Liver Disease

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.

Liver stiffness measurement with magnetic resonance elastography (MRE) may prove predictive of future cirrhosis risk in patients with nonalcoholic fatty liver disease (NAFLD), according to researchers from the Mayo Clinic in Rochester, Minn.

“These data expand the role of MRE from an accurate diagnostic method to a prognostic noninvasive imaging biomarker that can risk-stratify patients with NAFLD and guide the timing of surveillance and further refine their clinical management,” wrote Tolga Gidener, MD, and colleagues. The study authors added that the research further expands “the role of MRE beyond liver fibrosis estimation by adding a predictive feature to improve individualized disease monitoring and patient counseling.” Their study was published in Clinical Gastroenterology and Hepatology.

Currently, there are no established noninvasive strategies that can effectively identify patients with NAFLD who are at high risk of progression to cirrhosis and liver-related complications. While fibrosis stage on histology may predict liver-associated outcomes in these patients, this approach is invasive, time consuming, and is generally not well tolerated by patients.

Although the technique has been noted for its high success rate and excellent levels of reliability and reproducibility, a possible limitation of MRE is its cost. That said, standalone MRE is reimbursed under Medicare Category I Current Procedural Terminology code 76391 with a cost of $240.02. However, there is also a lack of data on whether baseline liver stiffness measurement by MRE can predict progression of NAFLD to cirrhosis.

To gauge the role of baseline liver stiffness measurement by MRE, Dr. Gidener and colleagues performed a retrospective cohort study that evaluated hard liver–related outcomes in 829 adult patients with NAFLD with or without cirrhosis (median age, 58 years; 54% female) who underwent MRE during 2007-2019.

Patients in the study were followed from the first MRE until death, last clinical encounter, or the end of the study. Clinical outcomes assessed in individual chart review included cirrhosis, hepatic decompensation, and death.

At baseline, the median liver stiffness measurement was 2.8 kPa in 639 patients with NAFLD but without cirrhosis. Over a median 4-year follow-up period, a total of 20 patients developed cirrhosis, with an overall annual incidence rate of 1%.

Baseline liver stiffness measurement by MRE was significantly predictive of subsequent cirrhosis (hazard ratio, 2.93; 95% confidence interval, 1.86-4.62; P < .0001) per 1-kPa difference in liver stiffness measurement at baseline.

According to the researchers, the probability of future cirrhosis development can be ascertained using current liver stiffness measurement. As such, a greater than 1% probability threshold can be reached in 5 years in patients with a measurement of 2 kPa, 3 years in patients with a measurement of 3 kPA, and 1 year in patients with 4-5 kPa. “These time frames inform about estimated time to progression to hard outcomes and provide guidance for subsequent noninvasive monitoring for disease progression,” wrote the researchers.

The baseline liver stiffness measurement by MRE was also significantly predictive of future hepatic decompensation or death (HR, 1.32; 95% CI, 1.13-1.56; P = .0007) per 1-kPa increment in the liver stiffness measurement. Likewise, the 1-year probability of subsequent hepatic decompensation or death in patients with cirrhosis and baseline liver stiffness measurement of 5 kPa versus 8 kPa was 9% versus 20%, respectively. In terms of covariates, age was the only factor that increased the risk of hepatic decompensation or death.

While the current study offers a glimpse into the potential clinical implications of liver stiffness measurement by MRE in NAFLD, the researchers suggest the applicability of the findings are limited by the study’s small sample size, relatively short follow-up duration, and the small number of cirrhosis events.

The researchers received study funding from the National Institute of Diabetes and Digestive and Kidney Diseases, American College of Gastroenterology, National Institutes of Health, and the Department of Defense. The researchers disclosed no other relevant conflicts of interest.

Liver stiffness measurement with magnetic resonance elastography (MRE) may prove predictive of future cirrhosis risk in patients with nonalcoholic fatty liver disease (NAFLD), according to researchers from the Mayo Clinic in Rochester, Minn.

“These data expand the role of MRE from an accurate diagnostic method to a prognostic noninvasive imaging biomarker that can risk-stratify patients with NAFLD and guide the timing of surveillance and further refine their clinical management,” wrote Tolga Gidener, MD, and colleagues. The study authors added that the research further expands “the role of MRE beyond liver fibrosis estimation by adding a predictive feature to improve individualized disease monitoring and patient counseling.” Their study was published in Clinical Gastroenterology and Hepatology.

Currently, there are no established noninvasive strategies that can effectively identify patients with NAFLD who are at high risk of progression to cirrhosis and liver-related complications. While fibrosis stage on histology may predict liver-associated outcomes in these patients, this approach is invasive, time consuming, and is generally not well tolerated by patients.

Although the technique has been noted for its high success rate and excellent levels of reliability and reproducibility, a possible limitation of MRE is its cost. That said, standalone MRE is reimbursed under Medicare Category I Current Procedural Terminology code 76391 with a cost of $240.02. However, there is also a lack of data on whether baseline liver stiffness measurement by MRE can predict progression of NAFLD to cirrhosis.

To gauge the role of baseline liver stiffness measurement by MRE, Dr. Gidener and colleagues performed a retrospective cohort study that evaluated hard liver–related outcomes in 829 adult patients with NAFLD with or without cirrhosis (median age, 58 years; 54% female) who underwent MRE during 2007-2019.

Patients in the study were followed from the first MRE until death, last clinical encounter, or the end of the study. Clinical outcomes assessed in individual chart review included cirrhosis, hepatic decompensation, and death.

At baseline, the median liver stiffness measurement was 2.8 kPa in 639 patients with NAFLD but without cirrhosis. Over a median 4-year follow-up period, a total of 20 patients developed cirrhosis, with an overall annual incidence rate of 1%.

Baseline liver stiffness measurement by MRE was significantly predictive of subsequent cirrhosis (hazard ratio, 2.93; 95% confidence interval, 1.86-4.62; P < .0001) per 1-kPa difference in liver stiffness measurement at baseline.

According to the researchers, the probability of future cirrhosis development can be ascertained using current liver stiffness measurement. As such, a greater than 1% probability threshold can be reached in 5 years in patients with a measurement of 2 kPa, 3 years in patients with a measurement of 3 kPA, and 1 year in patients with 4-5 kPa. “These time frames inform about estimated time to progression to hard outcomes and provide guidance for subsequent noninvasive monitoring for disease progression,” wrote the researchers.

The baseline liver stiffness measurement by MRE was also significantly predictive of future hepatic decompensation or death (HR, 1.32; 95% CI, 1.13-1.56; P = .0007) per 1-kPa increment in the liver stiffness measurement. Likewise, the 1-year probability of subsequent hepatic decompensation or death in patients with cirrhosis and baseline liver stiffness measurement of 5 kPa versus 8 kPa was 9% versus 20%, respectively. In terms of covariates, age was the only factor that increased the risk of hepatic decompensation or death.

While the current study offers a glimpse into the potential clinical implications of liver stiffness measurement by MRE in NAFLD, the researchers suggest the applicability of the findings are limited by the study’s small sample size, relatively short follow-up duration, and the small number of cirrhosis events.

The researchers received study funding from the National Institute of Diabetes and Digestive and Kidney Diseases, American College of Gastroenterology, National Institutes of Health, and the Department of Defense. The researchers disclosed no other relevant conflicts of interest.

Liver stiffness measurement with magnetic resonance elastography (MRE) may prove predictive of future cirrhosis risk in patients with nonalcoholic fatty liver disease (NAFLD), according to researchers from the Mayo Clinic in Rochester, Minn.

“These data expand the role of MRE from an accurate diagnostic method to a prognostic noninvasive imaging biomarker that can risk-stratify patients with NAFLD and guide the timing of surveillance and further refine their clinical management,” wrote Tolga Gidener, MD, and colleagues. The study authors added that the research further expands “the role of MRE beyond liver fibrosis estimation by adding a predictive feature to improve individualized disease monitoring and patient counseling.” Their study was published in Clinical Gastroenterology and Hepatology.

Currently, there are no established noninvasive strategies that can effectively identify patients with NAFLD who are at high risk of progression to cirrhosis and liver-related complications. While fibrosis stage on histology may predict liver-associated outcomes in these patients, this approach is invasive, time consuming, and is generally not well tolerated by patients.

Although the technique has been noted for its high success rate and excellent levels of reliability and reproducibility, a possible limitation of MRE is its cost. That said, standalone MRE is reimbursed under Medicare Category I Current Procedural Terminology code 76391 with a cost of $240.02. However, there is also a lack of data on whether baseline liver stiffness measurement by MRE can predict progression of NAFLD to cirrhosis.

To gauge the role of baseline liver stiffness measurement by MRE, Dr. Gidener and colleagues performed a retrospective cohort study that evaluated hard liver–related outcomes in 829 adult patients with NAFLD with or without cirrhosis (median age, 58 years; 54% female) who underwent MRE during 2007-2019.

Patients in the study were followed from the first MRE until death, last clinical encounter, or the end of the study. Clinical outcomes assessed in individual chart review included cirrhosis, hepatic decompensation, and death.

At baseline, the median liver stiffness measurement was 2.8 kPa in 639 patients with NAFLD but without cirrhosis. Over a median 4-year follow-up period, a total of 20 patients developed cirrhosis, with an overall annual incidence rate of 1%.

Baseline liver stiffness measurement by MRE was significantly predictive of subsequent cirrhosis (hazard ratio, 2.93; 95% confidence interval, 1.86-4.62; P < .0001) per 1-kPa difference in liver stiffness measurement at baseline.

According to the researchers, the probability of future cirrhosis development can be ascertained using current liver stiffness measurement. As such, a greater than 1% probability threshold can be reached in 5 years in patients with a measurement of 2 kPa, 3 years in patients with a measurement of 3 kPA, and 1 year in patients with 4-5 kPa. “These time frames inform about estimated time to progression to hard outcomes and provide guidance for subsequent noninvasive monitoring for disease progression,” wrote the researchers.

The baseline liver stiffness measurement by MRE was also significantly predictive of future hepatic decompensation or death (HR, 1.32; 95% CI, 1.13-1.56; P = .0007) per 1-kPa increment in the liver stiffness measurement. Likewise, the 1-year probability of subsequent hepatic decompensation or death in patients with cirrhosis and baseline liver stiffness measurement of 5 kPa versus 8 kPa was 9% versus 20%, respectively. In terms of covariates, age was the only factor that increased the risk of hepatic decompensation or death.

While the current study offers a glimpse into the potential clinical implications of liver stiffness measurement by MRE in NAFLD, the researchers suggest the applicability of the findings are limited by the study’s small sample size, relatively short follow-up duration, and the small number of cirrhosis events.

The researchers received study funding from the National Institute of Diabetes and Digestive and Kidney Diseases, American College of Gastroenterology, National Institutes of Health, and the Department of Defense. The researchers disclosed no other relevant conflicts of interest.

A new study sought to establish a new, clinically relevant mouse model of nonalcoholic steatohepatitis (NASH) that closely reflects human disease as well as the multitissue dynamics involved in the progression and regression of the condition, according to the researchers. This study focused on the association between progression of NASH and consumption of a Western diet, as well as the development of HCC.

The study used a model consisting of hyperphagic mice that lacked a functional ALMS1 gene (Foz/Foz), in addition to wild-type littermates. The model ultimately defined “the key signaling and cytokine pathways that are critical for disease development and resolution” associated with NASH, wrote Souradipta Ganguly, PhD, of the University of California, San Diego, and colleagues. The report was published in Cellular and Molecular Gastroenterology and Hepatology.

According to the researchers, this study is unique given “current rodent models of NASH do not reproduce the complete spectrum of metabolic and histologic” nonalcoholic fatty liver disease (NAFLD) phenotypes. Likewise, the lack of “systemic studies in a single rodent model of NASH that closely recapitulates the human pathology” reinforces the importance of the new model, the researchers added.

Over time, NASH can progress to cirrhosis and hepatocellular carcinoma (HCC). Studies that fed wild-type mice a Western diet have largely failed to mimic the full pathology of NASH to fibrosis to HCC. In addition, the models in these studies fail to reflect the multitissue injuries frequently observed in NASH.

To circumvent these challenges, Dr. Ganguly and colleagues used ALMS1-mutated mice to develop a rodent model of metabolic syndrome that included NASH with fibrosis, chronic kidney disease, and cardiovascular disease. The ALMS1 mutation also resulted in the mice becoming hyperphagic, which increases hunger and leads to early-onset obesity, among other conditions characteristic of metabolic syndrome.

Researchers fed the hyperphagic Foz/Foz mice and wild-type littermates a Western diet or standard diet during a 12-week period for NASH/fibrosis and a 24-week period for HCC. After NASH was established, mice were switched back to normal chow to see if the condition regressed.

Macronutrient distribution of the study’s Western diet included 40% fat, 15% protein, and 44% carbohydrates, based on total caloric content. In contrast, the standard chow included 12% fat, 23% protein, and 65% carbohydrates from total calories.

Within 1-2 weeks, Foz mice fed the Western diet were considered steatotic. These mice subsequently developed NASH by 4 weeks of the study and grade 3 fibrosis by 12 weeks. The researchers concurrently observed the development of chronic kidney injury in the animals. Mice continuing to the 24 weeks ultimately progressed to cirrhosis and HCC; these mice demonstrated reduced survival due to cardiac dysfunction.

Mice that developed NASH were then switched to a diet consisting of normal chow. Following this switch, NASH began to regress, and survival improved. These mice did not appear to develop HCC, and total liver weight was significantly reduced compared with the mice that didn’t enter the regression phase of the study. The researchers wrote that the resolution of hepatic steatosis was also consistent with improved glucose tolerance.

In transcriptomic and histologic analyses, the researchers found strong concordance between Foz/Foz mice NASH liver and human NASH.

The study also found that early disruption of gut barrier, microbial dysbiosis, lipopolysaccharide leakage, and intestinal inflammation preceded NASH in the Foz/Foz mice fed the Western diet, resulting in acute-phase liver inflammation. The early inflammation was reflected by an increase in several chemokines and cytokines by 1-2 weeks. As NASH progressed, the liver cytokine/chemokine profile continued to evolve, leading to monocyte recruitment predominance. “Further studies will elaborate the roles of these NASH-specific microbiomial features in the development and progression of NASH fibrosis,” wrote the researchers.

The study received financial support Janssen, in addition to funding from an ALF Liver Scholar award, ACTRI/National Institutes of Health, the SDDRC, and the NIAAA/National Institutes of Health. The authors disclosed no conflicts.

A new study sought to establish a new, clinically relevant mouse model of nonalcoholic steatohepatitis (NASH) that closely reflects human disease as well as the multitissue dynamics involved in the progression and regression of the condition, according to the researchers. This study focused on the association between progression of NASH and consumption of a Western diet, as well as the development of HCC.

The study used a model consisting of hyperphagic mice that lacked a functional ALMS1 gene (Foz/Foz), in addition to wild-type littermates. The model ultimately defined “the key signaling and cytokine pathways that are critical for disease development and resolution” associated with NASH, wrote Souradipta Ganguly, PhD, of the University of California, San Diego, and colleagues. The report was published in Cellular and Molecular Gastroenterology and Hepatology.

According to the researchers, this study is unique given “current rodent models of NASH do not reproduce the complete spectrum of metabolic and histologic” nonalcoholic fatty liver disease (NAFLD) phenotypes. Likewise, the lack of “systemic studies in a single rodent model of NASH that closely recapitulates the human pathology” reinforces the importance of the new model, the researchers added.

Over time, NASH can progress to cirrhosis and hepatocellular carcinoma (HCC). Studies that fed wild-type mice a Western diet have largely failed to mimic the full pathology of NASH to fibrosis to HCC. In addition, the models in these studies fail to reflect the multitissue injuries frequently observed in NASH.

To circumvent these challenges, Dr. Ganguly and colleagues used ALMS1-mutated mice to develop a rodent model of metabolic syndrome that included NASH with fibrosis, chronic kidney disease, and cardiovascular disease. The ALMS1 mutation also resulted in the mice becoming hyperphagic, which increases hunger and leads to early-onset obesity, among other conditions characteristic of metabolic syndrome.

Researchers fed the hyperphagic Foz/Foz mice and wild-type littermates a Western diet or standard diet during a 12-week period for NASH/fibrosis and a 24-week period for HCC. After NASH was established, mice were switched back to normal chow to see if the condition regressed.

Macronutrient distribution of the study’s Western diet included 40% fat, 15% protein, and 44% carbohydrates, based on total caloric content. In contrast, the standard chow included 12% fat, 23% protein, and 65% carbohydrates from total calories.

Within 1-2 weeks, Foz mice fed the Western diet were considered steatotic. These mice subsequently developed NASH by 4 weeks of the study and grade 3 fibrosis by 12 weeks. The researchers concurrently observed the development of chronic kidney injury in the animals. Mice continuing to the 24 weeks ultimately progressed to cirrhosis and HCC; these mice demonstrated reduced survival due to cardiac dysfunction.

Mice that developed NASH were then switched to a diet consisting of normal chow. Following this switch, NASH began to regress, and survival improved. These mice did not appear to develop HCC, and total liver weight was significantly reduced compared with the mice that didn’t enter the regression phase of the study. The researchers wrote that the resolution of hepatic steatosis was also consistent with improved glucose tolerance.

In transcriptomic and histologic analyses, the researchers found strong concordance between Foz/Foz mice NASH liver and human NASH.

The study also found that early disruption of gut barrier, microbial dysbiosis, lipopolysaccharide leakage, and intestinal inflammation preceded NASH in the Foz/Foz mice fed the Western diet, resulting in acute-phase liver inflammation. The early inflammation was reflected by an increase in several chemokines and cytokines by 1-2 weeks. As NASH progressed, the liver cytokine/chemokine profile continued to evolve, leading to monocyte recruitment predominance. “Further studies will elaborate the roles of these NASH-specific microbiomial features in the development and progression of NASH fibrosis,” wrote the researchers.

The study received financial support Janssen, in addition to funding from an ALF Liver Scholar award, ACTRI/National Institutes of Health, the SDDRC, and the NIAAA/National Institutes of Health. The authors disclosed no conflicts.

A new study sought to establish a new, clinically relevant mouse model of nonalcoholic steatohepatitis (NASH) that closely reflects human disease as well as the multitissue dynamics involved in the progression and regression of the condition, according to the researchers. This study focused on the association between progression of NASH and consumption of a Western diet, as well as the development of HCC.

The study used a model consisting of hyperphagic mice that lacked a functional ALMS1 gene (Foz/Foz), in addition to wild-type littermates. The model ultimately defined “the key signaling and cytokine pathways that are critical for disease development and resolution” associated with NASH, wrote Souradipta Ganguly, PhD, of the University of California, San Diego, and colleagues. The report was published in Cellular and Molecular Gastroenterology and Hepatology.

According to the researchers, this study is unique given “current rodent models of NASH do not reproduce the complete spectrum of metabolic and histologic” nonalcoholic fatty liver disease (NAFLD) phenotypes. Likewise, the lack of “systemic studies in a single rodent model of NASH that closely recapitulates the human pathology” reinforces the importance of the new model, the researchers added.

Over time, NASH can progress to cirrhosis and hepatocellular carcinoma (HCC). Studies that fed wild-type mice a Western diet have largely failed to mimic the full pathology of NASH to fibrosis to HCC. In addition, the models in these studies fail to reflect the multitissue injuries frequently observed in NASH.

To circumvent these challenges, Dr. Ganguly and colleagues used ALMS1-mutated mice to develop a rodent model of metabolic syndrome that included NASH with fibrosis, chronic kidney disease, and cardiovascular disease. The ALMS1 mutation also resulted in the mice becoming hyperphagic, which increases hunger and leads to early-onset obesity, among other conditions characteristic of metabolic syndrome.

Researchers fed the hyperphagic Foz/Foz mice and wild-type littermates a Western diet or standard diet during a 12-week period for NASH/fibrosis and a 24-week period for HCC. After NASH was established, mice were switched back to normal chow to see if the condition regressed.

Macronutrient distribution of the study’s Western diet included 40% fat, 15% protein, and 44% carbohydrates, based on total caloric content. In contrast, the standard chow included 12% fat, 23% protein, and 65% carbohydrates from total calories.

Within 1-2 weeks, Foz mice fed the Western diet were considered steatotic. These mice subsequently developed NASH by 4 weeks of the study and grade 3 fibrosis by 12 weeks. The researchers concurrently observed the development of chronic kidney injury in the animals. Mice continuing to the 24 weeks ultimately progressed to cirrhosis and HCC; these mice demonstrated reduced survival due to cardiac dysfunction.

Mice that developed NASH were then switched to a diet consisting of normal chow. Following this switch, NASH began to regress, and survival improved. These mice did not appear to develop HCC, and total liver weight was significantly reduced compared with the mice that didn’t enter the regression phase of the study. The researchers wrote that the resolution of hepatic steatosis was also consistent with improved glucose tolerance.

In transcriptomic and histologic analyses, the researchers found strong concordance between Foz/Foz mice NASH liver and human NASH.

The study also found that early disruption of gut barrier, microbial dysbiosis, lipopolysaccharide leakage, and intestinal inflammation preceded NASH in the Foz/Foz mice fed the Western diet, resulting in acute-phase liver inflammation. The early inflammation was reflected by an increase in several chemokines and cytokines by 1-2 weeks. As NASH progressed, the liver cytokine/chemokine profile continued to evolve, leading to monocyte recruitment predominance. “Further studies will elaborate the roles of these NASH-specific microbiomial features in the development and progression of NASH fibrosis,” wrote the researchers.

The study received financial support Janssen, in addition to funding from an ALF Liver Scholar award, ACTRI/National Institutes of Health, the SDDRC, and the NIAAA/National Institutes of Health. The authors disclosed no conflicts.

People beginning treatment with the immunosuppressive drugs tocilizumab (Actemra) or tofacitinib (Xeljanz) are infrequently screened for hepatitis B virus (HBV) infection, according to a new study of patients with rheumatic diseases who are starting one of the two treatments.

“Perhaps not unexpectedly, these screening patterns conform more with recommendations from the American College of Rheumatology, which do not explicitly stipulate universal HBV screening,” wrote lead author Amir M. Mohareb, MD, of Massachusetts General Hospital in Boston. The study was published in The Journal of Rheumatology.

To determine the frequency of HBV screening among this specific population, the researchers conducted a retrospective, cross-sectional study of patients 18 years or older within the Mass General Brigham health system in the Boston area who initiated either of the two drugs before Dec. 31, 2018. Tocilizumab was approved by the Food and Drug Administration on Jan. 11, 2010, and tofacitinib was approved on Nov. 6, 2012.

The final study population included 678 patients on tocilizumab and 391 patients on tofacitinib. The mean age of the patients in each group was 61 years for tocilizumab and 60 years for tofacitinib. A large majority were female (78% of the tocilizumab group, 88% of the tofacitinib group) and 84% of patients in both groups were white. Their primary diagnosis was rheumatoid arthritis (53% of the tocilizumab group, 77% of the tofacitinib group), and most of them – 57% of patients on tocilizumab and 72% of patients on tofacitinib – had a history of being on both conventional synthetic and biologic disease-modifying antirheumatic drugs (DMARDs).

HBV screening patterns were classified into three categories: complete (all three of the HBV surface antigen [HBsAg], total core antibody [anti-HBcAb], and surface antibody [HBsAb] tests); partial (any one to two tests); and none. Of the 678 patients on tocilizumab, 194 (29%) underwent complete screening, 307 (45%) underwent partial screening, and 177 (26%) had no screening. Of the 391 patients on tofacitinib, 94 (24%) underwent complete screening, 195 (50%) underwent partial screening, and 102 (26%) had none.

Inappropriate testing – defined as either HBV e-antigen (HBeAg), anti-HBcAb IgM, or HBV DNA without a positive HBsAg or total anti-HBcAb – occurred in 22% of patients on tocilizumab and 23% of patients on tofacitinib. After multivariable analysis, the authors found that Whites were less likely to undergo complete screening (odds ratio, 0.74; 95% confidence interval, 0.57-0.95) compared to non-Whites. Previous use of immunosuppressive agents such as conventional synthetic DMARDs (OR, 1.05; 95% CI, 0.72-1.55) and biologic DMARDs with or without prior csDMARDs (OR, 0.73; 95% CI, 0.48-1.12) was not associated with a likelihood of complete appropriate screening.

“These data add to the evidence indicating that clinicians are not completing pretreatment screening for latent infections prior to patients starting high-risk immunosuppressant drugs,” Gabriela Schmajuk, MD, of the University of California, San Francisco, said in an interview. “It can be dangerous, since a fraction of these patients may reactivate latent infections with HBV that can result in liver failure or death.

“On the bright side,” she added, “we have antivirals that can be given as prophylaxis against reactivation of latent HBV if patients do test positive.”

Dr. Schmajuk was previously the senior author of a similar study from the 2019 American College of Rheumatology annual meeting that found only a small percentage of patients who were new users of biologics or new synthetic DMARDs were screened for HBV or hepatitis C virus.

When asked if anything in the study stood out, she acknowledged being “somewhat surprised that patients with prior immunosuppression did not have higher rates of screening. One might expect that since those patients had more opportunities for screening – since they started new medications more times – they would have higher rates, but this did not appear to be the case.”

As a message to rheumatologists who may be starting their patients on any biologic or new synthetic DMARD, she reinforced that “we need universal HBV screening for patients starting these medications. Many clinicians are used to ordering a hepatitis B surface antigen test, but one key message is that we also need to be ordering hepatitis B core antibody tests. Patients with a positive core antibody are still at risk for reactivation.”

The authors noted their study’s limitations, including the data being retrospectively collected and some of the subjects potentially being screened in laboratories outside of the Mass General Brigham health system. In addition, they stated that their findings “may not be generalizable to nonrheumatologic settings or other immunomodulators,” although they added that studies of other patient populations have also uncovered “similarly low HBV screening frequencies.”

Several of the authors reported being supported by institutes within the National Institutes of Health. Beyond that, they declared no potential conflicts of interest.

People beginning treatment with the immunosuppressive drugs tocilizumab (Actemra) or tofacitinib (Xeljanz) are infrequently screened for hepatitis B virus (HBV) infection, according to a new study of patients with rheumatic diseases who are starting one of the two treatments.

“Perhaps not unexpectedly, these screening patterns conform more with recommendations from the American College of Rheumatology, which do not explicitly stipulate universal HBV screening,” wrote lead author Amir M. Mohareb, MD, of Massachusetts General Hospital in Boston. The study was published in The Journal of Rheumatology.

To determine the frequency of HBV screening among this specific population, the researchers conducted a retrospective, cross-sectional study of patients 18 years or older within the Mass General Brigham health system in the Boston area who initiated either of the two drugs before Dec. 31, 2018. Tocilizumab was approved by the Food and Drug Administration on Jan. 11, 2010, and tofacitinib was approved on Nov. 6, 2012.

The final study population included 678 patients on tocilizumab and 391 patients on tofacitinib. The mean age of the patients in each group was 61 years for tocilizumab and 60 years for tofacitinib. A large majority were female (78% of the tocilizumab group, 88% of the tofacitinib group) and 84% of patients in both groups were white. Their primary diagnosis was rheumatoid arthritis (53% of the tocilizumab group, 77% of the tofacitinib group), and most of them – 57% of patients on tocilizumab and 72% of patients on tofacitinib – had a history of being on both conventional synthetic and biologic disease-modifying antirheumatic drugs (DMARDs).

HBV screening patterns were classified into three categories: complete (all three of the HBV surface antigen [HBsAg], total core antibody [anti-HBcAb], and surface antibody [HBsAb] tests); partial (any one to two tests); and none. Of the 678 patients on tocilizumab, 194 (29%) underwent complete screening, 307 (45%) underwent partial screening, and 177 (26%) had no screening. Of the 391 patients on tofacitinib, 94 (24%) underwent complete screening, 195 (50%) underwent partial screening, and 102 (26%) had none.

Inappropriate testing – defined as either HBV e-antigen (HBeAg), anti-HBcAb IgM, or HBV DNA without a positive HBsAg or total anti-HBcAb – occurred in 22% of patients on tocilizumab and 23% of patients on tofacitinib. After multivariable analysis, the authors found that Whites were less likely to undergo complete screening (odds ratio, 0.74; 95% confidence interval, 0.57-0.95) compared to non-Whites. Previous use of immunosuppressive agents such as conventional synthetic DMARDs (OR, 1.05; 95% CI, 0.72-1.55) and biologic DMARDs with or without prior csDMARDs (OR, 0.73; 95% CI, 0.48-1.12) was not associated with a likelihood of complete appropriate screening.

“These data add to the evidence indicating that clinicians are not completing pretreatment screening for latent infections prior to patients starting high-risk immunosuppressant drugs,” Gabriela Schmajuk, MD, of the University of California, San Francisco, said in an interview. “It can be dangerous, since a fraction of these patients may reactivate latent infections with HBV that can result in liver failure or death.

“On the bright side,” she added, “we have antivirals that can be given as prophylaxis against reactivation of latent HBV if patients do test positive.”

Dr. Schmajuk was previously the senior author of a similar study from the 2019 American College of Rheumatology annual meeting that found only a small percentage of patients who were new users of biologics or new synthetic DMARDs were screened for HBV or hepatitis C virus.

When asked if anything in the study stood out, she acknowledged being “somewhat surprised that patients with prior immunosuppression did not have higher rates of screening. One might expect that since those patients had more opportunities for screening – since they started new medications more times – they would have higher rates, but this did not appear to be the case.”

As a message to rheumatologists who may be starting their patients on any biologic or new synthetic DMARD, she reinforced that “we need universal HBV screening for patients starting these medications. Many clinicians are used to ordering a hepatitis B surface antigen test, but one key message is that we also need to be ordering hepatitis B core antibody tests. Patients with a positive core antibody are still at risk for reactivation.”

The authors noted their study’s limitations, including the data being retrospectively collected and some of the subjects potentially being screened in laboratories outside of the Mass General Brigham health system. In addition, they stated that their findings “may not be generalizable to nonrheumatologic settings or other immunomodulators,” although they added that studies of other patient populations have also uncovered “similarly low HBV screening frequencies.”

Several of the authors reported being supported by institutes within the National Institutes of Health. Beyond that, they declared no potential conflicts of interest.

People beginning treatment with the immunosuppressive drugs tocilizumab (Actemra) or tofacitinib (Xeljanz) are infrequently screened for hepatitis B virus (HBV) infection, according to a new study of patients with rheumatic diseases who are starting one of the two treatments.

“Perhaps not unexpectedly, these screening patterns conform more with recommendations from the American College of Rheumatology, which do not explicitly stipulate universal HBV screening,” wrote lead author Amir M. Mohareb, MD, of Massachusetts General Hospital in Boston. The study was published in The Journal of Rheumatology.

To determine the frequency of HBV screening among this specific population, the researchers conducted a retrospective, cross-sectional study of patients 18 years or older within the Mass General Brigham health system in the Boston area who initiated either of the two drugs before Dec. 31, 2018. Tocilizumab was approved by the Food and Drug Administration on Jan. 11, 2010, and tofacitinib was approved on Nov. 6, 2012.

The final study population included 678 patients on tocilizumab and 391 patients on tofacitinib. The mean age of the patients in each group was 61 years for tocilizumab and 60 years for tofacitinib. A large majority were female (78% of the tocilizumab group, 88% of the tofacitinib group) and 84% of patients in both groups were white. Their primary diagnosis was rheumatoid arthritis (53% of the tocilizumab group, 77% of the tofacitinib group), and most of them – 57% of patients on tocilizumab and 72% of patients on tofacitinib – had a history of being on both conventional synthetic and biologic disease-modifying antirheumatic drugs (DMARDs).

HBV screening patterns were classified into three categories: complete (all three of the HBV surface antigen [HBsAg], total core antibody [anti-HBcAb], and surface antibody [HBsAb] tests); partial (any one to two tests); and none. Of the 678 patients on tocilizumab, 194 (29%) underwent complete screening, 307 (45%) underwent partial screening, and 177 (26%) had no screening. Of the 391 patients on tofacitinib, 94 (24%) underwent complete screening, 195 (50%) underwent partial screening, and 102 (26%) had none.

Inappropriate testing – defined as either HBV e-antigen (HBeAg), anti-HBcAb IgM, or HBV DNA without a positive HBsAg or total anti-HBcAb – occurred in 22% of patients on tocilizumab and 23% of patients on tofacitinib. After multivariable analysis, the authors found that Whites were less likely to undergo complete screening (odds ratio, 0.74; 95% confidence interval, 0.57-0.95) compared to non-Whites. Previous use of immunosuppressive agents such as conventional synthetic DMARDs (OR, 1.05; 95% CI, 0.72-1.55) and biologic DMARDs with or without prior csDMARDs (OR, 0.73; 95% CI, 0.48-1.12) was not associated with a likelihood of complete appropriate screening.

“These data add to the evidence indicating that clinicians are not completing pretreatment screening for latent infections prior to patients starting high-risk immunosuppressant drugs,” Gabriela Schmajuk, MD, of the University of California, San Francisco, said in an interview. “It can be dangerous, since a fraction of these patients may reactivate latent infections with HBV that can result in liver failure or death.

“On the bright side,” she added, “we have antivirals that can be given as prophylaxis against reactivation of latent HBV if patients do test positive.”

Dr. Schmajuk was previously the senior author of a similar study from the 2019 American College of Rheumatology annual meeting that found only a small percentage of patients who were new users of biologics or new synthetic DMARDs were screened for HBV or hepatitis C virus.

When asked if anything in the study stood out, she acknowledged being “somewhat surprised that patients with prior immunosuppression did not have higher rates of screening. One might expect that since those patients had more opportunities for screening – since they started new medications more times – they would have higher rates, but this did not appear to be the case.”

As a message to rheumatologists who may be starting their patients on any biologic or new synthetic DMARD, she reinforced that “we need universal HBV screening for patients starting these medications. Many clinicians are used to ordering a hepatitis B surface antigen test, but one key message is that we also need to be ordering hepatitis B core antibody tests. Patients with a positive core antibody are still at risk for reactivation.”

The authors noted their study’s limitations, including the data being retrospectively collected and some of the subjects potentially being screened in laboratories outside of the Mass General Brigham health system. In addition, they stated that their findings “may not be generalizable to nonrheumatologic settings or other immunomodulators,” although they added that studies of other patient populations have also uncovered “similarly low HBV screening frequencies.”

Several of the authors reported being supported by institutes within the National Institutes of Health. Beyond that, they declared no potential conflicts of interest.

A multidisciplinary panel of U.S. experts released a “Call to Action” for improved screening, diagnosis, and treatment of patients with nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD) on July 26, an effort organized by the American Gastroenterological Association in collaboration with seven other U.S. medical organizations including several endocrinology groups.

The published statement, “Preparing for the NASH Epidemic: A Call to Action,” proposes several urgent steps for the U.S. clinical community to provide better-focused and better-coordinated care for patients at risk for developing or having NAFLD or NASH, particularly among “emerging” at-risk cohorts such as patients with diabetes and obesity. It appears in the journals Gastroenterology, Diabetes Care, Metabolism: Clinical and Experimental, and Obesity.

The statement’s central pitch is that improvements in care won’t be possible unless the several medical specialties that deal with affected or at-risk patients stop working “in separate silos,” and instead create “a collective action plan,” and also organize multidisciplinary teams that “integrate primary care, hepatology, obesity medicine, endocrinology, and diabetology via well-defined care pathways.”

“The overarching goal” is a “unified, international public health response to NAFLD and NASH,” said the statement, which stemmed from a conference held in July 2020 that included representatives from not only the lead gastroenterology group but also the American Diabetes Association, the American Association for the Study of Liver Diseases, the American Association of Clinical Endocrinologists, The Endocrine Society, The American Academy of Family Physicians, The Obesity Society, and the American College of Osteopathic Family Physicians.

The statement cites sobering prevalence numbers, with estimates that NAFLD exists in more than half the patients with type 2 diabetes, while NASH affects about a third, rates that translate into many millions of affected Americans, given recent estimates that the U.S. prevalence of type 2 diabetes exceeds 30 million people. And the numbers continue to rise along with increases in the prevalence of obesity and type 2 diabetes.

“It’s an enormously common disease, and there are not enough gastroenterologists, to say nothing of hepatologists, to care for every patient with NAFLD,” said Anna Mae Diehl, MD, a gastroenterologist and professor at Duke University in Durham, N.C., who was not involved with the conference nor in writing the statement.

Clinical care pathways coming soon

Another key part of this initiative is development of clinical care pathways that will have “careful explication of each step in screening, diagnosis, and treatment,” and will be designed to inform the practice of primary care physicians (PCPs) as well as clinicians from the various specialties that deal with these patients.

The clinical care pathways are on track to come out later in 2021, said Fasiha Kanwal, MD, a professor and chief of gastroenterology at Baylor College of Medicine in Houston, and lead author on the Call to Action document.

“The Pathways will include practical recommendations about whom to screen and when to refer, and the criteria primary care physicians can use for diagnosis and risk stratification,” Dr. Kanwal said in an interview. “Patients can benefit from a standardized approach.”

The new document also includes results from a recent survey about NAFLD and NASH management completed by 751 U.S. physicians, including 401 (53%) primary care physicians, 175 gastroenterologists, (23%) and 175 endocrinologists (23%; percentages total 99% because of rounding).

The results showed “significant gaps in knowledge about whom to screen and how to diagnose and treat patients at high risk for NASH,” concluded the statement’s authors. Barely more than a third of the respondents knew that almost all patients with severe obesity likely have NAFLD, and fewer than half the endocrinologists and the primary care physicians appreciated that NAFLD is very common among patients with type 2 diabetes.
 

‘Understanding of NAFLD is not there’

“I applaud this effort that calls attention to an emerging public health problem. This paper and survey are great ideas. The findings are not surprising, but they’re important,” said Dr. Diehl said in an interview. “Much more needs to be done” including changes in social behavior and government policies.

“The public’s understanding of NAFLD is not there,” and many physicians also have an incomplete understanding of NAFLD and more serious stages of metabolic liver disease. “Physicians know that patients with obesity are at risk for heart disease, diabetes, and stroke, but they may not always be aware that these patients can also have cirrhosis,” noted Dr. Diehl, who published in 2019 a call to action for NAFLD of her own with some associates.

“My referrals are fueled by primary care physicians who recognize patients with significant liver disease. It would be great to outline recommended practice; I have no doubt that providers will embrace this,” as well as the broader concept of multidisciplinary teams, another focus of the statement. Dr. Diehl cited the “Cancer Center model,” where an oncologist takes primary responsibility for caring for a cancer patient while coordinating care with other specialists, an approach facilitated by EMRs that allow seamless data and chart sharing and something that many health systems have either already adopted or are moving toward.

She said the NASH Call to Action may help catalyze broader application of this model to many more patients with NAFLD or NASH, and noted that some U.S. centers already use this approach – including Dr. Diehl’s program at Duke – which brings together her gastroenterology colleagues with cardiologists, radiologists, endocrinologists, and bariatric surgeons. But she noted that for most patients with metabolic liver disease, the hub clinician needs to be a PCP, especially for patients with earlier-stage disease, because the number of affected patients is so huge.

“Key steps toward establishing such teams include establishing protocols for risk stratification and referral, definition of roles and responsibilities, and buy-in from institutions and payers. Clearly a lot of work needs to occur to get to these multidisciplinary teams,” said Dr. Kanwal.

Ralph A. DeFronzo, MD, professor and deputy director of the Texas Diabetes Institute at UT Health San Antonio, who was not involved with the conference or statement, had a different take on what the future of NASH and NAFLD care may look like.

“Endocrinologists, hepatologists, and obesity experts will work within their individual specialties to diagnose and manage NASH,” he said in an interview. But he acknowledged that “an integrated effort by specialists would be important” to help “primary care physicians who are less familiar with the disease.”
 

Controversy over pioglitazone?

Dr. DeFronzo endorsed development of clinical care pathways as “important,” but also as a potential source of “controversy, especially with respect to treatment.”

The Call to Action statement cites lifestyle-based therapies, such as an appropriate diet; regular, moderate exercise; and elimination when possible of obesogenic medications as cornerstone interventions for patients with NAFLD or early-stage NASH, interventions that can be prescribed by PCPs. For patients with NASH and stage 2 or worse fibrosis, the statement endorses liver-directed pharmacotherapy. While noting that no agents currently carry a Food and Drug Administration–approved indication for treating NASH, the statement cites evidence that 800 IU/day of vitamin E improves steatosis in patients with NASH but not type 2 diabetes.

For patients with type 2 diabetes, the statement notes that results from five randomized trials indicated that pioglitazone could reverse steatohepatitis, findings that led to its recommendation in guidelines from a modest circle of medical groups, including the American Association for the Study of Liver Diseases and the European Association for the Study of Diabetes. However, the 2021 Standards of Medical Care in Diabetes from the American Diabetes Association gives these agents limited endorsement, saying: “Pioglitazone, vitamin E treatment, and liraglutide treatment of biopsy-proven nonalcoholic steatohepatitis have each been shown to improve liver histology, but effects on longer-term clinical outcomes are not known.”

“The strongest evidence by far is for pioglitazone for treating NAFLD and NASH,” said Dr. DeFronzo, a vocal proponent of the drug for this indication. But he added that “hepatologists don’t feel comfortable with drugs from the thiazolidinedione class,” which includes pioglitazone.

“We don’t yet know how to optimally configure the health system for NAFLD and NASH to make it more efficient and helpful to patients, but models exist, and the approach is evolving,” said Dr. Diehl.

Dr. Diehl and Dr. Kanwal had no relevant disclosures. Dr. DeFronzo has been a speaker on behalf of AstraZeneca and Novo Nordisk, has been an adviser to AstraZeneca, Boehringer Ingelheim, Intarcia, and Janssen, and has received research funding from AstraZeneca, Janssen and Merck.

[email protected]

A multidisciplinary panel of U.S. experts released a “Call to Action” for improved screening, diagnosis, and treatment of patients with nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD) on July 26, an effort organized by the American Gastroenterological Association in collaboration with seven other U.S. medical organizations including several endocrinology groups.

The published statement, “Preparing for the NASH Epidemic: A Call to Action,” proposes several urgent steps for the U.S. clinical community to provide better-focused and better-coordinated care for patients at risk for developing or having NAFLD or NASH, particularly among “emerging” at-risk cohorts such as patients with diabetes and obesity. It appears in the journals Gastroenterology, Diabetes Care, Metabolism: Clinical and Experimental, and Obesity.

The statement’s central pitch is that improvements in care won’t be possible unless the several medical specialties that deal with affected or at-risk patients stop working “in separate silos,” and instead create “a collective action plan,” and also organize multidisciplinary teams that “integrate primary care, hepatology, obesity medicine, endocrinology, and diabetology via well-defined care pathways.”

“The overarching goal” is a “unified, international public health response to NAFLD and NASH,” said the statement, which stemmed from a conference held in July 2020 that included representatives from not only the lead gastroenterology group but also the American Diabetes Association, the American Association for the Study of Liver Diseases, the American Association of Clinical Endocrinologists, The Endocrine Society, The American Academy of Family Physicians, The Obesity Society, and the American College of Osteopathic Family Physicians.

The statement cites sobering prevalence numbers, with estimates that NAFLD exists in more than half the patients with type 2 diabetes, while NASH affects about a third, rates that translate into many millions of affected Americans, given recent estimates that the U.S. prevalence of type 2 diabetes exceeds 30 million people. And the numbers continue to rise along with increases in the prevalence of obesity and type 2 diabetes.

“It’s an enormously common disease, and there are not enough gastroenterologists, to say nothing of hepatologists, to care for every patient with NAFLD,” said Anna Mae Diehl, MD, a gastroenterologist and professor at Duke University in Durham, N.C., who was not involved with the conference nor in writing the statement.

Clinical care pathways coming soon

Another key part of this initiative is development of clinical care pathways that will have “careful explication of each step in screening, diagnosis, and treatment,” and will be designed to inform the practice of primary care physicians (PCPs) as well as clinicians from the various specialties that deal with these patients.

The clinical care pathways are on track to come out later in 2021, said Fasiha Kanwal, MD, a professor and chief of gastroenterology at Baylor College of Medicine in Houston, and lead author on the Call to Action document.

“The Pathways will include practical recommendations about whom to screen and when to refer, and the criteria primary care physicians can use for diagnosis and risk stratification,” Dr. Kanwal said in an interview. “Patients can benefit from a standardized approach.”

The new document also includes results from a recent survey about NAFLD and NASH management completed by 751 U.S. physicians, including 401 (53%) primary care physicians, 175 gastroenterologists, (23%) and 175 endocrinologists (23%; percentages total 99% because of rounding).

The results showed “significant gaps in knowledge about whom to screen and how to diagnose and treat patients at high risk for NASH,” concluded the statement’s authors. Barely more than a third of the respondents knew that almost all patients with severe obesity likely have NAFLD, and fewer than half the endocrinologists and the primary care physicians appreciated that NAFLD is very common among patients with type 2 diabetes.
 

‘Understanding of NAFLD is not there’

“I applaud this effort that calls attention to an emerging public health problem. This paper and survey are great ideas. The findings are not surprising, but they’re important,” said Dr. Diehl said in an interview. “Much more needs to be done” including changes in social behavior and government policies.

“The public’s understanding of NAFLD is not there,” and many physicians also have an incomplete understanding of NAFLD and more serious stages of metabolic liver disease. “Physicians know that patients with obesity are at risk for heart disease, diabetes, and stroke, but they may not always be aware that these patients can also have cirrhosis,” noted Dr. Diehl, who published in 2019 a call to action for NAFLD of her own with some associates.

“My referrals are fueled by primary care physicians who recognize patients with significant liver disease. It would be great to outline recommended practice; I have no doubt that providers will embrace this,” as well as the broader concept of multidisciplinary teams, another focus of the statement. Dr. Diehl cited the “Cancer Center model,” where an oncologist takes primary responsibility for caring for a cancer patient while coordinating care with other specialists, an approach facilitated by EMRs that allow seamless data and chart sharing and something that many health systems have either already adopted or are moving toward.

She said the NASH Call to Action may help catalyze broader application of this model to many more patients with NAFLD or NASH, and noted that some U.S. centers already use this approach – including Dr. Diehl’s program at Duke – which brings together her gastroenterology colleagues with cardiologists, radiologists, endocrinologists, and bariatric surgeons. But she noted that for most patients with metabolic liver disease, the hub clinician needs to be a PCP, especially for patients with earlier-stage disease, because the number of affected patients is so huge.

“Key steps toward establishing such teams include establishing protocols for risk stratification and referral, definition of roles and responsibilities, and buy-in from institutions and payers. Clearly a lot of work needs to occur to get to these multidisciplinary teams,” said Dr. Kanwal.

Ralph A. DeFronzo, MD, professor and deputy director of the Texas Diabetes Institute at UT Health San Antonio, who was not involved with the conference or statement, had a different take on what the future of NASH and NAFLD care may look like.

“Endocrinologists, hepatologists, and obesity experts will work within their individual specialties to diagnose and manage NASH,” he said in an interview. But he acknowledged that “an integrated effort by specialists would be important” to help “primary care physicians who are less familiar with the disease.”
 

Controversy over pioglitazone?

Dr. DeFronzo endorsed development of clinical care pathways as “important,” but also as a potential source of “controversy, especially with respect to treatment.”

The Call to Action statement cites lifestyle-based therapies, such as an appropriate diet; regular, moderate exercise; and elimination when possible of obesogenic medications as cornerstone interventions for patients with NAFLD or early-stage NASH, interventions that can be prescribed by PCPs. For patients with NASH and stage 2 or worse fibrosis, the statement endorses liver-directed pharmacotherapy. While noting that no agents currently carry a Food and Drug Administration–approved indication for treating NASH, the statement cites evidence that 800 IU/day of vitamin E improves steatosis in patients with NASH but not type 2 diabetes.

For patients with type 2 diabetes, the statement notes that results from five randomized trials indicated that pioglitazone could reverse steatohepatitis, findings that led to its recommendation in guidelines from a modest circle of medical groups, including the American Association for the Study of Liver Diseases and the European Association for the Study of Diabetes. However, the 2021 Standards of Medical Care in Diabetes from the American Diabetes Association gives these agents limited endorsement, saying: “Pioglitazone, vitamin E treatment, and liraglutide treatment of biopsy-proven nonalcoholic steatohepatitis have each been shown to improve liver histology, but effects on longer-term clinical outcomes are not known.”

“The strongest evidence by far is for pioglitazone for treating NAFLD and NASH,” said Dr. DeFronzo, a vocal proponent of the drug for this indication. But he added that “hepatologists don’t feel comfortable with drugs from the thiazolidinedione class,” which includes pioglitazone.

“We don’t yet know how to optimally configure the health system for NAFLD and NASH to make it more efficient and helpful to patients, but models exist, and the approach is evolving,” said Dr. Diehl.

Dr. Diehl and Dr. Kanwal had no relevant disclosures. Dr. DeFronzo has been a speaker on behalf of AstraZeneca and Novo Nordisk, has been an adviser to AstraZeneca, Boehringer Ingelheim, Intarcia, and Janssen, and has received research funding from AstraZeneca, Janssen and Merck.

[email protected]

A multidisciplinary panel of U.S. experts released a “Call to Action” for improved screening, diagnosis, and treatment of patients with nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD) on July 26, an effort organized by the American Gastroenterological Association in collaboration with seven other U.S. medical organizations including several endocrinology groups.

The published statement, “Preparing for the NASH Epidemic: A Call to Action,” proposes several urgent steps for the U.S. clinical community to provide better-focused and better-coordinated care for patients at risk for developing or having NAFLD or NASH, particularly among “emerging” at-risk cohorts such as patients with diabetes and obesity. It appears in the journals Gastroenterology, Diabetes Care, Metabolism: Clinical and Experimental, and Obesity.

The statement’s central pitch is that improvements in care won’t be possible unless the several medical specialties that deal with affected or at-risk patients stop working “in separate silos,” and instead create “a collective action plan,” and also organize multidisciplinary teams that “integrate primary care, hepatology, obesity medicine, endocrinology, and diabetology via well-defined care pathways.”

“The overarching goal” is a “unified, international public health response to NAFLD and NASH,” said the statement, which stemmed from a conference held in July 2020 that included representatives from not only the lead gastroenterology group but also the American Diabetes Association, the American Association for the Study of Liver Diseases, the American Association of Clinical Endocrinologists, The Endocrine Society, The American Academy of Family Physicians, The Obesity Society, and the American College of Osteopathic Family Physicians.

The statement cites sobering prevalence numbers, with estimates that NAFLD exists in more than half the patients with type 2 diabetes, while NASH affects about a third, rates that translate into many millions of affected Americans, given recent estimates that the U.S. prevalence of type 2 diabetes exceeds 30 million people. And the numbers continue to rise along with increases in the prevalence of obesity and type 2 diabetes.

“It’s an enormously common disease, and there are not enough gastroenterologists, to say nothing of hepatologists, to care for every patient with NAFLD,” said Anna Mae Diehl, MD, a gastroenterologist and professor at Duke University in Durham, N.C., who was not involved with the conference nor in writing the statement.

Clinical care pathways coming soon

Another key part of this initiative is development of clinical care pathways that will have “careful explication of each step in screening, diagnosis, and treatment,” and will be designed to inform the practice of primary care physicians (PCPs) as well as clinicians from the various specialties that deal with these patients.

The clinical care pathways are on track to come out later in 2021, said Fasiha Kanwal, MD, a professor and chief of gastroenterology at Baylor College of Medicine in Houston, and lead author on the Call to Action document.

“The Pathways will include practical recommendations about whom to screen and when to refer, and the criteria primary care physicians can use for diagnosis and risk stratification,” Dr. Kanwal said in an interview. “Patients can benefit from a standardized approach.”

The new document also includes results from a recent survey about NAFLD and NASH management completed by 751 U.S. physicians, including 401 (53%) primary care physicians, 175 gastroenterologists, (23%) and 175 endocrinologists (23%; percentages total 99% because of rounding).

The results showed “significant gaps in knowledge about whom to screen and how to diagnose and treat patients at high risk for NASH,” concluded the statement’s authors. Barely more than a third of the respondents knew that almost all patients with severe obesity likely have NAFLD, and fewer than half the endocrinologists and the primary care physicians appreciated that NAFLD is very common among patients with type 2 diabetes.
 

‘Understanding of NAFLD is not there’

“I applaud this effort that calls attention to an emerging public health problem. This paper and survey are great ideas. The findings are not surprising, but they’re important,” said Dr. Diehl said in an interview. “Much more needs to be done” including changes in social behavior and government policies.

“The public’s understanding of NAFLD is not there,” and many physicians also have an incomplete understanding of NAFLD and more serious stages of metabolic liver disease. “Physicians know that patients with obesity are at risk for heart disease, diabetes, and stroke, but they may not always be aware that these patients can also have cirrhosis,” noted Dr. Diehl, who published in 2019 a call to action for NAFLD of her own with some associates.

“My referrals are fueled by primary care physicians who recognize patients with significant liver disease. It would be great to outline recommended practice; I have no doubt that providers will embrace this,” as well as the broader concept of multidisciplinary teams, another focus of the statement. Dr. Diehl cited the “Cancer Center model,” where an oncologist takes primary responsibility for caring for a cancer patient while coordinating care with other specialists, an approach facilitated by EMRs that allow seamless data and chart sharing and something that many health systems have either already adopted or are moving toward.

She said the NASH Call to Action may help catalyze broader application of this model to many more patients with NAFLD or NASH, and noted that some U.S. centers already use this approach – including Dr. Diehl’s program at Duke – which brings together her gastroenterology colleagues with cardiologists, radiologists, endocrinologists, and bariatric surgeons. But she noted that for most patients with metabolic liver disease, the hub clinician needs to be a PCP, especially for patients with earlier-stage disease, because the number of affected patients is so huge.

“Key steps toward establishing such teams include establishing protocols for risk stratification and referral, definition of roles and responsibilities, and buy-in from institutions and payers. Clearly a lot of work needs to occur to get to these multidisciplinary teams,” said Dr. Kanwal.

Ralph A. DeFronzo, MD, professor and deputy director of the Texas Diabetes Institute at UT Health San Antonio, who was not involved with the conference or statement, had a different take on what the future of NASH and NAFLD care may look like.

“Endocrinologists, hepatologists, and obesity experts will work within their individual specialties to diagnose and manage NASH,” he said in an interview. But he acknowledged that “an integrated effort by specialists would be important” to help “primary care physicians who are less familiar with the disease.”
 

Controversy over pioglitazone?

Dr. DeFronzo endorsed development of clinical care pathways as “important,” but also as a potential source of “controversy, especially with respect to treatment.”

The Call to Action statement cites lifestyle-based therapies, such as an appropriate diet; regular, moderate exercise; and elimination when possible of obesogenic medications as cornerstone interventions for patients with NAFLD or early-stage NASH, interventions that can be prescribed by PCPs. For patients with NASH and stage 2 or worse fibrosis, the statement endorses liver-directed pharmacotherapy. While noting that no agents currently carry a Food and Drug Administration–approved indication for treating NASH, the statement cites evidence that 800 IU/day of vitamin E improves steatosis in patients with NASH but not type 2 diabetes.

For patients with type 2 diabetes, the statement notes that results from five randomized trials indicated that pioglitazone could reverse steatohepatitis, findings that led to its recommendation in guidelines from a modest circle of medical groups, including the American Association for the Study of Liver Diseases and the European Association for the Study of Diabetes. However, the 2021 Standards of Medical Care in Diabetes from the American Diabetes Association gives these agents limited endorsement, saying: “Pioglitazone, vitamin E treatment, and liraglutide treatment of biopsy-proven nonalcoholic steatohepatitis have each been shown to improve liver histology, but effects on longer-term clinical outcomes are not known.”

“The strongest evidence by far is for pioglitazone for treating NAFLD and NASH,” said Dr. DeFronzo, a vocal proponent of the drug for this indication. But he added that “hepatologists don’t feel comfortable with drugs from the thiazolidinedione class,” which includes pioglitazone.

“We don’t yet know how to optimally configure the health system for NAFLD and NASH to make it more efficient and helpful to patients, but models exist, and the approach is evolving,” said Dr. Diehl.

Dr. Diehl and Dr. Kanwal had no relevant disclosures. Dr. DeFronzo has been a speaker on behalf of AstraZeneca and Novo Nordisk, has been an adviser to AstraZeneca, Boehringer Ingelheim, Intarcia, and Janssen, and has received research funding from AstraZeneca, Janssen and Merck.

[email protected]

Patients with hepatocellular carcinoma (HCC) can be offered transarterial radioembolization (TARE) as a safe and effective first-line treatment or adjunct to other locoregional therapies, authors of a large multicenter study reported.

Among 422 patients with HCC treated with TARE in eight European countries, the median overall survival was 16.5 months, with fewer than 10% of patients experiencing grade 3 or greater adverse events, reported Frank Kolligs, MD, from Helios Hospital Berlin-Buch.

“This exploratory study evaluated factors that can influence the application and outcome of transarterial radioembolization in clinical practice. TARE is generally applied according to guideline recommendations, and randomized, controlled trials are needed to confirm the effect of personalized dosimetry on the effectiveness of TARE,” he said in an oral abstract presented at the meeting sponsored by the European Association for the Study of the Liver.

Intriguingly, the investigators found evidence suggesting that patients whose treatments were planned using a partition model had better survival outcomes than those patients who treatments were based on calculated body surface area or measured BSA (mBSA), but this finding will need to be explored in more detail, Dr. Kolligs said.

The partition model incorporates variables such as tumor volume and liver volume, shunt fractions, the ratio of radiation uptake between tumor and normal tissues, vascular anatomy and other factors to estimate the optimal dose.
 

Study design

Dr. Kolligs and colleagues looked at prospective data from the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) Registry for SIR-Spheres Therapy to evaluate the real-world clinical application of TARE with yttrium Y-90 resin microspheres in Europe, clinical outcomes, safety, and quality of life.

They selected data from centers with a minimum of 10 cases performed in the previous 12 months and at least 40 total cases overall.

The patients included adults 18 years and older scheduled for treatment with Y-90 resin microspheres for primary or metastatic liver tumors, with no specific exclusion criteria. The patients were followed for at least 24 months at recommended intervals of every 3 months. The first patient was enrolled in January 2015, and the last follow-up visit was in December 2019. A total of 422 registry patients had a diagnosis of HCC and were included in the study.

The median age was 68 years (range, 60-74), 80.8% were male, 70.9% had cirrhosis, 14.5% had ascites, and 8.5% had extrahepatic disease. About 32% of patients had one tumor nodule, 33% had two to five nodules, and the remainder had either more than five or an uncountable number.

In all, 14% of patients had Barcelona Clinic Liver Cancer stage A disease, 51.4% had stage B, 33.6% had stage C, and 0.9% stage D.

About one-third of patients had portal vein occlusion. Tumors were in both left and right lobes in 35.5%, the left lobe alone in 12.1%, and the right lobe alone in 52.4%.

Half of all patients (50.2%) received TARE as first-line therapy, 44.8% had it following surgery (17.1%), ablation (14.7%), and/or transarterial chemoembolization (; 23%). In addition, 9.7% of patients received systemic therapy prior to TARE, primarily with sorafenib (Nexavar).

Treatment intent was palliative for 57.3% of patients, and tumor downsizing/downstaging in 32.5% (remainder unspecified).
 

Survival and prognostic factors

As noted before, median overall survival was 16.5 months. Median progression-free survival was 6.1 months, and median hepatic PFS was 6.7 months.

Factors prognostic for better overall survival included hepatitis B or C virus as the cirrhosis cause versus alcohol (hazard ratio for death, 0.51 for each; P = .0060 for HBV and P = .0007 for HCV); unilobar versus bilobar tumors (HR, 0.67; P = .0422 for left-lobe; HR 0.55; P < .0001 for right); prior surgery (HR, 0.67; P = .0258); prior ablation (HR, 0.65; P = .0394); and curative versus palliative intent (HR, 0.53; P < .0001).

Factors associated with worse overall survival were presence of ascites (HR 1.75, P = .001); presence of extrahepatic disease before TARE (HR, 1.81, P = .0037); tumor burden greater than 5 nodules (HR, 1.67; P = .0073); main portal vein occlusion (HR, 2.14; P = .0064); lobar portal vein occlusion (HR, 1.77; P = .0083); total bilirubin greater than 1.5 mg/dL (HR, 1.69; P = .0094); albumin-bilirubin grade A2 (HR, 1.66; P = .0005); ALB1 grade A3 (HR, 3.92; P < .0001); and BSA/mBSA versus partition-model dosimetry (HR, 1.89; P < .0001).

The safety analysis showed that 36.7% of patients had at least one adverse event, but only 7.1% had at least one grade 3 or greater event.

Grade 3 or greater events were abdominal pain (nine patients), fatigue (six), nausea (three), radioembolization-induced liver disease (three), vomiting (two), and GI ulceration (one). Fifteen additional patients had other unspecified events.

The investigators acknowledged broad inclusion criteria, relatively high rates of loss to follow-up, and differences in national guidelines and local standards of practice as potential limitations to their findings.

In the question-and-answer following the presentation, session comoderator María Varela, MD, PhD, a pathologist in the liver unit at the Hospital Universitario Central de Asturia, Oviedo, Spain, questioned why about one-third of patients received TARE for downstaging, but only 13 underwent subsequent surgical resection.

“We don’t have a detailed analysis of this subgroup of patients who received curative intent as yet, ” Dr. Kolligs said.

Pierre Nahon, MD, from the University of Paris and Hôpital Jean Verdier in Bondy, France, commented that, among this heterogenous population, one of the best indications for TARE is probably localized HCC with adjacent portal vein thrombosis.

He asked whether the investigators had examined overall survival among patients with localized unilobar HCC with adjacent small portal vein thrombosis.

“We find that patients with portal vein occlusion have a worse prognosis in the total group,” Dr. Kolligs replied. “To look into the question whether partial thrombosis with a small tumor might benefit is an interesting question, and we should look into that, but I don’t have any data on that yet.”

Another audience member asked: “According to your data, which patients are the best candidates for radioembolization?”

“According to these data, the best candidates are of course patients with good liver function, ascites should ideally not be present, and what is probably is important is that we identify or include patients without extrahepatic disease,” he said.

The study was sponsored by CIRSE. Dr. Kolligs disclosed speaking activities and consulting for several companies. Dr. Varela disclosed speaking for several companies and advisory board activity for Bayer. Dr. Nahon disclosed honoraria and consulting fees from several companies.

Patients with hepatocellular carcinoma (HCC) can be offered transarterial radioembolization (TARE) as a safe and effective first-line treatment or adjunct to other locoregional therapies, authors of a large multicenter study reported.

Among 422 patients with HCC treated with TARE in eight European countries, the median overall survival was 16.5 months, with fewer than 10% of patients experiencing grade 3 or greater adverse events, reported Frank Kolligs, MD, from Helios Hospital Berlin-Buch.

“This exploratory study evaluated factors that can influence the application and outcome of transarterial radioembolization in clinical practice. TARE is generally applied according to guideline recommendations, and randomized, controlled trials are needed to confirm the effect of personalized dosimetry on the effectiveness of TARE,” he said in an oral abstract presented at the meeting sponsored by the European Association for the Study of the Liver.

Intriguingly, the investigators found evidence suggesting that patients whose treatments were planned using a partition model had better survival outcomes than those patients who treatments were based on calculated body surface area or measured BSA (mBSA), but this finding will need to be explored in more detail, Dr. Kolligs said.

The partition model incorporates variables such as tumor volume and liver volume, shunt fractions, the ratio of radiation uptake between tumor and normal tissues, vascular anatomy and other factors to estimate the optimal dose.
 

Study design

Dr. Kolligs and colleagues looked at prospective data from the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) Registry for SIR-Spheres Therapy to evaluate the real-world clinical application of TARE with yttrium Y-90 resin microspheres in Europe, clinical outcomes, safety, and quality of life.

They selected data from centers with a minimum of 10 cases performed in the previous 12 months and at least 40 total cases overall.

The patients included adults 18 years and older scheduled for treatment with Y-90 resin microspheres for primary or metastatic liver tumors, with no specific exclusion criteria. The patients were followed for at least 24 months at recommended intervals of every 3 months. The first patient was enrolled in January 2015, and the last follow-up visit was in December 2019. A total of 422 registry patients had a diagnosis of HCC and were included in the study.

The median age was 68 years (range, 60-74), 80.8% were male, 70.9% had cirrhosis, 14.5% had ascites, and 8.5% had extrahepatic disease. About 32% of patients had one tumor nodule, 33% had two to five nodules, and the remainder had either more than five or an uncountable number.

In all, 14% of patients had Barcelona Clinic Liver Cancer stage A disease, 51.4% had stage B, 33.6% had stage C, and 0.9% stage D.

About one-third of patients had portal vein occlusion. Tumors were in both left and right lobes in 35.5%, the left lobe alone in 12.1%, and the right lobe alone in 52.4%.

Half of all patients (50.2%) received TARE as first-line therapy, 44.8% had it following surgery (17.1%), ablation (14.7%), and/or transarterial chemoembolization (; 23%). In addition, 9.7% of patients received systemic therapy prior to TARE, primarily with sorafenib (Nexavar).

Treatment intent was palliative for 57.3% of patients, and tumor downsizing/downstaging in 32.5% (remainder unspecified).
 

Survival and prognostic factors

As noted before, median overall survival was 16.5 months. Median progression-free survival was 6.1 months, and median hepatic PFS was 6.7 months.

Factors prognostic for better overall survival included hepatitis B or C virus as the cirrhosis cause versus alcohol (hazard ratio for death, 0.51 for each; P = .0060 for HBV and P = .0007 for HCV); unilobar versus bilobar tumors (HR, 0.67; P = .0422 for left-lobe; HR 0.55; P < .0001 for right); prior surgery (HR, 0.67; P = .0258); prior ablation (HR, 0.65; P = .0394); and curative versus palliative intent (HR, 0.53; P < .0001).

Factors associated with worse overall survival were presence of ascites (HR 1.75, P = .001); presence of extrahepatic disease before TARE (HR, 1.81, P = .0037); tumor burden greater than 5 nodules (HR, 1.67; P = .0073); main portal vein occlusion (HR, 2.14; P = .0064); lobar portal vein occlusion (HR, 1.77; P = .0083); total bilirubin greater than 1.5 mg/dL (HR, 1.69; P = .0094); albumin-bilirubin grade A2 (HR, 1.66; P = .0005); ALB1 grade A3 (HR, 3.92; P < .0001); and BSA/mBSA versus partition-model dosimetry (HR, 1.89; P < .0001).

The safety analysis showed that 36.7% of patients had at least one adverse event, but only 7.1% had at least one grade 3 or greater event.

Grade 3 or greater events were abdominal pain (nine patients), fatigue (six), nausea (three), radioembolization-induced liver disease (three), vomiting (two), and GI ulceration (one). Fifteen additional patients had other unspecified events.

The investigators acknowledged broad inclusion criteria, relatively high rates of loss to follow-up, and differences in national guidelines and local standards of practice as potential limitations to their findings.

In the question-and-answer following the presentation, session comoderator María Varela, MD, PhD, a pathologist in the liver unit at the Hospital Universitario Central de Asturia, Oviedo, Spain, questioned why about one-third of patients received TARE for downstaging, but only 13 underwent subsequent surgical resection.

“We don’t have a detailed analysis of this subgroup of patients who received curative intent as yet, ” Dr. Kolligs said.

Pierre Nahon, MD, from the University of Paris and Hôpital Jean Verdier in Bondy, France, commented that, among this heterogenous population, one of the best indications for TARE is probably localized HCC with adjacent portal vein thrombosis.

He asked whether the investigators had examined overall survival among patients with localized unilobar HCC with adjacent small portal vein thrombosis.

“We find that patients with portal vein occlusion have a worse prognosis in the total group,” Dr. Kolligs replied. “To look into the question whether partial thrombosis with a small tumor might benefit is an interesting question, and we should look into that, but I don’t have any data on that yet.”

Another audience member asked: “According to your data, which patients are the best candidates for radioembolization?”

“According to these data, the best candidates are of course patients with good liver function, ascites should ideally not be present, and what is probably is important is that we identify or include patients without extrahepatic disease,” he said.

The study was sponsored by CIRSE. Dr. Kolligs disclosed speaking activities and consulting for several companies. Dr. Varela disclosed speaking for several companies and advisory board activity for Bayer. Dr. Nahon disclosed honoraria and consulting fees from several companies.

Patients with hepatocellular carcinoma (HCC) can be offered transarterial radioembolization (TARE) as a safe and effective first-line treatment or adjunct to other locoregional therapies, authors of a large multicenter study reported.

Among 422 patients with HCC treated with TARE in eight European countries, the median overall survival was 16.5 months, with fewer than 10% of patients experiencing grade 3 or greater adverse events, reported Frank Kolligs, MD, from Helios Hospital Berlin-Buch.

“This exploratory study evaluated factors that can influence the application and outcome of transarterial radioembolization in clinical practice. TARE is generally applied according to guideline recommendations, and randomized, controlled trials are needed to confirm the effect of personalized dosimetry on the effectiveness of TARE,” he said in an oral abstract presented at the meeting sponsored by the European Association for the Study of the Liver.

Intriguingly, the investigators found evidence suggesting that patients whose treatments were planned using a partition model had better survival outcomes than those patients who treatments were based on calculated body surface area or measured BSA (mBSA), but this finding will need to be explored in more detail, Dr. Kolligs said.

The partition model incorporates variables such as tumor volume and liver volume, shunt fractions, the ratio of radiation uptake between tumor and normal tissues, vascular anatomy and other factors to estimate the optimal dose.
 

Study design

Dr. Kolligs and colleagues looked at prospective data from the Cardiovascular and Interventional Radiological Society of Europe (CIRSE) Registry for SIR-Spheres Therapy to evaluate the real-world clinical application of TARE with yttrium Y-90 resin microspheres in Europe, clinical outcomes, safety, and quality of life.

They selected data from centers with a minimum of 10 cases performed in the previous 12 months and at least 40 total cases overall.

The patients included adults 18 years and older scheduled for treatment with Y-90 resin microspheres for primary or metastatic liver tumors, with no specific exclusion criteria. The patients were followed for at least 24 months at recommended intervals of every 3 months. The first patient was enrolled in January 2015, and the last follow-up visit was in December 2019. A total of 422 registry patients had a diagnosis of HCC and were included in the study.

The median age was 68 years (range, 60-74), 80.8% were male, 70.9% had cirrhosis, 14.5% had ascites, and 8.5% had extrahepatic disease. About 32% of patients had one tumor nodule, 33% had two to five nodules, and the remainder had either more than five or an uncountable number.

In all, 14% of patients had Barcelona Clinic Liver Cancer stage A disease, 51.4% had stage B, 33.6% had stage C, and 0.9% stage D.

About one-third of patients had portal vein occlusion. Tumors were in both left and right lobes in 35.5%, the left lobe alone in 12.1%, and the right lobe alone in 52.4%.

Half of all patients (50.2%) received TARE as first-line therapy, 44.8% had it following surgery (17.1%), ablation (14.7%), and/or transarterial chemoembolization (; 23%). In addition, 9.7% of patients received systemic therapy prior to TARE, primarily with sorafenib (Nexavar).

Treatment intent was palliative for 57.3% of patients, and tumor downsizing/downstaging in 32.5% (remainder unspecified).
 

Survival and prognostic factors

As noted before, median overall survival was 16.5 months. Median progression-free survival was 6.1 months, and median hepatic PFS was 6.7 months.

Factors prognostic for better overall survival included hepatitis B or C virus as the cirrhosis cause versus alcohol (hazard ratio for death, 0.51 for each; P = .0060 for HBV and P = .0007 for HCV); unilobar versus bilobar tumors (HR, 0.67; P = .0422 for left-lobe; HR 0.55; P < .0001 for right); prior surgery (HR, 0.67; P = .0258); prior ablation (HR, 0.65; P = .0394); and curative versus palliative intent (HR, 0.53; P < .0001).

Factors associated with worse overall survival were presence of ascites (HR 1.75, P = .001); presence of extrahepatic disease before TARE (HR, 1.81, P = .0037); tumor burden greater than 5 nodules (HR, 1.67; P = .0073); main portal vein occlusion (HR, 2.14; P = .0064); lobar portal vein occlusion (HR, 1.77; P = .0083); total bilirubin greater than 1.5 mg/dL (HR, 1.69; P = .0094); albumin-bilirubin grade A2 (HR, 1.66; P = .0005); ALB1 grade A3 (HR, 3.92; P < .0001); and BSA/mBSA versus partition-model dosimetry (HR, 1.89; P < .0001).

The safety analysis showed that 36.7% of patients had at least one adverse event, but only 7.1% had at least one grade 3 or greater event.

Grade 3 or greater events were abdominal pain (nine patients), fatigue (six), nausea (three), radioembolization-induced liver disease (three), vomiting (two), and GI ulceration (one). Fifteen additional patients had other unspecified events.

The investigators acknowledged broad inclusion criteria, relatively high rates of loss to follow-up, and differences in national guidelines and local standards of practice as potential limitations to their findings.

In the question-and-answer following the presentation, session comoderator María Varela, MD, PhD, a pathologist in the liver unit at the Hospital Universitario Central de Asturia, Oviedo, Spain, questioned why about one-third of patients received TARE for downstaging, but only 13 underwent subsequent surgical resection.

“We don’t have a detailed analysis of this subgroup of patients who received curative intent as yet, ” Dr. Kolligs said.

Pierre Nahon, MD, from the University of Paris and Hôpital Jean Verdier in Bondy, France, commented that, among this heterogenous population, one of the best indications for TARE is probably localized HCC with adjacent portal vein thrombosis.

He asked whether the investigators had examined overall survival among patients with localized unilobar HCC with adjacent small portal vein thrombosis.

“We find that patients with portal vein occlusion have a worse prognosis in the total group,” Dr. Kolligs replied. “To look into the question whether partial thrombosis with a small tumor might benefit is an interesting question, and we should look into that, but I don’t have any data on that yet.”

Another audience member asked: “According to your data, which patients are the best candidates for radioembolization?”

“According to these data, the best candidates are of course patients with good liver function, ascites should ideally not be present, and what is probably is important is that we identify or include patients without extrahepatic disease,” he said.

The study was sponsored by CIRSE. Dr. Kolligs disclosed speaking activities and consulting for several companies. Dr. Varela disclosed speaking for several companies and advisory board activity for Bayer. Dr. Nahon disclosed honoraria and consulting fees from several companies.

Moderate fibrosis in patients with alcoholic liver disease is not a benign condition, say investigators who studied the natural history of ALD according to biopsy-proven fibrosis stage.

In a study of 422 patients who were followed for a median of 43 months, 5.8% of patients with no or minimal fibrosis had a liver decompensation event. This compares with 21% (hazard ratio, 3.8; 95% confidence interval, 1.9-7.5; P < .01) of patients with significant fibrosis and 45% (HR, 9.6; 95% CI, 5.2-18.0; P < .01) of patients with advanced fibrosis, said Ditlev Nytoft Rasmussen, PhD, in an oral presentation at the meeting sponsored by the European Association for the Study of the Liver.

“The most obvious implication of this study is that the stage of fibrosis is a very strong predictor for the prognosis in early asymptomatic alcohol-related liver disease,” he said.

The findings suggest that gastroenterologists do not need to follow patients with no or only minor fibrosis, but patients with significant (F2) fibrosis, or greater, should be closely followed, said Dr. Rasmussen, who is with the FLASH Center for Liver Research at Odense (Denmark) University.

A gastroenterologist who was not involved in the study commented on the excess mortality the investigators saw.

“The really striking finding here to me is the excess mortality in the significant fibrosis group. They are not healthy, and some of that excess mortality does appear to be liver related, but some of it may not be liver related,“ said Esperance A. Schaefer, MD, MPH, of Massachusetts General Hospital in Boston.

“I think it will be important to be vigilant about the causes of death that are not liver related in patients with significant and advanced fibrosis, and the healthy group,” she said in an interview.

Ewan H. Forrest, MD, from the University of Glasgow, who was not involved in the study, said: “These are a challenging group of patients to identify with early disease. You quite rightly raise the question of how we should follow-up with these patients.”
 

Managing asymptomatic patients

Although noninvasive tests can identify ALD in the early fibrotic stage, it’s unclear how patients with early asymptomatic disease should be managed, Dr. Rasmussen said.

This uncertainty prompted FLASH investigators to study patients with ALD to determine how fibrosis affected outcomes such as decompensation, hospitalization, and death.

They looked at a prospective cohort of patients diagnosed with ALD by biopsy and transient elastography (FibroScan) from 2013 to 2018. Follow-up data for the patients were collected retrospectively from electronic health records or charts.

The patients, who all had alcohol overuse and no history of decompensation or other etiologies at baseline, were classified into three groups: 225 liver-healthy patients with minimal to no fibrosis (F1 or transient elastography <6 kPa kPa); 104 patients with significant fibrosis (F2); and, 93 patients with advanced fibrosis (F3 or F4).

The median patient age was 57 years, and 75% of the patients were men. The patients were followed for 1,149 patient-years.
 

Findings and outcomes

During follow-up, 53 patients died, and 51 had a decompensation event: overt hepatoencephalopathy, ascites, variceal bleeding, hepatorenal syndrome, or jaundice. Of the 51 patients, 27 died.

There was a protocol change during the study, with the new protocol stating that patients with transient elastography below 6 kPa could not undergo biopsy. Based on the 106 patients who had both a FibroScan and biopsy, of whom 20% had F2 fibrosis, the investigators calculated that 14 patients who did not undergo biopsy may have been incorrectly classified as having healthy livers, Dr. Rasmussen said.

Patients with healthy livers had a significantly better decompensation-free survival rates, with only 5.8% of those with healthy livers having a decompensation event out to 4.5 years, compared with 21% of patients with significant fibrosis or advanced fibrosis.

Within the first year of follow-up, 98% of patients with healthy livers were alive and free of decompensations, compared with 94% with significant fibrosis and 84% with advanced fibrosis. The respective rates at 3 years were 95%, 82%, and 55%.

The percentage of hospital admissions that were liver related was 5% in the healthy-liver group, 24% in the significant group, and 47% in the advanced group.

Ongoing alcohol use during follow-up was also a significant predictor of worse decompensation-free survival (HR, 1.6; P = .04), with two in three decompensation events occurring in patients with alcohol overuse. The effect of alcohol was less strong than fibrosis stage, however, Dr. Rasmussen noted.

Dr. Schaefer said that “we see individuals who with heavy alcohol use progress much more rapidly than you’d anticipate with the rule of thumb that you see in other diseases of one fibrosis stage every 5-7 years.”

Among the strengths of this study included the use of biopsy and the inclusion of all stages of fibrosis. The investigators acknowledged as potential limitations the retrospective collection of follow-up data, reliance on medical charts to estimate alcohol consumption, and the single-center design.

The study was supported by grants from the European Union’s Horizon 2020 research and innovation program and the Novo Nordisk Foundation Challenge program. Dr. Rasmussen, Dr. Schaefer, and Dr. Forrest reported no conflicts of interest to disclose.

Moderate fibrosis in patients with alcoholic liver disease is not a benign condition, say investigators who studied the natural history of ALD according to biopsy-proven fibrosis stage.

In a study of 422 patients who were followed for a median of 43 months, 5.8% of patients with no or minimal fibrosis had a liver decompensation event. This compares with 21% (hazard ratio, 3.8; 95% confidence interval, 1.9-7.5; P < .01) of patients with significant fibrosis and 45% (HR, 9.6; 95% CI, 5.2-18.0; P < .01) of patients with advanced fibrosis, said Ditlev Nytoft Rasmussen, PhD, in an oral presentation at the meeting sponsored by the European Association for the Study of the Liver.

“The most obvious implication of this study is that the stage of fibrosis is a very strong predictor for the prognosis in early asymptomatic alcohol-related liver disease,” he said.

The findings suggest that gastroenterologists do not need to follow patients with no or only minor fibrosis, but patients with significant (F2) fibrosis, or greater, should be closely followed, said Dr. Rasmussen, who is with the FLASH Center for Liver Research at Odense (Denmark) University.

A gastroenterologist who was not involved in the study commented on the excess mortality the investigators saw.

“The really striking finding here to me is the excess mortality in the significant fibrosis group. They are not healthy, and some of that excess mortality does appear to be liver related, but some of it may not be liver related,“ said Esperance A. Schaefer, MD, MPH, of Massachusetts General Hospital in Boston.

“I think it will be important to be vigilant about the causes of death that are not liver related in patients with significant and advanced fibrosis, and the healthy group,” she said in an interview.

Ewan H. Forrest, MD, from the University of Glasgow, who was not involved in the study, said: “These are a challenging group of patients to identify with early disease. You quite rightly raise the question of how we should follow-up with these patients.”
 

Managing asymptomatic patients

Although noninvasive tests can identify ALD in the early fibrotic stage, it’s unclear how patients with early asymptomatic disease should be managed, Dr. Rasmussen said.

This uncertainty prompted FLASH investigators to study patients with ALD to determine how fibrosis affected outcomes such as decompensation, hospitalization, and death.

They looked at a prospective cohort of patients diagnosed with ALD by biopsy and transient elastography (FibroScan) from 2013 to 2018. Follow-up data for the patients were collected retrospectively from electronic health records or charts.

The patients, who all had alcohol overuse and no history of decompensation or other etiologies at baseline, were classified into three groups: 225 liver-healthy patients with minimal to no fibrosis (F1 or transient elastography <6 kPa kPa); 104 patients with significant fibrosis (F2); and, 93 patients with advanced fibrosis (F3 or F4).

The median patient age was 57 years, and 75% of the patients were men. The patients were followed for 1,149 patient-years.
 

Findings and outcomes

During follow-up, 53 patients died, and 51 had a decompensation event: overt hepatoencephalopathy, ascites, variceal bleeding, hepatorenal syndrome, or jaundice. Of the 51 patients, 27 died.

There was a protocol change during the study, with the new protocol stating that patients with transient elastography below 6 kPa could not undergo biopsy. Based on the 106 patients who had both a FibroScan and biopsy, of whom 20% had F2 fibrosis, the investigators calculated that 14 patients who did not undergo biopsy may have been incorrectly classified as having healthy livers, Dr. Rasmussen said.

Patients with healthy livers had a significantly better decompensation-free survival rates, with only 5.8% of those with healthy livers having a decompensation event out to 4.5 years, compared with 21% of patients with significant fibrosis or advanced fibrosis.

Within the first year of follow-up, 98% of patients with healthy livers were alive and free of decompensations, compared with 94% with significant fibrosis and 84% with advanced fibrosis. The respective rates at 3 years were 95%, 82%, and 55%.

The percentage of hospital admissions that were liver related was 5% in the healthy-liver group, 24% in the significant group, and 47% in the advanced group.

Ongoing alcohol use during follow-up was also a significant predictor of worse decompensation-free survival (HR, 1.6; P = .04), with two in three decompensation events occurring in patients with alcohol overuse. The effect of alcohol was less strong than fibrosis stage, however, Dr. Rasmussen noted.

Dr. Schaefer said that “we see individuals who with heavy alcohol use progress much more rapidly than you’d anticipate with the rule of thumb that you see in other diseases of one fibrosis stage every 5-7 years.”

Among the strengths of this study included the use of biopsy and the inclusion of all stages of fibrosis. The investigators acknowledged as potential limitations the retrospective collection of follow-up data, reliance on medical charts to estimate alcohol consumption, and the single-center design.

The study was supported by grants from the European Union’s Horizon 2020 research and innovation program and the Novo Nordisk Foundation Challenge program. Dr. Rasmussen, Dr. Schaefer, and Dr. Forrest reported no conflicts of interest to disclose.

Moderate fibrosis in patients with alcoholic liver disease is not a benign condition, say investigators who studied the natural history of ALD according to biopsy-proven fibrosis stage.

In a study of 422 patients who were followed for a median of 43 months, 5.8% of patients with no or minimal fibrosis had a liver decompensation event. This compares with 21% (hazard ratio, 3.8; 95% confidence interval, 1.9-7.5; P < .01) of patients with significant fibrosis and 45% (HR, 9.6; 95% CI, 5.2-18.0; P < .01) of patients with advanced fibrosis, said Ditlev Nytoft Rasmussen, PhD, in an oral presentation at the meeting sponsored by the European Association for the Study of the Liver.

“The most obvious implication of this study is that the stage of fibrosis is a very strong predictor for the prognosis in early asymptomatic alcohol-related liver disease,” he said.

The findings suggest that gastroenterologists do not need to follow patients with no or only minor fibrosis, but patients with significant (F2) fibrosis, or greater, should be closely followed, said Dr. Rasmussen, who is with the FLASH Center for Liver Research at Odense (Denmark) University.

A gastroenterologist who was not involved in the study commented on the excess mortality the investigators saw.

“The really striking finding here to me is the excess mortality in the significant fibrosis group. They are not healthy, and some of that excess mortality does appear to be liver related, but some of it may not be liver related,“ said Esperance A. Schaefer, MD, MPH, of Massachusetts General Hospital in Boston.

“I think it will be important to be vigilant about the causes of death that are not liver related in patients with significant and advanced fibrosis, and the healthy group,” she said in an interview.

Ewan H. Forrest, MD, from the University of Glasgow, who was not involved in the study, said: “These are a challenging group of patients to identify with early disease. You quite rightly raise the question of how we should follow-up with these patients.”
 

Managing asymptomatic patients

Although noninvasive tests can identify ALD in the early fibrotic stage, it’s unclear how patients with early asymptomatic disease should be managed, Dr. Rasmussen said.

This uncertainty prompted FLASH investigators to study patients with ALD to determine how fibrosis affected outcomes such as decompensation, hospitalization, and death.

They looked at a prospective cohort of patients diagnosed with ALD by biopsy and transient elastography (FibroScan) from 2013 to 2018. Follow-up data for the patients were collected retrospectively from electronic health records or charts.

The patients, who all had alcohol overuse and no history of decompensation or other etiologies at baseline, were classified into three groups: 225 liver-healthy patients with minimal to no fibrosis (F1 or transient elastography <6 kPa kPa); 104 patients with significant fibrosis (F2); and, 93 patients with advanced fibrosis (F3 or F4).

The median patient age was 57 years, and 75% of the patients were men. The patients were followed for 1,149 patient-years.
 

Findings and outcomes

During follow-up, 53 patients died, and 51 had a decompensation event: overt hepatoencephalopathy, ascites, variceal bleeding, hepatorenal syndrome, or jaundice. Of the 51 patients, 27 died.

There was a protocol change during the study, with the new protocol stating that patients with transient elastography below 6 kPa could not undergo biopsy. Based on the 106 patients who had both a FibroScan and biopsy, of whom 20% had F2 fibrosis, the investigators calculated that 14 patients who did not undergo biopsy may have been incorrectly classified as having healthy livers, Dr. Rasmussen said.

Patients with healthy livers had a significantly better decompensation-free survival rates, with only 5.8% of those with healthy livers having a decompensation event out to 4.5 years, compared with 21% of patients with significant fibrosis or advanced fibrosis.

Within the first year of follow-up, 98% of patients with healthy livers were alive and free of decompensations, compared with 94% with significant fibrosis and 84% with advanced fibrosis. The respective rates at 3 years were 95%, 82%, and 55%.

The percentage of hospital admissions that were liver related was 5% in the healthy-liver group, 24% in the significant group, and 47% in the advanced group.

Ongoing alcohol use during follow-up was also a significant predictor of worse decompensation-free survival (HR, 1.6; P = .04), with two in three decompensation events occurring in patients with alcohol overuse. The effect of alcohol was less strong than fibrosis stage, however, Dr. Rasmussen noted.

Dr. Schaefer said that “we see individuals who with heavy alcohol use progress much more rapidly than you’d anticipate with the rule of thumb that you see in other diseases of one fibrosis stage every 5-7 years.”

Among the strengths of this study included the use of biopsy and the inclusion of all stages of fibrosis. The investigators acknowledged as potential limitations the retrospective collection of follow-up data, reliance on medical charts to estimate alcohol consumption, and the single-center design.

The study was supported by grants from the European Union’s Horizon 2020 research and innovation program and the Novo Nordisk Foundation Challenge program. Dr. Rasmussen, Dr. Schaefer, and Dr. Forrest reported no conflicts of interest to disclose.