The first and only FDA-approved treatment for adults with noncirrhotic NASH with moderate to advanced fibrosis
This indication is approved under accelerated approval based on improvement of NASH and fibrosis. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
NASH=nonalcoholic steatohepatitis.
INDICATION AND IMPORTANT SAFETY INFORMATION
INDICATION
Rezdiffra is indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis). This indication is approved under accelerated approval based on improvement of NASH and fibrosis. Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials. Limitation of Use: Avoid use in patients with decompensated cirrhosis.
WARNINGS AND PRECAUTIONS
Hepatotoxicity
Hepatotoxicity has been observed in one patient. Please see full Prescribing Information for more details on this specific
case of Hepatotoxicity [see Warnings and Precautions (5.1)]. Monitor patients during treatment for elevations in liver tests and for the development of liver-related adverse reactions. Monitor for symptoms and signs of hepatotoxicity (e.g., fatigue, nausea, vomiting, right upper quadrant pain or tenderness, jaundice, fever, rash, and/or eosinophilia [>5%]). If hepatotoxicity is suspected, discontinue Rezdiffra and continue to monitor the patient. If laboratory values return to baseline, weigh the potential risks against the benefits of restarting Rezdiffra. If laboratory values do not return to baseline, consider DI-ALH or autoimmune liver disease in the evaluation of elevations in liver tests.
Gallbladder-Related Adverse Reactions
In clinical trials, cholelithiasis, acute cholecystitis, and obstructive pancreatitis (gallstone) were observed more often in Rezdiffra-treated patients than in placebo-treated patients. If cholelithiasis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated. If an acute
Gallbladder-Related Adverse Reactions (cont.)
gallbladder event is suspected, interrupt Rezdiffra treatment until the event is resolved.
Drug Interaction with Certain Statins
Dosage adjustment for certain statins is recommended. Monitor for statin-related adverse reactions including but not limited to elevation of liver tests, myopathy, and rhabdomyolysis. Please see the upcoming Drug Interaction section of the Important Safety Information for more details.
ADVERSE REACTIONS
The most common adverse reactions with Rezdiffra (reported in ≥ 5% of patients and higher compared to placebo) are: diarrhea, nausea, pruritus, vomiting, constipation, abdominal pain, and dizziness. Diarrhea and nausea were the most common causes of treatment discontinuation.
Hypersensitivity Reactions
Reactions such as urticaria and rash, which may reflect drug hypersensitivity, were obser ved in patients receiving Rezdiffra.
Laboratory Abnormalities
Increases in mean ALT and AST levels were observed in the first 4 weeks after initiating treatment with Rezdiffra. The mean elevation in ALT and AST values was less than 1.5 times baseline at 4 weeks after treatment initiation. These values returned to baseline around 8 weeks after initiating treatment.
• Strong or Moderate CYP2C8 Inhibitors: Resmetirom is a CYP2C8 substrate. Concomitant use with strong CYP2C8 inhibitors (e.g., gemfibrozil) is not recommended. Reduce dosage if used concomitantly with a moderate CYP2C8 inhibitor (e.g., clopidogrel).
• Organic Anion-Transporting Polypeptides (OATP) 1B1 and OATP1B3 Inhibitors: Resmetirom is an OATP1B1 and OATP1B3 substrate. Concomitant use with OATP1B1 or OATP1B3 inhibitors (e.g., cyclosporine) is not recommended.
Clinically Significant Interactions Affecting Other Drugs
• Statins
- Limit daily rosuvastatin and simvastatin dosage to 20 mg
- Limit daily pravastatin and atorvastatin dosage to 40 mg
• CYP2C8 Substrates: Resmetirom is a weak CYP2C8 inhibitor. Monitor patients more frequently for substraterelated adverse reactions if Rezdiffra is co-administered with CYP2C8 substrates where minimal concentration changes may lead to serious adverse reactions.
USE IN SPECIFIC POPULATIONS
Pregnancy
There are no available data on Rezdiffra use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and fetus
Pregnancy (cont.)
related to underlying NASH with liver fibrosis, such as increased risks of gestational diabetes, hypertensive complications, preterm birth, and postpartum hemorrhage. Report pregnancies to Madrigal Pharmaceuticals, Inc.’s Adverse Event reporting line at 1-800-905-0324 and https://www.madrigalpharma.com/contact/.
Lactation
There is no information regarding the presence of Rezdiffra in human or animal milk, the effects on the breast-fed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Rezdiffra and any potential adverse effects on the breastfed infant from Rezdiffra or from the underlying maternal condition.
Pediatric Use
The safety and effectiveness have not been established in pediatric patients.
Geriatric Use
No overall differences in effectiveness but numerically higher incidence of adverse reactions have been observed in patients ≥65 years of age compared to younger adult patients.
Renal Impairment
The recommended dosage in patients with mild or moderate renal impairment is the same as in patients with normal kidney function. Rezdiffra has not been studied in patients with severe renal impairment.
Hepatic Impairment
Avoid use in patients with decompensated cirrhosis (consistent with moderate to severe hepatic impairment). Moderate or severe hepatic impairment (Child-Pugh Class B or C) increases resmetirom Cmax and AUC, which may increase the risk of adverse reactions.
No dosage adjustment is recommended for patients with mild hepatic impairment (Child-Pugh Class A).
The safety and effectiveness have not been established in patients with NASH cirrhosis.
Please see Brief Summary on the following pages and full Prescribing Information at www.madrigalpharma.com/Rezdiffra-USPI.
Visit RezdiffraHCP.com to learn more and get patients started.
REZDIFFRA™ (resmetirom)
Brief Summary of full Prescribing Information
INDICATIONS AND USAGE
REZDIFFRA is indicated in conjunction with diet and exercise for the treatment of adults with noncirrhotic nonalcoholic steatohepatitis (NASH) with moderate to advanced liver fibrosis (consistent with stages F2 to F3 fibrosis).
This indication is approved under accelerated approval based on improvement of NASH and fibrosis [see Clinical Studies (14) in the full Prescribing Information] Continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.
Limitations of Use
Avoid use of REZDIFFRA in patients with decompensated cirrhosis [see Use in Specific Populations (8.7), Clinical Pharmacology (12.3) in the full Prescribing Information]
CONTRAINDICATIONS
None.
WARNINGS AND PRECAUTIONS
Hepatotoxicity
Hepatotoxicity has been observed with use of REZDIFFRA. One patient had normal alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TB) levels at baseline, who received REZDIFFRA 80 mg daily, developed substantial elevations of liver biochemistries that resolved when treatment was interrupted. After reinitiating REZDIFFRA, the patient had elevations of ALT, AST, and TB. Peak values observed were 58 x upper limit of normal (ULN) for ALT, 66 x ULN for AST, 15 x ULN for TB, with no elevation of alkaline phosphatase (ALP). Elevations in liver enzymes were accompanied by elevations in immunoglobulin G levels, suggesting drug-induced autoimmune-like hepatitis (DI-ALH). The liver tests returned to baseline following hospitalization and discontinuation of REZDIFFRA without any therapeutic intervention.
Monitor patients during treatment with REZDIFFRA for elevations in liver tests and for the development of liver-related adverse reactions. Monitor for symptoms and signs of hepatotoxicity (e.g., fatigue, nausea, vomiting, right upper quadrant pain or tenderness, jaundice, fever, rash, and/or eosinophilia [>5%]). If hepatotoxicity is suspected, discontinue REZDIFFRA and continue to monitor the patient. If laboratory values return to baseline, weigh the potential risks against the benefits of restarting REZDIFFRA. If laboratory values do not return to baseline, consider DI-ALH or autoimmune liver disease in the evaluation of elevations in liver tests.
Gallbladder-Related Adverse Reactions
In clinical trials, cholelithiasis, acute cholecystitis, and obstructive pancreatitis (gallstone) were observed more often in REZDIFFRA-treated patients than in placebotreated patients. If cholelithiasis is suspected, gallbladder diagnostic studies and appropriate clinical follow-up are indicated. If an acute gallbladder event is suspected, interrupt REZDIFFRA treatment until the event is resolved [see Adverse Reactions (6.1) in the full Prescribing Information]
Drug Interaction with Certain Statins
An increase in exposure of atorvastatin, pravastatin, rosuvastatin and simvastatin was observed when concomitantly administered with REZDIFFRA [see Clinical Pharmacology (12.3) in the full Prescribing Information] , which may increase the risk of adverse reactions related to these drugs. Dosage adjustment for certain statins is recommended [see Drug Interactions (7.2) in the full Prescribing Information]. Monitor for statin-related adverse reactions including but not limited to elevation of liver tests, myopathy, and rhabdomyolysis.
ADVERSE REACTIONS
The following clinically significant adverse reactions are described elsewhere in labeling:
• Hepatotoxicity [see Warnings and Precautions (5.1) in the full Prescribing Information]
• Gallbladder-Related Adverse Reactions [see Warnings and Precautions (5.2) in the full Prescribing Information]
Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in clinical trials of another drug and may not reflect the rates observed in clinical practice.
The safety of REZDIFFRA was evaluated in two randomized, double-blind, placebocontrolled trials that enrolled a total of 2019 patients.
Trial 1
Trial 1 included patients who had noncirrhotic NASH with stages F2 and F3 fibrosis at eligibility (n=888) [see Clinical Studies (14) in the full Prescribing Information] .
Adverse Reactions Leading to Discontinuations
The exposure-adjusted incidence rates (EAIRs) per 100 person-years (PY) for treatment discontinuation due to any adverse reaction were higher in the REZDIFFRA dosage arms: 4 per 100 PY, 5 per 100 PY, and 8 per 100 PY in placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respectively. Diarrhea and nausea were the most common causes of treatment discontinuation.
Common Adverse Reactions
Table 1 displays EAIRs per 100 PY for the common adverse reactions that occurred in at least 5% of patients with F2 or F3 fibrosis treated in either drug arm with REZDIFFRA and were greater than that reported for placebo.
Table 1: Exposure-Adjusted Incidence Rates (EAIR) of Common Adverse Reactions Reported with REZDIFFRA in Adult Patients with Noncirrhotic NASH (Trial 1)a, b, c
Adverse Reaction
Placebo N=294 n (EAIRd)
REZDIFFRA 80 mg Once Daily N=298 n (EAIRd)
REZDIFFRA 100 mg Once Daily N=296 n (EAIRd)
Diarrhea52 (14)78 (23)98 (33)
Nausea36 (9)65 (18)51 (15)
Pruritus18 (4)24 (6)36 (10)
Vomiting15 (4)27 (7)30 (8)
Constipation18 (4)20 (5)28 (8)
Abdominal pain18 (4)22 (5)27 (7)
Dizziness6 (1)17 (4)17 (4)
a Population includes adult patients with noncirrhotic NASH with liver fibrosis (stages F2 and F3 at eligibility).
b Median exposure duration was 68 weeks for placebo, 74 weeks for REZDIFFRA 80 mg once daily, and 66 weeks for REZDIFFRA 100 mg once daily.
c EAIRs are per 100 person-years (PY) where total PYs were 435, 435, and 407 for placebo, 80 mg once daily, and 100 mg once daily arms, respectively.
d The EAIR per 100 PY can be interpreted as an estimated number of first occurrences of the adverse reaction of interest if 100 patients are treated for one year. Abbreviations: EAIR, exposure-adjusted incidence rate; PY, person-years; NASH, nonalcoholic steatohepatitis
Gastrointestinal Adverse Reactions
The incidence of gastrointestinal adverse reactions was higher for the REZDIFFRA drug arms compared to placebo. The EAIRs for gastrointestinal adverse reactions were 57 per 100 PY, 73 per 100 PY, and 89 per 100 PY in the placebo, REZDIFFRA 80 mg once daily, REZDIFFRA 100 mg once daily arms, respectively.
Diarrhea typically began early in treatment initiation and was mild to moderate in severity. The median time (Q1 to Q3) to a diarrheal event was 39 (2 to 195) days, 17 (3 to 70) days, and 6 (2 to 54) days in the placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respectively.
Median duration of diarrhea was 9 days for placebo compared to 20 days for both REZDIFFRA 80 mg once daily and REZDIFFRA 100 mg once daily dosage arms.
Nausea also began early in treatment and was mild to moderate in severity. Among patients with nausea, the median time (Q1 to Q3) to a nausea event was 85 (24 to 347) days, 28 (2 to 162) days, and 5 (2 to 40) days in the placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respectively. Median duration of nausea was 17 days, 26 days, and 28 days for patients in the placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respectively. Vomiting and abdominal pain adverse reactions were mild to moderate in severity.
Hypersensitivity Reactions
Reactions such as urticaria and rash, which may reflect drug hypersensitivity, were observed in patients receiving REZDIFFRA. The EAIRs for urticaria were 0.2 per 100 PY, 0.7 per 100 PY, and 1.5 per 100 PY in the placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily arms, respectively. The EAIRs for rash were 3 per 100 PY in the placebo and REZDIFFRA 80 mg once daily arms compared to 5 per 100 PY in the REZDIFFRA 100 mg once daily arm.
Gallbladder-Related Adverse Reactions
A higher incidence of cholelithiasis, acute cholecystitis, and obstructive pancreatitis (gallstone) was observed in the treatment arms compared to placebo. However, the EAIRs for these events were less than 1 per 100 PY for all treatment arms.
Less Common Adverse Reactions
Additional adverse reactions that occurred more frequently in the REZDIFFRA arms compared to placebo, in less 5% of patients, included decreased appetite, flatulence, abnormal feces, dysgeusia, vertigo, arrhythmia, palpitations, depression, erythema, hypoglycemia, tendinopathy, abnormal uterine bleeding.
Laboratory Abnormalities
Liver Tests
Increases in mean alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels were observed in the first 4 weeks after initiating treatment with REZDIFFRA. In both REZDIFFRA dosage arms, the mean elevation in ALT and AST values was less than 1.5 times baseline at 4 weeks after treatment initiation. These values returned to baseline around 8 weeks after initiating treatment.
Table 2 presents the frequency of liver test elevations during Trial 1.
Table 2: Frequency of Liver Test Elevations in Trial 1
Placebo (%)
REZDIFFRA 80 mg Once Daily (%)
REZDIFFRA 100 mg Once Daily (%)
ALT > 3x ULN 101113
ALT > 5x ULN 222
AST > 3x ULN 10912
AST > 5x ULN 214
TBa > 2x ULN 213
a TB elevations include patients with Gilbert syndrome.
Thyroid Function Tests
A decrease in levels of prohormone free T4 (FT4) of mean 2%, 13%, and 17% was seen at 12 months in patients treated with placebo, REZDIFFRA 80 mg once daily, and REZDIFFRA 100 mg once daily, respectively, with minimal changes in active hormone T3 or in TSH. There were no clinical findings associated with FT4 decreases.
Additional Safety Data
The safety evaluation of REZDIFFRA also included an analysis of an additional randomized placebo-controlled safety trial which included 969 patients from a relevant patient population (placebo [n=318], REZDIFFRA 80 mg once daily [n=327], and REZDIFFRA 100 mg once daily [n=324]).
Data from the safety trial was combined with data from NASH patients with F2 and F3 fibrosis at eligibility (n=888) and data from an additional 162 patients from a relevant patient population enrolled in Trial 1. In the combined safety population (n=2019), the median (Q1 to Q3) age of patients at baseline was 58 (50 to 65) years; 55% were female, 28% were Hispanic, 89% were White, 2% were Asian, and 4% were Black or African American.
The safety profile from this combined analysis was similar to that in Trial 1, other than the one case of hepatotoxicity in the safety trial [see Warnings and Precautions (5.1) in the full Prescribing Information].
USE IN SPECIFIC POPULATIONS
Pregnancy
Risk Summary
There are no available data on REZDIFFRA use in pregnant women to evaluate for a drug-associated risk of major birth defects, miscarriage, or other adverse maternal or fetal outcomes. There are risks to the mother and fetus related to underlying NASH with liver fibrosis (see Clinical Considerations) . In animal reproduction studies, adverse effects on embryo-fetal development occurred in pregnant rabbits treated with resmetirom at 3.5 times the maximum recommended dose during organogenesis. These effects were associated with maternal toxicity, whereas no embryo-fetal effects were observed at lower dose levels with better tolerance in pregnant rabbits. No embryo-fetal developmental effects occurred in pregnant rats treated with resmetirom or the metabolite MGL-3623. A pre- and postnatal development study in rats with maternal dosing of resmetirom during organogenesis through lactation showed a decrease in birthweight and increased incidence of stillbirths and mortality (postnatal days 1-4) at 37 times the maximum recommended dose (see Data). These effects were associated with marked suppression of maternal T4, T3, and TSH levels.
The background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, and other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.
Report pregnancies to Madrigal Pharmaceuticals, Inc. Adverse Event reporting line at 1-800-905-0324 and https://www.madrigalpharma.com/contact/.
There are risks to the mother and fetus related to underlying maternal NASH with liver fibrosis, such as increased risks of gestational diabetes, hypertensive complications, preterm birth, and postpartum hemorrhage.
Data
Animal Data
No effects on embryo-fetal development were observed in pregnant rats treated orally with up to 100 mg/kg/day (21 times the maximum recommended dose based on AUC [area under the plasma concentration-time curve]) or in pregnant rabbits treated orally with up to 30 mg/kg/day (2.8 times the maximum recommended dose based on AUC) during the period of organogenesis. Oral administration of 75 mg/kg/day in pregnant rabbits (3.5 times the maximum recommended dose based on AUC) produced an increase in post-implantation loss and decreases in viable fetuses and fetal weight. These effects were likely due to maternal toxicity (i.e., marked reductions in weight gain and food consumption).
A pre- and postnatal development study was performed using oral administration of 3, 30, or 100 mg/kg/day in female rats during organogenesis through lactation. Treatment with 100 mg/kg/day (37 times the maximum recommended dose based on AUC) produced increases in number of stillborn, pup deaths during postnatal days 1-4, and pups with absence of milk in stomach. Birthweight was decreased by 10% in this dose group, with recovery to normal body weight thereafter. The effects in offspring were associated with marked reductions in maternal plasma levels of T4 (88% decrease), T3 (79% decrease), and TSH (44% decrease). No effects on postnatal development were observed at doses up to 30 mg/kg/day (7.2 times the maximum recommended dose based on AUC). This study lacked a complete evaluation of physical and neurobehavioral development in offspring; however, no effects of resmetirom were noted in tests of learning and memory.
The metabolite MGL-3623 was tested for its effects on embryo-fetal development. No effects were observed in pregnant rats treated orally with up to 100 mg/kg/day MGL-3623 (4.7 times the maximum recommended dose based on AUC for MGL3623) during the period of organogenesis.
Lactation
Risk Summary
There is no information regarding the presence of REZDIFFRA in human or animal milk, the effects on the breast-fed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for REZDIFFRA and any potential adverse effects on the breastfed infant from REZDIFFRA or from the underlying maternal condition.
Pediatric Use
The safety and effectiveness of REZDIFFRA have not been established in pediatric patients.
Geriatric Use
In Trial 1, of the 594 patients with NASH who received at least one dose of REZDIFFRA, 149 (25%) were 65 years of age and older and 13 (2%) were 75 years of age and older [see Clinical Studies (14) in the full Prescribing Information]. No overall differences in effectiveness but numerically higher incidence of adverse reactions have been observed in patients 65 years of age and older compared to younger adult patients.
Renal Impairment
The recommended dosage in patients with mild or moderate renal impairment is the same as in patients with normal kidney function. REZDIFFRA has not been studied in patients with severe renal impairment [see Clinical Pharmacology (12.3) in the full Prescribing Information]
Hepatic Impairment
Avoid use of REZDIFFRA in patients with decompensated cirrhosis (consistent with moderate to severe hepatic impairment). Moderate or severe hepatic impairment (Child-Pugh Class B or C) increases resmetirom C max and AUC [see Clinical Pharmacology (12.3) in the full Prescribing Information] , which may increase the risk of adverse reactions.
No dosage adjustment is recommended for patients with mild hepatic impairment (Child-Pugh Class A) [see Clinical Pharmacology (12.3) in the full Prescribing Information]
The safety and effectiveness of REZDIFFRA have not been established in patients with NASH cirrhosis.
For more detailed information, please read the full Prescribing Information.
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When it comes to treating patients with MASH, liver stiffness alone cannot be relied on to assess treatment response in the short term. The best predictor of treatment responses was a decrease in steatosis (identified as ≥30% reduction in MRI-PDFF) .
SUPERIORACCURACY
Velacur Determined Fat Fraction (VDFF), estimates MRI-PDFF at the point of care
By combining features of MRE and SWE technology
Velacur enables measurements with30X volume and 2X depth when compared to VCTE
Automatic wave detection helps to improve scan quality
Short learning curve: scan time decreases by 42% after an average of 25 scans
AI overlay aids liver identification and visualization
SUPERIORROI
Quick procedure, average scan time of 7.57min after learning curve
Low capital cost, high reimbursement
Study Finds 3 in 4 Overweight, Obese Adults Have Steatotic Liver Disease
As much as 75% of overweight and obese individuals have steatotic liver disease, according to results of a recent cross-sectional, observational study.
In addition, the study further delved into subcategories of steatotic liver disease (SLD), finding that in this population, the prevalences of metabolic dysfunction–associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), and mixed metabolic dysfunction and ALD were 67.3%, 2.6% and 4.8%, respectively. The prevalences of advanced fibrosis and cirrhosis were 10.8% and 4.5%, respectively.
The study focused on adults 40 to 75 years of age with a body mass index of 25 kg/m2 or higher recruited from primary care and community settings in Southern California (Gut 2024;73[12]:2045-2053). The researchers assessed the prevalence of SLD-related conditions, advanced fibrosis and cirrhosis in these patients using advanced MRI techniques, including MRI proton density fat fraction (MRI-PDFF) and
magnetic resonance elastography (MRE). They found significant associations between advanced fibrosis and factors such as metabolic syndrome, diabetes mellitus and obesity, as well as notable differences in liver biomarkers and imaging characteristics between people with and without advanced fibrosis.
Improved Accuracy With Prospective Data
Previous studies that did not focus on overweight and obese patients showed a much lower prevalence of SLD. For instance, according to data from the 2017-2020 National Health and Nutrition Examination Survey (NHANES), the prevalence of SLD—defined as a controlled attenuation parameter (CAP) larger than 300 dB/m—was found to be 28.8% (Dig Dis Sci 2023;68[4]:1237-1252).
This latest study is different in two main ways, according to senior investigator Rohit Loomba, MD, MHSc, the chief of gastroenterology and hepatology at the University of California, San Diego and director of the UCSD MASLD Research Center.
“Our study focuses on adults with obesity from Southern California. In contrast, the NHANES study surveys a much broader population of adults and children, including individuals with normal BMI, from across the United States.”
In addition, “our cohort study is the first to examine the prevalences of SLD subcategories using advanced MRI methods such as MRI-PDFF and 2D MRE along with CAP and vibration-controlled transient elastography [VCTE]. This rigorous phenotyping approach lends credibility to our findings,” Dr. Loomba told GEN Priority Report. “Furthermore, phosphatidylethanol levels are unavailable in NHANES or any previous study of SLD, which represents another major strength of this study, given its prospective study design.”
Data to Improve Screening
Jonathan G. Stine, MD, MSc, an associate professor of medicine and public health sciences at Penn State College of Medicine and the research director at Penn State Health Liver Center, in
Hershey, Pa., told GEN Priority Report that the study’s findings are “highly significant.”
“The study suggests that SLD is more common in these [overweight and obese] individuals than previously thought, which could prompt earlier and more aggressive screening and intervention strategies, potentially altering the standard of care or at least furthering conversation about a high-risk population to screen,” said Dr. Stine, who was not involved with the research.
‘ While metabolic risk factors are straightforward to detect and quantify in clinical practice, alcohol use is not.’
—Rohit Loomba, MD, MHSc University of California, San Diego
Dr. Loomba agreed, saying his findings “lend additional support for the American Association for the Study of Liver Diseases practice guidance [Hepatology 2023;77(5):1797-1835], which states that patients with obesity have a higher risk of MASLD and may be considered for screening using the FIB-4 [Fibrosis-4] index as a starting point.”
However, Dr. Loomba cautioned that it might not be so intuitive knowing when to screen for alcohol use. “While metabolic risk factors are straightforward to detect and quantify in clinical practice, alcohol use is not. Self-reporting methods are highly subjective, impractical to implement at the population level, and are not used by providers in primary care, gastroenterology or hepatology. Therefore, additional research is needed to identify objective biomarkers of alcohol use before specific protocols and interventions can be recommended.”
The findings from this latest study still have the potential to influence future clinical practices, Dr. Stine said. “Clinically, these results push our conversation along further regarding the need for earlier and more frequent screening for liver disease in at-risk populations, as well as more personalized treatment strategies that address both metabolic and alcohol-related factors in liver disease management.”
—Kristen Dascoli
Dr. Loomba reported financial relationships with more than 20 pharmaceutical companies. Dr. Stine reported financial relationships with AstraZeneca, Galectin, Kowa, Novo Nordisk and Zydus.
Reports From The Liver Meeting 2024
Study Assesses DILI Due to Medications For Alcohol Use Disorder
Medications for alcohol use disorder generally are safe with respect to drug-induced liver injury, except for disulfiram, according to a new prospective analysis presented at The Liver Meeting 2024.
“The field of medical management of alcohol use disorder [AUD] is growing in importance and is underscored by the growing burden of acute and chronic alcohol-associated liver disease. Pharmacotherapy is an important component of treatment to try and help patients with their addiction. Beyond surviving the first few months after presentation, the long-term ability to abstain from alcohol use is an important determinant of long-term outcomes,” said copresenter Marwan Ghabril, MD, a hepatologist at the Indiana University School of Medicine, in Indianapolis.
He and his co-investigators conducted a prospective study of 1,975 individuals with highconfidence DILI who were enrolled between September 2004 and March 2024, examining those taking medications for AUD (MAUD; abstract 2438).
Among the 13 DILI cases attributed to MAUD, the probable cause was determined to be disulfiram in 11 cases, naltrexone in one case and baclofen in one case. No DILI cases were associated with acamprosate.
The average age of the disulfiram cases was 43.8 years, with a range of 31.5 to 61.3 years, and 72.7% were female. The ages were 61 and 59.7 years in the baclofen and naltrexone cases, respectively, and both were female. The outcomes were severe in some, including two liver transplants and one resulting death.
Looking at a group of patients with available
DILI HLA data (456 control cases not attributable to disulfiram and nine cases attributable to disulfiram), the investigators found associations between disulfiram-related DILI risk and two HLA alleles: HLA-C*01:02 (odds ratio [OR], 6.29; 95% CI, 1.10-24.1; P=0.020) and HLA-DRB1*09:01 (OR, 10.16; 95% CI, 1.01-52.7; P=0.024).
DILI attributable to disulfiram had some phenotypic patterns, including mild inflammation focused in the portal area, with no apparent necrosis or damage to the parenchyma, as well as bile duct injury in portal areas, canalicular cholestasis, and extensive confluent necrosis with ductular reaction and a solitary nodule of hepatocytes.
“The majority of idiosyncratic DILI from MAUD is related to disulfiram. Other agents certainly can do it, but they’re much less likely to do so and are, therefore, safer. There is also emerging corroborating data from other studies suggesting that naltrexone and acamprosate are quite a bit safer than disulfiram as relates to the risk of idiosyncratic hepatotoxicity,” Dr. Ghabril told Gastroenterology & Endoscopy News.
The take-home message is that physicians should feel comfortable using MAUDs but avoid disulfiram, he said. “DILI is still rare, but why use disulfiram when we have effective and safer alternatives?”
—Jim Kling Dr. Ghabril reported no relevant financial disclosures.
Reports From The Liver Meeting 2024
Looking at Disease Course And Mortality in MASH Patients
Anew natural history study of patients with metabolic dysfunction–associated steatohepatitis shows a six-year mortality rate of 10% in patients with compensated cirrhosis.
The new data supplement what is known from clinical trials, which may not be representative of the broader population, according to Sidney Barritt IV, MD, MPH, who presented the study at The Liver Meeting 2024 (abstract 2357).
“The purpose of this study is to observe their natural history, … disease course, [and] predictors of progression of disease and, ultimately, to be a source of phase four post-marketing surveillance once medications are available for the treatment of this disorder,” said Dr. Barritt, a professor of medicine at the University of North Carolina at Chapel Hill.
The researchers analyzed data on 1,949 patients (1,084 with non-cirrhotic MASH, 495 with compensated cirrhosis and 370 with decompensated cirrhosis) enrolled in the TARGET-NASH database between August 2016 and January 2024. About one-third of the patients in the study had been biopsied, but most diagnoses were made based on clinical criteria, “just like they are in routine clinical practice,” Dr. Barritt said.
Compared with non-cirrhotic MASH patients, those with compensated cirrhosis had increased rates of all-cause mortality (hazard ratio [HR], 13.62; 95% CI, 6.13-30.29) and progression to decompensated cirrhosis (HR, 52.24; 95% CI, 24.28-112.40) over six years of follow-up. The risk for all-cause mortality was about 10% in patients with compensated cirrhosis and 30% in those with decompensated cirrhosis over that period.
Progression from MASH to compensated cirrhosis was 1.39 per 100 person-years, and from compensated to decompensated cirrhosis was 3.53 per 100 person-years. Among individuals with MASH, 6% progressed to compensated cirrhosis in six years, and 14% with compensated cirrhosis had a decompensation event.
The findings revealed some characteristics of MASH patients. “Our population of patients with MASH progressed relatively slowly to cirrhosis, granted [the study included] all fibrosis stages of MASH,” Dr. Barritt told Gastroenterology & Endoscopy News.
In contrast, he added, “the progression of patients with decompensated cirrhosis happened relatively quickly.” By 12 months, 10% of the cohort with decompensated cirrhosis had died, and by 36 months, approximately 20% of that group had died. “That’s relatively rapid progression and a large disease burden, and frequently patients with decompensated cirrhosis are not part of clinical trials, so this is a way to follow these patients over time,” Dr. Barritt said.
The findings “speak to that critical unmet need for a non-transplant intervention to try to help these people, especially those with compensated cirrhosis.”
—Jim Kling
The study was funded by Merck. Dr. Barritt reported financial relationships with Boehringer Ingelheim, Madrigal, Merck, Mirum and Target RWE.
Reports From The Liver Meeting 2024
One Year of Elafibranor Improves GLOBE And UK-PBC Prognostic Scores
Among patients with primary biliary cholangitis, the peroxisome proliferator−activated receptor agonist
elafibranor is predicted to increase transplant-free survival and reduce mortality over 15 years, according to a new analysis of data from the phase 3 ELATIVE trial.
Elafibranor (Iqirvo, Ipsen) has activity against both PPAR-alpha and PPAR-delta and is the first PPAR agonist approved for PBC.
In the ELATIVE trial, investigators evaluated patients treated with 80 mg of elafibranor (n=108) or placebo (n=53) daily over 52 weeks and found that 51% of the treatment group had biochemical responses, compared with 4% of the placebo group.
One of the secondary end points of the trial was prediction of the need for a liver transplant or death within one year using the GLOBE (death and transplant) and UK-PBC prognostic (transplant only) scores, which were collected at baseline and weeks 4, 13, 26, 39 and 52. Both scores rely on levels of alkaline phosphatase, bilirubin, aspartate aminotransferase, alanine aminotransferase, albumin and platelets.
“They project likelihood of being free of death and liver transplantation for a much longer period of time than some of the more traditional scores, so as a risk assessment tool, we find that to be very helpful,” said Kris Kowdley, MD, the director of Liver Institute Northwest, presenting the new analysis during an oral session at The Liver Meeting 2024 (abstract 0043).
Dr. Kowdley reported that there was a clear between-group separation in both scores. Starting at week 13, the change in GLOBE hovered around −0.35 in the elafibranor group, compared with +0.1 for placebo. The change in UK-PBC was between −0.20 and −0.25 for the elafibranor
group, starting by week 4, compared with −0.05 to +0.05 for placebo.
The researchers estimated that over 15 years, elafibranor would be associated with a 4.9% increase in the transplant-free survival rate versus 0.7% for the placebo group based on the GLOBE score at 52 weeks. Based on the 52-week UK-PBC score, elafibranor would be associated with a 1.6% increase versus a 0.4% decrease for placebo. Dr. Kowdley reported that the estimated effects were maintained regardless of disease stage or biochemical response.
“We conclude that treatment with elafibranor was associated with improvements in predicted transplant-free survival in patients with PBC,” Dr. Kowdley said.
During the question-and-answer period following the presentation, an attendee noted that GLOBE and UK-PBC were developed based on patients treated with ursodeoxycholic acid and suggested that the models might not fit drugs that have anti-inflammatory or antifibrotic activity. Dr. Kowdley conceded the point but responded that given “the fact that you see this reduction as early as four weeks, I think it’s largely driven by alkaline phosphatase, and is, therefore, an anticholestatic response.”
—Jim Kling
Dr. Kowdley reported financial relationships with 89bio, AbbVie, AstraZeneca, Boehringer Ingelheim, Gilead, GSK, High Tide, Inipharm, Intercept, Ipsen, Madrigal, Mirum, NGM, Novo Nordisk, Pfizer, Pliant, Protagonist and Zydus.
Echosens raises the standard for liver disease assessment with next-generation FibroScan® — now with the Liver Health Management (LHM) platform
New Guided VCTETM technology is compatible with LHM Connect — the new, innovative, cloud-based solution for FibroScan® , which assists in providing accessible, comprehensive liver care for patients.
Endorsed by Healthcare Professionals
Improved Guidance
Two new Guided VCTETM indicators — one for liver stiffness, and one for CAPTM of the optimal measurement location.
Faster Examinations
exam time reduction with Guided VCTETM — 96% of patients can be scanned in less than 4 minutes1 , including patients with BMI>30.
Based on the two new Guided VCTETM indicators, AutoScan automatically triggers 10 valid measurements through a single click, enabling streamlined scanning and a likely improved operator experience.
Now, Echosens has the Liver Health Management platform where it makes it very user-friendly, even for someone who is not a liver specialist. When we do a FibroScan® exam and generate a report, it’s easy to send it to the referral who sent us the patient. They are able to scan it into their EMR and read and interpret what the values mean. This is more personal and easier to follow.
– Dr. Angelo Paredes Gastroenterologist, Transplant Hepatologist Middletown,
Accelerated FDA Approval Ushers
In New Era in Primary Biliary Cholangitis Treatment
Experts are hailing the FDA’s recent accelerated approval of seladelpar for the treatment of primary biliary cholangitis as a critical advancement for patients with PBC, particularly those who have an inadequate response or are intolerant to the standard first-line treatment, ursodeoxycholic acid (UDCA).
The approval was based on results from a series of clinical trials that demonstrated the safety and efficacy of seladelpar (Livdelzi, Gilead), a selective peroxisome proliferator−activated receptor-delta agonist, in improving liver function and alleviating symptoms in PBC patients.
“We see far too many patients with insufficient response to the current therapies and symptoms such as itch that go unresolved and impair quality of life,” Gideon Hirschfield, MB BChir, FRCP, PhD, the principal investigator in the phase 3 and open-label seladelpar extension trials, told GEN Priority Report.
‘ We see far too many patients with insufficient response to the current therapies and symptoms such as itch that go unresolved and impair quality of life. … When you give seladelpar, you see a durable response.’
—Gideon Hirschfield, MB BChir, FRCP, PhD Toronto General Hospital
“These patients have an unmet need, but when you give seladelpar, you see a durable response. You see symptoms get better. You see improvement in blood levels,” said Dr. Hirschfield, the Lily and Terry Horner Chair in Autoimmune Liver Disease Research at Toronto General Hospital.
RESPONSE Trial Shows Enzyme Normalizations
Dr. Hirschfield and his co-investigators demonstrated the safety and efficacy of seladelpar in the RESPONSE trial, a pivotal phase 3, 12-month, double-blind, placebo-controlled study in 193 patients who had an inadequate response to or could not tolerate UDCA (N Engl J Med 2024;390[9]:783-794). Participants were randomized to receive seladelpar (10 mg daily) or placebo. The results were highly promising, with 62% of patients in the seladelpar group achieving a biochemical response at 12 months compared with 20% in the placebo group (P<0.001).
Additionally, 25% of seladelpar-treated patients achieved complete normalization of alkaline phosphatase (ALP), compared with none of the placebo controls (P<0.001).
“These findings are particularly important because elevated ALP is associated with worse clinical outcomes in PBC, and its normalization is a crucial therapeutic goal,” said Anurag Maheshwari, MD, a liver disease specialist at the Center for Liver and Hepatobiliary Diseases at Mercy Medical Center, in Baltimore, who was not involved in the study. “It’s rare to find a treatment that normalizes levels, so this makes seladelpar a very attractive addition to our armament of PBC therapies.”
In the RESPONSE trial, pruritus, a common and debilitating symptom of PBC, was significantly reduced in patients treated with seladelpar. Among those with moderate to severe pruritus at baseline, seladelpar reduced the pruritus numerical rating scale score by an average of 3.2 points, versus a reduction of 1.7 points in the placebo group. This improvement in pruritus, a key secondary end point of the trial, distinguishes seladelpar from obeticholic acid, which has been associated with worsening pruritus.
“It seems that seladelpar is unique in PBC treatments because it uniquely targets [interleukin]-31, which is the mechanism of itching,” Dr. Maheshwari said. “This a very big advancement, particularly for patients whose quality of life suffers due to itching.”
Sustained Results Seen In Open-Label Studies
A two-year, open-label extension of another seladelpar trial confirmed the sustained efficacy of seladelpar with continued reductions in ALP levels and stable bilirubin levels (Aliment Pharmacol Ther 2023;59[2]:186-200). The safety profile of seladelpar remained favorable over the extended treatment period, and the treatment was well tolerated, with a similar incidence of adverse events in the seladelpar and placebo groups.
This extension study demonstrated that the improvements in liver biochemistry observed during the initial 12 months were maintained, and in some cases further enhanced, with prolonged
treatment. The reduction in ALP was particularly notable, and the pruritus relief provided by seladelpar was sustained over the long term.
The ASSURE study, another ongoing openlabel trial that includes patients who participated in earlier seladelpar trials (179 from legacy trials and 158 from the RESPONSE trial), is allowing for extended observation of the drug’s effects. The interim data, shown at DDW 2024 and the EASL Congress 2024, revealed that roughly 70% of legacy and RESPONSE trial participants achieved a composite biochemical response (ALP <1.67 × upper limit of normal [ULN], ALP decrease ≥15%, and total bilirubin ≤1 × ULN). In addition, more than 30% of patients achieved full normalization of ALP, reinforcing seladelpar’s efficacy in controlling cholestasis.
‘ It’s rare to find a treatment that normalizes levels, so this makes seladelpar a very attractive addition to our armament of PBC therapies.’
—Anurag Maheshwari, MD Mercy Medical Center, Baltimore
Given that approximately 40% of PBC patients have a suboptimal response to UDCA, the availability of a well-tolerated and effective treatment that normalizes ALP levels, reduces pruritus and maintains a favorable safety profile over the long term makes it a valuable tool in treating PBC, according to Dr. Maheshwari.
“There’s understandable excitement about the potency, efficacy and durability of seladelpar to produce a rapid response to normalize blood levels and address the symptoms that plague patients,” Dr. Hirschfield said. “And this is achieved with a well-tolerated daily oral [medication], so patients won’t feel burdened by treatment either.”
—Jordan Davidson
Dr. Hirschfield reported financial relationships with CymaBay, Escient, Falk, Gilead, GSK, Intercept, Ipsen, Mirum and Pliant. Dr. Maheshwari reported no relevant financial disclosures.
Complex Interplay Between MASLD And Chronic HBV Infections
Theprevalence of metabolic dysfunction–associated steatotic liver disease has increased worldwide and is particularly problematic among patients with chronic hepatitis B virus, according to new research.
Of the approximately 254 million people with HBV surface antigen (HBsAg)-positive chronic HBV, 16% to 67% may have concurrent MASLD (Lancet Gastroenterol Hepatol 2020;5[2]:167-228; bit.ly/3Zqrq7y). The interplay between the two diseases is complex. Large cohort studies have suggested that MASLD may be protective against HBV by suppressing viral replication, yet co-occurrence may still worsen liver disease outcomes such as cirrhosis and hepatocellular carcinoma (HCC) (Front Physiol 2024;15:1347459).
The new research, from investigators at the University of Calgary, in Alberta, sheds some light on the mechanisms involved in this complicated relationship between disease states, finding that even when HBV is suppressed, coexisting MASLD leads to activation of systemic inflammatory pathways and metabolic dysregulation that may ultimately aggravate HBV-related liver fibrosis progression (J Viral Hepat 2024 Aug 7. https://doi.org/10.1111/jvh.13979).
This prospective cross-sectional cohort study enrolled 53 adults aged 18 to 60 years with chronic HBV, both with and without severe hepatic steatosis and metabolic syndrome risk factors, who were treatment-naive and had no end-stage liver disease such as cirrhosis or HCC. In addition, 12 HBV-negative individuals with MASLD were recruited for immune assay control.
The investigators assessed HBV replication status using standard and novel viral biomarkers, HBV variants by deep sequencing of the HBV surface and core genes, and serum cytokine levels and ex vivo functional HBV-specific cellular immune responses to whole recombinant HBsAg and HBV core antigen, a marker of viral replication found in infected hepatocytes. They found that those with more severe hepatic steatosis showed increased peripheral systemic
and Th1 cytokine levels and cellular response to whole viral proteins. Patients with metabolic syndrome and steatosis showed lower HBV markers (P<0.01), higher HBV surface diversity (P=0.02) and greater frequency of HBV variants associated with host antiviral immune escape.
“Individuals with more hepatic steatosis showed low-level viremia, unique HBV variants and systemic anti-viral immune responses, potentially impacting liver disease progression. Overall, the accumulated study data are consistent with other published work showing lower HBV viremia, including novel replication biomarkers, in CHB [chronic HBV] patients with comorbid MASLD,” wrote the researchers, led by Claudia Coffin, MD, MSc, a professor of medicine and the medical director of the University of Calgary Viral Hepatitis Clinic. “Moreover, our study data show an association between hepatic steatosis and HBV genome changes, systemic inflammation and host-antiviral specific immune responses, determined by assessment of HBV [surface] gene diversity and variants, serum cytokines and [interferon]-gamma cellular responses to recombinant HBV proteins.”
Cautioning that larger and longer studies that include patients with more diverse HBV genotypes are needed, the researchers noted their findings suggest that MASLD-associated immune–inflammatory profiles may enhance HBV-specific T-cell responses in patients with both CHB and MASLD, achieving higher rates of a functional CHB cure.
—Gina Shaw
Dr. Coffin reported financial relationships with Altimmune Pharmaceuticals, Gilead, GlaxoSmithKline, Janssen and Roche.
Supported by
Endo-Hepatology: Olympus® Ultrasound Portfolio for the Management of Patients With Liver Diseases
Faculty
Kenneth J. Chang, MD
Executive Director, Digestive Health Institute
Professor of Medicine
University of California, Irvine Health
Irvine, California
Marvin Ryou, MD
Director of Innovation
Endoscopy Center at Brigham and Women’s Hospital
Associate Professor of Medicine
Harvard Medical School
Boston, Massachusetts
Introduction
In the United States, liver diseases are becoming increasingly common, with nonalcoholic fatty liver disease (NAFLD) being the most prevalent.1,2 It is estimated that 100 million individuals (30%) are affected by NAFLD,1,2 with approximately 16% of these patients advancing to nonalcoholic steatohepatitis (NASH), a severe progression of unmanaged NAFLD.1,2 Of these patients, 12% develop cirrhosis, irreversibly damaging the liver. 3 The increase in prevalence is attributed to a number of risk factors including obesity, insulin resistance, and metabolic syndrome and corresponding complications.1,3
Traditionally, the role of endoscopy had focused on the assessment and treatment of esophageal and gastric varices.4 Gastroenterologists and hepatologists would defer to radiologists to initiate and review liver imaging, while interventional radiologists reviewed liver biopsy and initiated the management of portal hypertension.4,5
“Ideally, it would be preferred to have the assessment and treatment of liver disease and portal hypertension performed and assimilated by the primary liver/gastrointestinal specialist,” said Kenneth J. Chang, MD, the executive director of the Digestive Health Institute and a professor of medicine at the University of California, Irvine Health.
Recent advancements in endoscopic ultrasound (EUS) have expanded the role of endoscopy to integrate imaging, shear wave elastography, liver biopsy, contrast harmonic imaging, and portal pressure gradient measurement for the diagnosis and management of patients with liver diseases, creating an emerging field known as endo-hepatology.4-6 The concept was initially introduced over a decade ago by Chang and colleagues who recognized the benefits of EUS, combining ultrasound and advanced endoscopic technologies to not only provide quality images in real time but also perform accurate diagnoses and determine appropriate interventions in the liver.4,5,7,8 “Endoscopic options for the patient with suspected or known liver disease have expanded to the point where the concept of an endoscopic ‘one-stop shop’ can now be realized,” said Marvin Ryou, MD, the director of innovation at the Endoscopy Center at Brigham and Women’s Hospital and an associate professor of medicine at Harvard Medical School, in Boston, Massachusetts. “For example, patients undergoing an upper endoscopy for variceal screening can also undergo simultaneous EUS-guided assessments of liver fibrosis, portal pressure measurements, and liver biopsy.” The shift toward EUS-guided technology is supported through the integration of the Olympus product portfolio featuring tools and imaging modalities designed to enhance visualization and precision and manage affected patients efficiently.
Olympus® EUS Portfolio
Olympus offers a comprehensive EUS portfolio of ultrasound processors, echoendoscopes, and devices that physicians can use to diagnose and manage liver disease. These tools, including the
THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES
ALOKA ARIETTA™ 850 ultrasound processor and the GF-UCT180 EUS linear array echoendoscope, support access and visualization for the physician to assess and identify lesions and determine therapeutic and interventional measures. With advanced features such as shear wave measurement (SWM) and contrast harmonic imaging, the Olympus® EUS portfolio provides clinicians with a streamlined approach to identify lesions during a single procedure.9,10 In addition, the Olympus EZ Shot™ 3 Plus fine needle biopsy (FNB) needle for use in EUS-guided liver biopsy (EUS-LB) enhances access to difficult-to-reach lesions with precision.11
ARIETTA 850 Ultrasound Processor and GF-UCT180 Linear Scope
The ARIETTA 850 premium ultrasound processor features several imaging modalities, such as SWM and contrast harmonic imaging, that along with the GF-UCT180 provide enhanced imaging with high resolution for a comprehensive examination of the liver.9,10 The GF-UCT180 features a groove on the forceps elevator that stabilizes the device exiting the 3.7-mm–diameter instrument channel, supporting reliable and precise operation for the user.10
Shear Wave Measurement
EUS-guided SWM is an advanced feature used to assess tissue stiffness, such as liver fibrosis (Figure 1). SWM is determined by calculating the propagation velocity of shear waves through tissue,
generated from a “push-pulse.”12 Waves will move faster in stiffer tissues and slower in softer tissues.12,13
Traditionally, liver fibrosis is estimated using a percutanteous approach (ie, transient elastography [TE] more commonly known as FibroScan) in which a probe is placed in the intercostal space over the right liver lobe and a vibration pulse generates shear waves.12 The velocity of the shear waves is calculated at certain depths and expressed in kilopascals.12 This approach has limitations such as suboptimal performance in obese patients or those with ascites.12,14 Also, because transabdominal approaches are obtained over the right hepatic lobe, it is unclear whether the presence of hepatic fibrosis can be determined without an assessment of the left lobe.15
EUS-SWM uses a transgastric approach to provide real-time visualization of the parenchyma and can be performed without the limitations often encountered with obese patients when using the percutaneous approach.15,16 “Some of the advantages of EUSSWM are that the procedure can be performed on patients who are morbidly obese, and both the right and left hepatic lobes can be assessed, along with stiffness of the spleen,” Dr Chang said. “Realtime visualization with EUS-SWM also allows for accurate placement of the transducer.”
Clinical data have compared EUS-guided SWM and TE in assessing hepatic fibrosis. Diehl and colleagues compared these 2 modalities and how well they correlated to histologic METAVIR (Meta-analysis of Histological Data in Viral Hepatitis) scores for assessing liver fibrosis using liver biopsy as the gold standard.17 A total of 52 patients were enrolled in the study and underwent TE of the right liver lobe and EUS-SWM and EUS-LB of both the right and left lobes.17 The most common etiology of liver disease was NASH.17
Results showed that EUS-SWM and TE had comparable discrimination of all stages of fibrosis.17 Right-lobe EUS-SWM had a strong correlation with fibrosis stage (P=0.571; P<0.0001) and leftlobe EUS-SWM had a moderate correlation (P=0.368; P<0.0079).17 TE also had a strong but slightly lower correlation with fibrosis stage (P=0.552; P<0.0001).17 The investigators concluded that EUSSWM provides a comparable assessment to TE and can be used to assess liver stiffness—an estimate of hepatic fibrosis.17
EUS, endoscopic ultrasound.
Kohli and colleagues also conducted a study that compared TE with EUS-guided SWM in patients undergoing liver biopsy.15 A total of 42 patients underwent TE, EUS-SWM, and liver biopsy sampling. 15 The most common etiology of liver disease was NAFLD. 15 Technical success of EUS-SWM was achieved in 100% of patients and defined by the ability to obtain at least 10 values of elasticity, each with a net effective shear wave velocity of at least 60%, using the median for the final value for assessment of fibrosis.15
Figure 1. EUS-guided shear wave measurement of the liver.
Image courtesy of Amitpal Johal, MD.
TE was deemed unreliable in 8 patients, all of whom underwent EUS-SWM successfully.15 Results showed that left-lobe EUSSWM had a higher positive predictive value for advanced fibrosis and cirrhosis compared with TE, whereas the negative predictive value was similar between the 2 tests.15 The investigators concluded that EUS-SWM correlated well with liver histology and was a safe and reliable diagnostic test to assess liver fibrosis with accuracy comparable to TE.15
EUS-Guided Liver Biopsy
Liver biopsy continues to be the gold standard for obtaining hepatic tissue for histopathologic examination.5 Conventional methods of liver biopsy have been percutaneous and transjugular.5 Percutaneous liver biopsy is the standard procedure performed using palpation/percussion-guided or ultrasound-guided methods.5 This method is effective in obtaining hepatic tissue; however, it should not be performed on patients with severe coagulopathy, severe ascites, or those who are morbidly obese.5 Transjugular liver biopsy, which is primarily done by interventional radiology, is performed by accessing the right internal jugular vein, with the right hepatic vein most frequently cannulated.5 This procedure can be complex and is associated with various risks such as arrhythmias.5 Transjugular biopsy cannot be performed in patients with jugular vein thrombosis or hepatic vein obstruction.5,18
With EUS-LB, clinicians can sample both lobes of the liver and make several needle actuations within the liver with a single puncture through the liver capsule.19 Real-time ultrasound guidance of the needle into the liver, as well as Doppler confirmation that there is no blood flow within the needle track before it is removed affords rapid recovery time for the patient.19 Key steps performed during an EUS-LB include selecting a 19-gauge FNB needle; applying wet suction (ie, priming the lining of the needle with a heparin solution to prevent clot formation); and then performing a left and then right liver biopsy.
The procedure is convenient because it can be performed in patients already undergoing EUS for other indications (eg, assessment of varices or portal pressure measurement). Thus, the patient avoids an additional procedure to obtain a liver biopsy while already being sedated. Data have shown that liver specimens obtained via EUS-LB are generally equal to those obtained via a percutaneous or transjugular liver biopsy.20,21 Complication rates with EUS-LB also have been shown to be comparable to those of percutaneous or transjugular liver biopsies.20,21 “EUS-LB has expanded the ability of gastroenterology/hepatology specialists to perform these procedures; however, one of the biggest challenges is ensuring clinicians are properly trained on the appropriate technique,” Dr Chang said.
EZ Shot™ 3 Plus FNB for EUS-Guided Liver Biopsy
EUS-guided liver biopsy can be performed using the Olympus® EZ Shot 3 Plus FNB (Figure 2). This needle provides easy access, smooth puncturability, predictable trajectory, and distinct echogenicity to further optimize liver biopsy.11 The EZ Shot 3 Plus needles are available in gauges of 19, 22, and 25.11 The 19- and 22-gauge needles are comprised of nitinol allowing for flexibility to access difficult locations without compromising the scope position.22 The EZ Shot 3 Plus needle includes a multilayered metal coil sheath that facilitates excellent force transmission to the distal end of the device and reduces the amount of friction with the needle.11
The EZ Shot 3 Plus needle also features a Menghini-tip design that includes a sharp, continuous, smooth cutting edge to cut tissue specimens seamlessly with precise puncturability to help preserve the tissue’s cellular architecture.11 The design enables smooth puncturing even from oblique angles, reducing the potential for angle deviation.11 The resilient needle shape and design of the EZ Shot 3 Plus needle also provides a predictable and consistent trajectory while retaining its shape after fanning and multiple passes. The densely arranged needle dimples provide a distinct hyperechoic appearance on the ultrasound view for precise targeting.11
Figure 2. Olympus GF-UCT180 linear echoendoscope with EZ Shot 3 Plus FNB needle. FNB, fine needle biopsy. Image courtesy of Olympus America, Inc.
THE SCIENCE BEHIND POSITIVE PATIENT OUTCOMES
Conclusion
With an increasing number of patients with liver diseases, advances in EUS are expanding the field of endo-hepatology to provide gastroenterologists and hepatologists the tools to streamline diagnosis and management of the entire liver. As part of the comprehensive Olympus® EUS portfolio, the ARIETTA™ 850, GF-UCT180, and EZ Shot™ 3 Plus needle provide clinicians effective
References
1. Cotter TG, Rinella M. Gastroenterology. 2020;158(7):1851-1864.
5. Singh AD, Bazarbashi AN, Lindenmeyer CC. Clin Liver Dis (Hoboken). 2022;20(6):209-215.
6. Sbeit W, Kadah A, Mar A, et al. Diagnostics (Basel). 2020;10(9):688.
7. Chang KJ, Samarasena JB, Iwashita T, et al. Gastrointest Endosc Clin N Am 2012;22(2):379-385, xi.
8. Téllez-Ávila FI, Garcia-Saenz-de-Sicilia. Ann Hepatol. 2022;27(4):100730.
9. Data on file with FUJIFILM Healthcare Corporation.
10. Data on file with Olympus as of 07/2015.
11. Data on file with Olympus as of 06/2018.
tools to analyze liver fibrosis using SWM, and perform EUS-LB, which leads to more efficient patient care.
Potential complications that may be associated with EUS include, but are not limited to, the following: sore throat, infection, bleeding, perforation, and/or tumor seeding (when EUS-fine needle aspiration or biopsy is performed).
12. Chang PE, Goh GBB, Ngu JH, et al. World J Gastrointestinal Pharmacol Ther. 2016;7(1):91-106.
13. Dietrich CF, Dong Y. J Ultrason. 2016;16(66):281-287.
14. Cástera L, Foucher J, Bernard PH, et al. Hepatology. 2010;51(3):828-835.
15. Kohli DR, Mettman D, Andrews N, et al. Gastrointest Endosc. 2023;97(1): 35-41.e1.
16. Wang TJ, Ryou M. Clin Endosc. 2023;56(2):229-238.
22. Morgan NB. Mat Sci Eng A. 2004;378(1-2):16-23.
Disclosures: Dr Chang reported that he is a consultant to Apollo, Aqua Medical, Boston Scientific, Cook Medical, Creo Medical, EndoGastric Solutions, Erbe, Medtronic, Olympus, Ovesco, and Pentax. He also is on the speakers bureau of Cook Medical, EndoGastric Solutions, Erbe, Medtronic, and Olympus, and the advisory board for EndoGastric Solutions. Dr Ryou reported that he has received study support from and is a consultant to Olympus.
Disclaimer: This article is designed to be a summary of information. While it is detailed, it is not an exhaustive review. McMahon Publishing, Olympus, and the authors neither affirm or deny the accuracy of the information contained herein. No liability will be assumed for the use of the article, and the absence of typographical errors is not guaranteed. Readers are strongly urged to consult any relevant primary literature.
A Spectrum of Cirrhosis and Alcohol-Associated Hepatitis
ASHWANI K. SINGAL, MD, MS, FACG, FAASLD, AGAF
Professor of Medicine
Division of Gastroenterology, Hepatology, and Nutrition
Director, Clinical Trials Program Hepatology
University of Louisville School of Medicine
Transplant Hepatologist
Trager Transplant Center
UofL Health Jewish Hospital
Research Scientist
Robley Rex VA Medical Center Louisville, Kentucky
Alcohol-associated liver disease (ALD) is one of the most common liver diseases and its prevalence is increasing worldwide.1,2 A total of 123 million individuals globally and about 2.2 million in the United States had ALD cirrhosis in 2017.3
Alcohol contributes to about 48% of cirrhosis-related hospitalizations in the United States. ALD-associated admissions have about a 2-fold higher in-hospital mortality compared with cirrhosis hospitalizations due to other liver diseases (13.4% vs 7.6%).4 Currently, ALD is the leading indication for listing and receipt of liver transplant (LT) in this country and most parts of the world.5,6 In 2018, ALD contributed to more than 40% of the 6,524 LTs performed in the United States.6
ALD contributes to about 25% of cirrhosis-associated deaths in this country, with 332,268 deaths (241,000 in men) in 2017.3,7 ALDrelated mortality is especially high among Native Americans and people between the ages of 25 and 34 years.8,9-11
One of the main reasons for mortality due to ALD is development of alcohol-associated hepatitis (AH), a unique presentation that occurs with acute-on-chronic liver failure (ACLF); AH is associated with a potential mortality rate of 30% to 40% within a month of presentation12,13 and in-hospital mortality of approximately 40% to 45%.8,14 AH and ACLF are associated with a significant economic burden, with a $46,264 hospital cost per admission that amounted to more than $2 billion between 2006 and 2010.15,16
Diagnosis of ALD
Advanced ALD includes patients with stage 3 or bridging fibrosis, cirrhosis, and symptomatic AH, which develops in 4% to 8% of patients at some point during their life.1,17 In a patient who meets criteria for ALD (Table 1),18 diagnosis of definitive AH requires a liver biopsy (Figure 1).18,19 Diagnosis of AH as the precipitant for decompensation is important because the condition has a high short-term mortality of up to 40% if left untreated. The National Institute of Alcoholism and Alcohol Abuse (NIAAA) consortia proposed a set of clinical criteria for the diagnosis of probable AH.19 The accuracy of these criteria in diagnosing AH is higher than 90% in those with severe disease (Model for End-stage Liver Disease [MELD] score >20) but is only 67% in patients with moderate disease. In these patients and whenever the clinical diagnosis is uncertain (possible AH), a liver biopsy is recommended for confirming the diagnosis of AH.16,19,20 Many other noninvasive biomarkers are emerging for AH diagnosis, including cytokines, extracellular vesicles, and micro-RNA.21,22
Treatment of ALD
Comorbid Alcohol Use Disorder
Alcohol use disorder (AUD), a chronic disease characterized by relapses and remissions,23 is present in most patients with ALD. Achieving complete abstinence is the primary goal and is associated with decreases in morbidity and mortality in patients with ALD.24,25 Of note, heavy drinkers and patients surviving an episode of AH may have relapse rates as high as 60% in the short and long term.24 In low-resource settings, brief intervention and training of all providers should be encouraged. The main goals of the brief intervention are to educate the patient about the effects of alcohol and to stimulate their desire to discontinue alcohol intake. Although these interventions alone may not be sufficient, they might reinforce compliance with treatment and follow-up.26 Specific therapies targeted at AUD include behavioral and pharmacologic interventions.
Behavioral Therapies
Behavioral therapies are a key tool to identify triggers of relapse and maladaptive behavior. Options include 12-step facilitation, motivational enhancement therapy, and cognitive behavioral therapy. The 12-step facilitation process involves participation of the patient in interventions such as Alcoholics Anonymous meetings. Motivational enhancement therapy is focused on stimulating the patient’s own motivation for change and encouraging this change over time. Cognitive behavioral therapy focuses on identifying triggers that lead to alcohol use and aims to enhance coping skills to prevent relapse.26,27
Pharmacologic Therapies
The FDA-approved drugs to treat AUD include acamprosate, naltrexone, and disulfiram (Table 2).28 Acamprosate, which has not been studied in patients with ALD, is not metabolized in the liver and can be used safely in ALD patients. Its mechanism of action is not fully understood but is speculated to be antagonism of glutaminergic activity and promotion of gamma-aminobutyric acid (GABA) receptor agonism.29 In a randomized controlled trial of 24 patients with ALD (Child-Pugh classes A and B), acute administration of 666 mg of acamprosate was found to be safe, although data in patients with Child-Pugh C are limited.30 Naltrexone, which also has not been examined in patients with ALD, works by modulating the effect of alcohol on dopamine receptors.29 Disulfiram undergoes hepatic metabolism and has been
Table 1. Criteria for Diagnosis of ALD
Harmful alcohol use (>2 drinks/d in females and >3 drinks/d in males) during last 12 mo or more
Liver disease diagnosed in the presence of clinical signs of cirrhosis, biochemical liver abnormalities, or liver imaging findings (steatotic liver disease, portal hypertension, cirrhosis)
When liver aminotransferases are elevated, these are usually <400 IU/L, with AST:ALT ratio >1
Exclude other causes of liver disease:
• negative hepatitis B surface antigen and hepatitis C virus antibodies
• negative autoantibodies for autoimmune hepatitis and primary biliary cholangitis
• negative workup for genetic diseases: Wilson’s disease, hemochromatosis, and alpha-1 antitrypsin deficiency
ALD, alcohol-associated liver dsease; ALT, alanine aminotransferase; AST, aspartate aminotransferase; IU, international unit.
Based on reference 18.
associated with severe hepatotoxicity.31 Hence, its use in patients with any spectrum of ALD is not recommended.32
Of the several non–FDA-approved drugs, baclofen, a GABA receptor agonist, is the only drug that has been shown to be effective and safe in a controlled trial in patients with ALD and cirrhosis (Table 2).28,33 Baclofen has been endorsed by the American Association for the Study of Liver Diseases and the American College of Gastroenterology for the management of AUD in ALD patients.34,35 Gabapentin, although not studied in ALD patients, is considered to be safe and has been endorsed by the American Psychiatric Association for use in ALD patients.36 Clearly, there is an unmet need for large randomized controlled trials to examine pharmacologic therapies in patients with ALD, especially those with decompensated cirrhosis and/or AH.
Advanced decompensated symptomatic ALD
NIAAA Consortium Criteria for clinical diagnosis of AH
• Serum bilirubin >3 mg/dL
• AST:ALT ratio >1.5:1
• Absolute transferases value <400 IU/L
• Alcohol use until 8 wk prior to presentation
• Other causes of liver disease and biliary obstruction ruled out
Meets
Changes of AH on liver biopsy
• Steatosis
• Neutrophilic lobular infiltration
• Ductular or canalicular cholestasis
Figure 1. Spectrum and progression of ALD.
AH, alcohol-associated hepatitis; ALD, alcohol-associated liver disease; ALT, alanine aminotransferase; AST, aspartate aminotransferase; NIAAA, National Institute on Alcohol Abuse and Alcoholism.
Based on references 18 and 19.
However, treatment for AUD rarely is used in patients with ALD.37,38 In a retrospective study of more than 35,000 veterans with cirrhosis, AUD treatment was used in only 14% and pharmacologic treatment in less than 1% of patients.39 Barriers to AUD treatment in ALD patients can be related to patient or clinical factors, or be due to logistic, financial, or administrative reasons (Table 3).37,40,41 There is a clear need to develop strategies in addiction medicine training for hepatologists and gastroenterologists to provide comprehensive management of ALD patients on the dual pathology of liver disease and of ALD.42 Efforts and strategies are needed to establish multidisciplinary care models with integrated or at least concomitant treatment of AUD in the management of patients with ALD (Figure 2).28,39-41
Medical Treatment of Liver Disease
Alcohol-Associated Cirrhosis
The approach to treatment of liver disease complications in patients with alcohol-associated cirrhosis is similar to treatment of cirrhosis due to any other etiology. Patients with a MELD score higher than 17 that remains elevated despite at least 3 months of abstinence should be evaluated for LT eligibility.43 Clinicians need to recognize unique issues related to LT evaluation for patients with ALD, such as chronic pancreatitis, malabsorption, cardiomyopathy, peripheral neuropathy, cerebellar degeneration, alcohol withdrawal syndrome, Korsakoff psychosis, psychiatric comorbidities (anxiety, depression, insomnia), and other concomitant substance use disorders.
Alcohol-Associated Hepatitis
Corticosteroids are the only available pharmacotherapy for patients with severe episodes of AH.44,45 However, patients with active infection or sepsis, gastrointestinal bleeding, severe renal dysfunction, and hepatorenal syndrome are ineligible to receive corticosteroids.46 After these complications are controlled, corticosteroids may be initiated for short-term survival benefit. Corticosteroids provide survival benefit for a short-term period of 28 days; no benefit has been found in extending the period. Several meta-analyses have confirmed a 28-day survival benefit with prednisolone without an additional benefit beyond 1 month.44,45,47 Practice guidelines recommend corticosteroids for severe AH patients if there are no contraindications to their use.35,48-50 Pentoxifylline does not provide survival benefit in treatment-naive nonresponders to corticosteroids or as an adjuvant to corticosteroids.51 N-acetylcysteine (NAC) can be used as an adjuvant to corticosteroids. In one trial, NAC did not achieve the primary end point of improving 6-month survival, but patients in the active arm were protected from infections.52 In very sick patients, NAC administered intravenously may be used as recommended by the 2018 ACG guideline.35
In AH, usually the corticosteroids prednisolone 40 mg per day or methylprednisolone 32 mg per day are initiated. At day 7, the Lille score is used to assess response to treatment, with, on average, 60% of patients responding to therapy (Lille score ≤0.45).53 Patients should be closely followed for infections, especially nonresponders to treatment.54-56 Corticosteroids are continued for a maximum of 28 days in responders and discontinued on day 7 in nonresponders (Figure 3).48,49 A recent study showed that
if corticosteroids are used in a response-based approach with discontinuation in nonresponders at 1 week (Lille score >0.45), then the use of these drugs is associated with a mortality lowered to only 9% to 10% at 1 month.57
Emerging noninvasive biomarkers for predicting response to steroids include mitochondrial function of immune cells, gene expression for genes driving inflammation or hepatic regeneration, cytokines and chemokines, cytokeratin-18, bacterial DNA levels, and extracellular vesicles.22 Noninvasive biomarkers also could help personalize use of steroids to those who are likely to respond.22 In this regard, a recent international, multicenter study identified a therapeutic window of a MELD score of 25 to 29 as being associated with the best chances of response to corticosteroids.58
Protein−calorie malnutrition is frequent in patients with alcohol-associated cirrhosis and AH.59 A randomized controlled
trial evaluating intensive enteral nutrition failed to improve shortterm survival in patients with severe AH but confirmed higher risks for mortality in patients with a daily calorie intake less than 21.5 kcal/kg.60 It is recommended that intake for patients with AH, irrespective of the severity, be 35 to 40 kcal/kg per day with 1.2 to 1.5 g/kg per day of protein. Nighttime snacks improve nutritional status and nitrogen balance in patients with alcoholassociated cirrhosis and AH. Nutritional supplementation is recommended, especially when the caloric intake is severely reduced to less than 1,000 to 1,200 calories per day. The enteral route is recommended, except when it is not an option, such as in patients with ileus or small bowel obstruction.59,60
Liver Transplantation for ALD
Transplantation is an acceptable treatment for patients with alcohol-associated cirrhosis if the MELD score remains above 17
Pharmacotherapies for AUD in Patients With ALD
Drugs FDA-approved for use in AUD
Naltrexone Opioid antagonism modulates effect of alcohol on dopamine receptors
Acamprosate Modulation of glutaminemediated transmission
Drugs not FDA-approved for use in AUD
Topiramate Agonism of GABA and antagonism of glutamate receptors
Oral: 50 mg/d IM: 380 mg/mo
Oral: 666 mg 3 times daily
Avoid in ChildPugh C
PossibleAllowedDiarrhea, nausea, somnolence
AllowedNoneModify dose as needed
Diarrhea
BaclofenAgonism of GABA receptors
GabapentinAgonism of GABA receptors
VareniclineAntagonist to nicotine binding alpha-4 beta-2 receptor
Oral: Initially 25 mg/d, titrated up to 150 mg twice daily
Oral: 10-30 mg 3 times daily
Oral: 300-600 mg 3 times daily
Oral: 1 mg 2 times daily
Allowed; avoid in patients with hepatic encephalopathy
despite at least 3 months of abstinence from alcohol.34,35,61,62 Since the introduction of direct-acting antiviral therapies for hepatitis C viral infection, which was previously a driving reason for LT, the number of LTs for ALD now is increasing, and ALD is currently the leading indication for LT in the United States and many other countries.1,5,6,63 For example, ALD contributes to about 40% to 50% of all LTs performed here and in Europe.6,63
Evaluation for LT among candidates with liver disease due to ALD is similar to evaluation for any other liver disease etiology. Specific issues to be aware of during evaluation of ALD patients are neurologic (peripheral neuropathy, Wernicke’s encephalopathy, alcohol withdrawal syndrome, cerebellar degeneration, and alcohol-induced dementia), dilated cardiomyopathy, and gastrointestinal (chronic pancreatitis, malabsorption of folate and vitamin B12, alcohol-induced diarrhea, alcohol-induced suppression of hepcidin with increased iron absorption resulting in overload). Although
patient and graft survival are similar to those of LT recipients with other disease etiologies,64 the long-term outcomes of patients and grafts are affected mainly by malignancies, especially of the upper aerodigestive tract, and cardiovascular-related mortality.65
A minimum of 6 months of abstinence from alcohol (the 6-months rule), traditionally was used by transplant centers before considering LT evaluation in ALD patients. A period of 3 to 6 months of abstinence in ALD patients was suggested before assessment of improvement in liver disease, but it has not been recommended as a requirement by society guidelines.66 Although a pretransplant duration of abstinence correlates with risk for posttransplant alcohol relapse, a minimum 6 months of abstinence has not been shown to be a very strong predictor of maintenance of sobriety after LT.67 In fact, psychosocial support, young age, previous failed alcohol treatment attempts, and family history of AUD are stronger determinants of the risk for alcohol relapse after LT
Table 3. Potential Barriers to Co-Management of ALD and AUD and Proposed Solutions
Patientlevel
Lack of insight into AUD as a problem
Lack of reporting accurate alcohol use
• Counsel and educate patients on alcohol-related harms (brief intervention)
• Employ motivational interviewing
Monitor routinely using a battery of alcohol biomarkers and self-report screening measures (eg, AUDIT)
Lack of acceptance of AUD treatment• Counsel that AUD is a chronic disease and explain its treatment benefits
Concern for confidentiality and impact on their care
Perception of stigma
Social support systems
• Lack of transportation or insurance coverage
• Too sick to attend sessions in person
Clinicianlevel
Lack of recognition of implications of AUD and its screening
Lack of screening for ALD in at-risk asymptomatic individuals
Lack of corroboration of patient’s history with others’ accounts and biomarkers
• Employ motivational interviewing
Use a nonjudgmental and non-threatening approach in interviewing the patient
• Use educational campaigns from organizations to overcome perception of stigma
• Change the word “alcoholic” to “alcohol-associated” in medical charts, and in scientific and public articles on ALD
• Recommend family therapy and psychoeducation sessions
• Referral to mental health care for family/caregivers to receive social support
• Connect with social work support in arranging transportation or provide financial help
• Use digital platforms or telemedicine to provide treatment sessions
• Educate and increase awareness about AUD
• Use self-reported screening measures
Advocate for national-level policies on adequate time to allow for complete patient care, including screening for alcohol and substance use disorders
• Educate and increase awareness of adequate history taking
• Increase time for patient encounters
ALD, alcohol-associated liver disease; AUD, alcohol use disorder; AUDIT, Alcohol Use Disorder Identification Test; ED, emergency department. Based on reference 37.
than a history of harmful alcohol use prior to LT.67
Based on these data, the 6-months rule was challenged in a prospective case-control study of patients with severe AH that showed that the 26 patients undergoing early LT (without achieving 6 months of abstinence) had a survival benefit compared with that in 26 patients not selected to receive LT (77% vs 23%; P<0.001).68 Since the publication of this study in 2011, several retrospective and prospective studies have shown beneficial effects of early LT for ALD patients.69-71 In a recent meta-analysis of 9 studies of AH patients, 6-month survival was 85.4% after early LT, similar to that in patients with alcohol-associated cirrhosis receiving LT after at least 6 months of abstinence, and a survival percentage more than 16-fold higher than in patients not receiving early LT.72 In a separate mathematical model, early LT versus LT delayed beyond 6 months was associated with a 4-fold increased life expectancy.73
Alcohol use relapse after LT among recipients with AUD or harmful alcohol use is a genuine concern. The relapse rate of alcohol use after LT in ALD patients is quite heterogeneous because it depends on duration of post-transplant follow-up, the definition of relapse (any use or harmful consumption of alcohol), and the method of detection (self-report or use of specific biomarkers of alcohol consumption). Among patients with alcohol-associated cirrhosis receiving LT after a minimum of 6 months of abstinence, the annual rate of alcohol use relapse is 5.7% for any use of alcohol and 2.4% for harmful amounts.74 In the seminal Franco-Belgian prospective study on early LT in severe AH, 3 of 26 (12%) patients relapsed to alcohol use at 2 years of follow-up, with one of them engaging in harmful alcohol use.68 In a pooled analysis of 9 studies, the risk for any alcohol use after variable follow-up periods across studies was 22%, without any difference in regard to recipients with alcohol-associated cirrhosis and pretransplant
Clinicianlevel(continued)
Lack of awareness and experience with specific treatments for AUD and belief that basic education is sufficient
Lack of screening for ALD in at-risk asymptomatic individuals
Systemlevel
Lack of insurance coverage for AUD treatment
Train hepatologist in addiction medicine
Educate and increase awareness of using liver function tests and elastography to screen for ALD and to stage disease
Advocate for national policies to increase federal- and state-level funding for mental health care
Difficulty in combined billing by 2 specialistsEducate and support efforts to develop integrated care model for pre- and post-transplant care of ALD patients
Lack of adequate mental health resources and manpower
Siloed practices of addiction specialists and hepatologists
Increase federal and state mental health resources, including funding for mental health staff, clinics, and treatment provision
Increase communication between physicians and support staff to bridge transitions of care between inpatient, ED, and outpatient follow-up
Gender- and racial/ethnic-based disparitiesDevelop uniform protocols for screening, monitoring, and definition of relapse to alcohol use after liver transplant
Lack of continuity of patient care and specific protocols for AUD monitoring and care
Identify an expert in both fields as a local champion who, with administrative support and infrastructure, can lead the integration of hepatology and addiction medicine
abstinence of at least 6 months (odds ratio, 1.68; 95% CI, 0.793.58; P=0.2).72
Based on these data, society guidelines recommend considering early LT for ALD patients who continue to deteriorate despite optimal medical treatment and have excellent psychosocial support (Figure 3).34,35,48,49,61 With increasing experience and awareness of the benefit, use of early LT is increasing worldwide. For example, the number of LTs for AH increased about 5-fold, from 28 patients in 2014 to 138 patients in 2019.75 However, the use of early LT remains heterogeneous across centers and regions due to lack of validated selection criteria and protocol and several other logistical, systematic, or center/provider-related barriers.75,76
Selection of patients with liver disease and harmful alcohol use
Patient without apparent liver disease
Harmful alcohol use present
Address other clinical issues
for LT is an art, with the goal of minimizing the risk for relapse to alcohol use after LT. There are many scoring systems to determine the risk for alcohol relapse after LT. These scoring systems are quite accurate in identifying candidates with low risk for alcohol relapse, but the specificity of these scores for choosing those with moderate to high risk is modest. For example, the SALT score is based on 4 variables (number of daily alcohol drinks, previous failed rehabilitation attempts, previous legal issues related to alcohol, and substance use other than cannabis) derived from a prospective cohort in the ACCELERATE consortium in the United States.77 A score of at least 5 had 96% accuracy to predict candidates at low risk for alcohol relapse after LT but only 25% accuracy in predicting highrisk candidates. Hence the selection criteria across centers and
Patient with apparent liver disease
Harmful alcohol use present
Assess other causes of liver disease YES NO YES
Screen for ALD: liver panel and ultrasound
Noninvasive fibrosis risk evaluation
Low to medium risk
FIB-4 <3.25 or LSM <15 kPa
Integrated multidisciplinary clinic with hepatology and addiction teams NO
High risk
FIB-4 ≥3.25 or LSM ≥15 kPa
Follow with primary care
AUDIT ± DSM-5 assessments
AUDIT score >15
DSM-5 ≥4 symptoms (Moderate to severe AUD)
AUDIT score 8-15
DSM-5 2-3 symptoms (Mild AUD)
Brief intervention
If no improvement in AUD on close follow-up
ALD, alcohol-associated liver disease; AUD, alcohol use disorder; AUDIT, Alcohol Use Disorder Identification Test; DSM-5, Diagnostic and Statistical Manual of Mental Disorders, 5th Edition; FIB-4, fibrosis-4; LSM, liver stiffness measurement.
Figure 2. Integrated approach to management of dual pathology of AUD and ALD.
providers remain subjective and heterogeneous. Currently, a large multicenter European study is ongoing to examine the role of early LT in ALD, and patients are selected for LT based on a rigorous objective score calculated from psychosocial assessment variables. Multicenter, prospective observational studies clearly are needed as the basis for developing a uniform protocol for patient selection and post-transplant follow-up.
Emerging Pharmacologic Therapies
Use of corticosteroids, the only pharmacologic treatment option for patients with ALD and severe AH, is a suboptimal treatment. Over the last several years, the lack of animal models mimicking human phenotype, along with a multifactorial complex pathogenesis of ALD, limited the development of effective pharmacologic treatments for ALD.48,78 For the past decade, research funding by the NIAAA has helped in identifying several new therapies targeted at the gut–liver axis, hepatic inflammation, apoptosis oxidative stress, and hepatic regeneration.15 However, results are negative on several of these agents, including the interleukin-1 receptor antagonists anakinra (Kineret, Biovitrum AB)57 and canakinumab (Ilaris, Novartis), the apoptosis signal−regulating kinase 1 inhibitor selonsertib (Gilead), as well as NAC, the vasodilator pentoxifylline, and prophylactic antibiotics.52 Fortunately, some promising targets have emerged with a potential for efficacy and safety in patients with severe AH.57,79-88
Recent studies have highlighted these promising research avenues. IL-22, an important cytokine of the IL-10 family driving hepatic regeneration, also has been shown to be a promising target, according to a pilot phase 2a study of the IL-22 agonist F-652 (Generon).79 In this study, 18 AH patients were recruited, and divided into 3 dosing groups of 6 patients, which included 3 with moderate and 3 with severe AH in each dosing group. At 28 days of treatment, the response rate with F-652, based on Lille score, was 83%—higher than the historical 56% among steroid-treated patients. In this study, IL-22 was associated with reduced inflammatory cytokine levels and increased markers of regeneration at 28 and 42 days compared with levels at baseline.
Granulocyte colony-stimulating factor has shown encouraging data in several randomized, placebo-controlled studies in patients with ACLF and severe AH patients. However, the results were heterogeneous, with promising results reported from Asia but not Europe.80-85 Results from ongoing multicenter studies in the United States are awaited to help determine the role of this drug in patients with severe AH.
In addition, a recently completed randomized trial in patients with moderate AH showed benefit from Lactobacillus rhamnosus GG (Culturelle, i-Health) on liver disease at 1 month as well as a reduction in alcohol use at 6 months.86
Larsucosterol or DUR-928 (Durcet), an endogenous sulfated oxysterol, is an epigenetic regulator that upregulates hepatic regeneration and downregulates hepatic inflammation. In a pivotal pilot study of 19 patients with AH (12 with severe disease), DUR928 resulted in an 89% response rate (higher than historically treated patients with steroids) and a median Lille score of 0.15 (range, 0.02-0.25) with DUR-928 versus 0.5 (range, 0.2-0.86) with corticosteroids.87
Fecal microbiome transplantation also has been studied in ALD. In 1 study, FMT improved liver disease and patient survival in 18 patients with severe AH who were ineligible to receive corticosteroids.88 Other studies have found increased survival with FMT.89,90 In another randomized controlled pilot study comparing FMT and standard medical care in 20 ALD patients, FMT improved markers of inflammation in peripheral blood (IL-6 and lipopolysaccharide-binding protein levels), and this was associated with improved liver disease and psychometric assessment and reduced craving for alcohol.91
Current clinical trial designs compared with traditional corticosteroid trials before the publication of the STOPAH study have evolved in several ways.40,92-95 First, they now include patients with moderate AH (MELD score <20), as these patients have about a 9% risk for short-term mortality at 28 days. Second, the end points of patient survival or liver disease severity have been extended to 3 to 6 months instead of 1 month. Third, there is greater acceptability of MELD and Lille scores as primary end points as surrogates for patient survival.93,94
Furthermore, recognition of difficulties and challenges in recruiting patients with ALD or AH into clinical trials has fostered relationships with industries to drive many of the multicenter clinical trials.40,95,96 Learning from the drug development space in patients with metabolic dysfunction–associated steatohepatitis (MASH), we recognize that combination therapy simultaneously targeting inflammation and hepatic regeneration has potential.97 Refining criteria for the clinical diagnosis of AH,19 changing the semantics from “alcoholic” to “alcohol-associated,”1,49,61 and integrating treatment of AUD with liver disease97 hopefully will overcome challenges in patient recruitment and foster development of FDA-approved effective pharmacologic therapies for patients with ALD and AH.98 In addition, integrating treatment of AUD and liver disease in future clinical trials, as recommended by the NIAAA and FDA, potentially will be helpful in developing a dual-target drug (for both AUD and ALD) and bridge both the knowledge gap and clinical unmet need to find the level of alcohol use reduction necessary to improve the long-term outcome of patients with advanced ALD of decompensated cirrhosis and/or AH.99
Prognosis in ALD
Prognosis in patients with alcohol-associated cirrhosis depends on the liver reserve or MELD score, similar to patients with cirrhosis due to other etiologies.100 Control of risk factors, including alcohol intake, is the major determinant of long-term outcomes in these patients with alcohol-associated cirrhosis.101 In this regard, biomarkers of alcohol consumption are useful for following these patients during both pretransplant workup or post-transplant follow-up to identify those relapsing to alcohol consumption.102 However, patients with AH have high short-term mortality, especially in severe forms with ACLF.
Several prognostic scores have been developed, including static models using baseline variables at admission and dynamic models using baseline variables and variables at day 4 or 7 after admission.93,94
The Maddrey Discriminant Function (DF), the first static model introduced in 1978, was the most commonly used predictor of mortality.103 A score of greater than the 32 cutoff is an indicator of
Advanced ALD with jaundice
NIAAA Consortium Criteria for clinical diagnosis of AH
• Serum bilirubin >3 mg/dL
• AST and ALT <400 IU/mL, AST >50 IU/mL with AST:ALT ratio >1.5:1
• Alcohol use for >6 mo and abstinence <60 d prior to onset of jaundice
• Other causes of liver disease, biliary obstruction, and hepatocellular carcinoma ruled out
Meets all criteria
Liver biopsy not performed
Features of AH on liver biopsy
Probable AH Definite AH
Assess for severity with mDF or MELD score
MELD >20 or mDF >32 (severe AH)
Corticosteroids in eligible patients
• May enroll in clinical trials
Lille score at day 7 >0.45
Nonresponder and stop corticosteroids
Ineligible for LT
Enroll in clinical trials
MELD ≤20 or mDF ≥32 (moderate AH) Lille score at day 7 ≤0.45
Eligible for LT
Figure 3. Algorithm for the treatment of AH.
AH, alcohol-associated hepatitis; ALD, alcohol-associated liver disease; ALT, alanine aminotransferase; AST, aspartate aminotransferase; LT, liver transplant; mDF, modified Maddrey’s discriminant function; MELD, Model for End-stage Liver Disease; NIAAA, National Institute on Alcohol Abuse and Alcoholism.
Based on references 48 and 49.
ruled out Not meeting all criteria
Features of AH on liver biopsy
No specific pharmacologic treatment
• May enroll in clinical trials
Continue corticosteroids for 3 wk more
May consider early LT
high mortality and warrants corticosteroid treatment.104 The DF calculation requires prothrombin time, which is no longer reported in most clinical laboratories, posing a significant drawback. In addition, 10% to 17% of patients with a DF score below 32 still have high mortality from AH.101 The DF also does not take into account other clinical characteristics, such as renal failure, which commonly is associated with mortality in severe AH.105
The MELD score, originally developed to assess prognosis for patients undergoing a transjugular intrahepatic portosystemic shunt,106 has been used worldwide to estimate 3-month mortality among patients with cirrhosis,98 and is used by the United Network for Organ Sharing for organ allocation.107 It is based on serum creatinine, serum bilirubin, and the international normalized ratio (INR). A study done at the Himalayan Institute Hospital to compare MELD and DF scores as predictors of short-term outcomes in patients with AH demonstrated that MELD showed higher specificity than modified DF when looking at survival at 28 days after index admission. Another clinical trial also indicated that the MELD score was prognostically more accurate.106 Furthermore, MELD has the benefit of INR, which is standardized and takes into account serum creatinine, which predicts 1 of the most dreaded outcomes in AH: hepatorenal syndrome.104
The addition of serum sodium (MELD-Na)108 was proposed to improve the survival prediction of the MELD score, since hyponatremia is a sign of poor survival in patients with AH and those with end-stage liver disease (ESLD).105,109,110 A study demonstrated that the MELD-Na gives a better prediction of mortality than MELD in patients with ascites, whereas both were similar predictors of 180-day mortality.110
A retrospective, international, multicenter cohort study across 4 continents showed that a MELD score cutoff of 20 performs best in predicting 60- and 90-day mortality.58 This study also showed that corticosteroids provide maximum benefit at a MELD score between 25 and 39, while the benefit is moderate for patients with a score between 22 and 24 or 40 and 44. These data allow clinicians to identify patients who are most likely to respond to steroids and reduce the risk for complications, especially bacterial or fungal infections.
The newly released MELD version 3.0 performs as well as MELD for estimating disease severity and prognosis in AH patients.111
Other static scores are the Age-Bilirubin-INR-Creatinine score (ABIC) and the Glasgow Alcoholic Hepatitis Score (GAHS). ABIC characterizes patients into 3 risk categories (low, intermediate, and high), whereas GAHS is calculated using independent factors associated with increased mortality, such as age, white cell count, urea, INR, and bilirubin. A retrospective study of patients at Dubrava University Hospital showed that ABIC was the best predictor of 28-day mortality on admission when comparing mDF, GAHS, MELD, ABIC, and Lille scores.112 However, other studies demonstrated that MELD, MELD-Na, GAHS, and ABIC all performed similarly when predicting mortality in patients with AH.113,114
The Chronic Liver Failure (CLIF) Consortium ACLF (CLIF-C ACLF) score also has been used to predict mortality in AH.115 The CLIF-C ACLF score additionally considers West-Haven grade for hepatic encephalopathy, mean arterial pressure, use of vasopressors, oxygenation, and mechanical ventilation. The CLIF-C
ACLF score, based on number of organ failures, provides a better estimate of patient prognosis than the MELD score, especially for patients with a MELD score below 25.116
The Lille score is a dynamic model and incorporates baseline variables (age, albumin, bilirubin, creatinine, and prothrombin time) and serum bilirubin after 7 days. It traditionally is used to assess response to corticosteroid therapy on day 7 of treatment.
A Lille score higher than 0.45 is able to identify 75.6% of observed deaths, meaning that it has high sensitivity and specificity for early identification of patients at high risk for death in a 6-month period.117 The Lille score also can be calculated at day 4, with accuracy that is similar to that calculated at day 7.114
Other clinical variables such as renal function or hepatorenal syndrome, blood ammonia levels, and hepatic encephalopathy can predict short-term outcomes.118-121
New noninvasive biomarkers are on the horizon for predicting short-term mortality at baseline and for use during follow-up. They include levels of cytokines (chemokine ligand-2, IL-6, and IL-22), peripheral blood count and neutrophilia, quantification of extracellular vesicles, levels of bacterial lipopolysaccharide, M30:M65 ratio of macrophages, mitochondrial function studies, and gene expression studies for inflammatory and fatty regeneration genes.22
Liver biopsy has also been shown to have predictive value in terms of prognosis.122 The presence of marked intrahepatic and canalicular cholestasis and fibrosis are negative predictors. Alternatively, density of neutrophils in the liver biopsy tissue and mega-mitochondria positivity are signs of a good outcome in patients with an AH episode.122 The degree of portal hypertension and hepatic venous pressure gradient are directly related to mortality in the short term.123
Among survivors of an index episode of AH, including those who survived spontaneously or with medical treatment, the longterm outcome depends on underlying liver disease and control of risk factors.24,100 For example, patients who do not have underlying cirrhosis have a better long-term outcomes than patients with cirrhosis and complications from this disease. However, the single most important determinant of long-term outcomes is sobriety.100 This is reflected by a high frequency of these patients returning to drinking again, in spite of going through a severe episode of AH and requiring long-term hospitalization.24,48,100 For example, in the largest randomized controlled trial on the topic, one-third of patients returned to drinking at 3 months, and more than half of these patients returned to drinking at 1 year.48
These data show the clear benefit of AUD treatment integrated with other services, such as hepatology departments using services from addiction medicine right from the beginning when patients are hospitalized for AH. In addition, following these patients through their hospitalizations and transitioning them to outpatient follow-up is immensely valuable in reducing mortality in the long term and preventing morbidity and long-term complications. This was elegantly shown in a large Veterans Administration database, in which patients were enrolled in addiction treatment (behavioral or drug therapy), which resulted in a 13% reduced risk of long-term all-cause mortality versus patients who were not managed similarly.39
It is surprising and shocking that the use of addiction medicine
and services for control of AUD in established patients with ALD remains extremely rare, occurring in no more than 10% to 15% of cases.39,124 Barriers to integrating addiction medicine and hepatology care for these patients occur at many levels and include difficulties with accessing transportation and the need for frequent behavioral therapy sessions. Other barriers may not be for the patient but instead may be physician-, administration-, or systemrelated.41
Prevention of ALD
Alcohol consumption is the third most common preventable cause of any disease after smoking and hypertension.125 It is truly said that “prevention is better than cure,” and an ideal situation would be to prevent the occurrence of ALD by eliminating exposure to alcohol. Of the several federal approaches examined to achieve this aim, increases in pricing and taxation on alcohol sales, bans on marketing and advertising of alcohol, and decreases in availability of alcohol have been shown to be the most effective. For example, the amount of alcohol-related motor vehicle accidents and morbidity and the amount of ALD-related mortality
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Want to learn more? View the extended version of this review
were found to be inversely associated with the number of policies implemented in countries in South America.126 However, lobbying by the alcohol industry has hindered implementation of these federal approaches, resulting in increases in alcohol consumption in both the developed and developing parts of the world.126 Although there are barriers to reduce alcohol availability worldwide, physicians and other healthcare providers can play a role by screening for AUD and ALD at medical encounters as secondary prevention, and they can employ strategies to help patients with ALD maintain abstinence as tertiary prevention.
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Dr. Singal reported no relevant financial disclosures. He is a member of the Gastroenterology & Endoscopy News editorial board.
New Analyses Evaluate Resmetirom’s
Effects on MASH and Fibrosis
Patients with metabolic dysfunction–associated steatohepatitis and F2 or F3 fibrosis treated with resmetirom had improvements in both fibrosis and MASH over 52 weeks of treatment, according to several substudies from the phase 3 MAESTRO-NASH trial presented at EASL Congress 2024.
The ongoing randomized, double-blind, placebo-controlled trial involves 966 patients randomly assigned to receive 80 or 100 mg of resmetirom (Rezdiffra, Madrigal) or placebo daily for 54 months. At week 52, the researchers evaluated the resolution of MASH with no worsening of fibrosis or a reduction in fibrosis stage with no worsening of MASH, examining variables such as body mass index, metabolic alcohol-associated liver disease (MetALD), quality of life and disease complications.
Ashwani K. Singal, MD, MS, a professor of medicine at the University of Louisville, in Kentucky, and the chair of the American Gastroenterological Association Institute Council Liver & Biliary Section, said he found the results “very encouraging.” In an interview with GEN Priority Report, Dr. Singal said, “The important message is that
the patients are tolerating it. They are stable or improving, so providers can encourage patients to continue the treatment to improve long-term outcomes. When the study is completed in 2026, I won’t be surprised [if] everything comes in favor of the medication and there is full approval of the drug.”
Benefits With Higher BMI
A subanalysis of MAESTRO-NASH presented at EASL found that for patients with higher baseline body weight and BMI, resmetirom 100 mg was more effective than 80 mg in achieving the dual primary end points (abstract OS-117). However, there was no significant difference in efficacy between the two doses for patients with a lower BMI.
Patients weighing more than 100 kg had a 30%
proton density fat fraction (PDFF) response of 56.7% when taking 80 mg, compared with 72.5% with 100 mg. They also saw more improvement in fibrosis and MASH resolution with higher dosages (fibrosis: 80 mg, 22.5%; 100 mg, 32.5%; MASH resolution: 80 mg, 27%; 100 mg, 32.5%).
However, patients on both doses of resmetirom with a BMI less than 35 kg/m2 showed greater improvement in fibrosis and a lower rate of worsening than those with a BMI of 35 kg/m2 or higher.
Similar Response in MetALD
In another subanalysis, response rates for resmetirom were similar in patients with suspected MetALD and those without it (abstract SAT-263).
Of the 782 patients who had both a baseline and week 52 liver biopsy, 75 (9.6%) fell into MetALD category based on a carbohydrate deficient transferrin more than 2.5% and/or a phosphatidylethanol greater than 20 ng/mL, and 707 did not.
Response rates to resmetirom were similar in the two groups. MASH resolution was similar in the patients with and without MetALD (80 mg, 29% vs. 29.9%; 100 mg, 35% vs. 36%, respectively), as was fibrosis improvement (80 mg, 29% vs. 35%; 100 mg, 33.3% vs. 30%). Higher percentages of patients with MetALD achieved a 30% or higher reduction in MRI-PDFF (80 mg, 59.2% vs. 88%; 100 mg, 71.2% vs. 81%).
Enhancing Quality of Life
Patients with MASH who showed fibrosis improvement or MASH resolution when treated with resmetirom also experienced significant benefit across various aspects of health-related quality of life (HRQOL) after completing 52 weeks of treatment, according to another subanalysis (abstract FRI-202).
The study aimed to evaluate HRQOL in noncirrhotic MASH patients with confirmed or suspected fibrosis who received treatment with resmetirom, using the Chronic Liver Disease Questionnaire−NASH (score range, 1-7) and Liver Disease Quality of Life (score range, 0-100).
The pooled group of patients receiving 80or 100-mg dosages demonstrated significant improvements in multiple domains of HRQOL scores, including Worry (+0.46; minimally
Italian Study Predicts Fewer Complications in ResmetiromTreated Patients
Resmetirom is expected to reduce the risk for fibrosis progression and associated complications over five years in patients with MASLD and F2 or F3 fibrosis, according to results of a modeling study (abstract SAT-209-YI).
Similar findings were seen when these changes were projected over a lifetime for both F2 and F3 fibrosis in MASLD patients.
The researchers, led by Grazia Pennisi, MD, PhD, from the University of Palermo, in Italy, used data from 12 studies and multiple sources on patients with MASLD to construct models of fibrosis progression and related complications. They created a Markov model to illustrate how MASLD advances from F2 and F3 fibrosis to these complications and to evaluate the effect of resmetirom treatment on the disease’s natural progression.
In the modeling, patients with baseline F2 fibrosis taking resmetirom had lower odds than those not taking the drug of experiencing complications including compensated cirrhosis (5.16 vs. 6.82), decompensated cirrhosis (0.25 vs. 0.3), hepatocellular carcinoma (0.25 vs. 0.32), and mortality, which was categorized as liver-related mortality (0.15 vs. 0.16), cardiovascular mortality (1.02 vs. 1.1) and extrahepatic mortality (1.07 vs. 1.2). The trend was the same for patients with baseline F3 fibrosis.
The researchers said ongoing sensitivity analyses are looking at how changes in transition probabilities, treatment effectiveness and treatment duration might influence these results.
—N.C.
clinically important difference [MCID], 41%), Role Emotional (+3.0; MCID, 28%), Health Distress (+8.1; MCID, 38%), Stigma (+3.5; MCID, 39%), and total Liver Disease Quality of Life (+2.2; MCID, 35%). Patients who responded to resmetirom showed similar improvements in HRQOL scores, whereas the placebo group and nonresponders did not show improvements.
—Norah Chinn
The MAESTRO-NASH study is supported by Madrigal. Dr. Singal reported no relevant financial disclosures. He is a member of the Gastroenterology & Endoscopy News editorial board.
When diagnosing hepatorenal syndrome–acute kidney injury (HRS-AKI), start with “CARE”
