Hepatology

A noninvasive enhanced liver fibrosis (ELF) blood test identifies patients with nonalcoholic fatty liver disease (NAFLD) who are at increased risk of advanced fibrosis, according to a new study.

According to the study researchers, when combined with the fibrosis-4 (FIB-4) score the ELF test may be a reliable method that can assess for advanced fibrosis in clinical practice.

Despite the utility of identifying advanced fibrosis in the NAFLD population, significant barriers exist to “risk stratifying patients in clinical practice owing to the need for liver biopsy,” wrote study authors Zobair M. Younossi, MD, of the Inova Health System in Falls Church, Va., and colleagues in JAMA Network Open.

“NASH [nonalcoholic steatohepatitis] can only be diagnosed by biopsy and liver pathology yet validated noninvasive tests that accurately diagnose NASH don’t exist,” said Dr. Younossi in an interview. “Developing noninvasive tests to accurately risk stratify patients with significant fibrosis in NASH is highly desirable in clinical practice. A blood test such as ELF can open the opportunity to order this test anywhere in the country.”

The ELF test reflects extracellular matrix metabolism as opposed to tests that assess alterations in hepatic function. The study authors explain that the noninvasive ELF test is a “blood-derived panel of biomarkers consisting of three components: type III procollagen peptide, hyaluronic acid, and tissue inhibitor of metalloproteinase-1.”

To gain a further understanding of the role of ELF in predicting the risk of nonalcoholic steatohepatitis (NASH) in NAFLD, Dr. Younossi and colleagues performed a retrospective, cross-sectional analysis of outpatients within a community-based liver clinic from 2001 in 2020. The study cohort included 829 patients (mean age, 53.1 years) with NAFLD, which was characterized by steatosis greater than 5% without any other liver disease or excessive alcohol use.

In the overall study population, the mean FIB-4 score was 1.34. In the 463 patients with liver biopsy, approximately 24.4% presented with bridging fibrosis or cirrhosis. A total of 79 (17.1%) of the 462 patients with transient elastography data presented with liver stiffness results of 9.6 kPa or greater, which according to the researchers was indicative of advanced fibrosis.

Biopsy determined that those with advanced fibrosis in the study had significantly increased ELF scores versus patients without advanced fibrosis (10.1 vs. 8.6, respectively; P <.001). Moreover, patients with advanced fibrosis had significantly greater liver stiffness as determined by transient elastography (10.0 vs. 9.0; P <.001).

In the NAFLD population, the ELF test demonstrated excellent performance in identifying patients with advanced fibrosis, as reflected by an area under the receiver operating characteristic curve of 0.81 (95% confidence interval, 0.77-0.85) for those whose fibrosis was diagnosed by biopsy as well as 0.79 (95% CI, 0.75-0.82) for fibrosis diagnosed by transient elastography. Similar performances of the ELF score were reported among those with NAFLD who were aged 65 years or older (AUROC, 0.74; 95% CI, 0.58-0.87) or patients who had type 2 diabetes (AUROC, 0.78; 95% CI, 0.71-0.84).

The researchers regarded the combination of an ELF score of 7.2 or greater with a FIB-4 score of 0.74 or greater, as indicative of a negative predictive value of 95.1% (95% CI, 91.8%-98.4%) and a sensitivity of 92.5% (95% CI, 87.4%-97.5%). According to the investigators, these values “can reliably rule out advanced fibrosis.”

Additionally, the combination of an ELF score of 9.8 or greater with a FIB-4 score of 2.9 or greater, was associated with a positive predictive value of 95.0% (95% CI, 85.5%-100%) and a specificity of 99.7% (95% CI, 99.1%-100%), suggesting this combination can conversely “be used to rule in advanced fibrosis,” the researchers wrote.

Serologic approaches for predicting the risk of NASH are more widely available and “easier” to use than radiologic approaches, but the former may not be as reliable or accurate as the latter, explained Tibor Krisko, MD, a gastroenterologist at Weill Cornell Medicine and New York-Presbyterian, in an interview. “The choice of which serologic test is utilized is often guided by what is available in a region/practice, what the provider is familiar with, and what a given patient’s insurance covers,” said Dr. Krisko, who wasn’t involved in the study.

“The study by Dr. Younossi et al. perhaps confirms that ELF alone is unlikely to be the future standard of care, and the authors weave this to a conclusion and strength, highlighting that the combination had excellent accuracy,” commented Dr. Krisko. “This is an exciting and important area of research and clinical practice advancement, but all of these serological tests have limitations, such as their lack in liver specificity, their risk of being affected by clearance rate, and the fact that they are not biomarkers but rather surrogate markers.”

Therefore, added Dr. Krisko, clinicians should continue to consider each patient’s clinical picture carefully and utilize radiographic methods liberally, particularly when serologic results are deemed ambiguous.

Dr. Younossi reported conflicts of interest with several pharmaceutical companies. No funding was reported for the study. Dr. Krisko had no relevant conflicts to disclose.

A noninvasive enhanced liver fibrosis (ELF) blood test identifies patients with nonalcoholic fatty liver disease (NAFLD) who are at increased risk of advanced fibrosis, according to a new study.

According to the study researchers, when combined with the fibrosis-4 (FIB-4) score the ELF test may be a reliable method that can assess for advanced fibrosis in clinical practice.

Despite the utility of identifying advanced fibrosis in the NAFLD population, significant barriers exist to “risk stratifying patients in clinical practice owing to the need for liver biopsy,” wrote study authors Zobair M. Younossi, MD, of the Inova Health System in Falls Church, Va., and colleagues in JAMA Network Open.

“NASH [nonalcoholic steatohepatitis] can only be diagnosed by biopsy and liver pathology yet validated noninvasive tests that accurately diagnose NASH don’t exist,” said Dr. Younossi in an interview. “Developing noninvasive tests to accurately risk stratify patients with significant fibrosis in NASH is highly desirable in clinical practice. A blood test such as ELF can open the opportunity to order this test anywhere in the country.”

The ELF test reflects extracellular matrix metabolism as opposed to tests that assess alterations in hepatic function. The study authors explain that the noninvasive ELF test is a “blood-derived panel of biomarkers consisting of three components: type III procollagen peptide, hyaluronic acid, and tissue inhibitor of metalloproteinase-1.”

To gain a further understanding of the role of ELF in predicting the risk of nonalcoholic steatohepatitis (NASH) in NAFLD, Dr. Younossi and colleagues performed a retrospective, cross-sectional analysis of outpatients within a community-based liver clinic from 2001 in 2020. The study cohort included 829 patients (mean age, 53.1 years) with NAFLD, which was characterized by steatosis greater than 5% without any other liver disease or excessive alcohol use.

In the overall study population, the mean FIB-4 score was 1.34. In the 463 patients with liver biopsy, approximately 24.4% presented with bridging fibrosis or cirrhosis. A total of 79 (17.1%) of the 462 patients with transient elastography data presented with liver stiffness results of 9.6 kPa or greater, which according to the researchers was indicative of advanced fibrosis.

Biopsy determined that those with advanced fibrosis in the study had significantly increased ELF scores versus patients without advanced fibrosis (10.1 vs. 8.6, respectively; P <.001). Moreover, patients with advanced fibrosis had significantly greater liver stiffness as determined by transient elastography (10.0 vs. 9.0; P <.001).

In the NAFLD population, the ELF test demonstrated excellent performance in identifying patients with advanced fibrosis, as reflected by an area under the receiver operating characteristic curve of 0.81 (95% confidence interval, 0.77-0.85) for those whose fibrosis was diagnosed by biopsy as well as 0.79 (95% CI, 0.75-0.82) for fibrosis diagnosed by transient elastography. Similar performances of the ELF score were reported among those with NAFLD who were aged 65 years or older (AUROC, 0.74; 95% CI, 0.58-0.87) or patients who had type 2 diabetes (AUROC, 0.78; 95% CI, 0.71-0.84).

The researchers regarded the combination of an ELF score of 7.2 or greater with a FIB-4 score of 0.74 or greater, as indicative of a negative predictive value of 95.1% (95% CI, 91.8%-98.4%) and a sensitivity of 92.5% (95% CI, 87.4%-97.5%). According to the investigators, these values “can reliably rule out advanced fibrosis.”

Additionally, the combination of an ELF score of 9.8 or greater with a FIB-4 score of 2.9 or greater, was associated with a positive predictive value of 95.0% (95% CI, 85.5%-100%) and a specificity of 99.7% (95% CI, 99.1%-100%), suggesting this combination can conversely “be used to rule in advanced fibrosis,” the researchers wrote.

Serologic approaches for predicting the risk of NASH are more widely available and “easier” to use than radiologic approaches, but the former may not be as reliable or accurate as the latter, explained Tibor Krisko, MD, a gastroenterologist at Weill Cornell Medicine and New York-Presbyterian, in an interview. “The choice of which serologic test is utilized is often guided by what is available in a region/practice, what the provider is familiar with, and what a given patient’s insurance covers,” said Dr. Krisko, who wasn’t involved in the study.

“The study by Dr. Younossi et al. perhaps confirms that ELF alone is unlikely to be the future standard of care, and the authors weave this to a conclusion and strength, highlighting that the combination had excellent accuracy,” commented Dr. Krisko. “This is an exciting and important area of research and clinical practice advancement, but all of these serological tests have limitations, such as their lack in liver specificity, their risk of being affected by clearance rate, and the fact that they are not biomarkers but rather surrogate markers.”

Therefore, added Dr. Krisko, clinicians should continue to consider each patient’s clinical picture carefully and utilize radiographic methods liberally, particularly when serologic results are deemed ambiguous.

Dr. Younossi reported conflicts of interest with several pharmaceutical companies. No funding was reported for the study. Dr. Krisko had no relevant conflicts to disclose.

A noninvasive enhanced liver fibrosis (ELF) blood test identifies patients with nonalcoholic fatty liver disease (NAFLD) who are at increased risk of advanced fibrosis, according to a new study.

According to the study researchers, when combined with the fibrosis-4 (FIB-4) score the ELF test may be a reliable method that can assess for advanced fibrosis in clinical practice.

Despite the utility of identifying advanced fibrosis in the NAFLD population, significant barriers exist to “risk stratifying patients in clinical practice owing to the need for liver biopsy,” wrote study authors Zobair M. Younossi, MD, of the Inova Health System in Falls Church, Va., and colleagues in JAMA Network Open.

“NASH [nonalcoholic steatohepatitis] can only be diagnosed by biopsy and liver pathology yet validated noninvasive tests that accurately diagnose NASH don’t exist,” said Dr. Younossi in an interview. “Developing noninvasive tests to accurately risk stratify patients with significant fibrosis in NASH is highly desirable in clinical practice. A blood test such as ELF can open the opportunity to order this test anywhere in the country.”

The ELF test reflects extracellular matrix metabolism as opposed to tests that assess alterations in hepatic function. The study authors explain that the noninvasive ELF test is a “blood-derived panel of biomarkers consisting of three components: type III procollagen peptide, hyaluronic acid, and tissue inhibitor of metalloproteinase-1.”

To gain a further understanding of the role of ELF in predicting the risk of nonalcoholic steatohepatitis (NASH) in NAFLD, Dr. Younossi and colleagues performed a retrospective, cross-sectional analysis of outpatients within a community-based liver clinic from 2001 in 2020. The study cohort included 829 patients (mean age, 53.1 years) with NAFLD, which was characterized by steatosis greater than 5% without any other liver disease or excessive alcohol use.

In the overall study population, the mean FIB-4 score was 1.34. In the 463 patients with liver biopsy, approximately 24.4% presented with bridging fibrosis or cirrhosis. A total of 79 (17.1%) of the 462 patients with transient elastography data presented with liver stiffness results of 9.6 kPa or greater, which according to the researchers was indicative of advanced fibrosis.

Biopsy determined that those with advanced fibrosis in the study had significantly increased ELF scores versus patients without advanced fibrosis (10.1 vs. 8.6, respectively; P <.001). Moreover, patients with advanced fibrosis had significantly greater liver stiffness as determined by transient elastography (10.0 vs. 9.0; P <.001).

In the NAFLD population, the ELF test demonstrated excellent performance in identifying patients with advanced fibrosis, as reflected by an area under the receiver operating characteristic curve of 0.81 (95% confidence interval, 0.77-0.85) for those whose fibrosis was diagnosed by biopsy as well as 0.79 (95% CI, 0.75-0.82) for fibrosis diagnosed by transient elastography. Similar performances of the ELF score were reported among those with NAFLD who were aged 65 years or older (AUROC, 0.74; 95% CI, 0.58-0.87) or patients who had type 2 diabetes (AUROC, 0.78; 95% CI, 0.71-0.84).

The researchers regarded the combination of an ELF score of 7.2 or greater with a FIB-4 score of 0.74 or greater, as indicative of a negative predictive value of 95.1% (95% CI, 91.8%-98.4%) and a sensitivity of 92.5% (95% CI, 87.4%-97.5%). According to the investigators, these values “can reliably rule out advanced fibrosis.”

Additionally, the combination of an ELF score of 9.8 or greater with a FIB-4 score of 2.9 or greater, was associated with a positive predictive value of 95.0% (95% CI, 85.5%-100%) and a specificity of 99.7% (95% CI, 99.1%-100%), suggesting this combination can conversely “be used to rule in advanced fibrosis,” the researchers wrote.

Serologic approaches for predicting the risk of NASH are more widely available and “easier” to use than radiologic approaches, but the former may not be as reliable or accurate as the latter, explained Tibor Krisko, MD, a gastroenterologist at Weill Cornell Medicine and New York-Presbyterian, in an interview. “The choice of which serologic test is utilized is often guided by what is available in a region/practice, what the provider is familiar with, and what a given patient’s insurance covers,” said Dr. Krisko, who wasn’t involved in the study.

“The study by Dr. Younossi et al. perhaps confirms that ELF alone is unlikely to be the future standard of care, and the authors weave this to a conclusion and strength, highlighting that the combination had excellent accuracy,” commented Dr. Krisko. “This is an exciting and important area of research and clinical practice advancement, but all of these serological tests have limitations, such as their lack in liver specificity, their risk of being affected by clearance rate, and the fact that they are not biomarkers but rather surrogate markers.”

Therefore, added Dr. Krisko, clinicians should continue to consider each patient’s clinical picture carefully and utilize radiographic methods liberally, particularly when serologic results are deemed ambiguous.

Dr. Younossi reported conflicts of interest with several pharmaceutical companies. No funding was reported for the study. Dr. Krisko had no relevant conflicts to disclose.

This article was updated Nov. 5, 2021.

A newly updated version of the Model for End-Stage Liver Disease (MELD) score was effective for predicting short-term mortality in patients with end-stage liver disease and addressed important determinants of wait list outcomes that haven’t been addressed in previous versions, according to findings from a recent study. The new model, termed MELD 3.0, includes new variables such as female sex, serum albumin, and updated creatinine cutoffs.

Thomas Northcut/Getty Images

“We believe that the new model represents an opportunity to lower wait list mortality in the United States and propose it to be considered to replace the current version of MELD in determining allocation priorities in liver transplantation,” wrote study authors W. Ray Kim, MD, of Stanford (Calif.) University and colleagues in Gastroenterology.

In patients with end-stage liver disease, the MELD score was shown to be a reliable predictor of short-term survival, according to the researchers. The original version of MELD consists of international normalized ratio of prothrombin time and serum concentrations of bilirubin and creatinine; MELDNa consists of the same with the addition of serum concentrations of total sodium. Since 2016, MELDNa has been utilized in the United States to allocate livers for transplant.

Despite the utility of the current MELD score, questions have been raised concerning the accuracy of the tool’s ability to predict mortality, including a study by Sumeet K. Asrani, MD, MSc, and colleagues. Changes in liver disease epidemiology, the introduction of newer therapies that alter prognosis, as well as increasing age and prevalence of comorbidities in transplant-eligible patients are several drivers for these concerns, according to Dr. Kim and colleagues. Also, there is an increasing concern regarding women and their potential disadvantages in the current system: At least one study has suggested that serum creatinine may overestimate renal function and consequently underestimate mortality risk in female patients, compared with men with the same creatinine level.

Dr. Kim and colleagues sought to further optimize the fit of the current MELD score by considering alternative interactions and including other variables relevant to predicting short-term mortality in patients awaiting liver transplant. The study included patients who are registered on the Organ Procurement and Transplantation Network Standard Transplant Analysis and Research files newly wait-listed from 2016 through 2018. The full cohort was divided 70:30 into a development set (n = 20,587) and a validation set (n = 8,823); there were no significant differences between the sets in respect to age, sex, race, or liver disease severity.

The investigators used univariable and multivariable regression models to predict 90-day survival following wait list registration. The 90-day Kaplan-Meier survival rate in the development set was 91.3%. Additionally, model fit was tested, and the investigators used the Liver Simulated Allocation Model to estimate the impact of replacing the current version of the MELD with MELD 3.0.

In the final MELD 3.0 model, the researchers included several additional variables such as female sex and serum albumin. Additionally, the final model was characterized by interactions between bilirubin and sodium as well as between albumin and creatinine. Also, an adjustment to the current version of MELD lowering the upper bound for creatinine from 4.0 mg/dL to 3.0 mg/dL.

The MELD 3.0 featured significantly better discrimination, compared with the MELDNa (C-statistic = 0.8693 vs. 0.8622, respectively; P < .01). In addition, the researchers wrote that the new MELD 3.0 score “correctly reclassified a net of 8.8% of decedents to a higher MELD tier, affording them a meaningfully higher chance of transplantation, particularly in women.” The MELD 3.0 score with albumin also led to fewer wait-list deaths, compared with the MELDNa, according to the Liver Simulated Allocation Model analysis (P = .02); the number for MELD 3.0 without albumin was not statistically significant.

According to the investigators, a cause of concern for the MELD 3.0 was the addition of albumin, as this variable may be vulnerable to manipulation. In addition, the researchers note that, while differences in wait list mortality and survival based on race/ethnicity were observed in the study, they were unable to describe the exact root causes of worse outcomes among patients belonging to minority groups. “Thus, inclusion in a risk prediction score without fully understanding the underlying reasons for the racial disparity may have unintended consequences,” the researchers wrote.

“Based on recent data consisting of liver transplant candidates in the United States, we identify additional variables that are meaningfully associated with short-term mortality, including female sex and serum albumin. We also found evidence to support lowering the serum creatinine ceiling to 3 mg/dL,” they wrote. “Based on these data, we created an updated version of the MELD score, which improves mortality prediction compared to the current MELDNa model, including the recognition of female sex as a risk factor for death.”

The researchers reported no conflicts of interest with the pharmaceutical industry. No funding was reported for the study.

This article was updated Nov. 5, 2021.

A newly updated version of the Model for End-Stage Liver Disease (MELD) score was effective for predicting short-term mortality in patients with end-stage liver disease and addressed important determinants of wait list outcomes that haven’t been addressed in previous versions, according to findings from a recent study. The new model, termed MELD 3.0, includes new variables such as female sex, serum albumin, and updated creatinine cutoffs.

Thomas Northcut/Getty Images

“We believe that the new model represents an opportunity to lower wait list mortality in the United States and propose it to be considered to replace the current version of MELD in determining allocation priorities in liver transplantation,” wrote study authors W. Ray Kim, MD, of Stanford (Calif.) University and colleagues in Gastroenterology.

In patients with end-stage liver disease, the MELD score was shown to be a reliable predictor of short-term survival, according to the researchers. The original version of MELD consists of international normalized ratio of prothrombin time and serum concentrations of bilirubin and creatinine; MELDNa consists of the same with the addition of serum concentrations of total sodium. Since 2016, MELDNa has been utilized in the United States to allocate livers for transplant.

Despite the utility of the current MELD score, questions have been raised concerning the accuracy of the tool’s ability to predict mortality, including a study by Sumeet K. Asrani, MD, MSc, and colleagues. Changes in liver disease epidemiology, the introduction of newer therapies that alter prognosis, as well as increasing age and prevalence of comorbidities in transplant-eligible patients are several drivers for these concerns, according to Dr. Kim and colleagues. Also, there is an increasing concern regarding women and their potential disadvantages in the current system: At least one study has suggested that serum creatinine may overestimate renal function and consequently underestimate mortality risk in female patients, compared with men with the same creatinine level.

Dr. Kim and colleagues sought to further optimize the fit of the current MELD score by considering alternative interactions and including other variables relevant to predicting short-term mortality in patients awaiting liver transplant. The study included patients who are registered on the Organ Procurement and Transplantation Network Standard Transplant Analysis and Research files newly wait-listed from 2016 through 2018. The full cohort was divided 70:30 into a development set (n = 20,587) and a validation set (n = 8,823); there were no significant differences between the sets in respect to age, sex, race, or liver disease severity.

The investigators used univariable and multivariable regression models to predict 90-day survival following wait list registration. The 90-day Kaplan-Meier survival rate in the development set was 91.3%. Additionally, model fit was tested, and the investigators used the Liver Simulated Allocation Model to estimate the impact of replacing the current version of the MELD with MELD 3.0.

In the final MELD 3.0 model, the researchers included several additional variables such as female sex and serum albumin. Additionally, the final model was characterized by interactions between bilirubin and sodium as well as between albumin and creatinine. Also, an adjustment to the current version of MELD lowering the upper bound for creatinine from 4.0 mg/dL to 3.0 mg/dL.

The MELD 3.0 featured significantly better discrimination, compared with the MELDNa (C-statistic = 0.8693 vs. 0.8622, respectively; P < .01). In addition, the researchers wrote that the new MELD 3.0 score “correctly reclassified a net of 8.8% of decedents to a higher MELD tier, affording them a meaningfully higher chance of transplantation, particularly in women.” The MELD 3.0 score with albumin also led to fewer wait-list deaths, compared with the MELDNa, according to the Liver Simulated Allocation Model analysis (P = .02); the number for MELD 3.0 without albumin was not statistically significant.

According to the investigators, a cause of concern for the MELD 3.0 was the addition of albumin, as this variable may be vulnerable to manipulation. In addition, the researchers note that, while differences in wait list mortality and survival based on race/ethnicity were observed in the study, they were unable to describe the exact root causes of worse outcomes among patients belonging to minority groups. “Thus, inclusion in a risk prediction score without fully understanding the underlying reasons for the racial disparity may have unintended consequences,” the researchers wrote.

“Based on recent data consisting of liver transplant candidates in the United States, we identify additional variables that are meaningfully associated with short-term mortality, including female sex and serum albumin. We also found evidence to support lowering the serum creatinine ceiling to 3 mg/dL,” they wrote. “Based on these data, we created an updated version of the MELD score, which improves mortality prediction compared to the current MELDNa model, including the recognition of female sex as a risk factor for death.”

The researchers reported no conflicts of interest with the pharmaceutical industry. No funding was reported for the study.

This article was updated Nov. 5, 2021.

A newly updated version of the Model for End-Stage Liver Disease (MELD) score was effective for predicting short-term mortality in patients with end-stage liver disease and addressed important determinants of wait list outcomes that haven’t been addressed in previous versions, according to findings from a recent study. The new model, termed MELD 3.0, includes new variables such as female sex, serum albumin, and updated creatinine cutoffs.

Thomas Northcut/Getty Images

“We believe that the new model represents an opportunity to lower wait list mortality in the United States and propose it to be considered to replace the current version of MELD in determining allocation priorities in liver transplantation,” wrote study authors W. Ray Kim, MD, of Stanford (Calif.) University and colleagues in Gastroenterology.

In patients with end-stage liver disease, the MELD score was shown to be a reliable predictor of short-term survival, according to the researchers. The original version of MELD consists of international normalized ratio of prothrombin time and serum concentrations of bilirubin and creatinine; MELDNa consists of the same with the addition of serum concentrations of total sodium. Since 2016, MELDNa has been utilized in the United States to allocate livers for transplant.

Despite the utility of the current MELD score, questions have been raised concerning the accuracy of the tool’s ability to predict mortality, including a study by Sumeet K. Asrani, MD, MSc, and colleagues. Changes in liver disease epidemiology, the introduction of newer therapies that alter prognosis, as well as increasing age and prevalence of comorbidities in transplant-eligible patients are several drivers for these concerns, according to Dr. Kim and colleagues. Also, there is an increasing concern regarding women and their potential disadvantages in the current system: At least one study has suggested that serum creatinine may overestimate renal function and consequently underestimate mortality risk in female patients, compared with men with the same creatinine level.

Dr. Kim and colleagues sought to further optimize the fit of the current MELD score by considering alternative interactions and including other variables relevant to predicting short-term mortality in patients awaiting liver transplant. The study included patients who are registered on the Organ Procurement and Transplantation Network Standard Transplant Analysis and Research files newly wait-listed from 2016 through 2018. The full cohort was divided 70:30 into a development set (n = 20,587) and a validation set (n = 8,823); there were no significant differences between the sets in respect to age, sex, race, or liver disease severity.

The investigators used univariable and multivariable regression models to predict 90-day survival following wait list registration. The 90-day Kaplan-Meier survival rate in the development set was 91.3%. Additionally, model fit was tested, and the investigators used the Liver Simulated Allocation Model to estimate the impact of replacing the current version of the MELD with MELD 3.0.

In the final MELD 3.0 model, the researchers included several additional variables such as female sex and serum albumin. Additionally, the final model was characterized by interactions between bilirubin and sodium as well as between albumin and creatinine. Also, an adjustment to the current version of MELD lowering the upper bound for creatinine from 4.0 mg/dL to 3.0 mg/dL.

The MELD 3.0 featured significantly better discrimination, compared with the MELDNa (C-statistic = 0.8693 vs. 0.8622, respectively; P < .01). In addition, the researchers wrote that the new MELD 3.0 score “correctly reclassified a net of 8.8% of decedents to a higher MELD tier, affording them a meaningfully higher chance of transplantation, particularly in women.” The MELD 3.0 score with albumin also led to fewer wait-list deaths, compared with the MELDNa, according to the Liver Simulated Allocation Model analysis (P = .02); the number for MELD 3.0 without albumin was not statistically significant.

According to the investigators, a cause of concern for the MELD 3.0 was the addition of albumin, as this variable may be vulnerable to manipulation. In addition, the researchers note that, while differences in wait list mortality and survival based on race/ethnicity were observed in the study, they were unable to describe the exact root causes of worse outcomes among patients belonging to minority groups. “Thus, inclusion in a risk prediction score without fully understanding the underlying reasons for the racial disparity may have unintended consequences,” the researchers wrote.

“Based on recent data consisting of liver transplant candidates in the United States, we identify additional variables that are meaningfully associated with short-term mortality, including female sex and serum albumin. We also found evidence to support lowering the serum creatinine ceiling to 3 mg/dL,” they wrote. “Based on these data, we created an updated version of the MELD score, which improves mortality prediction compared to the current MELDNa model, including the recognition of female sex as a risk factor for death.”

The researchers reported no conflicts of interest with the pharmaceutical industry. No funding was reported for the study.

Drinking more than three cups of caffeinated coffee a day is associated with less liver stiffness, according to an analysis of a nationally representative survey, which was recently published in Clinical Gastroenterology and Hepatology.

amenic181/Getty Images

The study is likely the most rigorous look to date on the benefits of coffee on liver health in the U.S. It was based on data from the National Health and Nutrition Examination Survey (NHANES), in which participants were asked about what they eat and drink. Crucially, in 2017, NHANES began to include elastography (FibroScan), of participants’ liver stiffness, not because of suspected problems with the liver but as across-the-board evaluations of all participants.

“Because it’s an unselected population for FibroScan and because of the detail, the granularity, the richness of the information from the nutritional surveys that they do, this is the closest we’re ever going to get to a linkage between what people are eating or drinking and the health of their liver, absent a longitudinal study where we set out to follow people for many, many years,” said Elliot Tapper, MD, assistant professor of gastroenterology at the University of Michigan, Ann Arbor, and the study’s senior author.

Researchers examined data from about 4,500 patients who had participated in the NHANES study in 2017-2018. The participants were aged 20 years or older, with an average age of 48; 73% were overweight, about the national average.

The researchers found no association between coffee consumption and controlled attenuation parameter (CAP), a measure of fatty liver. But they found a link between coffee and liver stiffness.

Those who drank more than three cups of coffee daily had a liver stiffness measure (LSM) that was 0.9 kilopascals (kPa) lower than others (P = .03). Drinking more than three cups a day also was found to be protective against an LSM of 9.5 kPa or higher, the threshold for advanced liver fibrosis (OR, 0.4; P = .05). Decaffeinated coffee was not found to be associated with LSM.

Caffeine is an antagonist to adenosine receptors in the liver cell that, if blocked, stops the production of scar tissue, according to the researchers. But when they looked at estimated caffeine consumption, calculated through the detailed, trained interviews performed by nutritionists, there was no association with liver stiffness. That said, Dr. Tapper noted that this could be due to the imperfection of making those estimations.

“If we had to hypothesize about a mechanism, it would most likely be caffeine, and the reason we couldn’t see that here is because these are estimated milligrams of caffeine per coffee – but the way that we brew coffee, and the beans that we’re using, are so highly variable it just can’t be captured in this kind of database,” he said.

He said the data will be reassuring to clinicians who suggest coffee-drinking to patients.

“There are hepatologists around the world who are actively recommending coffee – they’ll feel empowered by these data,” he said. “I would still like to see more robust longitudinal data before I start spending our precious time counseling patients about coffee. There are many other data-driven interventions for the management of liver disease that we should be focusing our time on.”

Moreover, he said that the data will be important for patients who are particularly interested in natural remedies.

“For patients who are very interested in a natural supplement, to feel like they’re taking an active role in the health of their liver, I will tell them to avoid carbohydrates and increase their exercise – and that it is OK to add coffee to their daily routine.”

A study based on a UK database found that coffee was associated with protection against chronic liver disease, but the association was seen for both caffeinated and decaffeinated drinks, noted Nathan Davies, PhD, professor of biochemistry at the Institute of the Liver and Digestive Health at the University College London.

Dr. Davies, a registered nutritionist who has studied coffee’s effects on the liver, said that while including elastography in the Michigan study is interesting, it “does not necessarily by itself add greatly” to the evidence base.

The outcomes from both studies do suggest a positive effect for coffee, but he said it’s important to remember that liver disease develops over years and decades.

“Looking at a snapshot moment does not necessarily reflect an individual’s behavior during the onset and development of their condition,” he said. “As such, there are a number of behavioral and nutritional factors that could be contributing to the observed effect over a period of years.”

He pointed out that while different coffee and brewing types affect the amount of caffeine in a cup, all cups of coffee in this study were treated the same way. He noted there was no apparent dose-dependent effect, which would have been expected if there is an active ingredient that affects liver stiffness.

“In general, my advice is to improve diet, take more exercise, and reduce alcohol consumption, which is likely to be more effective in preventing liver disease – and its progression – than drinking an extra cup of coffee,” Dr. Davies said. “That being said, for patients at increased risk for liver disease who currently drink three cups or more of coffee daily, it may be prudent for them to continue because this level of consumption might be actively lowering their chances of developing more serious disease.”

Dr. Tapper has done consulting for Novartis, Axcella and Allergan, has served on advisory boards for Mallinckrodt, Bausch Health, Kaleido, and Novo Nordisk, and has unrestricted research grants from Gilead and Valeant. The remaining authors disclose no conflicts. Dr. Davies reported no relevant disclosures.

Drinking more than three cups of caffeinated coffee a day is associated with less liver stiffness, according to an analysis of a nationally representative survey, which was recently published in Clinical Gastroenterology and Hepatology.

amenic181/Getty Images

The study is likely the most rigorous look to date on the benefits of coffee on liver health in the U.S. It was based on data from the National Health and Nutrition Examination Survey (NHANES), in which participants were asked about what they eat and drink. Crucially, in 2017, NHANES began to include elastography (FibroScan), of participants’ liver stiffness, not because of suspected problems with the liver but as across-the-board evaluations of all participants.

“Because it’s an unselected population for FibroScan and because of the detail, the granularity, the richness of the information from the nutritional surveys that they do, this is the closest we’re ever going to get to a linkage between what people are eating or drinking and the health of their liver, absent a longitudinal study where we set out to follow people for many, many years,” said Elliot Tapper, MD, assistant professor of gastroenterology at the University of Michigan, Ann Arbor, and the study’s senior author.

Researchers examined data from about 4,500 patients who had participated in the NHANES study in 2017-2018. The participants were aged 20 years or older, with an average age of 48; 73% were overweight, about the national average.

The researchers found no association between coffee consumption and controlled attenuation parameter (CAP), a measure of fatty liver. But they found a link between coffee and liver stiffness.

Those who drank more than three cups of coffee daily had a liver stiffness measure (LSM) that was 0.9 kilopascals (kPa) lower than others (P = .03). Drinking more than three cups a day also was found to be protective against an LSM of 9.5 kPa or higher, the threshold for advanced liver fibrosis (OR, 0.4; P = .05). Decaffeinated coffee was not found to be associated with LSM.

Caffeine is an antagonist to adenosine receptors in the liver cell that, if blocked, stops the production of scar tissue, according to the researchers. But when they looked at estimated caffeine consumption, calculated through the detailed, trained interviews performed by nutritionists, there was no association with liver stiffness. That said, Dr. Tapper noted that this could be due to the imperfection of making those estimations.

“If we had to hypothesize about a mechanism, it would most likely be caffeine, and the reason we couldn’t see that here is because these are estimated milligrams of caffeine per coffee – but the way that we brew coffee, and the beans that we’re using, are so highly variable it just can’t be captured in this kind of database,” he said.

He said the data will be reassuring to clinicians who suggest coffee-drinking to patients.

“There are hepatologists around the world who are actively recommending coffee – they’ll feel empowered by these data,” he said. “I would still like to see more robust longitudinal data before I start spending our precious time counseling patients about coffee. There are many other data-driven interventions for the management of liver disease that we should be focusing our time on.”

Moreover, he said that the data will be important for patients who are particularly interested in natural remedies.

“For patients who are very interested in a natural supplement, to feel like they’re taking an active role in the health of their liver, I will tell them to avoid carbohydrates and increase their exercise – and that it is OK to add coffee to their daily routine.”

A study based on a UK database found that coffee was associated with protection against chronic liver disease, but the association was seen for both caffeinated and decaffeinated drinks, noted Nathan Davies, PhD, professor of biochemistry at the Institute of the Liver and Digestive Health at the University College London.

Dr. Davies, a registered nutritionist who has studied coffee’s effects on the liver, said that while including elastography in the Michigan study is interesting, it “does not necessarily by itself add greatly” to the evidence base.

The outcomes from both studies do suggest a positive effect for coffee, but he said it’s important to remember that liver disease develops over years and decades.

“Looking at a snapshot moment does not necessarily reflect an individual’s behavior during the onset and development of their condition,” he said. “As such, there are a number of behavioral and nutritional factors that could be contributing to the observed effect over a period of years.”

He pointed out that while different coffee and brewing types affect the amount of caffeine in a cup, all cups of coffee in this study were treated the same way. He noted there was no apparent dose-dependent effect, which would have been expected if there is an active ingredient that affects liver stiffness.

“In general, my advice is to improve diet, take more exercise, and reduce alcohol consumption, which is likely to be more effective in preventing liver disease – and its progression – than drinking an extra cup of coffee,” Dr. Davies said. “That being said, for patients at increased risk for liver disease who currently drink three cups or more of coffee daily, it may be prudent for them to continue because this level of consumption might be actively lowering their chances of developing more serious disease.”

Dr. Tapper has done consulting for Novartis, Axcella and Allergan, has served on advisory boards for Mallinckrodt, Bausch Health, Kaleido, and Novo Nordisk, and has unrestricted research grants from Gilead and Valeant. The remaining authors disclose no conflicts. Dr. Davies reported no relevant disclosures.

Drinking more than three cups of caffeinated coffee a day is associated with less liver stiffness, according to an analysis of a nationally representative survey, which was recently published in Clinical Gastroenterology and Hepatology.

amenic181/Getty Images

The study is likely the most rigorous look to date on the benefits of coffee on liver health in the U.S. It was based on data from the National Health and Nutrition Examination Survey (NHANES), in which participants were asked about what they eat and drink. Crucially, in 2017, NHANES began to include elastography (FibroScan), of participants’ liver stiffness, not because of suspected problems with the liver but as across-the-board evaluations of all participants.

“Because it’s an unselected population for FibroScan and because of the detail, the granularity, the richness of the information from the nutritional surveys that they do, this is the closest we’re ever going to get to a linkage between what people are eating or drinking and the health of their liver, absent a longitudinal study where we set out to follow people for many, many years,” said Elliot Tapper, MD, assistant professor of gastroenterology at the University of Michigan, Ann Arbor, and the study’s senior author.

Researchers examined data from about 4,500 patients who had participated in the NHANES study in 2017-2018. The participants were aged 20 years or older, with an average age of 48; 73% were overweight, about the national average.

The researchers found no association between coffee consumption and controlled attenuation parameter (CAP), a measure of fatty liver. But they found a link between coffee and liver stiffness.

Those who drank more than three cups of coffee daily had a liver stiffness measure (LSM) that was 0.9 kilopascals (kPa) lower than others (P = .03). Drinking more than three cups a day also was found to be protective against an LSM of 9.5 kPa or higher, the threshold for advanced liver fibrosis (OR, 0.4; P = .05). Decaffeinated coffee was not found to be associated with LSM.

Caffeine is an antagonist to adenosine receptors in the liver cell that, if blocked, stops the production of scar tissue, according to the researchers. But when they looked at estimated caffeine consumption, calculated through the detailed, trained interviews performed by nutritionists, there was no association with liver stiffness. That said, Dr. Tapper noted that this could be due to the imperfection of making those estimations.

“If we had to hypothesize about a mechanism, it would most likely be caffeine, and the reason we couldn’t see that here is because these are estimated milligrams of caffeine per coffee – but the way that we brew coffee, and the beans that we’re using, are so highly variable it just can’t be captured in this kind of database,” he said.

He said the data will be reassuring to clinicians who suggest coffee-drinking to patients.

“There are hepatologists around the world who are actively recommending coffee – they’ll feel empowered by these data,” he said. “I would still like to see more robust longitudinal data before I start spending our precious time counseling patients about coffee. There are many other data-driven interventions for the management of liver disease that we should be focusing our time on.”

Moreover, he said that the data will be important for patients who are particularly interested in natural remedies.

“For patients who are very interested in a natural supplement, to feel like they’re taking an active role in the health of their liver, I will tell them to avoid carbohydrates and increase their exercise – and that it is OK to add coffee to their daily routine.”

A study based on a UK database found that coffee was associated with protection against chronic liver disease, but the association was seen for both caffeinated and decaffeinated drinks, noted Nathan Davies, PhD, professor of biochemistry at the Institute of the Liver and Digestive Health at the University College London.

Dr. Davies, a registered nutritionist who has studied coffee’s effects on the liver, said that while including elastography in the Michigan study is interesting, it “does not necessarily by itself add greatly” to the evidence base.

The outcomes from both studies do suggest a positive effect for coffee, but he said it’s important to remember that liver disease develops over years and decades.

“Looking at a snapshot moment does not necessarily reflect an individual’s behavior during the onset and development of their condition,” he said. “As such, there are a number of behavioral and nutritional factors that could be contributing to the observed effect over a period of years.”

He pointed out that while different coffee and brewing types affect the amount of caffeine in a cup, all cups of coffee in this study were treated the same way. He noted there was no apparent dose-dependent effect, which would have been expected if there is an active ingredient that affects liver stiffness.

“In general, my advice is to improve diet, take more exercise, and reduce alcohol consumption, which is likely to be more effective in preventing liver disease – and its progression – than drinking an extra cup of coffee,” Dr. Davies said. “That being said, for patients at increased risk for liver disease who currently drink three cups or more of coffee daily, it may be prudent for them to continue because this level of consumption might be actively lowering their chances of developing more serious disease.”

Dr. Tapper has done consulting for Novartis, Axcella and Allergan, has served on advisory boards for Mallinckrodt, Bausch Health, Kaleido, and Novo Nordisk, and has unrestricted research grants from Gilead and Valeant. The remaining authors disclose no conflicts. Dr. Davies reported no relevant disclosures.

In patients with unresectable or metastatic hepatocellular carcinoma (HCC), donafenib was superior to sorafenib in improving overall survival (OS), according to a head-to-head study published in the Journal of Clinical Oncology. This novel multikinase inhibitor and deuterated sorafenib derivative also showed improved safety and tolerability, rendering it a potential first-line monotherapy for patients with advanced HCC.

“An improvement in the pharmacotherapy of advanced HCC remains a clinical need,” wrote Feng Bi, MD, of Sichuan University, in Chengdu, China, and colleagues.

Liver cancer is one of the most common cancers worldwide, with HCC representing 90% of liver malignancies. HCC most commonly occurs in people with liver disease, particularly in those with chronic hepatitis B and C and although rare, HCC is the ninth leading cause of cancer deaths in the United States. Most patients are diagnosed at the advanced stage with a median survival of 6-8 months. Sorafenib, the standard first-line therapy for advanced HCC, has demonstrated the median OS of 10.7 to 14.7 months. No other monotherapy has shown a significant improvement in OS, compared with sorafenib. Donafenib has shown favorable efficacy and safety in phase 1 studies.

This phase 2-3 trial evaluated the efficacy and safety of first-line donafenib, compared with sorafenib, in 668 Chinese patients with advanced HCC. Patients were randomly assigned to receive twice-daily oral donafenib 0.2 g or sorafenib 0.4 g until intolerable toxicity or disease progression. The primary end point was OS, tested for noninferiority and superiority. 

Compared with sorafenib, donafenib significantly prolonged OS, 10.3 and 12.1 months, respectively, (hazard ratio, 95% confidence interval, 0.699-0.988; 0.83; P = .0245), and the superiority criteria for OS were met. Donafenib also presented improved safety and tolerability. Common drug-related adverse events, such as hand-foot skin reactions and diarrhea, and drug-related grade 3 or higher adverse events, occurred in fewer patients receiving donafenib than sorafenib, (38% vs. 50%; P = .0018). The authors noted that this lower frequency in adverse events with donafenib “contributed to improved patient adherence and decreased levels of drug interruption and discontinuation.”

Donafenib is a novel, oral, small-molecule, multikinase inhibitor that suppresses tumor cell proliferation and angiogenesis by inhibiting vascular endothelial growth factor receptors and platelet-derived growth factor receptors, and Raf kinases. It is a derivative of sorafenib and in June 2021, it was approved in China as a treatment for unresectable hepatocellular carcinoma for patients who have not received systemic treatment. It is not yet available in the United States.

“This pivotal head-to-head comparison study is the first to demonstrate noninferiority and superiority of a monotherapy, donafenib, with statistically significant extension in OS over sorafenib for first-line treatment of advanced HCC,” the authors wrote. “Compared with international trials, patients in this study presented with more severe baseline disease states, further emphasizing the positive response observed with donafenib.”

Another study, published in the same issue of the Journal of Clinical Oncology, compared tremelimumab and durvalumab as monotherapies and in combination for patients with unresectable HCC, found that use a single priming dose of tremelimumab combined with durvalumab showed the best benefit-risk profile.

In patients with unresectable or metastatic hepatocellular carcinoma (HCC), donafenib was superior to sorafenib in improving overall survival (OS), according to a head-to-head study published in the Journal of Clinical Oncology. This novel multikinase inhibitor and deuterated sorafenib derivative also showed improved safety and tolerability, rendering it a potential first-line monotherapy for patients with advanced HCC.

“An improvement in the pharmacotherapy of advanced HCC remains a clinical need,” wrote Feng Bi, MD, of Sichuan University, in Chengdu, China, and colleagues.

Liver cancer is one of the most common cancers worldwide, with HCC representing 90% of liver malignancies. HCC most commonly occurs in people with liver disease, particularly in those with chronic hepatitis B and C and although rare, HCC is the ninth leading cause of cancer deaths in the United States. Most patients are diagnosed at the advanced stage with a median survival of 6-8 months. Sorafenib, the standard first-line therapy for advanced HCC, has demonstrated the median OS of 10.7 to 14.7 months. No other monotherapy has shown a significant improvement in OS, compared with sorafenib. Donafenib has shown favorable efficacy and safety in phase 1 studies.

This phase 2-3 trial evaluated the efficacy and safety of first-line donafenib, compared with sorafenib, in 668 Chinese patients with advanced HCC. Patients were randomly assigned to receive twice-daily oral donafenib 0.2 g or sorafenib 0.4 g until intolerable toxicity or disease progression. The primary end point was OS, tested for noninferiority and superiority. 

Compared with sorafenib, donafenib significantly prolonged OS, 10.3 and 12.1 months, respectively, (hazard ratio, 95% confidence interval, 0.699-0.988; 0.83; P = .0245), and the superiority criteria for OS were met. Donafenib also presented improved safety and tolerability. Common drug-related adverse events, such as hand-foot skin reactions and diarrhea, and drug-related grade 3 or higher adverse events, occurred in fewer patients receiving donafenib than sorafenib, (38% vs. 50%; P = .0018). The authors noted that this lower frequency in adverse events with donafenib “contributed to improved patient adherence and decreased levels of drug interruption and discontinuation.”

Donafenib is a novel, oral, small-molecule, multikinase inhibitor that suppresses tumor cell proliferation and angiogenesis by inhibiting vascular endothelial growth factor receptors and platelet-derived growth factor receptors, and Raf kinases. It is a derivative of sorafenib and in June 2021, it was approved in China as a treatment for unresectable hepatocellular carcinoma for patients who have not received systemic treatment. It is not yet available in the United States.

“This pivotal head-to-head comparison study is the first to demonstrate noninferiority and superiority of a monotherapy, donafenib, with statistically significant extension in OS over sorafenib for first-line treatment of advanced HCC,” the authors wrote. “Compared with international trials, patients in this study presented with more severe baseline disease states, further emphasizing the positive response observed with donafenib.”

Another study, published in the same issue of the Journal of Clinical Oncology, compared tremelimumab and durvalumab as monotherapies and in combination for patients with unresectable HCC, found that use a single priming dose of tremelimumab combined with durvalumab showed the best benefit-risk profile.

In patients with unresectable or metastatic hepatocellular carcinoma (HCC), donafenib was superior to sorafenib in improving overall survival (OS), according to a head-to-head study published in the Journal of Clinical Oncology. This novel multikinase inhibitor and deuterated sorafenib derivative also showed improved safety and tolerability, rendering it a potential first-line monotherapy for patients with advanced HCC.

“An improvement in the pharmacotherapy of advanced HCC remains a clinical need,” wrote Feng Bi, MD, of Sichuan University, in Chengdu, China, and colleagues.

Liver cancer is one of the most common cancers worldwide, with HCC representing 90% of liver malignancies. HCC most commonly occurs in people with liver disease, particularly in those with chronic hepatitis B and C and although rare, HCC is the ninth leading cause of cancer deaths in the United States. Most patients are diagnosed at the advanced stage with a median survival of 6-8 months. Sorafenib, the standard first-line therapy for advanced HCC, has demonstrated the median OS of 10.7 to 14.7 months. No other monotherapy has shown a significant improvement in OS, compared with sorafenib. Donafenib has shown favorable efficacy and safety in phase 1 studies.

This phase 2-3 trial evaluated the efficacy and safety of first-line donafenib, compared with sorafenib, in 668 Chinese patients with advanced HCC. Patients were randomly assigned to receive twice-daily oral donafenib 0.2 g or sorafenib 0.4 g until intolerable toxicity or disease progression. The primary end point was OS, tested for noninferiority and superiority. 

Compared with sorafenib, donafenib significantly prolonged OS, 10.3 and 12.1 months, respectively, (hazard ratio, 95% confidence interval, 0.699-0.988; 0.83; P = .0245), and the superiority criteria for OS were met. Donafenib also presented improved safety and tolerability. Common drug-related adverse events, such as hand-foot skin reactions and diarrhea, and drug-related grade 3 or higher adverse events, occurred in fewer patients receiving donafenib than sorafenib, (38% vs. 50%; P = .0018). The authors noted that this lower frequency in adverse events with donafenib “contributed to improved patient adherence and decreased levels of drug interruption and discontinuation.”

Donafenib is a novel, oral, small-molecule, multikinase inhibitor that suppresses tumor cell proliferation and angiogenesis by inhibiting vascular endothelial growth factor receptors and platelet-derived growth factor receptors, and Raf kinases. It is a derivative of sorafenib and in June 2021, it was approved in China as a treatment for unresectable hepatocellular carcinoma for patients who have not received systemic treatment. It is not yet available in the United States.

“This pivotal head-to-head comparison study is the first to demonstrate noninferiority and superiority of a monotherapy, donafenib, with statistically significant extension in OS over sorafenib for first-line treatment of advanced HCC,” the authors wrote. “Compared with international trials, patients in this study presented with more severe baseline disease states, further emphasizing the positive response observed with donafenib.”

Another study, published in the same issue of the Journal of Clinical Oncology, compared tremelimumab and durvalumab as monotherapies and in combination for patients with unresectable HCC, found that use a single priming dose of tremelimumab combined with durvalumab showed the best benefit-risk profile.

Updated milestones for professional development aim to help specialists in gastroenterology and transplant hepatology achieve knowledge, skills, and attitudes that will help them establish their own practices.

The new version, Milestones 2.0, represents the latest milestones created by the Accreditation Council for Graduate Medical Education, including six core competencies developed initially in 1999: Patient care (PC), medical knowledge (MK), interpersonal and communication skills (ICS), professionalism (PROF), systems-based practice (SBP), and practice-based learning and improvement (PBLI).

In 2013, the Oversight Working Network, working with gastroenterology societies, developed a companion document of 13 entrustable professional activities (EPAs) aimed at gastroenterologists: These include management of various individual disorders such as liver or pancreatic diseases, performance of specific diagnostic procedures, and managing patient adverse events and nutritional status.

Milestones 1.0 encountered some resistance from the graduate education community. Too many of the milestones were deemed to be too vague or were described using language that was too complex. Some viewed the milestones as burdensome, and a review suggested hundreds of different ways to describe ICS and PROF, leading to confusion.

In an effort to improve matters, the ACGME made some changes. The first involved standardizing milestones used for ICS, PROF, SBP, and PBLI so that they could be used across disciplines. They also developed PC and MK milestones tailored to each specialty.

In the latest article on the topic, appearing in Gastroenterology, the authors led by Brijen J. Shah, MD, of the Icahn School of Medicine at Mount Sinai, New York, outlined a second group of changes, which included development of specialty-specific milestones aimed at gastroenterology and transplant hepatology.
 

Development

The new set of milestones includes 17 for gastroenterology and 16 for transplant hepatology.

There are four PC milestones, which include taking a history and conducting patient examinations, patient management, and two more related to cognitive and technical components of procedures. The MK milestones include competency in gastrointestinal and liver diseases (MK1) and medical reasoning (MK2). These milestones are different from the internal medicine milestones met by graduating residents. MK1 includes specialty-specific disorders and diagnostic, therapeutic, and pharmacologic options for treatment or prevention. MK2 encompasses differential diagnoses and how cognitive bias can influence decision-making, a new concept introduced in Milestones 2.0.

Because the skills represented in the four other core milestones (ICS, PROF, SBP, and PBLI) are “common across specialties,” the authors drafted subcompetencies for these four areas with “harmonized” language for use by every specialty. These harmonized milestones were then tailored for each specialty. An important change occurred with SBP because transplant hepatology poses unique challenges in this domain. They ultimately split SBP into two, with SBP1 focusing on unique liver transplant regulatory requirements and SBP2 covering organ allocation and Model for End-Stage Liver Disease (MELD) score exceptions.
 

Public response

The researchers sought out comment on the updated milestones from program directors and coordinators, and published on the ACGME website, and members of the working group also shared it with faculty, fellows, and specialty societies. Overall, 48 respondents assessed “whether the updated milestone provided a realistic measure of knowledge, skills, and behavior; whether it discriminated between different levels of competency; whether the respondent knew how to assess the milestone effectively; and whether the Supplemental Guide was a useful resource in understanding the milestone.” They rated each on a scale of 1 (strongly disagree) to 4 (strongly agree). They could also provide free-text comments.

Respondents agreed that milestones realistically measure progression (mean, 3.49), could distinguish levels of competency (mean, 3.41), could be used accurately (mean, 3.43), and were explained well by the supplemental guide (mean, 3.42). No trends that suggested a need for additional action were found in the free-text comments.
 

Role of milestones

The milestones can be used to develop learning objectives, which in turn can be worked into clinical rotations and learning activities. For instance, the inpatient consult rotation could be used to address the SBP2 (organ allocation/MELD score exemptions), SBP3 (the physician’s role in the health care system), PBLI1 (evidence-based medicine), and some of the PC (patient care) milestones.

The milestones should not be used as an assessment method by supervisors, the authors cautioned, but rather should be used by the Clinical Competency Committee to assess trainees at various time points. The committee may combine milestones with direct observation, chart-simulated recall, multiple evaluations, and other factors to determine a trainee’s progress.

An institution’s program directors can use the milestones to adjust curriculum development and ensure that any gaps are filled. Milestones can be used at multiple times throughout training: When trainees repeat rotations, they can be used to determine year-to-year progress. Trainees who are not progressing adequately may be identified earlier on, then offered supplemental learning opportunities. On the other hand, trainees who exceed expectations may be offered additional opportunities.

Trainees can also use milestones in self-directed learning, though they should work with the program director and clinical faculty to identify gaps in their learning as well as any deficiencies.

The authors have no relevant financial disclosures.

Updated milestones for professional development aim to help specialists in gastroenterology and transplant hepatology achieve knowledge, skills, and attitudes that will help them establish their own practices.

The new version, Milestones 2.0, represents the latest milestones created by the Accreditation Council for Graduate Medical Education, including six core competencies developed initially in 1999: Patient care (PC), medical knowledge (MK), interpersonal and communication skills (ICS), professionalism (PROF), systems-based practice (SBP), and practice-based learning and improvement (PBLI).

In 2013, the Oversight Working Network, working with gastroenterology societies, developed a companion document of 13 entrustable professional activities (EPAs) aimed at gastroenterologists: These include management of various individual disorders such as liver or pancreatic diseases, performance of specific diagnostic procedures, and managing patient adverse events and nutritional status.

Milestones 1.0 encountered some resistance from the graduate education community. Too many of the milestones were deemed to be too vague or were described using language that was too complex. Some viewed the milestones as burdensome, and a review suggested hundreds of different ways to describe ICS and PROF, leading to confusion.

In an effort to improve matters, the ACGME made some changes. The first involved standardizing milestones used for ICS, PROF, SBP, and PBLI so that they could be used across disciplines. They also developed PC and MK milestones tailored to each specialty.

In the latest article on the topic, appearing in Gastroenterology, the authors led by Brijen J. Shah, MD, of the Icahn School of Medicine at Mount Sinai, New York, outlined a second group of changes, which included development of specialty-specific milestones aimed at gastroenterology and transplant hepatology.
 

Development

The new set of milestones includes 17 for gastroenterology and 16 for transplant hepatology.

There are four PC milestones, which include taking a history and conducting patient examinations, patient management, and two more related to cognitive and technical components of procedures. The MK milestones include competency in gastrointestinal and liver diseases (MK1) and medical reasoning (MK2). These milestones are different from the internal medicine milestones met by graduating residents. MK1 includes specialty-specific disorders and diagnostic, therapeutic, and pharmacologic options for treatment or prevention. MK2 encompasses differential diagnoses and how cognitive bias can influence decision-making, a new concept introduced in Milestones 2.0.

Because the skills represented in the four other core milestones (ICS, PROF, SBP, and PBLI) are “common across specialties,” the authors drafted subcompetencies for these four areas with “harmonized” language for use by every specialty. These harmonized milestones were then tailored for each specialty. An important change occurred with SBP because transplant hepatology poses unique challenges in this domain. They ultimately split SBP into two, with SBP1 focusing on unique liver transplant regulatory requirements and SBP2 covering organ allocation and Model for End-Stage Liver Disease (MELD) score exceptions.
 

Public response

The researchers sought out comment on the updated milestones from program directors and coordinators, and published on the ACGME website, and members of the working group also shared it with faculty, fellows, and specialty societies. Overall, 48 respondents assessed “whether the updated milestone provided a realistic measure of knowledge, skills, and behavior; whether it discriminated between different levels of competency; whether the respondent knew how to assess the milestone effectively; and whether the Supplemental Guide was a useful resource in understanding the milestone.” They rated each on a scale of 1 (strongly disagree) to 4 (strongly agree). They could also provide free-text comments.

Respondents agreed that milestones realistically measure progression (mean, 3.49), could distinguish levels of competency (mean, 3.41), could be used accurately (mean, 3.43), and were explained well by the supplemental guide (mean, 3.42). No trends that suggested a need for additional action were found in the free-text comments.
 

Role of milestones

The milestones can be used to develop learning objectives, which in turn can be worked into clinical rotations and learning activities. For instance, the inpatient consult rotation could be used to address the SBP2 (organ allocation/MELD score exemptions), SBP3 (the physician’s role in the health care system), PBLI1 (evidence-based medicine), and some of the PC (patient care) milestones.

The milestones should not be used as an assessment method by supervisors, the authors cautioned, but rather should be used by the Clinical Competency Committee to assess trainees at various time points. The committee may combine milestones with direct observation, chart-simulated recall, multiple evaluations, and other factors to determine a trainee’s progress.

An institution’s program directors can use the milestones to adjust curriculum development and ensure that any gaps are filled. Milestones can be used at multiple times throughout training: When trainees repeat rotations, they can be used to determine year-to-year progress. Trainees who are not progressing adequately may be identified earlier on, then offered supplemental learning opportunities. On the other hand, trainees who exceed expectations may be offered additional opportunities.

Trainees can also use milestones in self-directed learning, though they should work with the program director and clinical faculty to identify gaps in their learning as well as any deficiencies.

The authors have no relevant financial disclosures.

Updated milestones for professional development aim to help specialists in gastroenterology and transplant hepatology achieve knowledge, skills, and attitudes that will help them establish their own practices.

The new version, Milestones 2.0, represents the latest milestones created by the Accreditation Council for Graduate Medical Education, including six core competencies developed initially in 1999: Patient care (PC), medical knowledge (MK), interpersonal and communication skills (ICS), professionalism (PROF), systems-based practice (SBP), and practice-based learning and improvement (PBLI).

In 2013, the Oversight Working Network, working with gastroenterology societies, developed a companion document of 13 entrustable professional activities (EPAs) aimed at gastroenterologists: These include management of various individual disorders such as liver or pancreatic diseases, performance of specific diagnostic procedures, and managing patient adverse events and nutritional status.

Milestones 1.0 encountered some resistance from the graduate education community. Too many of the milestones were deemed to be too vague or were described using language that was too complex. Some viewed the milestones as burdensome, and a review suggested hundreds of different ways to describe ICS and PROF, leading to confusion.

In an effort to improve matters, the ACGME made some changes. The first involved standardizing milestones used for ICS, PROF, SBP, and PBLI so that they could be used across disciplines. They also developed PC and MK milestones tailored to each specialty.

In the latest article on the topic, appearing in Gastroenterology, the authors led by Brijen J. Shah, MD, of the Icahn School of Medicine at Mount Sinai, New York, outlined a second group of changes, which included development of specialty-specific milestones aimed at gastroenterology and transplant hepatology.
 

Development

The new set of milestones includes 17 for gastroenterology and 16 for transplant hepatology.

There are four PC milestones, which include taking a history and conducting patient examinations, patient management, and two more related to cognitive and technical components of procedures. The MK milestones include competency in gastrointestinal and liver diseases (MK1) and medical reasoning (MK2). These milestones are different from the internal medicine milestones met by graduating residents. MK1 includes specialty-specific disorders and diagnostic, therapeutic, and pharmacologic options for treatment or prevention. MK2 encompasses differential diagnoses and how cognitive bias can influence decision-making, a new concept introduced in Milestones 2.0.

Because the skills represented in the four other core milestones (ICS, PROF, SBP, and PBLI) are “common across specialties,” the authors drafted subcompetencies for these four areas with “harmonized” language for use by every specialty. These harmonized milestones were then tailored for each specialty. An important change occurred with SBP because transplant hepatology poses unique challenges in this domain. They ultimately split SBP into two, with SBP1 focusing on unique liver transplant regulatory requirements and SBP2 covering organ allocation and Model for End-Stage Liver Disease (MELD) score exceptions.
 

Public response

The researchers sought out comment on the updated milestones from program directors and coordinators, and published on the ACGME website, and members of the working group also shared it with faculty, fellows, and specialty societies. Overall, 48 respondents assessed “whether the updated milestone provided a realistic measure of knowledge, skills, and behavior; whether it discriminated between different levels of competency; whether the respondent knew how to assess the milestone effectively; and whether the Supplemental Guide was a useful resource in understanding the milestone.” They rated each on a scale of 1 (strongly disagree) to 4 (strongly agree). They could also provide free-text comments.

Respondents agreed that milestones realistically measure progression (mean, 3.49), could distinguish levels of competency (mean, 3.41), could be used accurately (mean, 3.43), and were explained well by the supplemental guide (mean, 3.42). No trends that suggested a need for additional action were found in the free-text comments.
 

Role of milestones

The milestones can be used to develop learning objectives, which in turn can be worked into clinical rotations and learning activities. For instance, the inpatient consult rotation could be used to address the SBP2 (organ allocation/MELD score exemptions), SBP3 (the physician’s role in the health care system), PBLI1 (evidence-based medicine), and some of the PC (patient care) milestones.

The milestones should not be used as an assessment method by supervisors, the authors cautioned, but rather should be used by the Clinical Competency Committee to assess trainees at various time points. The committee may combine milestones with direct observation, chart-simulated recall, multiple evaluations, and other factors to determine a trainee’s progress.

An institution’s program directors can use the milestones to adjust curriculum development and ensure that any gaps are filled. Milestones can be used at multiple times throughout training: When trainees repeat rotations, they can be used to determine year-to-year progress. Trainees who are not progressing adequately may be identified earlier on, then offered supplemental learning opportunities. On the other hand, trainees who exceed expectations may be offered additional opportunities.

Trainees can also use milestones in self-directed learning, though they should work with the program director and clinical faculty to identify gaps in their learning as well as any deficiencies.

The authors have no relevant financial disclosures.

American children gained a lot of weight in the last year, setting a dangerous trajectory towards metabolic disease that requires urgent policy change, according to a new report from the Robert Wood Johnson Foundation.

“Our nation’s safety net is fragile, outdated, and out of reach for millions of eligible kids and caregivers,” said Jamie Bussel, senior program officer at the RWJF, and senior author of the report. She added that the pandemic further fractured an already broken system that disproportionately overlooks “children of color and those who live farthest from economic opportunity”.
 

It’s time to think ‘bigger and better’

Ms. Bussel said, during a press conference, that congress responded to the pandemic with “an array of policy solutions,” but it’s now time to think ‘bigger and better.’

“There have been huge flexibilities deployed across the safety net program and these have been really important reliefs, but the fact is many of them are temporary emergency relief measures,” she explained.

For the past 3 years, the RWJF’s annual State of Childhood Obesity report has drawn national and state obesity data from large surveys including the National Survey of Children’s Health, the Youth Risk Behavior Surveillance System, the WIC Participant and Program Characteristics Survey, and the National Health and Nutrition Examination Survey.

Similar to in past years, this year’s data show that rates of obesity and overweight have remained relatively steady and have been highest among minority and low-income populations. For example, data from the 2019-2020 National Survey of Children’s Health, along with an analysis conducted by the Health Resources and Services Administration’s Maternal and Child Health Bureau, show that one in six – or 16.2% – of youth aged 10-17 years have obesity.

While non-Hispanic Asian children had the lowest obesity rate (8.1%), followed by non-Hispanic White children (12.1%), rates were significantly higher for Hispanic (21.4%), non-Hispanic Black (23.8%), and non-Hispanic American Indian/Alaska Native (28.7%) children, according to the report.

“Additional years of data are needed to assess whether obesity rates changed after the onset of the pandemic,” explained Ms. Bussel.
 

Digging deeper

Other studies included in this year’s report were specifically designed to measure the impact of the pandemic, and show a distinct rise in overweight and obesity, especially in younger children. For example, a retrospective cohort study using data from Kaiser Permanente Southern California showed the rate of overweight and obesity in children aged 5-11 years rose to 45.7% between March 2020 and January 2021, up from 36.2% before the pandemic.

Another of these studies, which was based on national electronic health records of more than 430,000 children, showed the obesity rate crept from 19.3% to 22.4% between August 2019 and August 2020.

“The lid we had been trying desperately to put on the obesity epidemic has come off again,” said Sandra G Hassink, MD, MSc, who is medical director of the American Academy of Pediatrics Institute for Healthy Childhood Weight.

“In the absence of COVID we had been seeing slow upticks in the numbers – and in some groups we’d been thinking maybe we were headed toward stabilization – but these numbers blow that out of the water ... COVID has escalated the rates,” she said in an interview.

“Unfortunately, these two crises – the COVID pandemic, the childhood obesity epidemic – in so many ways have exacerbated one another,” said Ms. Bussel. “It’s not a huge surprise that we’re seeing an increase in childhood obesity rates given the complete and utter disruption of every single system that circumscribes our lives.”
 

The systems that feed obesity

Addressing childhood obesity requires targeting far beyond healthy eating and physical activity, Ms. Bussel said.

“As important is whether that child has a safe place to call home. Does mom or dad or their care provider have a stable income? Is there reliable transportation? Is their access to health insurance? Is there access to high-quality health care? ... All of those factors influence the child and the family’s opportunities to live well, be healthy, and be at a healthy weight,” she noted.

The report includes a list of five main policy recommendations.

• Making free, universal school meal programs permanent.
• Extending eligibility for WIC, the Special Supplemental Nutrition Program for Women, Infants, and Children, to postpartum mothers and to children through age 6.
• Extending and expanding other programs, such as the Child Tax Credit.
• Closing the Medicaid coverage gap.
• Developing a consistent approach to collecting obesity data organized by race, ethnicity, and income level.

“Collectively, over at least the course of the last generation or two, our policy approach to obesity prevention has not been sufficient. But that doesn’t mean all of our policy approaches have been failures,” Ms. Bussel said during an interview. “Policy change does not always need to be dramatic to have a real impact on families.”

Fighting complacency

For Dr. Hassink, one of the barriers to change is society’s level of acceptance. She said an identifiable explanation for pandemic weight gain doesn’t mean society should simply shrug it off.

“If we regarded childhood obesity as the population level catastrophe that it is for chronic disease maybe people would be activated around these policy changes,” she said.

“We’re accepting a disease process that wreaks havoc on people,” noted Dr. Hassink, who was not involved in the new report. “I think it’s hard for people to realize the magnitude of the disease burden that we’re seeing. If you’re in a weight management clinic or any pediatrician’s office you would see it – you would see kids coming in with liver disease, 9-year-olds on [continuous positive airway pressure] for sleep apnea, kids needing their hips pinned because they had a hip fracture because of obesity.

“So, those of us that see the disease burden see what’s behind those numbers. The sadness of what we’re talking about is we know a lot about what could push the dial and help reduce this epidemic and we’re not doing what we already know,” added Dr. Hassink.

Ms. Bussel and Dr. Hassink reported no conflicts.

American children gained a lot of weight in the last year, setting a dangerous trajectory towards metabolic disease that requires urgent policy change, according to a new report from the Robert Wood Johnson Foundation.

“Our nation’s safety net is fragile, outdated, and out of reach for millions of eligible kids and caregivers,” said Jamie Bussel, senior program officer at the RWJF, and senior author of the report. She added that the pandemic further fractured an already broken system that disproportionately overlooks “children of color and those who live farthest from economic opportunity”.
 

It’s time to think ‘bigger and better’

Ms. Bussel said, during a press conference, that congress responded to the pandemic with “an array of policy solutions,” but it’s now time to think ‘bigger and better.’

“There have been huge flexibilities deployed across the safety net program and these have been really important reliefs, but the fact is many of them are temporary emergency relief measures,” she explained.

For the past 3 years, the RWJF’s annual State of Childhood Obesity report has drawn national and state obesity data from large surveys including the National Survey of Children’s Health, the Youth Risk Behavior Surveillance System, the WIC Participant and Program Characteristics Survey, and the National Health and Nutrition Examination Survey.

Similar to in past years, this year’s data show that rates of obesity and overweight have remained relatively steady and have been highest among minority and low-income populations. For example, data from the 2019-2020 National Survey of Children’s Health, along with an analysis conducted by the Health Resources and Services Administration’s Maternal and Child Health Bureau, show that one in six – or 16.2% – of youth aged 10-17 years have obesity.

While non-Hispanic Asian children had the lowest obesity rate (8.1%), followed by non-Hispanic White children (12.1%), rates were significantly higher for Hispanic (21.4%), non-Hispanic Black (23.8%), and non-Hispanic American Indian/Alaska Native (28.7%) children, according to the report.

“Additional years of data are needed to assess whether obesity rates changed after the onset of the pandemic,” explained Ms. Bussel.
 

Digging deeper

Other studies included in this year’s report were specifically designed to measure the impact of the pandemic, and show a distinct rise in overweight and obesity, especially in younger children. For example, a retrospective cohort study using data from Kaiser Permanente Southern California showed the rate of overweight and obesity in children aged 5-11 years rose to 45.7% between March 2020 and January 2021, up from 36.2% before the pandemic.

Another of these studies, which was based on national electronic health records of more than 430,000 children, showed the obesity rate crept from 19.3% to 22.4% between August 2019 and August 2020.

“The lid we had been trying desperately to put on the obesity epidemic has come off again,” said Sandra G Hassink, MD, MSc, who is medical director of the American Academy of Pediatrics Institute for Healthy Childhood Weight.

“In the absence of COVID we had been seeing slow upticks in the numbers – and in some groups we’d been thinking maybe we were headed toward stabilization – but these numbers blow that out of the water ... COVID has escalated the rates,” she said in an interview.

“Unfortunately, these two crises – the COVID pandemic, the childhood obesity epidemic – in so many ways have exacerbated one another,” said Ms. Bussel. “It’s not a huge surprise that we’re seeing an increase in childhood obesity rates given the complete and utter disruption of every single system that circumscribes our lives.”
 

The systems that feed obesity

Addressing childhood obesity requires targeting far beyond healthy eating and physical activity, Ms. Bussel said.

“As important is whether that child has a safe place to call home. Does mom or dad or their care provider have a stable income? Is there reliable transportation? Is their access to health insurance? Is there access to high-quality health care? ... All of those factors influence the child and the family’s opportunities to live well, be healthy, and be at a healthy weight,” she noted.

The report includes a list of five main policy recommendations.

• Making free, universal school meal programs permanent.
• Extending eligibility for WIC, the Special Supplemental Nutrition Program for Women, Infants, and Children, to postpartum mothers and to children through age 6.
• Extending and expanding other programs, such as the Child Tax Credit.
• Closing the Medicaid coverage gap.
• Developing a consistent approach to collecting obesity data organized by race, ethnicity, and income level.

“Collectively, over at least the course of the last generation or two, our policy approach to obesity prevention has not been sufficient. But that doesn’t mean all of our policy approaches have been failures,” Ms. Bussel said during an interview. “Policy change does not always need to be dramatic to have a real impact on families.”

Fighting complacency

For Dr. Hassink, one of the barriers to change is society’s level of acceptance. She said an identifiable explanation for pandemic weight gain doesn’t mean society should simply shrug it off.

“If we regarded childhood obesity as the population level catastrophe that it is for chronic disease maybe people would be activated around these policy changes,” she said.

“We’re accepting a disease process that wreaks havoc on people,” noted Dr. Hassink, who was not involved in the new report. “I think it’s hard for people to realize the magnitude of the disease burden that we’re seeing. If you’re in a weight management clinic or any pediatrician’s office you would see it – you would see kids coming in with liver disease, 9-year-olds on [continuous positive airway pressure] for sleep apnea, kids needing their hips pinned because they had a hip fracture because of obesity.

“So, those of us that see the disease burden see what’s behind those numbers. The sadness of what we’re talking about is we know a lot about what could push the dial and help reduce this epidemic and we’re not doing what we already know,” added Dr. Hassink.

Ms. Bussel and Dr. Hassink reported no conflicts.

American children gained a lot of weight in the last year, setting a dangerous trajectory towards metabolic disease that requires urgent policy change, according to a new report from the Robert Wood Johnson Foundation.

“Our nation’s safety net is fragile, outdated, and out of reach for millions of eligible kids and caregivers,” said Jamie Bussel, senior program officer at the RWJF, and senior author of the report. She added that the pandemic further fractured an already broken system that disproportionately overlooks “children of color and those who live farthest from economic opportunity”.
 

It’s time to think ‘bigger and better’

Ms. Bussel said, during a press conference, that congress responded to the pandemic with “an array of policy solutions,” but it’s now time to think ‘bigger and better.’

“There have been huge flexibilities deployed across the safety net program and these have been really important reliefs, but the fact is many of them are temporary emergency relief measures,” she explained.

For the past 3 years, the RWJF’s annual State of Childhood Obesity report has drawn national and state obesity data from large surveys including the National Survey of Children’s Health, the Youth Risk Behavior Surveillance System, the WIC Participant and Program Characteristics Survey, and the National Health and Nutrition Examination Survey.

Similar to in past years, this year’s data show that rates of obesity and overweight have remained relatively steady and have been highest among minority and low-income populations. For example, data from the 2019-2020 National Survey of Children’s Health, along with an analysis conducted by the Health Resources and Services Administration’s Maternal and Child Health Bureau, show that one in six – or 16.2% – of youth aged 10-17 years have obesity.

While non-Hispanic Asian children had the lowest obesity rate (8.1%), followed by non-Hispanic White children (12.1%), rates were significantly higher for Hispanic (21.4%), non-Hispanic Black (23.8%), and non-Hispanic American Indian/Alaska Native (28.7%) children, according to the report.

“Additional years of data are needed to assess whether obesity rates changed after the onset of the pandemic,” explained Ms. Bussel.
 

Digging deeper

Other studies included in this year’s report were specifically designed to measure the impact of the pandemic, and show a distinct rise in overweight and obesity, especially in younger children. For example, a retrospective cohort study using data from Kaiser Permanente Southern California showed the rate of overweight and obesity in children aged 5-11 years rose to 45.7% between March 2020 and January 2021, up from 36.2% before the pandemic.

Another of these studies, which was based on national electronic health records of more than 430,000 children, showed the obesity rate crept from 19.3% to 22.4% between August 2019 and August 2020.

“The lid we had been trying desperately to put on the obesity epidemic has come off again,” said Sandra G Hassink, MD, MSc, who is medical director of the American Academy of Pediatrics Institute for Healthy Childhood Weight.

“In the absence of COVID we had been seeing slow upticks in the numbers – and in some groups we’d been thinking maybe we were headed toward stabilization – but these numbers blow that out of the water ... COVID has escalated the rates,” she said in an interview.

“Unfortunately, these two crises – the COVID pandemic, the childhood obesity epidemic – in so many ways have exacerbated one another,” said Ms. Bussel. “It’s not a huge surprise that we’re seeing an increase in childhood obesity rates given the complete and utter disruption of every single system that circumscribes our lives.”
 

The systems that feed obesity

Addressing childhood obesity requires targeting far beyond healthy eating and physical activity, Ms. Bussel said.

“As important is whether that child has a safe place to call home. Does mom or dad or their care provider have a stable income? Is there reliable transportation? Is their access to health insurance? Is there access to high-quality health care? ... All of those factors influence the child and the family’s opportunities to live well, be healthy, and be at a healthy weight,” she noted.

The report includes a list of five main policy recommendations.

• Making free, universal school meal programs permanent.
• Extending eligibility for WIC, the Special Supplemental Nutrition Program for Women, Infants, and Children, to postpartum mothers and to children through age 6.
• Extending and expanding other programs, such as the Child Tax Credit.
• Closing the Medicaid coverage gap.
• Developing a consistent approach to collecting obesity data organized by race, ethnicity, and income level.

“Collectively, over at least the course of the last generation or two, our policy approach to obesity prevention has not been sufficient. But that doesn’t mean all of our policy approaches have been failures,” Ms. Bussel said during an interview. “Policy change does not always need to be dramatic to have a real impact on families.”

Fighting complacency

For Dr. Hassink, one of the barriers to change is society’s level of acceptance. She said an identifiable explanation for pandemic weight gain doesn’t mean society should simply shrug it off.

“If we regarded childhood obesity as the population level catastrophe that it is for chronic disease maybe people would be activated around these policy changes,” she said.

“We’re accepting a disease process that wreaks havoc on people,” noted Dr. Hassink, who was not involved in the new report. “I think it’s hard for people to realize the magnitude of the disease burden that we’re seeing. If you’re in a weight management clinic or any pediatrician’s office you would see it – you would see kids coming in with liver disease, 9-year-olds on [continuous positive airway pressure] for sleep apnea, kids needing their hips pinned because they had a hip fracture because of obesity.

“So, those of us that see the disease burden see what’s behind those numbers. The sadness of what we’re talking about is we know a lot about what could push the dial and help reduce this epidemic and we’re not doing what we already know,” added Dr. Hassink.

Ms. Bussel and Dr. Hassink reported no conflicts.

A combination of magnetic resonance elastography and blood levels of fibrosis-4 index (MEFIB) outperformed FibroScan-AST (FAST) in determining the presence of significant fibrosis among patients with nonalcoholic fatty liver disease (NAFLD), according to a new prospective cohort analysis.

© parisvas/Thinkstock

Liver fibrosis is the most important prognostic factor for NAFLD, but the invasiveness, propensity for sampling error, and interoperator variability of biopsy have prompted efforts to develop alternatives. FAST, which uses vibration-controlled transient elastography (VCTE), controlled attenuation parameter (CAP), and aspartate aminotransferase levels, and MEFIB have been developed as candidates, but they had not been directly compared in screening. The findings suggest that MEFIB may be a better tool for identifying NAFLD patients at heightened risk of nonalcoholic steatohepatitis (NASH), as well as which patients could be candidates for pharmacotherapy interventions and clinical trials.

Although there are no drugs currently approved for high-risk NAFLD patients, many clinical trials are underway. Patients with stage 2 or higher fibrosis are candidates for clinical trials, but many trials experience a high screening failure rate. A noninvasive method that can identify clinical trial candidates while avoiding liver biopsy would be a welcome addition, Nobuharu Tamaki, MD, PhD, of the NAFLD Research Center, division of gastroenterology and hepatology, department of medicine, at the University of California, San Diego, and colleagues explained in Hepatology.

“We suspect that these are the patients; if there is going to be a drug approved, it will be for this patient population. So it’s important for prognosis, but it’s also important potentially for future treatment with new drugs,” said Zobair Younossi, MD, who was asked to comment on the study.

The researchers examined a cohort of 234 consecutive adults at UCSD and 314 consecutive adults at Yokohama (Japan) City University who underwent liver biopsy, magnetic resonance elastography (MRE), VCTE, and CAP assessment.

Significant fibrosis was found in 29.5% of the UCSD cohort and 66.2% of the Yokohama cohort.* MEFIB had a higher area under the receiver operating characteristic curve than FAST in the UCSD cohort (0.860 vs. 0.757; P = .005) and the Yokohama cohort (0.899 vs. 0.724; P < .001).

When the researchers employed MEFIB as a rule-in criteria (MRE value ≥3.3 kPa and FIB-4 ≥1.6), MEFIB had a positive predictive value of 91.2% in the UCSD cohort and 96.0% in the Yokohama cohort, versus 74.2% and 89.2% for FAST (≥0.67), respectively. Rule-out criteria included MRE less than 3.3 kPa and Fib-4 less than1.6 for MEFIB, as well as FAST of 0.35 or less; with those parameters, negative predictive value for significant fibrosis was 92.8% in the UCSD group and 85.6% in the Yokohama group for MEFIB, and 88.3% and 57.8% for FAST, respectively.

Most existing noninvasive tests do a pretty good job of excluding advanced fibrosis, but they don’t perform as well at identifying those with cirrhosis, according to Dr. Younossi. He added that MEFIB isn’t suitable for general population screening, but rather for case finding, in which it can be used to identify patients who are likely to have high risk for fibrosis. “Nevertheless, it seems like the combination of FIB-4 and MRE has very good performance for identifying and excluding NAFLD patients with moderate to advance fibrosis, at least in the two cohorts that were looked at,” said Dr. Younossi.

However, Dr. Younossi noted some potential limitations to the study. Both cohorts were from referral centers, making it likely that the included patients have higher prevalences of fibrosis than a typical practice patient population, making it important to validate the findings in a real-world setting. The approach also relies on magnetic resonance technology, which is costly and may not be readily available. “We need to potentially find other, simpler noninvasive test combinations that are easier to do than MRE,” said Dr. Younossi.

Several authors disclosed ties with numerous pharmaceutical and device companies, including Pfizer, AstraZeneca, and Siemens. Dr. Younossi has no relevant financial disclosures.

Correction, 1/18/22: An earlier version of this article misstated the percentage of each cohort that had significant fibrosis.

A combination of magnetic resonance elastography and blood levels of fibrosis-4 index (MEFIB) outperformed FibroScan-AST (FAST) in determining the presence of significant fibrosis among patients with nonalcoholic fatty liver disease (NAFLD), according to a new prospective cohort analysis.

© parisvas/Thinkstock

Liver fibrosis is the most important prognostic factor for NAFLD, but the invasiveness, propensity for sampling error, and interoperator variability of biopsy have prompted efforts to develop alternatives. FAST, which uses vibration-controlled transient elastography (VCTE), controlled attenuation parameter (CAP), and aspartate aminotransferase levels, and MEFIB have been developed as candidates, but they had not been directly compared in screening. The findings suggest that MEFIB may be a better tool for identifying NAFLD patients at heightened risk of nonalcoholic steatohepatitis (NASH), as well as which patients could be candidates for pharmacotherapy interventions and clinical trials.

Although there are no drugs currently approved for high-risk NAFLD patients, many clinical trials are underway. Patients with stage 2 or higher fibrosis are candidates for clinical trials, but many trials experience a high screening failure rate. A noninvasive method that can identify clinical trial candidates while avoiding liver biopsy would be a welcome addition, Nobuharu Tamaki, MD, PhD, of the NAFLD Research Center, division of gastroenterology and hepatology, department of medicine, at the University of California, San Diego, and colleagues explained in Hepatology.

“We suspect that these are the patients; if there is going to be a drug approved, it will be for this patient population. So it’s important for prognosis, but it’s also important potentially for future treatment with new drugs,” said Zobair Younossi, MD, who was asked to comment on the study.

The researchers examined a cohort of 234 consecutive adults at UCSD and 314 consecutive adults at Yokohama (Japan) City University who underwent liver biopsy, magnetic resonance elastography (MRE), VCTE, and CAP assessment.

Significant fibrosis was found in 29.5% of the UCSD cohort and 66.2% of the Yokohama cohort.* MEFIB had a higher area under the receiver operating characteristic curve than FAST in the UCSD cohort (0.860 vs. 0.757; P = .005) and the Yokohama cohort (0.899 vs. 0.724; P < .001).

When the researchers employed MEFIB as a rule-in criteria (MRE value ≥3.3 kPa and FIB-4 ≥1.6), MEFIB had a positive predictive value of 91.2% in the UCSD cohort and 96.0% in the Yokohama cohort, versus 74.2% and 89.2% for FAST (≥0.67), respectively. Rule-out criteria included MRE less than 3.3 kPa and Fib-4 less than1.6 for MEFIB, as well as FAST of 0.35 or less; with those parameters, negative predictive value for significant fibrosis was 92.8% in the UCSD group and 85.6% in the Yokohama group for MEFIB, and 88.3% and 57.8% for FAST, respectively.

Most existing noninvasive tests do a pretty good job of excluding advanced fibrosis, but they don’t perform as well at identifying those with cirrhosis, according to Dr. Younossi. He added that MEFIB isn’t suitable for general population screening, but rather for case finding, in which it can be used to identify patients who are likely to have high risk for fibrosis. “Nevertheless, it seems like the combination of FIB-4 and MRE has very good performance for identifying and excluding NAFLD patients with moderate to advance fibrosis, at least in the two cohorts that were looked at,” said Dr. Younossi.

However, Dr. Younossi noted some potential limitations to the study. Both cohorts were from referral centers, making it likely that the included patients have higher prevalences of fibrosis than a typical practice patient population, making it important to validate the findings in a real-world setting. The approach also relies on magnetic resonance technology, which is costly and may not be readily available. “We need to potentially find other, simpler noninvasive test combinations that are easier to do than MRE,” said Dr. Younossi.

Several authors disclosed ties with numerous pharmaceutical and device companies, including Pfizer, AstraZeneca, and Siemens. Dr. Younossi has no relevant financial disclosures.

Correction, 1/18/22: An earlier version of this article misstated the percentage of each cohort that had significant fibrosis.

A combination of magnetic resonance elastography and blood levels of fibrosis-4 index (MEFIB) outperformed FibroScan-AST (FAST) in determining the presence of significant fibrosis among patients with nonalcoholic fatty liver disease (NAFLD), according to a new prospective cohort analysis.

© parisvas/Thinkstock

Liver fibrosis is the most important prognostic factor for NAFLD, but the invasiveness, propensity for sampling error, and interoperator variability of biopsy have prompted efforts to develop alternatives. FAST, which uses vibration-controlled transient elastography (VCTE), controlled attenuation parameter (CAP), and aspartate aminotransferase levels, and MEFIB have been developed as candidates, but they had not been directly compared in screening. The findings suggest that MEFIB may be a better tool for identifying NAFLD patients at heightened risk of nonalcoholic steatohepatitis (NASH), as well as which patients could be candidates for pharmacotherapy interventions and clinical trials.

Although there are no drugs currently approved for high-risk NAFLD patients, many clinical trials are underway. Patients with stage 2 or higher fibrosis are candidates for clinical trials, but many trials experience a high screening failure rate. A noninvasive method that can identify clinical trial candidates while avoiding liver biopsy would be a welcome addition, Nobuharu Tamaki, MD, PhD, of the NAFLD Research Center, division of gastroenterology and hepatology, department of medicine, at the University of California, San Diego, and colleagues explained in Hepatology.

“We suspect that these are the patients; if there is going to be a drug approved, it will be for this patient population. So it’s important for prognosis, but it’s also important potentially for future treatment with new drugs,” said Zobair Younossi, MD, who was asked to comment on the study.

The researchers examined a cohort of 234 consecutive adults at UCSD and 314 consecutive adults at Yokohama (Japan) City University who underwent liver biopsy, magnetic resonance elastography (MRE), VCTE, and CAP assessment.

Significant fibrosis was found in 29.5% of the UCSD cohort and 66.2% of the Yokohama cohort.* MEFIB had a higher area under the receiver operating characteristic curve than FAST in the UCSD cohort (0.860 vs. 0.757; P = .005) and the Yokohama cohort (0.899 vs. 0.724; P < .001).

When the researchers employed MEFIB as a rule-in criteria (MRE value ≥3.3 kPa and FIB-4 ≥1.6), MEFIB had a positive predictive value of 91.2% in the UCSD cohort and 96.0% in the Yokohama cohort, versus 74.2% and 89.2% for FAST (≥0.67), respectively. Rule-out criteria included MRE less than 3.3 kPa and Fib-4 less than1.6 for MEFIB, as well as FAST of 0.35 or less; with those parameters, negative predictive value for significant fibrosis was 92.8% in the UCSD group and 85.6% in the Yokohama group for MEFIB, and 88.3% and 57.8% for FAST, respectively.

Most existing noninvasive tests do a pretty good job of excluding advanced fibrosis, but they don’t perform as well at identifying those with cirrhosis, according to Dr. Younossi. He added that MEFIB isn’t suitable for general population screening, but rather for case finding, in which it can be used to identify patients who are likely to have high risk for fibrosis. “Nevertheless, it seems like the combination of FIB-4 and MRE has very good performance for identifying and excluding NAFLD patients with moderate to advance fibrosis, at least in the two cohorts that were looked at,” said Dr. Younossi.

However, Dr. Younossi noted some potential limitations to the study. Both cohorts were from referral centers, making it likely that the included patients have higher prevalences of fibrosis than a typical practice patient population, making it important to validate the findings in a real-world setting. The approach also relies on magnetic resonance technology, which is costly and may not be readily available. “We need to potentially find other, simpler noninvasive test combinations that are easier to do than MRE,” said Dr. Younossi.

Several authors disclosed ties with numerous pharmaceutical and device companies, including Pfizer, AstraZeneca, and Siemens. Dr. Younossi has no relevant financial disclosures.

Correction, 1/18/22: An earlier version of this article misstated the percentage of each cohort that had significant fibrosis.

Alcohol intake and obesity are independent risk factors for morbidity among patients with cirrhosis, but the two factors do not appear to combine for a stronger effect (supra-additive), according to conclusions from a new analysis of participants in the UK Biobank study published in Hepatology.

Nikada/iStockphoto

The researchers analyzed data from the records of 489,285 individuals in the UK Biobank from May 2006 to July 2010. Researchers defined morbidity as first-time hospitalization for cirrhosis and calculated the cumulative incidence at 10 years among included individuals. The researchers defined obesity as body mass index of at least 30 kg/m² and healthy BMI as 20-25. Safe drinking was defined as having fewer than 22 units per week for males or fewer than 15 units for females, harmful drinking was defined as more than 50 units per week for males or more than 35 for females, and hazardous drinking was defined as 22-49 units per week for males and 15-35 for females. The researchers assumed 2 units in a pint of beer or cider, 1.5 units in a glass of wine and “other” drinks, and 1 unit per measure of spirits.

The mean age was 57.0 years, and 45.4% were male. Overall, 24.3% of subjects were obese, 76.5% had safe levels of alcohol consumption, 19.7% had hazardous alcohol consumption, and 3.8% were classified as harmful drinkers.

Overall, harmful drinking was associated with 5.0 times the 10-year cumulative incidence of cirrhosis morbidity among harmful versus safe drinkers (1.51% vs. 0.30%). However, among those with a healthy BMI, harmful was associated with an 8.6-fold increase of cirrhosis morbidity, compared with safe drinkers (1.38% vs. 0.16%). On the other hand, obese patients with harmful drinking habits had a 3.6-fold increase over obese safe drinkers (1.99% vs. 0.56%).

When looked at according to BMI, 10-year cumulative incidence was 3.1 times higher in patients who with obesity versus those who with healthy BMI (0.65% vs. 0.21%). This varied strongly with drinking: Safe drinkers who with obesity had 3.7 times the incidence, compared with safe drinkers with healthy BMI (0.56% vs. 0.15%), and harmful drinkers who were obese had a 1.4-fold increased incidence, compared with harmful drinkers of a healthy weight (1.99% vs. 1.38%).

“In contrast to some previous studies, we found little evidence that [obesity and drinking] interacted supra-additively to modulate the risk of cirrhosis morbidity,” the authors wrote. “On the contrary, through a relative risk lens, the association between alcohol intake and cirrhosis morbidity was actually weaker for individuals with obesity than for individuals with a healthy BMI (indicating a sub-additive relationship).”

Fine-Gray regression modelling seemed to confirm that the relationship was sub-additive. After controlling for various factors, researchers found that harmful drinkers had a 6.84-fold increased risk at a healthy BMI, while the risk was only 3.14 times higher in obese patients (P _interaction = 3.53 x 10^–6).

The findings contradict previous studies, which suggested that high BMI and harmful drinking combined may produce much higher risk than either factor alone, possibly because obesity might “prime” the liver to be vulnerable to the effects of alcohol.

The authors suggest that the differences in findings may be caused by methodological limitations of the earlier studies, such as reliance on self-reported BMI data; small sample sizes and a relatively small number of liver events among those with obesity and harmful alcohol consumption; and the failure to use a competing risk perspective. The latter is relevant because alcohol and obesity are risk factors for other potentially fatal health conditions.

But the current study is not without its own limitations, according to Nancy Reau, MD, who is a professor of medicine and chair of hepatology at Rush University Medical Center in Chicago, who was asked to comment on the findings. Dr. Reau pointed out that the authors found the highest frequency of complications was observed in people with harmful alcohol intake whose BMI was under 20. That group may be composed of subjects with sarcopenia and end-stage liver disease from alcohol use. “Until you can separate these from the truly healthy BMI but [with harmful alcohol use], you can’t interpret this arm,” said Dr. Reau.

Beyond that, the researchers found increased risks of harm among individuals regardless of BMI, but the risks were highest among those with BMI over 30. Dr. Reau posited that the frequency might have been significantly greater at BMI higher than 35 and 40, but the researchers didn’t report results among these subcategories.

“In no way does this suggest that we need to ignore alcohol use in our patients with NAFLD [nonalcoholic fatty liver disease] or [nonalcoholic steatohepatitis],” said Dr. Reau.

In fact, she pointed to a figure in the paper that showed the highest increase in frequency among those with harmful alcohol use and obesity. “It’s clear that both conditions are much more serious than just obesity alone. It is incredibly important to council our NAFLD patients on appropriate alcohol use, [since] problematic drinking increases their risk. Problematic drinking remains a serious problem and increased awareness and linking to addiction services is important,” she said.

The authors reported no conflicts of interest. Dr. Reau has no relevant financial disclosures.

Alcohol intake and obesity are independent risk factors for morbidity among patients with cirrhosis, but the two factors do not appear to combine for a stronger effect (supra-additive), according to conclusions from a new analysis of participants in the UK Biobank study published in Hepatology.

Nikada/iStockphoto

The researchers analyzed data from the records of 489,285 individuals in the UK Biobank from May 2006 to July 2010. Researchers defined morbidity as first-time hospitalization for cirrhosis and calculated the cumulative incidence at 10 years among included individuals. The researchers defined obesity as body mass index of at least 30 kg/m² and healthy BMI as 20-25. Safe drinking was defined as having fewer than 22 units per week for males or fewer than 15 units for females, harmful drinking was defined as more than 50 units per week for males or more than 35 for females, and hazardous drinking was defined as 22-49 units per week for males and 15-35 for females. The researchers assumed 2 units in a pint of beer or cider, 1.5 units in a glass of wine and “other” drinks, and 1 unit per measure of spirits.

The mean age was 57.0 years, and 45.4% were male. Overall, 24.3% of subjects were obese, 76.5% had safe levels of alcohol consumption, 19.7% had hazardous alcohol consumption, and 3.8% were classified as harmful drinkers.

Overall, harmful drinking was associated with 5.0 times the 10-year cumulative incidence of cirrhosis morbidity among harmful versus safe drinkers (1.51% vs. 0.30%). However, among those with a healthy BMI, harmful was associated with an 8.6-fold increase of cirrhosis morbidity, compared with safe drinkers (1.38% vs. 0.16%). On the other hand, obese patients with harmful drinking habits had a 3.6-fold increase over obese safe drinkers (1.99% vs. 0.56%).

When looked at according to BMI, 10-year cumulative incidence was 3.1 times higher in patients who with obesity versus those who with healthy BMI (0.65% vs. 0.21%). This varied strongly with drinking: Safe drinkers who with obesity had 3.7 times the incidence, compared with safe drinkers with healthy BMI (0.56% vs. 0.15%), and harmful drinkers who were obese had a 1.4-fold increased incidence, compared with harmful drinkers of a healthy weight (1.99% vs. 1.38%).

“In contrast to some previous studies, we found little evidence that [obesity and drinking] interacted supra-additively to modulate the risk of cirrhosis morbidity,” the authors wrote. “On the contrary, through a relative risk lens, the association between alcohol intake and cirrhosis morbidity was actually weaker for individuals with obesity than for individuals with a healthy BMI (indicating a sub-additive relationship).”

Fine-Gray regression modelling seemed to confirm that the relationship was sub-additive. After controlling for various factors, researchers found that harmful drinkers had a 6.84-fold increased risk at a healthy BMI, while the risk was only 3.14 times higher in obese patients (P _interaction = 3.53 x 10^–6).

The findings contradict previous studies, which suggested that high BMI and harmful drinking combined may produce much higher risk than either factor alone, possibly because obesity might “prime” the liver to be vulnerable to the effects of alcohol.

The authors suggest that the differences in findings may be caused by methodological limitations of the earlier studies, such as reliance on self-reported BMI data; small sample sizes and a relatively small number of liver events among those with obesity and harmful alcohol consumption; and the failure to use a competing risk perspective. The latter is relevant because alcohol and obesity are risk factors for other potentially fatal health conditions.

But the current study is not without its own limitations, according to Nancy Reau, MD, who is a professor of medicine and chair of hepatology at Rush University Medical Center in Chicago, who was asked to comment on the findings. Dr. Reau pointed out that the authors found the highest frequency of complications was observed in people with harmful alcohol intake whose BMI was under 20. That group may be composed of subjects with sarcopenia and end-stage liver disease from alcohol use. “Until you can separate these from the truly healthy BMI but [with harmful alcohol use], you can’t interpret this arm,” said Dr. Reau.

Beyond that, the researchers found increased risks of harm among individuals regardless of BMI, but the risks were highest among those with BMI over 30. Dr. Reau posited that the frequency might have been significantly greater at BMI higher than 35 and 40, but the researchers didn’t report results among these subcategories.

“In no way does this suggest that we need to ignore alcohol use in our patients with NAFLD [nonalcoholic fatty liver disease] or [nonalcoholic steatohepatitis],” said Dr. Reau.

In fact, she pointed to a figure in the paper that showed the highest increase in frequency among those with harmful alcohol use and obesity. “It’s clear that both conditions are much more serious than just obesity alone. It is incredibly important to council our NAFLD patients on appropriate alcohol use, [since] problematic drinking increases their risk. Problematic drinking remains a serious problem and increased awareness and linking to addiction services is important,” she said.

The authors reported no conflicts of interest. Dr. Reau has no relevant financial disclosures.

Alcohol intake and obesity are independent risk factors for morbidity among patients with cirrhosis, but the two factors do not appear to combine for a stronger effect (supra-additive), according to conclusions from a new analysis of participants in the UK Biobank study published in Hepatology.

Nikada/iStockphoto

The researchers analyzed data from the records of 489,285 individuals in the UK Biobank from May 2006 to July 2010. Researchers defined morbidity as first-time hospitalization for cirrhosis and calculated the cumulative incidence at 10 years among included individuals. The researchers defined obesity as body mass index of at least 30 kg/m² and healthy BMI as 20-25. Safe drinking was defined as having fewer than 22 units per week for males or fewer than 15 units for females, harmful drinking was defined as more than 50 units per week for males or more than 35 for females, and hazardous drinking was defined as 22-49 units per week for males and 15-35 for females. The researchers assumed 2 units in a pint of beer or cider, 1.5 units in a glass of wine and “other” drinks, and 1 unit per measure of spirits.

The mean age was 57.0 years, and 45.4% were male. Overall, 24.3% of subjects were obese, 76.5% had safe levels of alcohol consumption, 19.7% had hazardous alcohol consumption, and 3.8% were classified as harmful drinkers.

Overall, harmful drinking was associated with 5.0 times the 10-year cumulative incidence of cirrhosis morbidity among harmful versus safe drinkers (1.51% vs. 0.30%). However, among those with a healthy BMI, harmful was associated with an 8.6-fold increase of cirrhosis morbidity, compared with safe drinkers (1.38% vs. 0.16%). On the other hand, obese patients with harmful drinking habits had a 3.6-fold increase over obese safe drinkers (1.99% vs. 0.56%).

When looked at according to BMI, 10-year cumulative incidence was 3.1 times higher in patients who with obesity versus those who with healthy BMI (0.65% vs. 0.21%). This varied strongly with drinking: Safe drinkers who with obesity had 3.7 times the incidence, compared with safe drinkers with healthy BMI (0.56% vs. 0.15%), and harmful drinkers who were obese had a 1.4-fold increased incidence, compared with harmful drinkers of a healthy weight (1.99% vs. 1.38%).

“In contrast to some previous studies, we found little evidence that [obesity and drinking] interacted supra-additively to modulate the risk of cirrhosis morbidity,” the authors wrote. “On the contrary, through a relative risk lens, the association between alcohol intake and cirrhosis morbidity was actually weaker for individuals with obesity than for individuals with a healthy BMI (indicating a sub-additive relationship).”

Fine-Gray regression modelling seemed to confirm that the relationship was sub-additive. After controlling for various factors, researchers found that harmful drinkers had a 6.84-fold increased risk at a healthy BMI, while the risk was only 3.14 times higher in obese patients (P _interaction = 3.53 x 10^–6).

The findings contradict previous studies, which suggested that high BMI and harmful drinking combined may produce much higher risk than either factor alone, possibly because obesity might “prime” the liver to be vulnerable to the effects of alcohol.

The authors suggest that the differences in findings may be caused by methodological limitations of the earlier studies, such as reliance on self-reported BMI data; small sample sizes and a relatively small number of liver events among those with obesity and harmful alcohol consumption; and the failure to use a competing risk perspective. The latter is relevant because alcohol and obesity are risk factors for other potentially fatal health conditions.

But the current study is not without its own limitations, according to Nancy Reau, MD, who is a professor of medicine and chair of hepatology at Rush University Medical Center in Chicago, who was asked to comment on the findings. Dr. Reau pointed out that the authors found the highest frequency of complications was observed in people with harmful alcohol intake whose BMI was under 20. That group may be composed of subjects with sarcopenia and end-stage liver disease from alcohol use. “Until you can separate these from the truly healthy BMI but [with harmful alcohol use], you can’t interpret this arm,” said Dr. Reau.

Beyond that, the researchers found increased risks of harm among individuals regardless of BMI, but the risks were highest among those with BMI over 30. Dr. Reau posited that the frequency might have been significantly greater at BMI higher than 35 and 40, but the researchers didn’t report results among these subcategories.

“In no way does this suggest that we need to ignore alcohol use in our patients with NAFLD [nonalcoholic fatty liver disease] or [nonalcoholic steatohepatitis],” said Dr. Reau.

In fact, she pointed to a figure in the paper that showed the highest increase in frequency among those with harmful alcohol use and obesity. “It’s clear that both conditions are much more serious than just obesity alone. It is incredibly important to council our NAFLD patients on appropriate alcohol use, [since] problematic drinking increases their risk. Problematic drinking remains a serious problem and increased awareness and linking to addiction services is important,” she said.

The authors reported no conflicts of interest. Dr. Reau has no relevant financial disclosures.

For those of us treating patients with liver disease throughout the pandemic, we have anticipated evidence-based guidance regarding the contribution of specific liver disease phenotypes and immune suppression/transplantation on COVID-19 susceptibility and outcome. Now, data are emerging to help answer some of the major questions surrounding COVID-19 and the liver.

Does the virus itself cause liver disease?

The answer to this question is still a bit unclear. Multiple early reports^1-11 stated that hospitalized patients with SARS-CoV-2 infection frequently had elevated values on liver biochemistry tests. For example, the reported incidence of elevated serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels ranged from 14% to 83%, yet the magnitude of enzyme elevation was generally reported to be mild and normalized as COVID-19 symptoms improved.

Unsurprisingly, patients with severe liver injury (defined as AST and ALT levels more than five times the upper limit of normal) were more likely to have a complicated clinical course, including having elevated inflammatory markers and requiring intensive care unit admission, renal replacement therapy, and/or intubation. Currier and colleagues reported that patients with COVID-19 who had elevated AST and ALT levels had significantly higher odds of these same adverse outcomes and death.

This reflects the multifactorial pathogenesis of enzyme elevation, including a direct injurious effect of the virus on hepatocytes, cytokine or immune-mediated liver damage, drug hepatoxicity, or hypoxia and systemic inflammation.

Pellegrini and colleagues reported that 7% of patients infected with SARS-CoV-2 developed acute liver failure during their hospitalization, with a resulting mortality rate of 74%. Wagner and colleagues suggested that the pattern of peak elevated enzyme elevation was prognostic of severe clinical outcomes in hospitalized patients with COVID-19. Patients with a predominantly mixed pattern (AST/ALT and alkaline phosphatase elevations) had worse outcomes than those with a hepatocellular phenotype (isolated AST and/or ALT elevation).

Severe liver injury associated with SARS-CoV-2 infection is uncommon in children. However, elevated AST and ALT levels may be seen in association with multisystem inflammatory syndrome.^12-15
 

Are patients with preexisting chronic liver disease more susceptible to adverse outcomes?

Early observations suggested that patients with chronic liver disease, such as cirrhosis, who acquire SARS-CoV-2 have high rates of hospitalization and mortality. However, it is unclear whether all such patients are affected or whether certain subgroups are at higher risk.

In results that they hoped would allow for better risk stratification and personalization of care, Kim and colleagues reported that patients with alcohol-related liver disease, decompensated cirrhosis, and hepatocellular carcinoma have the highest risk for all-cause mortality from COVID-19. Separate presentations at Digestive Disease Week 2021 confirmed that patients with preexisting liver disease had a threefold higher rate of mortality, thromboembolism, acute respiratory distress syndrome, and a severe COVID-19 disease course, and that patients with both COVID-19 and cirrhosis had significantly higher rates of mortality (18% vs. 13%), ICU admission (46% vs. 34%), and longer lengths of stay than those without cirrhosis.

Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease, and its impact on the course of SARS-CoV-2 infection (and vice versa) is controversial. However, metabolic risk factors, such as obesity, diabetes mellitus, and hypertension, are known to be associated with severe illness from COVID-19. It was also reported that hepatic steatosis was associated with worse outcomes in patients with liver injury and SARS-CoV-2 infection, and that a higher proportion of patients with NAFLD required mechanical ventilation during their hospital course (47% vs. 17%) and had increased mortality (41% vs. 17%).
 

Do immunosuppressed patients face unique risks from infection?

Data from a limited case series, patient registries, and multicenter international studies have indicated that the clinical outcome of SARS-CoV-2 infection in adults with autoimmune hepatitis (AIH) was comparable to that noted in nonimmunosuppressed persons. However, it has also been suggested that a more complicated relationship exists between this virus and autoimmunity because immunosuppression may actually protect against the inappropriate immune response, or cytokine storm, engendered during severe SARS-CoV-2 infection.

The complexity of this relationship is further illustrated by a report from Bril and colleagues that described a case of AIH that developed after a patient had received a COVID-19 vaccine. The authors were careful to state that a causal relationship between receipt of the vaccine and the onset of AIH cannot be proven.
 

What’s the impact on liver transplant recipients?

Findings are limited regarding clinical outcomes and disease severity of SARS-CoV-2 infection in liver transplant recipients, but initial reports raised concern for high rates of adverse outcomes.^16-25

Tien and colleagues reported an increased risk for COVID-related death among liver transplant recipients. Separate international multicenter studies published in 2020 and 2021 found that liver transplant patients with COVID-19 had a significantly higher risk for hospitalization but no higher risk for mortality, thrombosis, or ICU requirement, compared with patients with COVID-19 who had not undergone liver transplantation. Increased age and the presence of comorbidities were determinants of the severity of SARS-CoV-2 infection and of mortality among liver transplant recipients.

Clearly, more data are needed to address the influence of liver transplantation in patients with COVID-19; however, some risk/protective factors have been cited. For example, Belli and colleagues reported that the use of tacrolimus was associated with a better outcome. Conversely, baseline immunosuppression containing mycophenolate mofetil was an independent predictor of severe COVID-19 in liver transplant recipients.
 

Do COVID-19 vaccines work differently in patients with liver disease?

Unfortunately, we haven’t been able to address many of our patients’ questions related to vaccine efficacy, safety, and durability. Data are limited because immunocompromised patients were excluded from the phase 3 trials of the COVID-19 vaccines.

We also need greater clarity on the robustness of the response to these vaccines in liver transplant recipients. Rabinowich and colleagues evaluated humoral antibody responses after vaccination with the mRNA-based vaccine BNT162b2 (BioNTech/Pfizer) and confirmed lower immunogenicity in liver transplant recipients. Antibodies were detectable in only 48% of patients, compared with 100% of healthy controls; in addition, antibody titers were significantly lower. Unfortunately, there are no data on the correlation of protection from SARS-CoV-2 with antibody titers.

Additional data will be required to assess vaccine effectiveness in protecting against severe COVID-19 as well as to determine the magnitude of humoral vaccine responses in recipients treated with high-dose steroids and mycophenolate mofetil. In addition, we eagerly await studies that determine whether booster doses are required.
 

What’s the bottom line?

In the face of the COVID-19 pandemic, our understanding of the impact on our patients remains a work in progress.

As we await more clarity, there are a few practical points of clinical relevance we take away from the literature, the recently released joint Statement on COVID-19 Vaccination in Solid Organ Transplant Recipients, and the American Association for the Study of Liver Diseases (AASLD) consensus statement. These suggest clinicians take the following steps:

• When assessing patients with SARS-CoV-2 infection and elevated AST and ALT levels, the first objective is to rule out etiologies unrelated to COVID-19, specifically other viruses and drug-induced injury, as well as nonhepatic causes (e.g., myositis, cardiac injury, ischemia).
• Reduction in immunosuppression in SARS-CoV-2–infected patients with AIH should be considered carefully and generally undertaken only in those with severe illness.
• Pretransplant SARS-CoV-2 vaccination is recommended for all liver transplant candidates and liver transplant recipients as well as their household members and caregivers, to reduce exposure for these patients, along with continued adherence to protective measures (masking and social distancing).
• Continuation of a stable posttransplant immunosuppression regimen at the time of vaccination is recommended to avoid the risk for organ rejection until more comprehensive data are available.

For updated responses to the evolving guidelines, visit the AASLD’s resource center.
 

William F. Balistreri, MD, is the Dorothy M.M. Kersten Professor of Pediatrics; director emeritus, pediatric liver care center; medical director emeritus, liver transplantation; and professor, University of Cincinnati College of Medicine, department of pediatrics, Cincinnati Children’s Hospital Medical Center. He has served as director of the division of gastroenterology, hepatology and nutrition at Cincinnati Children’s for 25 years and frequently covers gastroenterology, liver, and nutrition-related topics for this news organization. Dr Balistreri is currently editor-in-chief of the Journal of Pediatrics, having previously served as editor-in-chief of several journals and textbooks. He also became the first pediatrician to act as president of the American Association for the Study of Liver Diseases. He has disclosed no relevant financial relationships.

References

1. Bloom PB et al. Hepatology. 2021 Mar;73:890-900.

2. Guan WJ et al. N Engl J Med. 2020 Apr;382:1708-20.

3. Chen N et al. Lancet. 2020 Feb;395:507-13.

4. Fan Z et al. Clin Gastroenterol Hepatol. 2020 Jun;18:1561-6.

5. Huang C et al. Lancet. 2020 Feb;395:497-506.

6. Xu L et al. Liver Int. 2020 May;40:998-1004.

7. Zhang C et al. Lancet Gastroenterol Hepatol. 2020 May;5:428-30.

8. Richardson S et al. JAMA. 2020 May;323:2052-9.

9. Phipps MM et al. Hepatology. 2020 Sep;72:807-17.

10. Ferm S et al. Clin Gastroenterol Hepatol. 2020 Sep;18:2378-9.

11. Hundt MA et al. Hepatology. 2020 Oct;72:1169-76.

12. Zhou YH et al. Pediatr Obes. 2020 Dec;15:e12723.

13. Kehar M et al. J Pediatr Gastroenterol Nutr. 2021 Jun;72:807-814.

14. Lu X et al. N Engl J Med. 2020 Apr;382:1663-5.

15. Cantor A et al. Hepatology. 2020 Nov;72:1522-7.

16. Kim D et al. Clin Gastroenterol Hepatol. 2021 Jul;19:1469-79.

17. Colmenero J et al. J Hepatol. 2021 Jan;74:148-155.

18. Lee BT et al. Gastroenterology. 2020 Sep;159:1176-8.e2.

19. Becchetti C et al. Gut. 2020 Oct;69:1832-40.

20. Belli LS et al. Lancet Gastroenterol Hepatol. 2020 Aug;5:724-5.

21. Bhoori S et al. Lancet Gastroenterol Hepatol. 2020 Jun;5:532-3.

22. Rabiee A et al; COLD Consortium. Hepatology. 2020 Dec;72:1900-11.

23. Belli LS et al. Gastroenterology. 2021 Mar;160:1151-63.e3.

24. Webb GJ et al. Lancet Gastroenterol Hepatol. 2020 Nov;5:1008-16.

25. Marjot T et al. J Hepatol. 2021 Mar;74:567-77.

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

For those of us treating patients with liver disease throughout the pandemic, we have anticipated evidence-based guidance regarding the contribution of specific liver disease phenotypes and immune suppression/transplantation on COVID-19 susceptibility and outcome. Now, data are emerging to help answer some of the major questions surrounding COVID-19 and the liver.

Does the virus itself cause liver disease?

The answer to this question is still a bit unclear. Multiple early reports^1-11 stated that hospitalized patients with SARS-CoV-2 infection frequently had elevated values on liver biochemistry tests. For example, the reported incidence of elevated serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels ranged from 14% to 83%, yet the magnitude of enzyme elevation was generally reported to be mild and normalized as COVID-19 symptoms improved.

Unsurprisingly, patients with severe liver injury (defined as AST and ALT levels more than five times the upper limit of normal) were more likely to have a complicated clinical course, including having elevated inflammatory markers and requiring intensive care unit admission, renal replacement therapy, and/or intubation. Currier and colleagues reported that patients with COVID-19 who had elevated AST and ALT levels had significantly higher odds of these same adverse outcomes and death.

This reflects the multifactorial pathogenesis of enzyme elevation, including a direct injurious effect of the virus on hepatocytes, cytokine or immune-mediated liver damage, drug hepatoxicity, or hypoxia and systemic inflammation.

Pellegrini and colleagues reported that 7% of patients infected with SARS-CoV-2 developed acute liver failure during their hospitalization, with a resulting mortality rate of 74%. Wagner and colleagues suggested that the pattern of peak elevated enzyme elevation was prognostic of severe clinical outcomes in hospitalized patients with COVID-19. Patients with a predominantly mixed pattern (AST/ALT and alkaline phosphatase elevations) had worse outcomes than those with a hepatocellular phenotype (isolated AST and/or ALT elevation).

Severe liver injury associated with SARS-CoV-2 infection is uncommon in children. However, elevated AST and ALT levels may be seen in association with multisystem inflammatory syndrome.^12-15
 

Are patients with preexisting chronic liver disease more susceptible to adverse outcomes?

Early observations suggested that patients with chronic liver disease, such as cirrhosis, who acquire SARS-CoV-2 have high rates of hospitalization and mortality. However, it is unclear whether all such patients are affected or whether certain subgroups are at higher risk.

In results that they hoped would allow for better risk stratification and personalization of care, Kim and colleagues reported that patients with alcohol-related liver disease, decompensated cirrhosis, and hepatocellular carcinoma have the highest risk for all-cause mortality from COVID-19. Separate presentations at Digestive Disease Week 2021 confirmed that patients with preexisting liver disease had a threefold higher rate of mortality, thromboembolism, acute respiratory distress syndrome, and a severe COVID-19 disease course, and that patients with both COVID-19 and cirrhosis had significantly higher rates of mortality (18% vs. 13%), ICU admission (46% vs. 34%), and longer lengths of stay than those without cirrhosis.

Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease, and its impact on the course of SARS-CoV-2 infection (and vice versa) is controversial. However, metabolic risk factors, such as obesity, diabetes mellitus, and hypertension, are known to be associated with severe illness from COVID-19. It was also reported that hepatic steatosis was associated with worse outcomes in patients with liver injury and SARS-CoV-2 infection, and that a higher proportion of patients with NAFLD required mechanical ventilation during their hospital course (47% vs. 17%) and had increased mortality (41% vs. 17%).
 

Do immunosuppressed patients face unique risks from infection?

Data from a limited case series, patient registries, and multicenter international studies have indicated that the clinical outcome of SARS-CoV-2 infection in adults with autoimmune hepatitis (AIH) was comparable to that noted in nonimmunosuppressed persons. However, it has also been suggested that a more complicated relationship exists between this virus and autoimmunity because immunosuppression may actually protect against the inappropriate immune response, or cytokine storm, engendered during severe SARS-CoV-2 infection.

The complexity of this relationship is further illustrated by a report from Bril and colleagues that described a case of AIH that developed after a patient had received a COVID-19 vaccine. The authors were careful to state that a causal relationship between receipt of the vaccine and the onset of AIH cannot be proven.
 

What’s the impact on liver transplant recipients?

Findings are limited regarding clinical outcomes and disease severity of SARS-CoV-2 infection in liver transplant recipients, but initial reports raised concern for high rates of adverse outcomes.^16-25

Tien and colleagues reported an increased risk for COVID-related death among liver transplant recipients. Separate international multicenter studies published in 2020 and 2021 found that liver transplant patients with COVID-19 had a significantly higher risk for hospitalization but no higher risk for mortality, thrombosis, or ICU requirement, compared with patients with COVID-19 who had not undergone liver transplantation. Increased age and the presence of comorbidities were determinants of the severity of SARS-CoV-2 infection and of mortality among liver transplant recipients.

Clearly, more data are needed to address the influence of liver transplantation in patients with COVID-19; however, some risk/protective factors have been cited. For example, Belli and colleagues reported that the use of tacrolimus was associated with a better outcome. Conversely, baseline immunosuppression containing mycophenolate mofetil was an independent predictor of severe COVID-19 in liver transplant recipients.
 

Do COVID-19 vaccines work differently in patients with liver disease?

Unfortunately, we haven’t been able to address many of our patients’ questions related to vaccine efficacy, safety, and durability. Data are limited because immunocompromised patients were excluded from the phase 3 trials of the COVID-19 vaccines.

We also need greater clarity on the robustness of the response to these vaccines in liver transplant recipients. Rabinowich and colleagues evaluated humoral antibody responses after vaccination with the mRNA-based vaccine BNT162b2 (BioNTech/Pfizer) and confirmed lower immunogenicity in liver transplant recipients. Antibodies were detectable in only 48% of patients, compared with 100% of healthy controls; in addition, antibody titers were significantly lower. Unfortunately, there are no data on the correlation of protection from SARS-CoV-2 with antibody titers.

Additional data will be required to assess vaccine effectiveness in protecting against severe COVID-19 as well as to determine the magnitude of humoral vaccine responses in recipients treated with high-dose steroids and mycophenolate mofetil. In addition, we eagerly await studies that determine whether booster doses are required.
 

What’s the bottom line?

In the face of the COVID-19 pandemic, our understanding of the impact on our patients remains a work in progress.

As we await more clarity, there are a few practical points of clinical relevance we take away from the literature, the recently released joint Statement on COVID-19 Vaccination in Solid Organ Transplant Recipients, and the American Association for the Study of Liver Diseases (AASLD) consensus statement. These suggest clinicians take the following steps:

• When assessing patients with SARS-CoV-2 infection and elevated AST and ALT levels, the first objective is to rule out etiologies unrelated to COVID-19, specifically other viruses and drug-induced injury, as well as nonhepatic causes (e.g., myositis, cardiac injury, ischemia).
• Reduction in immunosuppression in SARS-CoV-2–infected patients with AIH should be considered carefully and generally undertaken only in those with severe illness.
• Pretransplant SARS-CoV-2 vaccination is recommended for all liver transplant candidates and liver transplant recipients as well as their household members and caregivers, to reduce exposure for these patients, along with continued adherence to protective measures (masking and social distancing).
• Continuation of a stable posttransplant immunosuppression regimen at the time of vaccination is recommended to avoid the risk for organ rejection until more comprehensive data are available.

For updated responses to the evolving guidelines, visit the AASLD’s resource center.
 

William F. Balistreri, MD, is the Dorothy M.M. Kersten Professor of Pediatrics; director emeritus, pediatric liver care center; medical director emeritus, liver transplantation; and professor, University of Cincinnati College of Medicine, department of pediatrics, Cincinnati Children’s Hospital Medical Center. He has served as director of the division of gastroenterology, hepatology and nutrition at Cincinnati Children’s for 25 years and frequently covers gastroenterology, liver, and nutrition-related topics for this news organization. Dr Balistreri is currently editor-in-chief of the Journal of Pediatrics, having previously served as editor-in-chief of several journals and textbooks. He also became the first pediatrician to act as president of the American Association for the Study of Liver Diseases. He has disclosed no relevant financial relationships.

References

1. Bloom PB et al. Hepatology. 2021 Mar;73:890-900.

2. Guan WJ et al. N Engl J Med. 2020 Apr;382:1708-20.

3. Chen N et al. Lancet. 2020 Feb;395:507-13.

4. Fan Z et al. Clin Gastroenterol Hepatol. 2020 Jun;18:1561-6.

5. Huang C et al. Lancet. 2020 Feb;395:497-506.

6. Xu L et al. Liver Int. 2020 May;40:998-1004.

7. Zhang C et al. Lancet Gastroenterol Hepatol. 2020 May;5:428-30.

8. Richardson S et al. JAMA. 2020 May;323:2052-9.

9. Phipps MM et al. Hepatology. 2020 Sep;72:807-17.

10. Ferm S et al. Clin Gastroenterol Hepatol. 2020 Sep;18:2378-9.

11. Hundt MA et al. Hepatology. 2020 Oct;72:1169-76.

12. Zhou YH et al. Pediatr Obes. 2020 Dec;15:e12723.

13. Kehar M et al. J Pediatr Gastroenterol Nutr. 2021 Jun;72:807-814.

14. Lu X et al. N Engl J Med. 2020 Apr;382:1663-5.

15. Cantor A et al. Hepatology. 2020 Nov;72:1522-7.

16. Kim D et al. Clin Gastroenterol Hepatol. 2021 Jul;19:1469-79.

17. Colmenero J et al. J Hepatol. 2021 Jan;74:148-155.

18. Lee BT et al. Gastroenterology. 2020 Sep;159:1176-8.e2.

19. Becchetti C et al. Gut. 2020 Oct;69:1832-40.

20. Belli LS et al. Lancet Gastroenterol Hepatol. 2020 Aug;5:724-5.

21. Bhoori S et al. Lancet Gastroenterol Hepatol. 2020 Jun;5:532-3.

22. Rabiee A et al; COLD Consortium. Hepatology. 2020 Dec;72:1900-11.

23. Belli LS et al. Gastroenterology. 2021 Mar;160:1151-63.e3.

24. Webb GJ et al. Lancet Gastroenterol Hepatol. 2020 Nov;5:1008-16.

25. Marjot T et al. J Hepatol. 2021 Mar;74:567-77.

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

For those of us treating patients with liver disease throughout the pandemic, we have anticipated evidence-based guidance regarding the contribution of specific liver disease phenotypes and immune suppression/transplantation on COVID-19 susceptibility and outcome. Now, data are emerging to help answer some of the major questions surrounding COVID-19 and the liver.

Does the virus itself cause liver disease?

The answer to this question is still a bit unclear. Multiple early reports^1-11 stated that hospitalized patients with SARS-CoV-2 infection frequently had elevated values on liver biochemistry tests. For example, the reported incidence of elevated serum aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels ranged from 14% to 83%, yet the magnitude of enzyme elevation was generally reported to be mild and normalized as COVID-19 symptoms improved.

Unsurprisingly, patients with severe liver injury (defined as AST and ALT levels more than five times the upper limit of normal) were more likely to have a complicated clinical course, including having elevated inflammatory markers and requiring intensive care unit admission, renal replacement therapy, and/or intubation. Currier and colleagues reported that patients with COVID-19 who had elevated AST and ALT levels had significantly higher odds of these same adverse outcomes and death.

This reflects the multifactorial pathogenesis of enzyme elevation, including a direct injurious effect of the virus on hepatocytes, cytokine or immune-mediated liver damage, drug hepatoxicity, or hypoxia and systemic inflammation.

Pellegrini and colleagues reported that 7% of patients infected with SARS-CoV-2 developed acute liver failure during their hospitalization, with a resulting mortality rate of 74%. Wagner and colleagues suggested that the pattern of peak elevated enzyme elevation was prognostic of severe clinical outcomes in hospitalized patients with COVID-19. Patients with a predominantly mixed pattern (AST/ALT and alkaline phosphatase elevations) had worse outcomes than those with a hepatocellular phenotype (isolated AST and/or ALT elevation).

Severe liver injury associated with SARS-CoV-2 infection is uncommon in children. However, elevated AST and ALT levels may be seen in association with multisystem inflammatory syndrome.^12-15
 

Are patients with preexisting chronic liver disease more susceptible to adverse outcomes?

Early observations suggested that patients with chronic liver disease, such as cirrhosis, who acquire SARS-CoV-2 have high rates of hospitalization and mortality. However, it is unclear whether all such patients are affected or whether certain subgroups are at higher risk.

In results that they hoped would allow for better risk stratification and personalization of care, Kim and colleagues reported that patients with alcohol-related liver disease, decompensated cirrhosis, and hepatocellular carcinoma have the highest risk for all-cause mortality from COVID-19. Separate presentations at Digestive Disease Week 2021 confirmed that patients with preexisting liver disease had a threefold higher rate of mortality, thromboembolism, acute respiratory distress syndrome, and a severe COVID-19 disease course, and that patients with both COVID-19 and cirrhosis had significantly higher rates of mortality (18% vs. 13%), ICU admission (46% vs. 34%), and longer lengths of stay than those without cirrhosis.

Nonalcoholic fatty liver disease (NAFLD) is currently the most common chronic liver disease, and its impact on the course of SARS-CoV-2 infection (and vice versa) is controversial. However, metabolic risk factors, such as obesity, diabetes mellitus, and hypertension, are known to be associated with severe illness from COVID-19. It was also reported that hepatic steatosis was associated with worse outcomes in patients with liver injury and SARS-CoV-2 infection, and that a higher proportion of patients with NAFLD required mechanical ventilation during their hospital course (47% vs. 17%) and had increased mortality (41% vs. 17%).
 

Do immunosuppressed patients face unique risks from infection?

Data from a limited case series, patient registries, and multicenter international studies have indicated that the clinical outcome of SARS-CoV-2 infection in adults with autoimmune hepatitis (AIH) was comparable to that noted in nonimmunosuppressed persons. However, it has also been suggested that a more complicated relationship exists between this virus and autoimmunity because immunosuppression may actually protect against the inappropriate immune response, or cytokine storm, engendered during severe SARS-CoV-2 infection.

The complexity of this relationship is further illustrated by a report from Bril and colleagues that described a case of AIH that developed after a patient had received a COVID-19 vaccine. The authors were careful to state that a causal relationship between receipt of the vaccine and the onset of AIH cannot be proven.
 

What’s the impact on liver transplant recipients?

Findings are limited regarding clinical outcomes and disease severity of SARS-CoV-2 infection in liver transplant recipients, but initial reports raised concern for high rates of adverse outcomes.^16-25

Tien and colleagues reported an increased risk for COVID-related death among liver transplant recipients. Separate international multicenter studies published in 2020 and 2021 found that liver transplant patients with COVID-19 had a significantly higher risk for hospitalization but no higher risk for mortality, thrombosis, or ICU requirement, compared with patients with COVID-19 who had not undergone liver transplantation. Increased age and the presence of comorbidities were determinants of the severity of SARS-CoV-2 infection and of mortality among liver transplant recipients.

Clearly, more data are needed to address the influence of liver transplantation in patients with COVID-19; however, some risk/protective factors have been cited. For example, Belli and colleagues reported that the use of tacrolimus was associated with a better outcome. Conversely, baseline immunosuppression containing mycophenolate mofetil was an independent predictor of severe COVID-19 in liver transplant recipients.
 

Do COVID-19 vaccines work differently in patients with liver disease?

Unfortunately, we haven’t been able to address many of our patients’ questions related to vaccine efficacy, safety, and durability. Data are limited because immunocompromised patients were excluded from the phase 3 trials of the COVID-19 vaccines.

We also need greater clarity on the robustness of the response to these vaccines in liver transplant recipients. Rabinowich and colleagues evaluated humoral antibody responses after vaccination with the mRNA-based vaccine BNT162b2 (BioNTech/Pfizer) and confirmed lower immunogenicity in liver transplant recipients. Antibodies were detectable in only 48% of patients, compared with 100% of healthy controls; in addition, antibody titers were significantly lower. Unfortunately, there are no data on the correlation of protection from SARS-CoV-2 with antibody titers.

Additional data will be required to assess vaccine effectiveness in protecting against severe COVID-19 as well as to determine the magnitude of humoral vaccine responses in recipients treated with high-dose steroids and mycophenolate mofetil. In addition, we eagerly await studies that determine whether booster doses are required.
 

What’s the bottom line?

In the face of the COVID-19 pandemic, our understanding of the impact on our patients remains a work in progress.

As we await more clarity, there are a few practical points of clinical relevance we take away from the literature, the recently released joint Statement on COVID-19 Vaccination in Solid Organ Transplant Recipients, and the American Association for the Study of Liver Diseases (AASLD) consensus statement. These suggest clinicians take the following steps:

• When assessing patients with SARS-CoV-2 infection and elevated AST and ALT levels, the first objective is to rule out etiologies unrelated to COVID-19, specifically other viruses and drug-induced injury, as well as nonhepatic causes (e.g., myositis, cardiac injury, ischemia).
• Reduction in immunosuppression in SARS-CoV-2–infected patients with AIH should be considered carefully and generally undertaken only in those with severe illness.
• Pretransplant SARS-CoV-2 vaccination is recommended for all liver transplant candidates and liver transplant recipients as well as their household members and caregivers, to reduce exposure for these patients, along with continued adherence to protective measures (masking and social distancing).
• Continuation of a stable posttransplant immunosuppression regimen at the time of vaccination is recommended to avoid the risk for organ rejection until more comprehensive data are available.

For updated responses to the evolving guidelines, visit the AASLD’s resource center.
 

William F. Balistreri, MD, is the Dorothy M.M. Kersten Professor of Pediatrics; director emeritus, pediatric liver care center; medical director emeritus, liver transplantation; and professor, University of Cincinnati College of Medicine, department of pediatrics, Cincinnati Children’s Hospital Medical Center. He has served as director of the division of gastroenterology, hepatology and nutrition at Cincinnati Children’s for 25 years and frequently covers gastroenterology, liver, and nutrition-related topics for this news organization. Dr Balistreri is currently editor-in-chief of the Journal of Pediatrics, having previously served as editor-in-chief of several journals and textbooks. He also became the first pediatrician to act as president of the American Association for the Study of Liver Diseases. He has disclosed no relevant financial relationships.

References

1. Bloom PB et al. Hepatology. 2021 Mar;73:890-900.

2. Guan WJ et al. N Engl J Med. 2020 Apr;382:1708-20.

3. Chen N et al. Lancet. 2020 Feb;395:507-13.

4. Fan Z et al. Clin Gastroenterol Hepatol. 2020 Jun;18:1561-6.

5. Huang C et al. Lancet. 2020 Feb;395:497-506.

6. Xu L et al. Liver Int. 2020 May;40:998-1004.

7. Zhang C et al. Lancet Gastroenterol Hepatol. 2020 May;5:428-30.

8. Richardson S et al. JAMA. 2020 May;323:2052-9.

9. Phipps MM et al. Hepatology. 2020 Sep;72:807-17.

10. Ferm S et al. Clin Gastroenterol Hepatol. 2020 Sep;18:2378-9.

11. Hundt MA et al. Hepatology. 2020 Oct;72:1169-76.

12. Zhou YH et al. Pediatr Obes. 2020 Dec;15:e12723.

13. Kehar M et al. J Pediatr Gastroenterol Nutr. 2021 Jun;72:807-814.

14. Lu X et al. N Engl J Med. 2020 Apr;382:1663-5.

15. Cantor A et al. Hepatology. 2020 Nov;72:1522-7.

16. Kim D et al. Clin Gastroenterol Hepatol. 2021 Jul;19:1469-79.

17. Colmenero J et al. J Hepatol. 2021 Jan;74:148-155.

18. Lee BT et al. Gastroenterology. 2020 Sep;159:1176-8.e2.

19. Becchetti C et al. Gut. 2020 Oct;69:1832-40.

20. Belli LS et al. Lancet Gastroenterol Hepatol. 2020 Aug;5:724-5.

21. Bhoori S et al. Lancet Gastroenterol Hepatol. 2020 Jun;5:532-3.

22. Rabiee A et al; COLD Consortium. Hepatology. 2020 Dec;72:1900-11.

23. Belli LS et al. Gastroenterology. 2021 Mar;160:1151-63.e3.

24. Webb GJ et al. Lancet Gastroenterol Hepatol. 2020 Nov;5:1008-16.

25. Marjot T et al. J Hepatol. 2021 Mar;74:567-77.

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

Emergency responders to the World Trade Center (WTC) attack in 2001 paid a significant physical cost for their service in the form of exposure to chemicals, dust, and airborne particulates causally linked to hepatotoxicity. As we near the 20th anniversary of these attacks, researchers have determined that those responders who arrived at the WTC site earlier have a significantly higher prevalence of hepatic steatosis compared with those who arrived in the days that followed.

U.S. Army Corps of Engineers file photo

“This research is some of the first to suggest that there may be a link between the amount of exposure experienced by responders to the WTC site and the higher likelihood of excessive accumulation of fat in their livers,” study author Artit Jirapatnakul, PhD, of Icahn School of Medicine at Mount Sinai, New York, said in an interview. These findings were published in the American Journal of Industrial Medicine.

The excessive accumulation of liver fat is an indicator of liver injury, which can also predict subsequent future disease, such as cirrhosis, liver failure, and liver cancer.

Dr. Jirapatnakul said that arrival time to the WTC disaster may prove an important factor for predicting the risk of liver disease in this population and directing treatment to them accordingly.

“By identifying individuals with markers of liver injury, such as excess fat, we can offer referral to liver specialists and thereby open the door to early treatment,” he said.

“Our most important message is that many liver diseases can be treated if caught early,” Dr. Jirapatnakul added. “Early detection requires proactive monitoring because most liver diseases have few, if any, symptoms during the early stages.”

More than 20,000 men and women who responded to the WTC site on Sept. 11, 2001, were exposed to particulate matter and chemicals known to cause liver damage and increase the risk of toxicant‐associated fatty liver disease. These responders have been offered screening and treatment of different conditions associated with the attack, including CT lung cancer screening for those meeting age and smoking status criteria.
 

Measuring the impact of response time on the liver

To investigate the dose-response association between WTC site exposure intensity and the risk of hepatic steatosis, Dr. Jirapatnakul and colleagues reviewed low-dose CT chest scans of all participants in the WTC General Responders Cohort (GRC) who had available laboratory data within a 12-month period from their first scan following the Sept. 11, 2001, attack. Only CT chest scans performed between Sept. 11, 2001, and Dec. 31, 2018, were collected and reviewed in the study.

A total of 1,788 WTC responders were included (83.7% were male; mean age at time of attack, 42.5 years). Up to 56% of WTC responders in the study were White, and 20.4% of responders were current smokers. The mean body mass index of the group was 30.1 kg/m².

The investigators stratified dust exposure into five groups according to when the responders arrived at the WTC site: Sept. 11, 2001, in the dust cloud; Sept. 11, no dust cloud (same-day arrival); Sept. 12 or 13 (second‐ and third‐day arrival); Sept. 14 to the end of September (fourth‐day arrival); and October and beyond.

The median duration between Sept. 11, 2001, and the earliest available CT scan was 11.3 years. Liver density was measured via Statistics‐based Liver Density Estimation from Imaging, a previously validated algorithm, with a slice thickness of 1.25 mm or below. On their earliest CT, approximately 14.4% (n = 258) of responders had liver attenuation < 40 Hounsfield units (HU). The prevalence of liver attenuation < 40 HU was 17% for responders who arrived on the day of the attack, 16% for responders who arrived at the site on Sept. 12 or 13, 10.9% for responders who arrived Sept. 14 through 30, and 9% for responders who arrived at the WTC site on Oct. 1, 2001, or later (P =.0015).

There was a statistically significant trend of increasing liver steatosis with earlier times of arrival (P <.0001). The WTC arrival time retained its status as a significant independent factor for decreased liver attenuation in an analysis adjusted for sex, age, race, smoking status, alcohol use, body mass index, diabetes, gastroesophageal reflux disease, and forced expiratory volume in 1 second.

Dr. Jirapatnakul said that the next step will be to determine whether WTC responders with excessive liver fat also have increased liver scarring. In addition, he and his colleagues are working to establish a registry to collect information on the impact of liver disease as it relates to quality of life in members of the WTC GRC.
 

Importance of disease severity

Another direction of future research will be to differentiate between those with only hepatic steatosis, those with inflammation from hepatic steatosis (steatohepatitis), and those with hepatic fibrosis which is the most concerning outcome from fatty liver diseases, according to Albert Do, MD, clinical director of the fatty liver disease program at Yale University, New Haven, Conn.

“It is the latter group of patients which we are most concerned about, given this is the group at highest risk for harm from liver disease,” added Dr. Do, who wasn’t involved in the research study. “The degree of steatosis is not closely linked with subsequent inflammation nor hepatic fibrosis, and so linkage of disease severity to specific occupational exposures and timing is needed to determine the allocation of support for patients who had suffered harm from fatty liver disease.”

Dr. Do noted that additional research will also need to identify the specific exposure that may be causing hepatic steatosis in early WTC responders. “Currently, only a small number of medications are known to cause this,” he explained, “and thus such knowledge will help us further understand occupational exposures and their associated risks.”

The researchers received study funding from the National Institute for Occupational Safety and Health. They disclosed conflicts of interest with Genentech, AstraZeneca, Pfizer, Bayer Healthcare, Gilead Sciences, and Boehringer Ingelheim. Dr. Do had no conflicts to declare.

Emergency responders to the World Trade Center (WTC) attack in 2001 paid a significant physical cost for their service in the form of exposure to chemicals, dust, and airborne particulates causally linked to hepatotoxicity. As we near the 20th anniversary of these attacks, researchers have determined that those responders who arrived at the WTC site earlier have a significantly higher prevalence of hepatic steatosis compared with those who arrived in the days that followed.

U.S. Army Corps of Engineers file photo

“This research is some of the first to suggest that there may be a link between the amount of exposure experienced by responders to the WTC site and the higher likelihood of excessive accumulation of fat in their livers,” study author Artit Jirapatnakul, PhD, of Icahn School of Medicine at Mount Sinai, New York, said in an interview. These findings were published in the American Journal of Industrial Medicine.

The excessive accumulation of liver fat is an indicator of liver injury, which can also predict subsequent future disease, such as cirrhosis, liver failure, and liver cancer.

Dr. Jirapatnakul said that arrival time to the WTC disaster may prove an important factor for predicting the risk of liver disease in this population and directing treatment to them accordingly.

“By identifying individuals with markers of liver injury, such as excess fat, we can offer referral to liver specialists and thereby open the door to early treatment,” he said.

“Our most important message is that many liver diseases can be treated if caught early,” Dr. Jirapatnakul added. “Early detection requires proactive monitoring because most liver diseases have few, if any, symptoms during the early stages.”

More than 20,000 men and women who responded to the WTC site on Sept. 11, 2001, were exposed to particulate matter and chemicals known to cause liver damage and increase the risk of toxicant‐associated fatty liver disease. These responders have been offered screening and treatment of different conditions associated with the attack, including CT lung cancer screening for those meeting age and smoking status criteria.
 

Measuring the impact of response time on the liver

To investigate the dose-response association between WTC site exposure intensity and the risk of hepatic steatosis, Dr. Jirapatnakul and colleagues reviewed low-dose CT chest scans of all participants in the WTC General Responders Cohort (GRC) who had available laboratory data within a 12-month period from their first scan following the Sept. 11, 2001, attack. Only CT chest scans performed between Sept. 11, 2001, and Dec. 31, 2018, were collected and reviewed in the study.

A total of 1,788 WTC responders were included (83.7% were male; mean age at time of attack, 42.5 years). Up to 56% of WTC responders in the study were White, and 20.4% of responders were current smokers. The mean body mass index of the group was 30.1 kg/m².

The investigators stratified dust exposure into five groups according to when the responders arrived at the WTC site: Sept. 11, 2001, in the dust cloud; Sept. 11, no dust cloud (same-day arrival); Sept. 12 or 13 (second‐ and third‐day arrival); Sept. 14 to the end of September (fourth‐day arrival); and October and beyond.

The median duration between Sept. 11, 2001, and the earliest available CT scan was 11.3 years. Liver density was measured via Statistics‐based Liver Density Estimation from Imaging, a previously validated algorithm, with a slice thickness of 1.25 mm or below. On their earliest CT, approximately 14.4% (n = 258) of responders had liver attenuation < 40 Hounsfield units (HU). The prevalence of liver attenuation < 40 HU was 17% for responders who arrived on the day of the attack, 16% for responders who arrived at the site on Sept. 12 or 13, 10.9% for responders who arrived Sept. 14 through 30, and 9% for responders who arrived at the WTC site on Oct. 1, 2001, or later (P =.0015).

There was a statistically significant trend of increasing liver steatosis with earlier times of arrival (P <.0001). The WTC arrival time retained its status as a significant independent factor for decreased liver attenuation in an analysis adjusted for sex, age, race, smoking status, alcohol use, body mass index, diabetes, gastroesophageal reflux disease, and forced expiratory volume in 1 second.

Dr. Jirapatnakul said that the next step will be to determine whether WTC responders with excessive liver fat also have increased liver scarring. In addition, he and his colleagues are working to establish a registry to collect information on the impact of liver disease as it relates to quality of life in members of the WTC GRC.
 

Importance of disease severity

Another direction of future research will be to differentiate between those with only hepatic steatosis, those with inflammation from hepatic steatosis (steatohepatitis), and those with hepatic fibrosis which is the most concerning outcome from fatty liver diseases, according to Albert Do, MD, clinical director of the fatty liver disease program at Yale University, New Haven, Conn.

“It is the latter group of patients which we are most concerned about, given this is the group at highest risk for harm from liver disease,” added Dr. Do, who wasn’t involved in the research study. “The degree of steatosis is not closely linked with subsequent inflammation nor hepatic fibrosis, and so linkage of disease severity to specific occupational exposures and timing is needed to determine the allocation of support for patients who had suffered harm from fatty liver disease.”

Dr. Do noted that additional research will also need to identify the specific exposure that may be causing hepatic steatosis in early WTC responders. “Currently, only a small number of medications are known to cause this,” he explained, “and thus such knowledge will help us further understand occupational exposures and their associated risks.”

The researchers received study funding from the National Institute for Occupational Safety and Health. They disclosed conflicts of interest with Genentech, AstraZeneca, Pfizer, Bayer Healthcare, Gilead Sciences, and Boehringer Ingelheim. Dr. Do had no conflicts to declare.

Emergency responders to the World Trade Center (WTC) attack in 2001 paid a significant physical cost for their service in the form of exposure to chemicals, dust, and airborne particulates causally linked to hepatotoxicity. As we near the 20th anniversary of these attacks, researchers have determined that those responders who arrived at the WTC site earlier have a significantly higher prevalence of hepatic steatosis compared with those who arrived in the days that followed.

U.S. Army Corps of Engineers file photo

“This research is some of the first to suggest that there may be a link between the amount of exposure experienced by responders to the WTC site and the higher likelihood of excessive accumulation of fat in their livers,” study author Artit Jirapatnakul, PhD, of Icahn School of Medicine at Mount Sinai, New York, said in an interview. These findings were published in the American Journal of Industrial Medicine.

The excessive accumulation of liver fat is an indicator of liver injury, which can also predict subsequent future disease, such as cirrhosis, liver failure, and liver cancer.

Dr. Jirapatnakul said that arrival time to the WTC disaster may prove an important factor for predicting the risk of liver disease in this population and directing treatment to them accordingly.

“By identifying individuals with markers of liver injury, such as excess fat, we can offer referral to liver specialists and thereby open the door to early treatment,” he said.

“Our most important message is that many liver diseases can be treated if caught early,” Dr. Jirapatnakul added. “Early detection requires proactive monitoring because most liver diseases have few, if any, symptoms during the early stages.”

More than 20,000 men and women who responded to the WTC site on Sept. 11, 2001, were exposed to particulate matter and chemicals known to cause liver damage and increase the risk of toxicant‐associated fatty liver disease. These responders have been offered screening and treatment of different conditions associated with the attack, including CT lung cancer screening for those meeting age and smoking status criteria.
 

Measuring the impact of response time on the liver

To investigate the dose-response association between WTC site exposure intensity and the risk of hepatic steatosis, Dr. Jirapatnakul and colleagues reviewed low-dose CT chest scans of all participants in the WTC General Responders Cohort (GRC) who had available laboratory data within a 12-month period from their first scan following the Sept. 11, 2001, attack. Only CT chest scans performed between Sept. 11, 2001, and Dec. 31, 2018, were collected and reviewed in the study.

A total of 1,788 WTC responders were included (83.7% were male; mean age at time of attack, 42.5 years). Up to 56% of WTC responders in the study were White, and 20.4% of responders were current smokers. The mean body mass index of the group was 30.1 kg/m².

The investigators stratified dust exposure into five groups according to when the responders arrived at the WTC site: Sept. 11, 2001, in the dust cloud; Sept. 11, no dust cloud (same-day arrival); Sept. 12 or 13 (second‐ and third‐day arrival); Sept. 14 to the end of September (fourth‐day arrival); and October and beyond.

The median duration between Sept. 11, 2001, and the earliest available CT scan was 11.3 years. Liver density was measured via Statistics‐based Liver Density Estimation from Imaging, a previously validated algorithm, with a slice thickness of 1.25 mm or below. On their earliest CT, approximately 14.4% (n = 258) of responders had liver attenuation < 40 Hounsfield units (HU). The prevalence of liver attenuation < 40 HU was 17% for responders who arrived on the day of the attack, 16% for responders who arrived at the site on Sept. 12 or 13, 10.9% for responders who arrived Sept. 14 through 30, and 9% for responders who arrived at the WTC site on Oct. 1, 2001, or later (P =.0015).

There was a statistically significant trend of increasing liver steatosis with earlier times of arrival (P <.0001). The WTC arrival time retained its status as a significant independent factor for decreased liver attenuation in an analysis adjusted for sex, age, race, smoking status, alcohol use, body mass index, diabetes, gastroesophageal reflux disease, and forced expiratory volume in 1 second.

Dr. Jirapatnakul said that the next step will be to determine whether WTC responders with excessive liver fat also have increased liver scarring. In addition, he and his colleagues are working to establish a registry to collect information on the impact of liver disease as it relates to quality of life in members of the WTC GRC.
 

Importance of disease severity

Another direction of future research will be to differentiate between those with only hepatic steatosis, those with inflammation from hepatic steatosis (steatohepatitis), and those with hepatic fibrosis which is the most concerning outcome from fatty liver diseases, according to Albert Do, MD, clinical director of the fatty liver disease program at Yale University, New Haven, Conn.

“It is the latter group of patients which we are most concerned about, given this is the group at highest risk for harm from liver disease,” added Dr. Do, who wasn’t involved in the research study. “The degree of steatosis is not closely linked with subsequent inflammation nor hepatic fibrosis, and so linkage of disease severity to specific occupational exposures and timing is needed to determine the allocation of support for patients who had suffered harm from fatty liver disease.”

Dr. Do noted that additional research will also need to identify the specific exposure that may be causing hepatic steatosis in early WTC responders. “Currently, only a small number of medications are known to cause this,” he explained, “and thus such knowledge will help us further understand occupational exposures and their associated risks.”

The researchers received study funding from the National Institute for Occupational Safety and Health. They disclosed conflicts of interest with Genentech, AstraZeneca, Pfizer, Bayer Healthcare, Gilead Sciences, and Boehringer Ingelheim. Dr. Do had no conflicts to declare.