. There has been no clear evidence about the efficacy of vaccination against various vaccine-preventable diseases in patients with IMIDs including IBD, but this global pandemic has led to huge progress in this field. This study by Sakuraba et al. helps us to interpret such information by putting 25 recent studies together. Unfortunately but not unexpectedly, patients with IMIDs were shown to have a lower serologic response to the vaccine, especially if they were treated with anti-TNF therapy. However, this study was incapable of showing the influence of other immunosuppressive therapies such as steroids, antimetabolites, and biologics. It is also still unclear whether their antibody titer would decrease sooner than that in the general population.
Large-scale registries of IBD patients suggest that their disease itself is not a risk for severe COVID-19; however, lower effectiveness of vaccination may result in a serious disadvantage in this patient population, compared with others. Therefore, results from this study strongly suggest that it is critical for patients with IBD not only to complete the regular two-dose vaccination but also to consider the booster shot to maintain immunity for the upcoming months. Further studies are needed to optimize the vaccination strategy specifically in this patient population.
Taku Kobayashi, MD, PhD, is the associate professor and vice director of the Center for Advanced IBD Research and Treatment and codirector of department of gastroenterology, Kitasato University Kitasato Institute Hospital, Tokyo. He has received lecture and advisory fees from Janssen, Pfizer, and Takeda.
Messenger RNA vaccines against COVID-19 play a certain role in controlling the pandemic. There has been no clear evidence about the efficacy of vaccination against various vaccine-preventable diseases in patients with IMIDs including IBD, but this global pandemic has led to huge progress in this field. This study by Sakuraba et al. helps us to interpret such information by putting 25 recent studies together. Unfortunately but not unexpectedly, patients with IMIDs were shown to have a lower serologic response to the vaccine, especially if they were treated with anti-TNF therapy. However, this study was incapable of showing the influence of other immunosuppressive therapies such as steroids, antimetabolites, and biologics. It is also still unclear whether their antibody titer would decrease sooner than that in the general population.
Large-scale registries of IBD patients suggest that their disease itself is not a risk for severe COVID-19; however, lower effectiveness of vaccination may result in a serious disadvantage in this patient population, compared with others. Therefore, results from this study strongly suggest that it is critical for patients with IBD not only to complete the regular two-dose vaccination but also to consider the booster shot to maintain immunity for the upcoming months. Further studies are needed to optimize the vaccination strategy specifically in this patient population.
Taku Kobayashi, MD, PhD, is the associate professor and vice director of the Center for Advanced IBD Research and Treatment and codirector of department of gastroenterology, Kitasato University Kitasato Institute Hospital, Tokyo. He has received lecture and advisory fees from Janssen, Pfizer, and Takeda.
Messenger RNA vaccines against COVID-19 play a certain role in controlling the pandemic. There has been no clear evidence about the efficacy of vaccination against various vaccine-preventable diseases in patients with IMIDs including IBD, but this global pandemic has led to huge progress in this field. This study by Sakuraba et al. helps us to interpret such information by putting 25 recent studies together. Unfortunately but not unexpectedly, patients with IMIDs were shown to have a lower serologic response to the vaccine, especially if they were treated with anti-TNF therapy. However, this study was incapable of showing the influence of other immunosuppressive therapies such as steroids, antimetabolites, and biologics. It is also still unclear whether their antibody titer would decrease sooner than that in the general population.
Large-scale registries of IBD patients suggest that their disease itself is not a risk for severe COVID-19; however, lower effectiveness of vaccination may result in a serious disadvantage in this patient population, compared with others. Therefore, results from this study strongly suggest that it is critical for patients with IBD not only to complete the regular two-dose vaccination but also to consider the booster shot to maintain immunity for the upcoming months. Further studies are needed to optimize the vaccination strategy specifically in this patient population.
Taku Kobayashi, MD, PhD, is the associate professor and vice director of the Center for Advanced IBD Research and Treatment and codirector of department of gastroenterology, Kitasato University Kitasato Institute Hospital, Tokyo. He has received lecture and advisory fees from Janssen, Pfizer, and Takeda.
Patients with immune-mediated inflammatory diseases (IMIDs), such as inflammatory bowel disease and rheumatic conditions, have a reduced serologic response to a two-dose vaccination regimen with mRNA COVID-19 vaccines, according to the findings of a meta-analysis.
“These results suggest that IMID patients receiving mRNA vaccines should complete the vaccine series without delay and support the strategy of providing a third dose of the vaccine,” wrote study authors Atsushi Sakuraba, MD, of the University of Chicago Medicine, and colleagues in Gastroenterology.
During the COVID-19 pandemic, concerns were raised about the susceptibility of patients with pre-existing conditions to infection with the novel coronavirus, the authors noted. Likewise, ongoing concerns have centered on the risk of worse COVID-19–related outcomes among patients with IMIDs who are treated with immunosuppressive agents.
Since the onset of the pandemic, several registries have been established to gauge the incidence and prognosis of COVID-19 in patients with IMID, including the Surveillance Epidemiology of Coronavirus Under Research Exclusion (SECURE)–Inflammatory Bowel Disease (IBD) registry and the COVID-19 Global Rheumatology Alliance 75 (C19-GRA), which includes patients with rheumatic diseases.
Authorization of COVID-19 mRNA vaccines provided hope that the COVID-19 pandemic could soon come to an end given the overwhelming safety and efficacy data supporting the use of these vaccines for preventing hospitalization and death. Despite these data, little is known regarding the efficacy of mRNA COVID-19 vaccines in patients with IMIDs and/or patients treated with immunosuppressive therapies, as these patients were excluded from the regulatory vaccine studies.
The study by Dr. Sakuraba and colleagues was a meta-analysis of 25 observational studies that reported serologic response rates to COVID-19 vaccination in a pooled cohort of 5,360 patients with IMIDs. Data regarding the reference population, medications, vaccination, and proportion of patients who achieved a serologic response were extracted from the observational studies and included in the meta-analysis.
In the analyzed studies, serologic response was evaluated separately after one or two vaccine doses. The researchers also examined the post-vaccine serologic response rate in patients with IMIDs versus controls without IMIDs.
A total of 23 studies used the BNT162b2 or mRNA-1273 vaccines, while 3 studies reported that 50% to 75.9% of patients received the AZD1222 vaccine. Some studies also included patients who received other COVID-19 vaccines, including CoronaVac, BBV152, and Ad26.COV2.S.
While 6 studies assessed serologic response to COVID-19 after just 1 dose, 20 studies assessed the post-vaccination serologic response following 2 doses. In most cases, researchers evaluated serologic response at 2 to 3 weeks after the first dose. After the second vaccine dose, most studies examined serologic response at 1 to 3 weeks.
The serologic response after 1 dose of the mRNA vaccines was 73.2% (95% CI 65.7-79.5). In a multivariate meta-regression analysis, the researchers found that a significantly greater proportion of patients with IMIDs who took anti-tumor necrosis factor (anti-TNF) therapies had a lower serologic response rate (coefficient, –2.60; 95% CI –4.49 to –0.72; P =.0069). The investigators indicated this “likely contributed to the difference in serologic response rates and overall heterogeneity.”
Studies with patients with IBD reported a lower serologic response rate compared with studies that included patients with rheumatoid arthritis (49.2% vs. 65.0%, respectively), which the investigators explained was likely reflective of the increased use of anti-TNF agents in patients with IBD.
After 2 doses of the mRNA vaccines, the pooled serologic response was 83.4% (95% CI, 76.8%-88.4%). Multivariate meta-regression found that a significantly greater proportion of patients who took anti-CD20 treatments had a lower serologic response (coefficient, -6.08; 95% CI -9.40 to -2.76; P <.001). The investigators found that older age was significantly associated with lower serologic response after 2 doses (coefficient, -0.044; 95% CI -0.083 to -0.0050; P =.027).
For the non-mRNA COVID-19 vaccines, the rates of serologic response after 2 doses were 93.5% with AZD1222, 22.9% with CoronaVac, and 55.6% with BBV152.
Compared with controls without IMIDs, those with IMIDs were significantly less likely to achieve a serologic response following 2 mRNA vaccine doses (odds ratio, 0.086; 95% CI 0.036-0.206; P <.001). The investigators noted that there were not enough studies to examine and compare serologic response rates to adenoviral or inactivated vaccines between patients and controls.
In terms of limitations, the researchers wrote that additional studies examining humoral and cellular immunity to COVID-19 vaccines are needed to determine vaccine efficacy and durability in patients with IMIDs. Additionally, there is a need for studies with larger patient populations to determine serologic response to COVID-19 vaccines in the broader IMID population.
The researchers reported no funding for the study and no relevant conflicts of interest with the pharmaceutical industry.
Patients with immune-mediated inflammatory diseases (IMIDs), such as inflammatory bowel disease and rheumatic conditions, have a reduced serologic response to a two-dose vaccination regimen with mRNA COVID-19 vaccines, according to the findings of a meta-analysis.
“These results suggest that IMID patients receiving mRNA vaccines should complete the vaccine series without delay and support the strategy of providing a third dose of the vaccine,” wrote study authors Atsushi Sakuraba, MD, of the University of Chicago Medicine, and colleagues in Gastroenterology.
During the COVID-19 pandemic, concerns were raised about the susceptibility of patients with pre-existing conditions to infection with the novel coronavirus, the authors noted. Likewise, ongoing concerns have centered on the risk of worse COVID-19–related outcomes among patients with IMIDs who are treated with immunosuppressive agents.
Since the onset of the pandemic, several registries have been established to gauge the incidence and prognosis of COVID-19 in patients with IMID, including the Surveillance Epidemiology of Coronavirus Under Research Exclusion (SECURE)–Inflammatory Bowel Disease (IBD) registry and the COVID-19 Global Rheumatology Alliance 75 (C19-GRA), which includes patients with rheumatic diseases.
Authorization of COVID-19 mRNA vaccines provided hope that the COVID-19 pandemic could soon come to an end given the overwhelming safety and efficacy data supporting the use of these vaccines for preventing hospitalization and death. Despite these data, little is known regarding the efficacy of mRNA COVID-19 vaccines in patients with IMIDs and/or patients treated with immunosuppressive therapies, as these patients were excluded from the regulatory vaccine studies.
The study by Dr. Sakuraba and colleagues was a meta-analysis of 25 observational studies that reported serologic response rates to COVID-19 vaccination in a pooled cohort of 5,360 patients with IMIDs. Data regarding the reference population, medications, vaccination, and proportion of patients who achieved a serologic response were extracted from the observational studies and included in the meta-analysis.
In the analyzed studies, serologic response was evaluated separately after one or two vaccine doses. The researchers also examined the post-vaccine serologic response rate in patients with IMIDs versus controls without IMIDs.
A total of 23 studies used the BNT162b2 or mRNA-1273 vaccines, while 3 studies reported that 50% to 75.9% of patients received the AZD1222 vaccine. Some studies also included patients who received other COVID-19 vaccines, including CoronaVac, BBV152, and Ad26.COV2.S.
While 6 studies assessed serologic response to COVID-19 after just 1 dose, 20 studies assessed the post-vaccination serologic response following 2 doses. In most cases, researchers evaluated serologic response at 2 to 3 weeks after the first dose. After the second vaccine dose, most studies examined serologic response at 1 to 3 weeks.
The serologic response after 1 dose of the mRNA vaccines was 73.2% (95% CI 65.7-79.5). In a multivariate meta-regression analysis, the researchers found that a significantly greater proportion of patients with IMIDs who took anti-tumor necrosis factor (anti-TNF) therapies had a lower serologic response rate (coefficient, –2.60; 95% CI –4.49 to –0.72; P =.0069). The investigators indicated this “likely contributed to the difference in serologic response rates and overall heterogeneity.”
Studies with patients with IBD reported a lower serologic response rate compared with studies that included patients with rheumatoid arthritis (49.2% vs. 65.0%, respectively), which the investigators explained was likely reflective of the increased use of anti-TNF agents in patients with IBD.
After 2 doses of the mRNA vaccines, the pooled serologic response was 83.4% (95% CI, 76.8%-88.4%). Multivariate meta-regression found that a significantly greater proportion of patients who took anti-CD20 treatments had a lower serologic response (coefficient, -6.08; 95% CI -9.40 to -2.76; P <.001). The investigators found that older age was significantly associated with lower serologic response after 2 doses (coefficient, -0.044; 95% CI -0.083 to -0.0050; P =.027).
For the non-mRNA COVID-19 vaccines, the rates of serologic response after 2 doses were 93.5% with AZD1222, 22.9% with CoronaVac, and 55.6% with BBV152.
Compared with controls without IMIDs, those with IMIDs were significantly less likely to achieve a serologic response following 2 mRNA vaccine doses (odds ratio, 0.086; 95% CI 0.036-0.206; P <.001). The investigators noted that there were not enough studies to examine and compare serologic response rates to adenoviral or inactivated vaccines between patients and controls.
In terms of limitations, the researchers wrote that additional studies examining humoral and cellular immunity to COVID-19 vaccines are needed to determine vaccine efficacy and durability in patients with IMIDs. Additionally, there is a need for studies with larger patient populations to determine serologic response to COVID-19 vaccines in the broader IMID population.
The researchers reported no funding for the study and no relevant conflicts of interest with the pharmaceutical industry.
FROM GASTROENTEROLOGY
Human CRP protects against acetaminophen-induced liver injury in mice
While often linked to deleterious outcomes in certain disease states, the hepatocyte-produced inflammatory marker C-reactive protein (CRP) may be a checkpoint that protects against acetaminophen-induced acute liver injury, according to research findings.
Based on the study findings, researchers believe long-term suppression of CRP function or expression may increase an individual’s susceptibility to acetaminophen-induced liver injury. In contrast, CRP “could be exploited as a promising therapeutic approach to treat hepatotoxicity caused by drug overdose” wrote study authors Hai-Yun Li, MD, of the Xi’an Jiaotong University in Shaanxi, China, and colleagues in Cellular and Molecular Gastroenterology and Hepatology.
According to Dr. Li and colleagues, a major cause of acute liver failure is acetaminophen-induced liver injury, but despite this risk, very few treatment options for this condition exist. The only approved treatment for this complication is N-acetyl cysteine (NAC).
Although CRP represents a marker for inflammation following tissue injury, a study from 2020 and one from 2018 suggest the protein regulates complement activation and may modulate responses of immune cells. The authors of the current study noted that few studies have explored what roles complement activation and modulated immune cell responses via CRP play in acetaminophen-induced acute liver injury.
To further elucidate the role of CRP in this setting, Dr. Li and researchers assessed the mechanisms of CRP action both in vitro as well as in CRP mice with Fcy receptor 2B knockout. The researchers suggested CRP may modulate immune cell responses via these receptors. Additionally, the investigators assessed CRP action in mice with C3 knockout, given previous studies suggesting C3 knockout may alleviate acetaminophen-induced liver injury in mice. The researchers also investigated hepatic expression of CRP mutants that were defective in complement interaction. Finally, the researchers sought to understand the therapeutic potential of the inflammatory marker by performing intraperitoneal administration of human CRP at 2 or 6 hours after induction of acetaminophen-induced acute liver injury in wild-type mice.
Injection of 300 mg/kg acetaminophen over 24 hours led to overt liver injury in wild-type mice, which was characterized by increased levels of circulating alanine transaminase and aspartate transaminase as well as massive necrosis of hepatocytes. The researchers noted that these manifestations were exacerbated significantly in the CRP knockout mice.
The intravenous administration of human CRP in the mice with the drug-induced liver injury rescued defects caused by mouse CRP knockout. Additionally, human CRP administration alleviated acetaminophen-induced acute liver injury in the wild-type mice. The researchers wrote that these findings demonstrate that endogenous and human CRP “are both protective,” at least in mouse models of acetaminophen-induced liver injury.
In a second experiment, the researchers examined the mechanisms involved in CRP protection in early phases of drug-induced liver injury. Based on the experiment, the researchers found that the knockout of an inhibitory Fcy receptor mediating the anti-inflammatory activities of CRP demonstrated only “marginal effects” on the protection of the protein in acetaminophen-induced liver injury. Overall, the investigators suggested that the inflammatory marker does not likely act via the cellular Fcy receptor 2B to inhibit early phases of acetaminophen-induced hepatocyte injury. Rather, the investigators explained that CRP may act via factor H, which is recruited by CRP in regulating complement activation, to inhibit overactivation of complement on injured hepatocytes. Ultimately, the researchers explained, this results in suppression of the late phase amplification of inflammation that is mediated by neutrophils’ C3a-dependent actions.
Finally, the researchers found that intraperitoneal administration of human CRP at 2.5 mg/kg in wild-type mice at 2 hours following induction of acetaminophen-induced liver injury led to “markedly reduced liver injury,” with an efficacy that was similar to that of 500 mg/kg N-acetylcysteine, the only available treatment approved for acetaminophen-induced liver injury.
The researchers noted that N-acetylcysteine is only effective during the early phases of the acetaminophen-induced liver injury and loses effectiveness at 6 hours following injury. In contrast, human CRP in this study was still highly effective at this time point. “Given that people can tolerate high levels of circulating CRP, the administration of this protein might be a promising option to treat [acetaminophen-induced liver injury] with minimal side effects,” the researchers wrote.
The study was funded by the National Natural Science Foundation of China. The researchers reported no conflicts of interest with any pharmaceutical companies.
This article was updated on Sep. 20, 2022.
Acetaminophen is one of the most widely used pain relievers in the world. Acetaminophen use is considered safe at therapeutic doses; however it is a dose-dependent hepatotoxin, and acetaminophen overdose is one of the leading causes of acute liver failure (ALF) in industrialized countries. Despite intensive efforts, the mechanisms involved in acetaminophen hepatotoxicity are not fully understood, which has hampered the availability of effective therapy for acetaminophen hepatotoxicity.
In Cellular and Molecular Gastroenterology and Hepatology, Li et al. uncovered a crucial role of C-reactive protein in acetaminophen-mediated ALF. Despite its well recognized role as an acute-phase protein in inflammation, CRP also regulates complement activation and hence the modulation of immune cell responses and the generation of anaphylotoxins via specific receptors. With use of models of genetic deletion of CRP in rats and mice, Li et al. demonstrate a protective role for CRP in acetaminophen-induced ALF by regulating the late phase of acetaminophen-induced liver failure via complement overactivation through antagonism of C3aR that prevented neutrophil recruitment.
From a clinically relevant perspective, the protective effect of CRP was more effective than the currently used therapeutic approach of giving N-acetylcysteine (NAC) to patients after acetaminophen hepatotoxicity. The superiority of CRP vs. NAC is related to the limited period for NAC administration after acetaminophen overdose, while the administration of CRP was effective even when given several hours after acetaminophen dosage, consistent with its ability to target the late phase of events involved in acetaminophen hepatotoxicity. Therefore, these findings identify CRP as a promising approach for acetaminophen hepatotoxicity with significant therapeutic advantage, compared with NAC treatment, which may change the paradigm of management of acetaminophen-induced liver failure.
Jose C. Fernandez-Checa, PhD, is a professor at the Spanish National Research Council at the Institute of Biomedical Research of Barcelona, investigator of the Institute of Biomedical Research August Pi i Sunyer, group leader of the Center for Biomedical Network Research on Hepatic and Digestive Diseases, and visiting professor at the department of medicine University of Southern California, Los Angeles. He has no relevant conflicts of interest.
Acetaminophen is one of the most widely used pain relievers in the world. Acetaminophen use is considered safe at therapeutic doses; however it is a dose-dependent hepatotoxin, and acetaminophen overdose is one of the leading causes of acute liver failure (ALF) in industrialized countries. Despite intensive efforts, the mechanisms involved in acetaminophen hepatotoxicity are not fully understood, which has hampered the availability of effective therapy for acetaminophen hepatotoxicity.
In Cellular and Molecular Gastroenterology and Hepatology, Li et al. uncovered a crucial role of C-reactive protein in acetaminophen-mediated ALF. Despite its well recognized role as an acute-phase protein in inflammation, CRP also regulates complement activation and hence the modulation of immune cell responses and the generation of anaphylotoxins via specific receptors. With use of models of genetic deletion of CRP in rats and mice, Li et al. demonstrate a protective role for CRP in acetaminophen-induced ALF by regulating the late phase of acetaminophen-induced liver failure via complement overactivation through antagonism of C3aR that prevented neutrophil recruitment.
From a clinically relevant perspective, the protective effect of CRP was more effective than the currently used therapeutic approach of giving N-acetylcysteine (NAC) to patients after acetaminophen hepatotoxicity. The superiority of CRP vs. NAC is related to the limited period for NAC administration after acetaminophen overdose, while the administration of CRP was effective even when given several hours after acetaminophen dosage, consistent with its ability to target the late phase of events involved in acetaminophen hepatotoxicity. Therefore, these findings identify CRP as a promising approach for acetaminophen hepatotoxicity with significant therapeutic advantage, compared with NAC treatment, which may change the paradigm of management of acetaminophen-induced liver failure.
Jose C. Fernandez-Checa, PhD, is a professor at the Spanish National Research Council at the Institute of Biomedical Research of Barcelona, investigator of the Institute of Biomedical Research August Pi i Sunyer, group leader of the Center for Biomedical Network Research on Hepatic and Digestive Diseases, and visiting professor at the department of medicine University of Southern California, Los Angeles. He has no relevant conflicts of interest.
Acetaminophen is one of the most widely used pain relievers in the world. Acetaminophen use is considered safe at therapeutic doses; however it is a dose-dependent hepatotoxin, and acetaminophen overdose is one of the leading causes of acute liver failure (ALF) in industrialized countries. Despite intensive efforts, the mechanisms involved in acetaminophen hepatotoxicity are not fully understood, which has hampered the availability of effective therapy for acetaminophen hepatotoxicity.
In Cellular and Molecular Gastroenterology and Hepatology, Li et al. uncovered a crucial role of C-reactive protein in acetaminophen-mediated ALF. Despite its well recognized role as an acute-phase protein in inflammation, CRP also regulates complement activation and hence the modulation of immune cell responses and the generation of anaphylotoxins via specific receptors. With use of models of genetic deletion of CRP in rats and mice, Li et al. demonstrate a protective role for CRP in acetaminophen-induced ALF by regulating the late phase of acetaminophen-induced liver failure via complement overactivation through antagonism of C3aR that prevented neutrophil recruitment.
From a clinically relevant perspective, the protective effect of CRP was more effective than the currently used therapeutic approach of giving N-acetylcysteine (NAC) to patients after acetaminophen hepatotoxicity. The superiority of CRP vs. NAC is related to the limited period for NAC administration after acetaminophen overdose, while the administration of CRP was effective even when given several hours after acetaminophen dosage, consistent with its ability to target the late phase of events involved in acetaminophen hepatotoxicity. Therefore, these findings identify CRP as a promising approach for acetaminophen hepatotoxicity with significant therapeutic advantage, compared with NAC treatment, which may change the paradigm of management of acetaminophen-induced liver failure.
Jose C. Fernandez-Checa, PhD, is a professor at the Spanish National Research Council at the Institute of Biomedical Research of Barcelona, investigator of the Institute of Biomedical Research August Pi i Sunyer, group leader of the Center for Biomedical Network Research on Hepatic and Digestive Diseases, and visiting professor at the department of medicine University of Southern California, Los Angeles. He has no relevant conflicts of interest.
While often linked to deleterious outcomes in certain disease states, the hepatocyte-produced inflammatory marker C-reactive protein (CRP) may be a checkpoint that protects against acetaminophen-induced acute liver injury, according to research findings.
Based on the study findings, researchers believe long-term suppression of CRP function or expression may increase an individual’s susceptibility to acetaminophen-induced liver injury. In contrast, CRP “could be exploited as a promising therapeutic approach to treat hepatotoxicity caused by drug overdose” wrote study authors Hai-Yun Li, MD, of the Xi’an Jiaotong University in Shaanxi, China, and colleagues in Cellular and Molecular Gastroenterology and Hepatology.
According to Dr. Li and colleagues, a major cause of acute liver failure is acetaminophen-induced liver injury, but despite this risk, very few treatment options for this condition exist. The only approved treatment for this complication is N-acetyl cysteine (NAC).
Although CRP represents a marker for inflammation following tissue injury, a study from 2020 and one from 2018 suggest the protein regulates complement activation and may modulate responses of immune cells. The authors of the current study noted that few studies have explored what roles complement activation and modulated immune cell responses via CRP play in acetaminophen-induced acute liver injury.
To further elucidate the role of CRP in this setting, Dr. Li and researchers assessed the mechanisms of CRP action both in vitro as well as in CRP mice with Fcy receptor 2B knockout. The researchers suggested CRP may modulate immune cell responses via these receptors. Additionally, the investigators assessed CRP action in mice with C3 knockout, given previous studies suggesting C3 knockout may alleviate acetaminophen-induced liver injury in mice. The researchers also investigated hepatic expression of CRP mutants that were defective in complement interaction. Finally, the researchers sought to understand the therapeutic potential of the inflammatory marker by performing intraperitoneal administration of human CRP at 2 or 6 hours after induction of acetaminophen-induced acute liver injury in wild-type mice.
Injection of 300 mg/kg acetaminophen over 24 hours led to overt liver injury in wild-type mice, which was characterized by increased levels of circulating alanine transaminase and aspartate transaminase as well as massive necrosis of hepatocytes. The researchers noted that these manifestations were exacerbated significantly in the CRP knockout mice.
The intravenous administration of human CRP in the mice with the drug-induced liver injury rescued defects caused by mouse CRP knockout. Additionally, human CRP administration alleviated acetaminophen-induced acute liver injury in the wild-type mice. The researchers wrote that these findings demonstrate that endogenous and human CRP “are both protective,” at least in mouse models of acetaminophen-induced liver injury.
In a second experiment, the researchers examined the mechanisms involved in CRP protection in early phases of drug-induced liver injury. Based on the experiment, the researchers found that the knockout of an inhibitory Fcy receptor mediating the anti-inflammatory activities of CRP demonstrated only “marginal effects” on the protection of the protein in acetaminophen-induced liver injury. Overall, the investigators suggested that the inflammatory marker does not likely act via the cellular Fcy receptor 2B to inhibit early phases of acetaminophen-induced hepatocyte injury. Rather, the investigators explained that CRP may act via factor H, which is recruited by CRP in regulating complement activation, to inhibit overactivation of complement on injured hepatocytes. Ultimately, the researchers explained, this results in suppression of the late phase amplification of inflammation that is mediated by neutrophils’ C3a-dependent actions.
Finally, the researchers found that intraperitoneal administration of human CRP at 2.5 mg/kg in wild-type mice at 2 hours following induction of acetaminophen-induced liver injury led to “markedly reduced liver injury,” with an efficacy that was similar to that of 500 mg/kg N-acetylcysteine, the only available treatment approved for acetaminophen-induced liver injury.
The researchers noted that N-acetylcysteine is only effective during the early phases of the acetaminophen-induced liver injury and loses effectiveness at 6 hours following injury. In contrast, human CRP in this study was still highly effective at this time point. “Given that people can tolerate high levels of circulating CRP, the administration of this protein might be a promising option to treat [acetaminophen-induced liver injury] with minimal side effects,” the researchers wrote.
The study was funded by the National Natural Science Foundation of China. The researchers reported no conflicts of interest with any pharmaceutical companies.
This article was updated on Sep. 20, 2022.
While often linked to deleterious outcomes in certain disease states, the hepatocyte-produced inflammatory marker C-reactive protein (CRP) may be a checkpoint that protects against acetaminophen-induced acute liver injury, according to research findings.
Based on the study findings, researchers believe long-term suppression of CRP function or expression may increase an individual’s susceptibility to acetaminophen-induced liver injury. In contrast, CRP “could be exploited as a promising therapeutic approach to treat hepatotoxicity caused by drug overdose” wrote study authors Hai-Yun Li, MD, of the Xi’an Jiaotong University in Shaanxi, China, and colleagues in Cellular and Molecular Gastroenterology and Hepatology.
According to Dr. Li and colleagues, a major cause of acute liver failure is acetaminophen-induced liver injury, but despite this risk, very few treatment options for this condition exist. The only approved treatment for this complication is N-acetyl cysteine (NAC).
Although CRP represents a marker for inflammation following tissue injury, a study from 2020 and one from 2018 suggest the protein regulates complement activation and may modulate responses of immune cells. The authors of the current study noted that few studies have explored what roles complement activation and modulated immune cell responses via CRP play in acetaminophen-induced acute liver injury.
To further elucidate the role of CRP in this setting, Dr. Li and researchers assessed the mechanisms of CRP action both in vitro as well as in CRP mice with Fcy receptor 2B knockout. The researchers suggested CRP may modulate immune cell responses via these receptors. Additionally, the investigators assessed CRP action in mice with C3 knockout, given previous studies suggesting C3 knockout may alleviate acetaminophen-induced liver injury in mice. The researchers also investigated hepatic expression of CRP mutants that were defective in complement interaction. Finally, the researchers sought to understand the therapeutic potential of the inflammatory marker by performing intraperitoneal administration of human CRP at 2 or 6 hours after induction of acetaminophen-induced acute liver injury in wild-type mice.
Injection of 300 mg/kg acetaminophen over 24 hours led to overt liver injury in wild-type mice, which was characterized by increased levels of circulating alanine transaminase and aspartate transaminase as well as massive necrosis of hepatocytes. The researchers noted that these manifestations were exacerbated significantly in the CRP knockout mice.
The intravenous administration of human CRP in the mice with the drug-induced liver injury rescued defects caused by mouse CRP knockout. Additionally, human CRP administration alleviated acetaminophen-induced acute liver injury in the wild-type mice. The researchers wrote that these findings demonstrate that endogenous and human CRP “are both protective,” at least in mouse models of acetaminophen-induced liver injury.
In a second experiment, the researchers examined the mechanisms involved in CRP protection in early phases of drug-induced liver injury. Based on the experiment, the researchers found that the knockout of an inhibitory Fcy receptor mediating the anti-inflammatory activities of CRP demonstrated only “marginal effects” on the protection of the protein in acetaminophen-induced liver injury. Overall, the investigators suggested that the inflammatory marker does not likely act via the cellular Fcy receptor 2B to inhibit early phases of acetaminophen-induced hepatocyte injury. Rather, the investigators explained that CRP may act via factor H, which is recruited by CRP in regulating complement activation, to inhibit overactivation of complement on injured hepatocytes. Ultimately, the researchers explained, this results in suppression of the late phase amplification of inflammation that is mediated by neutrophils’ C3a-dependent actions.
Finally, the researchers found that intraperitoneal administration of human CRP at 2.5 mg/kg in wild-type mice at 2 hours following induction of acetaminophen-induced liver injury led to “markedly reduced liver injury,” with an efficacy that was similar to that of 500 mg/kg N-acetylcysteine, the only available treatment approved for acetaminophen-induced liver injury.
The researchers noted that N-acetylcysteine is only effective during the early phases of the acetaminophen-induced liver injury and loses effectiveness at 6 hours following injury. In contrast, human CRP in this study was still highly effective at this time point. “Given that people can tolerate high levels of circulating CRP, the administration of this protein might be a promising option to treat [acetaminophen-induced liver injury] with minimal side effects,” the researchers wrote.
The study was funded by the National Natural Science Foundation of China. The researchers reported no conflicts of interest with any pharmaceutical companies.
This article was updated on Sep. 20, 2022.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Virtual center boosts liver transplant listings in rural area
A “virtual” liver transplant center servicing Vermont and New Hampshire has improved access to liver transplant listing among patients in rural areas of the region, according to a new analysis.
The virtual center was established in 2016 at Dartmouth Hitchcock Medical Center, and it allows patients to receive pre–liver transplant evaluations, testing, and care and posttransplant follow-up there rather than at the liver transplant center that conducts the surgery. The center includes two hepatologists, two associate care providers, and a nurse liver transplant coordinator at DHMC, and led to increased transplant listing in the vicinity, according to Margaret Liu, MD, who presented the study at the virtual annual meeting of the American Association for the Study of Liver Diseases.
“The initiation of this Virtual Liver Transplant Center has been able to provide patients with the ability to get a full liver transplant workup and evaluation at a center near their home rather than the often time-consuming and costly process of potentially multiple trips to a liver transplant center up to 250 miles away for a full transplant evaluation,” said Dr. Liu in an interview. Dr. Liu is an internal medicine resident at Dartmouth Hitchcock Medical Center.
“Our results did show that the initiation of a virtual liver transplant center correlated with an increased and sustained liver transplant listing rate within 60 miles of Dartmouth over that particular study period. Conversely there was no significant change in the listing rate of New Hampshire zip codes that were within 60 miles of the nearest transplant center during the same study period,” said Dr. Liu.
The center receives referrals of patients who are potential candidates for liver transplant listing from practices throughout New Hampshire and Vermont, or from their own center. Their specialists conduct full testing, including a full liver transplant workup that includes evaluation of the patient’s general health and social factors, prior to sending the patient to the actual liver transplant center for their evaluation and transplant surgery. “We essentially do all of the pre–liver transplant workup, a formal liver transplant evaluation, and then the whole packet gets sent to an actual liver transplant center to expedite the process of getting listed for liver transplant. We’re able to streamline the process, so they get everything done here at a hospital near their home. If that requires multiple trips, it’s a lot more doable for the patients,” said Dr. Liu.
The researchers defined urban areas as having more than 50,000 people per square mile and within 30 miles of the nearest hospital, and rural as fewer than 10,000 and more than 60 miles from the nearest hospital. They used the Scientific Registry of Transplant Recipients to determine the number of liver transplant listings per zip code.
Between 2015 and 2019, the frequency of liver transplant listings per 10,000 people remained nearly unchanged in the metropolitan area of southern New Hampshire, ranging from around 0.36 to 0.75. In the rural area within 60 miles of DHMC, the frequency increased from about 0.7 per 10,000 in 2015 to about 1.4 in 2016 and 0.9 in 2017. There was an increase to nearly 3 in 10,000 in 2018, and the frequency was just over 2 in 2019.
The model has the potential to be used in other areas, according to Dr. Liu. “This could potentially be implemented in other rural areas that do not have a transplant center or don’t have a formal liver transplant evaluation process,” said Dr. Liu.
While other centers may have taken on some aspects of liver transplant evaluation and posttransplant care, the Virtual Liver Transplant Center is unique in that a great deal of effort has gone into covering all of a patient’s needs for the liver transplant evaluation. “It’s really the formalization that, from what I have researched, has not been done before,” said Dr. Liu.
The model addresses transplant-listing disparity, as well as improves patient quality of life through reduction in travel, according to Mayur Brahmania, MD, of Western University, London, Ont., who moderated the session. “They’ve proven that they can get more of their patients listed over the study period, which I think is amazing. The next step, I think, would be about whether getting them onto the transplant list actually made a difference in terms of outcome – looking at their wait list mortality, looking at how many of these patients actually got a liver transplantation. That’s the ultimate outcome,” said Dr. Brahmania.
He also noted the challenge of setting up a virtual center. “You have to have allied health staff – addiction counselors, physical therapists, dietitians, social workers. You need to have the appropriate ancillary services like cardiac testing, pulmonary function testing. It’s quite an endeavor, and if the program isn’t too enthusiastic or doesn’t have a local champion, it’s really hard to get something like this started off. So kudos to them for taking on this challenge and getting this up and running over the last 5 years,” said Dr. Brahmania.
Dr. Liu and Dr. Brahmania have no relevant financial disclosures.
AGA applauds researchers who are working to raise our awareness of health disparities in digestive diseases. AGA is committed to addressing this important societal issue head on. Learn more about AGA’s commitment through the AGA Equity Project.
A “virtual” liver transplant center servicing Vermont and New Hampshire has improved access to liver transplant listing among patients in rural areas of the region, according to a new analysis.
The virtual center was established in 2016 at Dartmouth Hitchcock Medical Center, and it allows patients to receive pre–liver transplant evaluations, testing, and care and posttransplant follow-up there rather than at the liver transplant center that conducts the surgery. The center includes two hepatologists, two associate care providers, and a nurse liver transplant coordinator at DHMC, and led to increased transplant listing in the vicinity, according to Margaret Liu, MD, who presented the study at the virtual annual meeting of the American Association for the Study of Liver Diseases.
“The initiation of this Virtual Liver Transplant Center has been able to provide patients with the ability to get a full liver transplant workup and evaluation at a center near their home rather than the often time-consuming and costly process of potentially multiple trips to a liver transplant center up to 250 miles away for a full transplant evaluation,” said Dr. Liu in an interview. Dr. Liu is an internal medicine resident at Dartmouth Hitchcock Medical Center.
“Our results did show that the initiation of a virtual liver transplant center correlated with an increased and sustained liver transplant listing rate within 60 miles of Dartmouth over that particular study period. Conversely there was no significant change in the listing rate of New Hampshire zip codes that were within 60 miles of the nearest transplant center during the same study period,” said Dr. Liu.
The center receives referrals of patients who are potential candidates for liver transplant listing from practices throughout New Hampshire and Vermont, or from their own center. Their specialists conduct full testing, including a full liver transplant workup that includes evaluation of the patient’s general health and social factors, prior to sending the patient to the actual liver transplant center for their evaluation and transplant surgery. “We essentially do all of the pre–liver transplant workup, a formal liver transplant evaluation, and then the whole packet gets sent to an actual liver transplant center to expedite the process of getting listed for liver transplant. We’re able to streamline the process, so they get everything done here at a hospital near their home. If that requires multiple trips, it’s a lot more doable for the patients,” said Dr. Liu.
The researchers defined urban areas as having more than 50,000 people per square mile and within 30 miles of the nearest hospital, and rural as fewer than 10,000 and more than 60 miles from the nearest hospital. They used the Scientific Registry of Transplant Recipients to determine the number of liver transplant listings per zip code.
Between 2015 and 2019, the frequency of liver transplant listings per 10,000 people remained nearly unchanged in the metropolitan area of southern New Hampshire, ranging from around 0.36 to 0.75. In the rural area within 60 miles of DHMC, the frequency increased from about 0.7 per 10,000 in 2015 to about 1.4 in 2016 and 0.9 in 2017. There was an increase to nearly 3 in 10,000 in 2018, and the frequency was just over 2 in 2019.
The model has the potential to be used in other areas, according to Dr. Liu. “This could potentially be implemented in other rural areas that do not have a transplant center or don’t have a formal liver transplant evaluation process,” said Dr. Liu.
While other centers may have taken on some aspects of liver transplant evaluation and posttransplant care, the Virtual Liver Transplant Center is unique in that a great deal of effort has gone into covering all of a patient’s needs for the liver transplant evaluation. “It’s really the formalization that, from what I have researched, has not been done before,” said Dr. Liu.
The model addresses transplant-listing disparity, as well as improves patient quality of life through reduction in travel, according to Mayur Brahmania, MD, of Western University, London, Ont., who moderated the session. “They’ve proven that they can get more of their patients listed over the study period, which I think is amazing. The next step, I think, would be about whether getting them onto the transplant list actually made a difference in terms of outcome – looking at their wait list mortality, looking at how many of these patients actually got a liver transplantation. That’s the ultimate outcome,” said Dr. Brahmania.
He also noted the challenge of setting up a virtual center. “You have to have allied health staff – addiction counselors, physical therapists, dietitians, social workers. You need to have the appropriate ancillary services like cardiac testing, pulmonary function testing. It’s quite an endeavor, and if the program isn’t too enthusiastic or doesn’t have a local champion, it’s really hard to get something like this started off. So kudos to them for taking on this challenge and getting this up and running over the last 5 years,” said Dr. Brahmania.
Dr. Liu and Dr. Brahmania have no relevant financial disclosures.
AGA applauds researchers who are working to raise our awareness of health disparities in digestive diseases. AGA is committed to addressing this important societal issue head on. Learn more about AGA’s commitment through the AGA Equity Project.
A “virtual” liver transplant center servicing Vermont and New Hampshire has improved access to liver transplant listing among patients in rural areas of the region, according to a new analysis.
The virtual center was established in 2016 at Dartmouth Hitchcock Medical Center, and it allows patients to receive pre–liver transplant evaluations, testing, and care and posttransplant follow-up there rather than at the liver transplant center that conducts the surgery. The center includes two hepatologists, two associate care providers, and a nurse liver transplant coordinator at DHMC, and led to increased transplant listing in the vicinity, according to Margaret Liu, MD, who presented the study at the virtual annual meeting of the American Association for the Study of Liver Diseases.
“The initiation of this Virtual Liver Transplant Center has been able to provide patients with the ability to get a full liver transplant workup and evaluation at a center near their home rather than the often time-consuming and costly process of potentially multiple trips to a liver transplant center up to 250 miles away for a full transplant evaluation,” said Dr. Liu in an interview. Dr. Liu is an internal medicine resident at Dartmouth Hitchcock Medical Center.
“Our results did show that the initiation of a virtual liver transplant center correlated with an increased and sustained liver transplant listing rate within 60 miles of Dartmouth over that particular study period. Conversely there was no significant change in the listing rate of New Hampshire zip codes that were within 60 miles of the nearest transplant center during the same study period,” said Dr. Liu.
The center receives referrals of patients who are potential candidates for liver transplant listing from practices throughout New Hampshire and Vermont, or from their own center. Their specialists conduct full testing, including a full liver transplant workup that includes evaluation of the patient’s general health and social factors, prior to sending the patient to the actual liver transplant center for their evaluation and transplant surgery. “We essentially do all of the pre–liver transplant workup, a formal liver transplant evaluation, and then the whole packet gets sent to an actual liver transplant center to expedite the process of getting listed for liver transplant. We’re able to streamline the process, so they get everything done here at a hospital near their home. If that requires multiple trips, it’s a lot more doable for the patients,” said Dr. Liu.
The researchers defined urban areas as having more than 50,000 people per square mile and within 30 miles of the nearest hospital, and rural as fewer than 10,000 and more than 60 miles from the nearest hospital. They used the Scientific Registry of Transplant Recipients to determine the number of liver transplant listings per zip code.
Between 2015 and 2019, the frequency of liver transplant listings per 10,000 people remained nearly unchanged in the metropolitan area of southern New Hampshire, ranging from around 0.36 to 0.75. In the rural area within 60 miles of DHMC, the frequency increased from about 0.7 per 10,000 in 2015 to about 1.4 in 2016 and 0.9 in 2017. There was an increase to nearly 3 in 10,000 in 2018, and the frequency was just over 2 in 2019.
The model has the potential to be used in other areas, according to Dr. Liu. “This could potentially be implemented in other rural areas that do not have a transplant center or don’t have a formal liver transplant evaluation process,” said Dr. Liu.
While other centers may have taken on some aspects of liver transplant evaluation and posttransplant care, the Virtual Liver Transplant Center is unique in that a great deal of effort has gone into covering all of a patient’s needs for the liver transplant evaluation. “It’s really the formalization that, from what I have researched, has not been done before,” said Dr. Liu.
The model addresses transplant-listing disparity, as well as improves patient quality of life through reduction in travel, according to Mayur Brahmania, MD, of Western University, London, Ont., who moderated the session. “They’ve proven that they can get more of their patients listed over the study period, which I think is amazing. The next step, I think, would be about whether getting them onto the transplant list actually made a difference in terms of outcome – looking at their wait list mortality, looking at how many of these patients actually got a liver transplantation. That’s the ultimate outcome,” said Dr. Brahmania.
He also noted the challenge of setting up a virtual center. “You have to have allied health staff – addiction counselors, physical therapists, dietitians, social workers. You need to have the appropriate ancillary services like cardiac testing, pulmonary function testing. It’s quite an endeavor, and if the program isn’t too enthusiastic or doesn’t have a local champion, it’s really hard to get something like this started off. So kudos to them for taking on this challenge and getting this up and running over the last 5 years,” said Dr. Brahmania.
Dr. Liu and Dr. Brahmania have no relevant financial disclosures.
AGA applauds researchers who are working to raise our awareness of health disparities in digestive diseases. AGA is committed to addressing this important societal issue head on. Learn more about AGA’s commitment through the AGA Equity Project.
FROM THE LIVER MEETING
NAFLD, ALD prevalent among teens, young adults
Two-fifths of adolescents and young adults in the United States may have nonalcoholic fatty liver disease (NAFLD), many with significant or advanced fibrosis, results of a nationwide surveillance study suggest.
In addition, among those who drink alcohol in excess, slightly more than half may have alcohol-associated fatty liver disease (ALD) that may lead to moderate to severe fibrosis in a substantial proportion, said Naim Alkhouri, MD, from Arizona Liver Health, Peoria, during a presentation of the findings at The Liver Meeting 2021: American Association for the Study of Liver Diseases (AASLD), held online.
“Efforts should focus on increasing awareness of the burden of ALD and NAFLD in this population and [mitigating] modifiable risk factors to prevent disease development and disease progression to potentially advanced fibrosis and cirrhosis,” he said.
Liver stiffness measured
Unlike previous studies that relied on liver enzyme levels or ultrasonography to estimate the prevalence of fatty liver disease among adolescents and young adults in the United States, Dr. Alkhouri and colleagues used valid liver ultrasonographic elastography (FibroScan) measurements, recorded during 2017-2018, from the National Health and Nutrition Examination Survey (NHANES) database.
The sample included participants aged 15 to 39 years. Those with viral hepatitis, alanine aminotransferase (ALT) levels greater than 500 U/L, or pregnancy were excluded.
The investigators divided the participants into those with excessive alcohol consumption, defined using the NHANES Alcohol Use Questionnaire as having more than two drinks per day for males or more than one drink per day for females, and those with no excessive alcohol consumption.
The authors used controlled attenuation parameters to identify participants with suspected ALD or NAFLD.
They then used liver stiffness measurement cutoffs of greater than or equal to 7.5 kPa to identify moderate fibrosis and greater than or equal to 9.5 kPa to identify severe fibrosis in those with evidence of ALD and cutoffs of greater than or equal to 6.1 kPa and greater than or equal to 7.1 kPa, respectively, in those with suspected NAFLD.
The cutoffs were chosen to maximize sensitivity, as determined from published literature, Dr. Alkhouri said.
Uncovering a high prevalence of ALD and NAFLD
The final sample comprised 1,319 participants, including 100 with excessive alcohol use and 1,219 without.
The heavy drinkers were significantly more likely to be older, male, White, current smokers, have lower platelet counts, higher aspartate aminotransferase (AST) and ALT levels, and higher mean corpuscular volumes.
Among the excessive drinkers, 52% had ALD. Of this group, 87.7% had either no or mild fibrosis, and 12.3% had moderate to severe fibrosis.
Among patients with excessive alcohol consumption, significant predictors of ALD included male sex, higher body mass index, ALT greater than the upper limit of normal, and higher A1c percentage.
Among those who were moderate drinkers or abstemious, 40% had NAFLD. Of this subgroup, 68.9% had no or mild fibrosis, and 31.1% had moderate to severe fibrosis.
Predictors of NAFLD in this group included older age, male sex, higher body mass index, and elevated ALT, AST, albumin, platelet counts, and A1c.
Is drinking underreported?
In a question-and-answer session following the presentation, co-moderator Miriam B. Vos, MD, a pediatric hepatologist at Children’s Healthcare of Atlanta, asked Dr. Alkhouri about his confidence in the accuracy of the measurements of alcohol consumption and whether there could be significant overlap between the ALD and NAFLD populations.
Dr. Alkhouri noted that he and his colleagues relied on items 121 and 130 of the NHANES Alcohol Use Questionnaire, which are self-reported by participants.
“Obviously, we’re not going to get honest answers all the time,” he said. “We’ve seen even in NASH [nonalcoholic steatohepatitis] clinical trials that when patients say they do not drink any alcohol, if you actually look for alcohol metabolites, up to 20% may have some evidence of alcohol consumption.
“I’m sure there’s a lot of overlap, but there’s no formal assessment,” he added.
Dr. Alkhouri noted that among the cohort with ALD, obesity and increased A1c were prevalent, “so it goes both ways. I think NAFLD can also contribute to progression of ALD, and that’s why we need to study another entity called ‘both alcoholic and nonalcoholic fatty liver disease.’”
Dr. Vos suggested that biomarkers may be useful for detecting alcohol use among patients with NAFLD and for further study of the progression of NAFLD to ALD.
No source of funding for the study has been disclosed. Dr. Alkhouri and Dr. Vos reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Two-fifths of adolescents and young adults in the United States may have nonalcoholic fatty liver disease (NAFLD), many with significant or advanced fibrosis, results of a nationwide surveillance study suggest.
In addition, among those who drink alcohol in excess, slightly more than half may have alcohol-associated fatty liver disease (ALD) that may lead to moderate to severe fibrosis in a substantial proportion, said Naim Alkhouri, MD, from Arizona Liver Health, Peoria, during a presentation of the findings at The Liver Meeting 2021: American Association for the Study of Liver Diseases (AASLD), held online.
“Efforts should focus on increasing awareness of the burden of ALD and NAFLD in this population and [mitigating] modifiable risk factors to prevent disease development and disease progression to potentially advanced fibrosis and cirrhosis,” he said.
Liver stiffness measured
Unlike previous studies that relied on liver enzyme levels or ultrasonography to estimate the prevalence of fatty liver disease among adolescents and young adults in the United States, Dr. Alkhouri and colleagues used valid liver ultrasonographic elastography (FibroScan) measurements, recorded during 2017-2018, from the National Health and Nutrition Examination Survey (NHANES) database.
The sample included participants aged 15 to 39 years. Those with viral hepatitis, alanine aminotransferase (ALT) levels greater than 500 U/L, or pregnancy were excluded.
The investigators divided the participants into those with excessive alcohol consumption, defined using the NHANES Alcohol Use Questionnaire as having more than two drinks per day for males or more than one drink per day for females, and those with no excessive alcohol consumption.
The authors used controlled attenuation parameters to identify participants with suspected ALD or NAFLD.
They then used liver stiffness measurement cutoffs of greater than or equal to 7.5 kPa to identify moderate fibrosis and greater than or equal to 9.5 kPa to identify severe fibrosis in those with evidence of ALD and cutoffs of greater than or equal to 6.1 kPa and greater than or equal to 7.1 kPa, respectively, in those with suspected NAFLD.
The cutoffs were chosen to maximize sensitivity, as determined from published literature, Dr. Alkhouri said.
Uncovering a high prevalence of ALD and NAFLD
The final sample comprised 1,319 participants, including 100 with excessive alcohol use and 1,219 without.
The heavy drinkers were significantly more likely to be older, male, White, current smokers, have lower platelet counts, higher aspartate aminotransferase (AST) and ALT levels, and higher mean corpuscular volumes.
Among the excessive drinkers, 52% had ALD. Of this group, 87.7% had either no or mild fibrosis, and 12.3% had moderate to severe fibrosis.
Among patients with excessive alcohol consumption, significant predictors of ALD included male sex, higher body mass index, ALT greater than the upper limit of normal, and higher A1c percentage.
Among those who were moderate drinkers or abstemious, 40% had NAFLD. Of this subgroup, 68.9% had no or mild fibrosis, and 31.1% had moderate to severe fibrosis.
Predictors of NAFLD in this group included older age, male sex, higher body mass index, and elevated ALT, AST, albumin, platelet counts, and A1c.
Is drinking underreported?
In a question-and-answer session following the presentation, co-moderator Miriam B. Vos, MD, a pediatric hepatologist at Children’s Healthcare of Atlanta, asked Dr. Alkhouri about his confidence in the accuracy of the measurements of alcohol consumption and whether there could be significant overlap between the ALD and NAFLD populations.
Dr. Alkhouri noted that he and his colleagues relied on items 121 and 130 of the NHANES Alcohol Use Questionnaire, which are self-reported by participants.
“Obviously, we’re not going to get honest answers all the time,” he said. “We’ve seen even in NASH [nonalcoholic steatohepatitis] clinical trials that when patients say they do not drink any alcohol, if you actually look for alcohol metabolites, up to 20% may have some evidence of alcohol consumption.
“I’m sure there’s a lot of overlap, but there’s no formal assessment,” he added.
Dr. Alkhouri noted that among the cohort with ALD, obesity and increased A1c were prevalent, “so it goes both ways. I think NAFLD can also contribute to progression of ALD, and that’s why we need to study another entity called ‘both alcoholic and nonalcoholic fatty liver disease.’”
Dr. Vos suggested that biomarkers may be useful for detecting alcohol use among patients with NAFLD and for further study of the progression of NAFLD to ALD.
No source of funding for the study has been disclosed. Dr. Alkhouri and Dr. Vos reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Two-fifths of adolescents and young adults in the United States may have nonalcoholic fatty liver disease (NAFLD), many with significant or advanced fibrosis, results of a nationwide surveillance study suggest.
In addition, among those who drink alcohol in excess, slightly more than half may have alcohol-associated fatty liver disease (ALD) that may lead to moderate to severe fibrosis in a substantial proportion, said Naim Alkhouri, MD, from Arizona Liver Health, Peoria, during a presentation of the findings at The Liver Meeting 2021: American Association for the Study of Liver Diseases (AASLD), held online.
“Efforts should focus on increasing awareness of the burden of ALD and NAFLD in this population and [mitigating] modifiable risk factors to prevent disease development and disease progression to potentially advanced fibrosis and cirrhosis,” he said.
Liver stiffness measured
Unlike previous studies that relied on liver enzyme levels or ultrasonography to estimate the prevalence of fatty liver disease among adolescents and young adults in the United States, Dr. Alkhouri and colleagues used valid liver ultrasonographic elastography (FibroScan) measurements, recorded during 2017-2018, from the National Health and Nutrition Examination Survey (NHANES) database.
The sample included participants aged 15 to 39 years. Those with viral hepatitis, alanine aminotransferase (ALT) levels greater than 500 U/L, or pregnancy were excluded.
The investigators divided the participants into those with excessive alcohol consumption, defined using the NHANES Alcohol Use Questionnaire as having more than two drinks per day for males or more than one drink per day for females, and those with no excessive alcohol consumption.
The authors used controlled attenuation parameters to identify participants with suspected ALD or NAFLD.
They then used liver stiffness measurement cutoffs of greater than or equal to 7.5 kPa to identify moderate fibrosis and greater than or equal to 9.5 kPa to identify severe fibrosis in those with evidence of ALD and cutoffs of greater than or equal to 6.1 kPa and greater than or equal to 7.1 kPa, respectively, in those with suspected NAFLD.
The cutoffs were chosen to maximize sensitivity, as determined from published literature, Dr. Alkhouri said.
Uncovering a high prevalence of ALD and NAFLD
The final sample comprised 1,319 participants, including 100 with excessive alcohol use and 1,219 without.
The heavy drinkers were significantly more likely to be older, male, White, current smokers, have lower platelet counts, higher aspartate aminotransferase (AST) and ALT levels, and higher mean corpuscular volumes.
Among the excessive drinkers, 52% had ALD. Of this group, 87.7% had either no or mild fibrosis, and 12.3% had moderate to severe fibrosis.
Among patients with excessive alcohol consumption, significant predictors of ALD included male sex, higher body mass index, ALT greater than the upper limit of normal, and higher A1c percentage.
Among those who were moderate drinkers or abstemious, 40% had NAFLD. Of this subgroup, 68.9% had no or mild fibrosis, and 31.1% had moderate to severe fibrosis.
Predictors of NAFLD in this group included older age, male sex, higher body mass index, and elevated ALT, AST, albumin, platelet counts, and A1c.
Is drinking underreported?
In a question-and-answer session following the presentation, co-moderator Miriam B. Vos, MD, a pediatric hepatologist at Children’s Healthcare of Atlanta, asked Dr. Alkhouri about his confidence in the accuracy of the measurements of alcohol consumption and whether there could be significant overlap between the ALD and NAFLD populations.
Dr. Alkhouri noted that he and his colleagues relied on items 121 and 130 of the NHANES Alcohol Use Questionnaire, which are self-reported by participants.
“Obviously, we’re not going to get honest answers all the time,” he said. “We’ve seen even in NASH [nonalcoholic steatohepatitis] clinical trials that when patients say they do not drink any alcohol, if you actually look for alcohol metabolites, up to 20% may have some evidence of alcohol consumption.
“I’m sure there’s a lot of overlap, but there’s no formal assessment,” he added.
Dr. Alkhouri noted that among the cohort with ALD, obesity and increased A1c were prevalent, “so it goes both ways. I think NAFLD can also contribute to progression of ALD, and that’s why we need to study another entity called ‘both alcoholic and nonalcoholic fatty liver disease.’”
Dr. Vos suggested that biomarkers may be useful for detecting alcohol use among patients with NAFLD and for further study of the progression of NAFLD to ALD.
No source of funding for the study has been disclosed. Dr. Alkhouri and Dr. Vos reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Be cautious with HBV drug withdrawal
More than half of chronic hepatitis B e antigen–negative patients who withdraw from nucleoside or nucleotide analogue therapy experienced relapse within 4 years, according to a new study that looked at patients from 11 centers in Europe, North America, and Asia.
“We wanted to see if the patients stabilize after that year. Are they just having relapses within the first year, and then they’re inactive carriers? Especially patients who don’t achieve [hepatitis B surface antigen; HBsAg] loss. Is that mildly active disease? Would they have been better off being retreated, or are they better off [staying off] therapy? It is important to look at what happens among these patients who stop and if there is a way to tell which way they’re going to go,” said Grishma Hirode, who is a PhD candidate at the University of Toronto. Ms. Hirode presented the multinational study at the annual meeting of the American Association for the Study of Liver Diseases.
The study provided a clear picture: “They do not stabilize after 1 year. They have relapses, and these relapses aren’t mild fluctuations,” said Ms. Hirode. Another study, which was presented during the same session and investigated a national cohort in Taiwan, also found a high rate of flareups and retreatment out to 4 years.
The RETRACT-B study presented by Ms. Hirode collected data on 945 patients from 11 centers in North America, Europe, and Asia. Overall, 66% had at least one relapse within 1 year of drug withdrawal. At 2 years, 40% had a sustained remission without HBsAg loss, as had 20% at 4 years; 44% had sustained remission or HBsAg loss at 2 years, as did 30% at 4 years.
Subgroup analyses found differences between some populations: 48% of Whites and 28% of Asians had sustained remission or HBsAg loss, and 30% of Whites and 20% of Asians had sustained remission without HBsAg loss. Patients who were HBsAg positive at start of therapy were more likely to have a sustained remission or HBsAg loss (36% vs. 28%; P < .05) and to have a sustained remission without HBsAg loss (31% vs. 19%; P < .05). HBsAg levels below 100 IU/mL at cessation was also associated with a greater chance of sustained remission or HBsAg loss (58% vs. 24%; P < .05) and sustained remission without HBsAg loss (24% vs. 20%; P < .05). Not having a relapse within the first year after cessation was also associated with greater chance of sustained remission or HBsAg loss (50% versus 19%; P < .05) and sustained remission without HBsAg loss (37% vs. 13%; P < .05).
The Taiwan cohort study examined the repercussions of a government policy that limited reimbursement of nucleotide/nucleoside analogues to a fixed duration of time. Among 10,192 eligible patients, researchers at I-SHOU University found a 6.58% 4-year cumulative incidence of severe flare-ups after discontinuation (95% confidence interval, 5.91%-7.30%), defined as serum ALT levels higher than five times the upper limit of normal plus serum bilirubin levels above 2 mg/dL.
The overall incidence of flare-ups was 30.66% over 4 years (95% CI, 29.37%-31.96%). Higher risk of flareup was associated with older age (hazard ratio for each 10 years, 1.19; P<.0001), male sex (HR, 1.76; P < .0001), a diagnosis of cirrhosis (HR, 1.84; P < .0001), and a history of hepatic decompensation (HR, 1.45; P = .044).
The 4-year incidence of retreatment was 48.74% (95% CI, 46.55-50.90%)
The mortality rate was 0.63% at 4 years after a flareup (95% CI, 0.44-0.87%), and the combined rate of mortality or liver transplant was 0.79% (95% CI, 0.58-1.05%). Risk factors for higher mortality included older age (per 10 years; HR, 1.70; P < .0001), a diagnosis of cirrhosis (HR, 6.12; P < .0001), and hypertension (HR, 2.29; P = .029).
Selecting patients safely?
The results of both studies suggest that withdrawal from medication should be done cautiously, and patients monitored for relapse and retreatment, according to Anna Lok, MD, who was asked for comment. Dr. Lok is a professor of internal medicine, director of clinical hematology, and assistant dean for clinical research at the University of Michigan, Ann Arbor.
Between the two studies, “the message is that this approach can benefit some patients, but if the goal of treatment withdrawal is to increase the rate of hepatitis B surface antigen loss, only a small percentage of patients would benefit. Contrary to studies in Europe, the rates of HBsAg loss in studies with predominantly Asian patients are much lower,” said Dr. Lok.
The new studies provide guidance as for which patients might safely stop treatment; specifically, she suggested, young White patients who have a low HBsAg level when treatment is stopped. “But you probably shouldn’t be trying it in older Asian patients who still have high HBsAg titer, because the chance of them relapsing is very high and the chance of benefit is very low,” she said.
“One has to be very careful in selecting which patients you’re going to try this on. And if you do want to try, you’ve got to make sure that you monitor patients very carefully so treatment can be promptly resumed if necessary because some of the patients can have a severe flare and they can even develop liver failure, and this should never be tried in patients with cirrhosis” said Dr. Lok.
Ms. Hirode and Dr. Lok have no relevant financial disclosures.
More than half of chronic hepatitis B e antigen–negative patients who withdraw from nucleoside or nucleotide analogue therapy experienced relapse within 4 years, according to a new study that looked at patients from 11 centers in Europe, North America, and Asia.
“We wanted to see if the patients stabilize after that year. Are they just having relapses within the first year, and then they’re inactive carriers? Especially patients who don’t achieve [hepatitis B surface antigen; HBsAg] loss. Is that mildly active disease? Would they have been better off being retreated, or are they better off [staying off] therapy? It is important to look at what happens among these patients who stop and if there is a way to tell which way they’re going to go,” said Grishma Hirode, who is a PhD candidate at the University of Toronto. Ms. Hirode presented the multinational study at the annual meeting of the American Association for the Study of Liver Diseases.
The study provided a clear picture: “They do not stabilize after 1 year. They have relapses, and these relapses aren’t mild fluctuations,” said Ms. Hirode. Another study, which was presented during the same session and investigated a national cohort in Taiwan, also found a high rate of flareups and retreatment out to 4 years.
The RETRACT-B study presented by Ms. Hirode collected data on 945 patients from 11 centers in North America, Europe, and Asia. Overall, 66% had at least one relapse within 1 year of drug withdrawal. At 2 years, 40% had a sustained remission without HBsAg loss, as had 20% at 4 years; 44% had sustained remission or HBsAg loss at 2 years, as did 30% at 4 years.
Subgroup analyses found differences between some populations: 48% of Whites and 28% of Asians had sustained remission or HBsAg loss, and 30% of Whites and 20% of Asians had sustained remission without HBsAg loss. Patients who were HBsAg positive at start of therapy were more likely to have a sustained remission or HBsAg loss (36% vs. 28%; P < .05) and to have a sustained remission without HBsAg loss (31% vs. 19%; P < .05). HBsAg levels below 100 IU/mL at cessation was also associated with a greater chance of sustained remission or HBsAg loss (58% vs. 24%; P < .05) and sustained remission without HBsAg loss (24% vs. 20%; P < .05). Not having a relapse within the first year after cessation was also associated with greater chance of sustained remission or HBsAg loss (50% versus 19%; P < .05) and sustained remission without HBsAg loss (37% vs. 13%; P < .05).
The Taiwan cohort study examined the repercussions of a government policy that limited reimbursement of nucleotide/nucleoside analogues to a fixed duration of time. Among 10,192 eligible patients, researchers at I-SHOU University found a 6.58% 4-year cumulative incidence of severe flare-ups after discontinuation (95% confidence interval, 5.91%-7.30%), defined as serum ALT levels higher than five times the upper limit of normal plus serum bilirubin levels above 2 mg/dL.
The overall incidence of flare-ups was 30.66% over 4 years (95% CI, 29.37%-31.96%). Higher risk of flareup was associated with older age (hazard ratio for each 10 years, 1.19; P<.0001), male sex (HR, 1.76; P < .0001), a diagnosis of cirrhosis (HR, 1.84; P < .0001), and a history of hepatic decompensation (HR, 1.45; P = .044).
The 4-year incidence of retreatment was 48.74% (95% CI, 46.55-50.90%)
The mortality rate was 0.63% at 4 years after a flareup (95% CI, 0.44-0.87%), and the combined rate of mortality or liver transplant was 0.79% (95% CI, 0.58-1.05%). Risk factors for higher mortality included older age (per 10 years; HR, 1.70; P < .0001), a diagnosis of cirrhosis (HR, 6.12; P < .0001), and hypertension (HR, 2.29; P = .029).
Selecting patients safely?
The results of both studies suggest that withdrawal from medication should be done cautiously, and patients monitored for relapse and retreatment, according to Anna Lok, MD, who was asked for comment. Dr. Lok is a professor of internal medicine, director of clinical hematology, and assistant dean for clinical research at the University of Michigan, Ann Arbor.
Between the two studies, “the message is that this approach can benefit some patients, but if the goal of treatment withdrawal is to increase the rate of hepatitis B surface antigen loss, only a small percentage of patients would benefit. Contrary to studies in Europe, the rates of HBsAg loss in studies with predominantly Asian patients are much lower,” said Dr. Lok.
The new studies provide guidance as for which patients might safely stop treatment; specifically, she suggested, young White patients who have a low HBsAg level when treatment is stopped. “But you probably shouldn’t be trying it in older Asian patients who still have high HBsAg titer, because the chance of them relapsing is very high and the chance of benefit is very low,” she said.
“One has to be very careful in selecting which patients you’re going to try this on. And if you do want to try, you’ve got to make sure that you monitor patients very carefully so treatment can be promptly resumed if necessary because some of the patients can have a severe flare and they can even develop liver failure, and this should never be tried in patients with cirrhosis” said Dr. Lok.
Ms. Hirode and Dr. Lok have no relevant financial disclosures.
More than half of chronic hepatitis B e antigen–negative patients who withdraw from nucleoside or nucleotide analogue therapy experienced relapse within 4 years, according to a new study that looked at patients from 11 centers in Europe, North America, and Asia.
“We wanted to see if the patients stabilize after that year. Are they just having relapses within the first year, and then they’re inactive carriers? Especially patients who don’t achieve [hepatitis B surface antigen; HBsAg] loss. Is that mildly active disease? Would they have been better off being retreated, or are they better off [staying off] therapy? It is important to look at what happens among these patients who stop and if there is a way to tell which way they’re going to go,” said Grishma Hirode, who is a PhD candidate at the University of Toronto. Ms. Hirode presented the multinational study at the annual meeting of the American Association for the Study of Liver Diseases.
The study provided a clear picture: “They do not stabilize after 1 year. They have relapses, and these relapses aren’t mild fluctuations,” said Ms. Hirode. Another study, which was presented during the same session and investigated a national cohort in Taiwan, also found a high rate of flareups and retreatment out to 4 years.
The RETRACT-B study presented by Ms. Hirode collected data on 945 patients from 11 centers in North America, Europe, and Asia. Overall, 66% had at least one relapse within 1 year of drug withdrawal. At 2 years, 40% had a sustained remission without HBsAg loss, as had 20% at 4 years; 44% had sustained remission or HBsAg loss at 2 years, as did 30% at 4 years.
Subgroup analyses found differences between some populations: 48% of Whites and 28% of Asians had sustained remission or HBsAg loss, and 30% of Whites and 20% of Asians had sustained remission without HBsAg loss. Patients who were HBsAg positive at start of therapy were more likely to have a sustained remission or HBsAg loss (36% vs. 28%; P < .05) and to have a sustained remission without HBsAg loss (31% vs. 19%; P < .05). HBsAg levels below 100 IU/mL at cessation was also associated with a greater chance of sustained remission or HBsAg loss (58% vs. 24%; P < .05) and sustained remission without HBsAg loss (24% vs. 20%; P < .05). Not having a relapse within the first year after cessation was also associated with greater chance of sustained remission or HBsAg loss (50% versus 19%; P < .05) and sustained remission without HBsAg loss (37% vs. 13%; P < .05).
The Taiwan cohort study examined the repercussions of a government policy that limited reimbursement of nucleotide/nucleoside analogues to a fixed duration of time. Among 10,192 eligible patients, researchers at I-SHOU University found a 6.58% 4-year cumulative incidence of severe flare-ups after discontinuation (95% confidence interval, 5.91%-7.30%), defined as serum ALT levels higher than five times the upper limit of normal plus serum bilirubin levels above 2 mg/dL.
The overall incidence of flare-ups was 30.66% over 4 years (95% CI, 29.37%-31.96%). Higher risk of flareup was associated with older age (hazard ratio for each 10 years, 1.19; P<.0001), male sex (HR, 1.76; P < .0001), a diagnosis of cirrhosis (HR, 1.84; P < .0001), and a history of hepatic decompensation (HR, 1.45; P = .044).
The 4-year incidence of retreatment was 48.74% (95% CI, 46.55-50.90%)
The mortality rate was 0.63% at 4 years after a flareup (95% CI, 0.44-0.87%), and the combined rate of mortality or liver transplant was 0.79% (95% CI, 0.58-1.05%). Risk factors for higher mortality included older age (per 10 years; HR, 1.70; P < .0001), a diagnosis of cirrhosis (HR, 6.12; P < .0001), and hypertension (HR, 2.29; P = .029).
Selecting patients safely?
The results of both studies suggest that withdrawal from medication should be done cautiously, and patients monitored for relapse and retreatment, according to Anna Lok, MD, who was asked for comment. Dr. Lok is a professor of internal medicine, director of clinical hematology, and assistant dean for clinical research at the University of Michigan, Ann Arbor.
Between the two studies, “the message is that this approach can benefit some patients, but if the goal of treatment withdrawal is to increase the rate of hepatitis B surface antigen loss, only a small percentage of patients would benefit. Contrary to studies in Europe, the rates of HBsAg loss in studies with predominantly Asian patients are much lower,” said Dr. Lok.
The new studies provide guidance as for which patients might safely stop treatment; specifically, she suggested, young White patients who have a low HBsAg level when treatment is stopped. “But you probably shouldn’t be trying it in older Asian patients who still have high HBsAg titer, because the chance of them relapsing is very high and the chance of benefit is very low,” she said.
“One has to be very careful in selecting which patients you’re going to try this on. And if you do want to try, you’ve got to make sure that you monitor patients very carefully so treatment can be promptly resumed if necessary because some of the patients can have a severe flare and they can even develop liver failure, and this should never be tried in patients with cirrhosis” said Dr. Lok.
Ms. Hirode and Dr. Lok have no relevant financial disclosures.
FROM THE LIVER MEETING