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A Supplement to

Volume 3 • 2026

A Supplement to

Hepatology Insights

PBC Pruritus Treatment Pipeline, Noninvasive Liver Disease Assessment, Reports from EASL 2025 and TLM 2025, and More

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2026

Hepatology Insights Volume 3 • 2026

A Stepwise Approach to Patients With Abnormal Liver Enzymes

Major Developments in the PBC Pruritus Treatment Pipeline

Machine Learning Model Predicts Inpatient Cirrhosis Mortality

Liver Stiffness Emerges as Key Predictor of Outcomes in MASLD Patients

In Lieu of Biopsy: A Review of Noninvasive Liver Disease Assessments

First Reports From The Liver Meeting: MASLD, Pruritus in PBC, and More

Expert Picks From EASL 2025

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Hepatology Insights

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2026

A Stepwise Approach to Patients With Abnormal Liver Enzymes STANLEY MARTIN COHEN, MD, FAASLD, FACG Medical Director of Hepatology University Hospitals Cleveland Medical Center Professor of Medicine Case Western Reserve University School of Medicine Cleveland, Ohio

bnormal liver tests are a common occurrence in the United States.1 Based on National Health and Nutrition Examination Survey III data, approximately 7.9% of the population has an elevated level of aspartate aminotransferase (AST) or alanine aminotransferase (ALT).2 Because of this, abnormal liver tests are a common indication for referral to a gastroenterologist. This article outlines a stepwise, guideline-based approach to management of these patients.

The term “liver function tests,” or “LFTs,” is not exactly correct. Although some liver tests—such as bilirubin, albumin, and international normalized ratio—do relate to liver function, liver tests such as AST, ALT, and alkaline phosphatase pertain to liver injury and/or other structural issues. For this reason, this article uses the terms abnormal liver chemistries, tests, or enzymes and specifically focuses on the evaluation

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2026

of patients with abnormal ALT, AST, alkaline phosphatase, and/or bilirubin.

AST and ALT Assessing a patient with abnormal AST and ALT levels requires delving further into the definition of normal versus abnormal. Normal lab values generally are defined as the mean value of a healthy population ± 2 SDs, which is based on the control population that the various labs use. Upper limit of normal (ULN) levels for AST and ALT can vary by a factor of 2 to 4, depending on the lab. Studies have demonstrated that individuals with higher AST and ALT levels have increased morbidity and/or mortality,3-6 which likely represents underlying fatty liver disease and its associated metabolic risk factors as well as alcoholic liver disease. Some of the control populations used by labs to determine their specific ULN values have included individuals with these risk factors. Because of this, many have proposed the concept of a true normal AST and ALT level based on a control population that excludes patients with fatty liver risk factors and alcohol use, which would result in much lower ULN levels for AST and ALT.

Table 1. Patterns of AST and ALT In Liver Disease

In the 2017 clinical guideline on abnormal liver chemistries from the American College of Gastroenterology (ACG), based on numerous studies and surveys of many of the world’s leading hepatologists, we proposed that the true ULN for ALT should be 29 to 33 U/L in males and 19 to 25 U/L in females.7 However, using these lower ALT ULN values will significantly increase the number of patients defined as having elevated liver enzymes, up to 36% of men and 28% of women.8 This has clinical and financial implications, including more patients being referred for elevated liver enzymes, more testing, and increased costs. AST and ALT are preformed in liver cells and released as a result of hepatocellular injury. However, AST also is found in skeletal muscle, cardiac muscle, the kidneys, and the brain. ALT is present mostly in the liver and, thus, is a more specific marker of liver injury than AST. There are no specific clarifying tests to determine whether AST or ALT elevations stem from the liver.

Alkaline Phosphatase Alkaline phosphatase is found in the hepatocytes on the canalicular membrane. It increases in patients with cholestatic liver disease, due to either mechanical obstruction (eg, extrahepatic cholestasis) or impairment of bile formation/flow/filtration by the liver (eg, intrahepatic cholestasis). Hepatic elevations of alkaline phosphatase can occur in obstructive liver diseases, infiltrative liver diseases, primary cholestatic diseases, such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), and granulomatous liver diseases. Alkaline phosphatase also is

AST > ALT Alcoholic liver disease Budd-Chiari syndrome Cardiac disease Cirrhosis Congestive hepatopathy Ischemic hepatitis/shock liver Muscle disease

Table 2. Magnitude of AST and ALT Elevations in Liver Disease Type of liver disease

AST/ALT elevation, IU/L

Alcoholic liver disease

Usually <200-300

Atypical viral hepatitis such as severe herpes hepatitis

Any level, even >10,000

ALT > AST

Autoimmune hepatitis

Alpha-1 antitrypsin deﬁciency Autoimmune hepatitis Drug-induced liver injury Fatty liver disease Hemochromatosis Toxic hepatitis Pregnancy-related liver Viral hepatitis Wilson’s disease

Classic acute viral hepatitis A, B, C

Up to 3,000-5,000

Complete biliary obstruction

Up to 1,000

Fatty liver disease/MASH

Usually <200-300

ALT, alanine aminotransferase; AST, aspartate aminotransferase.

Shock liver/ischemic hepatitis

Any level, even >10,000

Toxic hepatitis ALT, alanine aminotransferase; AST, aspartate aminotransferase; MASH, metabolic dysfunction–associated steatohepatitis.

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found in other organs, including bone (the most common extrahepatic source), the placenta, the intestines, and the kidneys. The most common clarifying test used is a gammaglutamyl transferase (GGT). However, GGT can be elevated in patients with significant alcohol use, even in the absence of liver disease. Alkaline phosphatase isoenzymes also can be used as a clarifying test and can point to the specific origin of the elevation.

Bilirubin Bilirubin is a breakdown product of senescent red blood cells and generally circulates in the unconjugated form tightly bound to albumin. Conjugation of bilirubin makes it water-soluble,

Algorithmic Approach to Diagnosis In Setting of Elevated Liver Enzymes

History and physical exam to assess for: • Alcohol use • Fatty liver risk factors • Potentially hepatotoxic medications • Viral hepatitis risk factors

Unless there is obvious evidence of liver damage, clinicians may want to start with repeat liver tests to confirm elevations. Clinicians then should consider several factors, including ruling out nonhepatic causes of elevations, assessing the various common/uncommon causes of elevated liver enzymes, defining the pattern of elevations, assessing the magnitude of elevations, and looking into the timing of the elevations.

If cause not found, perform the following tests: • CBC • Hepatic function panel • Hepatitis B surface antibody • Hepatitis B surface antigen • Hepatitis C antibody • Iron panel and ferritin • Ultrasound

History, physical exam, and assessment as in Figure 1. Also assess for evidence of liver failure.

If still elevated, complete the full serological workup to include autoimmune and metabolic/genetic serologies.

If above is unrevealing, work on MASH risk factors and alcohol avoidance and repeat liver tests in 3 mo (if mild) or 6 mo (if borderline).

If above testing is unrevealing and ALT still elevated, consider referral to liver specialist and/or liver biopsy.

allowing it to be excreted in the bile and converted in the colon to urobilinogen, which is excreted in urine and stool. The main clarifying test for bilirubin elevation would be fractionation of the bilirubin. Fractionating the bilirubin may not be necessary in patients who present with obvious liver disease, including elevated AST, ALT, and/or alkaline phosphatase. Elevated conjugated (direct) bilirubin occurs with liver disease and/or cholestasis, and should prompt a liver workup. Potential etiologies include biliary obstruction, acute alcoholic hepatitis, postoperative jaundice, drug-induced liver injury, hepatitis, and multifactorial/ICU jaundice. Elevated unconjugated (indirect) bilirubin can be seen in conditions such as Gilbert’s syndrome (about 6% of the US population)9 or hemolysis and should prompt an initial assessment for nonhepatic causes.

If cause not found, perform the tests shown in Figure 1, plus the following: • Antinuclear antibody • Ceruloplasmin • Hepatitis A IgM • Hepatitis B core IgM • INR • Serum Ig levels • Smooth muscle antibody

If above testing is unrevealing and/or there is evidence of liver failure, provide urgent referral to liver specialist and/or consider liver biopsy.

Figure 1. Borderline-mild ALT elevation (<2-5 × ULN).

Figure 2. Moderate ALT elevation (5-15 × ULN).

CBC, complete blood count; MASH, metabolic dysfunction– associated steatohepatitis; ULN, upper limit of normal.

ALT, alanine aminotransferase; IgM, immunoglobulin M; INR, international normalized ratio; ULN, upper limit of normal.

Adapted from reference 7.

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The first step should be a thorough history and physical examination to assess for fatty liver disease risk factors, alcohol use, risk factors for autoimmune diseases, family history of liver disease, and a thorough evaluation of the patient’s medication history. Drug-induced liver injury can be precipitated by prescription medications, herbal supplements, and over-the-counter agents. Getting an accurate history of these potential agents can be very difficult. On exam, clinicians should look for obesity, stigmata of chronic liver disease, and any specific clues that may be related to liver disease, such as Kayser-Fleischer rings seen in Wilson’s disease. They also should make a quick assessment to ensure there is no evidence of liver failure, such as the development of coagulopathy and encephalopathy, because the workup is very different in that case and may require an emergent referral to a specialized liver center or liver transplant center. Clinicians then need to consider the most common liver diagnoses and assess the pretest probability of finding a particular etiology for the abnormal liver tests. Depending on the patient

History, physical exam, and assessment as in Figures 1 and 2.

If cause not found, perform the tests shown in Figures 1 and 2, plus the following: • Anti-LKM • CMV serologies • EBV serologies • HSV serologies • Serum drug panel • Urine drug panel • Doppler ultrasound

population, the most common liver issues include fatty liver disease, alcoholic liver disease, viral hepatitis, and drug-induced liver injury. With fatty liver disease and alcoholic liver disease being so common and increasing in frequency, especially for patients with minimal or mild liver enzyme elevations, sometimes starting by just working on these risk factors and then reassessing liver tests a few months later is a reasonable firstline approach. In general, clues to the more prevalent diseases should be sought before searching for less common liver issues such as metabolic/genetic diseases, autoimmune diseases, or PBC and PSC. Patients with milder liver enzyme elevations generally will start with a basic workup, such as viral hepatitis testing, iron panel/ferritin, and ultrasound. If unrevealing and the liver test abnormalities persist, then further evaluation can be done. On the other hand, patients with more significant elevations of liver enzymes at presentation should get more thorough evaluation earlier. Liver damage can be broken down into 4 patterns of liver enzyme elevations: 1. hepatocellular (disproportionate elevation of AST/ALT); 2. cholestatic (disproportionate elevation of alkaline phosphatase); 3. mixed (elevation of AST/ALT and alkaline phosphatase); and 4. isolated hyperbilirubinemia.

History, physical exam, and assessment as in Figures 1-3. Also assess for evidence of: • Ischemia • Rhabdomyolysis

If cause not found, perform the tests shown in Figures 1-3. Consider use of NAC with or without known history of acetaminophen use. Consider use of NAC with or without known history of acetaminophen use. If above testing is unrevealing and/or there is evidence of liver failure, provide urgent referral to liver specialist or liver transplant center and/or consider liver biopsy.

Figure 3. Severe ALT elevation (>15 × ULN). CMV, cytomegalovirus; EBV, Epstein-Barr virus; HSV, herpes simplex virus; LKM, liver-kidney microsomal; NAC, N-acetylcysteine; ULN, upper limit of normal. Adapted from reference 7.

If unrevealing and/or evidence of liver failure, provide urgent referral to liver specialist or liver transplant center and/or consider liver biopsy.

Figure 4. Massive ALT elevation (>10,000 IU/L). ALT, alanine aminotransferase; NAC, N-acetylcysteine. Adapted from reference 7.

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2026

Clinicians usually can just look at the lab tests to determine the pattern, or an R value can be calculated (>5, hepatocellular; 2-5, mixed; and <2, cholestatic). Table 1 shows the usual AST to ALT elevation patterns seen in multiple liver diseases. In many liver diseases, as cirrhosis develops, ALT levels will decrease and AST levels will increase proportionately. Thus, many liver diseases that begin as ALT predominant, such as viral hepatitis, can eventually show a pattern of AST > ALT in the later cirrhotic phases. Because this trend is not always understood, many patients are accused of having

active ongoing alcohol use as the cause of their AST > ALT liver test pattern. In addition, many patients have multiple underlying liver issues that can complicate the AST/ALT ratio. Table 2 shows the usual magnitude of AST/ALT elevations seen in various liver diseases. These can help to define the etiology and determine the rapidity and type of workup necessary. Again, patients can have a combination of liver diseases that can alter the magnitude, such as a patient with viral hepatitis and/or alcoholic liver disease who takes significant amounts of acetaminophen.

Normal Search for nonliver sources

Check GGT

Abnormal

History and physical exam Assess for: Potentially hepatotoxic medications ERCP or MRCP

Testing negative and alkaline phosphatase 1-2 × ULN

Assess for: AMA • Antinuclear antibody • Smooth muscle antibody • Ultrasound

Ultrasound shows ductal dilation

AMA-positive

Repeat alkaline phosphatase in 3-6 mo

Evaluate for PBC Testing negative and alkaline phosphatase >2 × ULN

Alkaline phosphatase persistently abnormal

Consider liver biopsy

Figure 5. Elevated alkaline phosphatase with normal bilirubin/AST/ALT. ALT, alanine aminotransferase; AMA, antimitochondrial antibody; AST, aspartate aminotransferase; ERCP, endoscopic retrograde cholangiopancreatography; GGT, gamma-glutamyl transferase; MRCP, magnetic resonance cholangiopancreatography; PBC, primary biliary cholangitis; ULN, upper limit of normal. Adapted from reference 7.

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2026

Clinicians also should try to define temporal relationships between potential liver insults and elevated liver enzymes. For example, although any medication theoretically can injure the liver, standardly, we would consider medications started more recently to be a more likely culprit. In addition, similar consideration would need to be given to risk factors such as recent foreign travel, recent parenteral risk factors, and recent evidence of hypotension and other cardiovascular instability that might correlate with ischemic hepatitis or shock liver.

In the 2017 ACG guideline, using our proposed levels for true normal ULN as discussed above, we broke down the magnitude of ALT elevations into 5 categories: borderline (<2 × ULN), mild (2-5 × ULN), moderate (5-15 × ULN), severe (>15 × ULN), and massive (>10,000 IU/L).6 These various categories are discussed in the ALT algorithms (Figures 1-4). Borderline and mild ALT elevations should be evaluated within a few months. Moderate, severe, and massive elevations should be evaluated immediately.

History and physical exam Assess for: Potentially hepatotoxic medications

Ultrasound shows ductal dilation Ultrasound

ERCP or MRCP

Ultrasound shows no ductal dilation

Testing negative and alkaline phosphatase 1-2 × ULN

Assess for: • AMA • Antinuclear antibody • Smooth muscle antibody

AMA-positive Evaluate for PBC

Repeat alkaline phosphatase in 3-6 mo

Alkaline phosphatase persistently abnormal

AMA-negative and alkaline phosphatase >2 × ULN

Consider liver biopsy or MRCP

Figure 6. Elevated alkaline phosphatase with elevated bilirubin/AST/ALT. ALT, alanine aminotransferase; AMA, antimitochondrial antibody; AST, aspartate aminotransferase; ERCP, endoscopic retrograde cholangiopancreatography; MRCP, magnetic resonance cholangiopancreatography; PBC, primary biliary cholangitis; ULN, upper limit of normal. Adapted from reference 7.

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Liver biopsy often is believed to be the gold standard for determining the etiology of elevated liver enzymes, but there are many potential issues associated with liver biopsy, including risk, adverse events, cost, and patient hesitancy. In addition, the biopsy report often is descriptive rather than diagnostic. These various factors should influence liver biopsy decisions.

Approach to Elevated ALT Because ALT is more liver specific than AST, the algorithms use ALT and are divided based on the magnitude of the

elevations (Figures 1-4). The initial extent and rapidity of the workup is based on the severity of the elevations. Higher ALT levels warrant more testing, including for uncommon causes of liver disease, at the initial visit. The guideline also suggests evaluation for signs of liver failure in patients with higher ALT levels. In addition, there is a lower threshold to consider liver biopsy in patients with more significant elevations. The use of N-acetylcysteine in patients with severe and massive elevations of ALT can be considered if there is suspicion of possible primary acetaminophen toxicity, acetaminophen toxicity on top

History and physical examination Assess AST, ALT, alkaline phosphatase Review medications Look for potential etiologies: • Alcoholic hepatitis • Biliary obstruction • Cirrhosis • ICU jaundice • Post-op jaundice • Sepsis

Ultrasound shows ductal dilation Ultrasound

Ultrasound shows no ductal dilation Assess for: • AMA • Antinuclear antibody • Smooth muscle antibody

Testing negative and bilirubin persistently abnormal

Consider liver biopsy

Figure 7. Elevated conjugated (direct) bilirubin. ALT, alanine aminotransferase; AMA, antimitochondrial antibody; AST, aspartate aminotransferase; ERCP, endoscopic retrograde cholangiopancreatography; MRCP, magnetic resonance cholangiopancreatography. Adapted from reference 7.

Hepatology Insights

ERCP or MRCP

2026

of another liver etiology, or concern for impending liver failure even in the absence of known acetaminophen use.

Approach to Elevated Alkaline Phosphatase The elevated alkaline phosphatase algorithms start by determining whether it is likely a liver source or a nonhepatic source via assessment of other liver tests and/or using a clarifying test, such as GGT or alkaline phosphatase isoenzymes (Figures 5 and 6). In patients with otherwise normal liver tests, as shown in Figure 5, the first step would be the clarifying test and then proceeding with the workup if the cause is related to the liver. However, in patients with other abnormal liver tests (Figure 6), the elevated alkaline phosphatase is assumed to be from a liver source, and the workup is started without clarifying tests.

Approach to Elevated Direct Bilirubin The first step with elevated bilirubin is fractionation of the bilirubin to determine whether it is unconjugated (indirect) or conjugated (direct) (Figure 7). For elevated unconjugated (indirect) bilirubin, the approach is to look for causes of elevations not related to liver disease (classically, Gilbert’s syndrome, hemolysis, or, occasionally, medications). Usually, if the indirect bilirubin levels are mildly elevated and there is no other evidence of an obvious etiology, a presumptive diagnosis of Gilbert’s syndrome can be made, with no further follow-up necessary. However, if the elevations persist

and are unexplained, symptomatic, worsening, and/or associated with abnormal ALT, then further workup could be considered. Figure 7 demonstrates the algorithm for elevated conjugated (direct) bilirubin. This workup is similar to that for patients with elevated alkaline phosphatase.

Conclusion Elevated liver enzymes are a common consult for gastroenterology providers. The true healthy ULN for ALT should likely be much lower than that proposed by the standard reference lab, with levels of 29 to 33 IU/L and 19 to 25 IU/L defining a true healthy normal for men and women, respectively. Clinicians should focus on history, including all medications, herbal supplements, and over-the-counter preparations, and physical examination to point toward any obvious clues to the etiology of the elevations and rule out advanced liver disease and/or evidence of liver failure. Clinicians should consider the pretest probability of a particular liver disease. They also should use the pattern, magnitude, and timing of liver enzyme elevations to help define the most likely etiology. Liver biopsy should be reserved for cases with unclear etiology. Finally, patients with significantly elevated liver enzymes and/or potential liver failure should be considered for early referral to a specialized liver center or liver transplant centers.

References 1.

Pratt DS, Kaplan MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med. 2000;342(17):1266-1271.

Clark JM, Brancati FL, Diehl AM. The prevalence and etiology of elevated aminotransferase levels in the United States. Am J Gastroenterol. 2003;98(5):960-967.

Arndt V, Brenner H, Rothenbacher D, et al. Elevated liver enzyme activity in construction workers: prevalence and impact on early retirement and all-cause mortality. Int Arch Occup Environ Health. 1998;71(6):405412. Kim HC, Nam CM, Jee SH, et al. Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study. BMJ. 2004;328(7446):983.

Lee TH, Kim WR, Benson JT, et al. Serum aminotransferase activity and mortality risk in a United States community. Hepatology. 2008;47(3):880-887.

Ruhl CE, Everhart JE. Elevated serum alanine aminotransferase and gamma-glutamyltransferase and mortality in the United States population. Gastroenterology. 2009;136(2):477-485.

Kwo PY, Cohen SM, Lim JK. ACG Clinical Guideline: evaluation of abnormal liver chemistries. Am J Gastroenterol. 2017;112(1):18-35.

Ruhl CE, Everhart JE. Upper limits of normal for alanine aminotransferase activity in the United States population. Hepatology. 2012;55(2):447-454.

Owens D, Evans J. Population studies on Gilbert’s syndrome. J Med Genet. 1975;12(2):152.

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2026

Major Developments in the PBC Pruritus Treatment Pipeline rospective new treatments for pruritus in primary biliary cholangitis

were on display at the EASL Congress 2025, with several abstracts

building on major developments in PBC treatments in recent months. Four drugs—seladelpar (Livdelzi, Gilead), elafibranor (Iqirvo, Ipsen), volixibat, and linerixibat—are at the center of these new developments.

Seladelpar and Elafibranor Seladelpar, a peroxisome proliferator–activated receptor delta agonist, and elafibranor, a peroxisome proliferator–activated receptor alpha and delta agonist, were conditionally approved to treat PBC in 2024 (N Engl J Med 2024;390[9]:783-794, 795-805). These drugs act on bile duct physiology, affecting bile acid synthesis, PBC-related inflammation, and possibly fibrosis, said

Image by Mark Somoza - Own work, CC BY 4.0, https://commons.wikimedia.org/w/index.php?curid=1257700

Two new drugs were conditionally approved last year to treat PBC in patients who are intolerant of or inadequately responsive to ursodeoxycholic acid. In addition, experimental drugs that target PBC-related itching have yielded good results in early trials. And finally, the PBC drug obeticholic acid was withdrawn from the market this year in response to a request from the FDA. “The past year and a half have been a time of monumental change for patients with primary biliary cholangitis and their caregivers,” said John E. Eaton, MD, an associate professor of medicine at Mayo Clinic, in Rochester, Minnesota. “The pipeline for itch-related therapies is promising.”

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2026

Sayed Obaidullah Aseem, MD, PhD, a gastroenterologist and hepatologist at Virginia Commonwealth University School of Medicine, in Richmond. Although such drugs were not specifically approved to treat PBC-related itching, research suggests they may help alleviate pruritus symptoms. Dr. Aseem was not an author on any of the studies included in this article. In one study that evaluated results from the phase 3 RESPONSE trial and its open-label extension, ASSURE, 193 patients received 10 mg of seladelpar or placebo daily (abstract THU-286). Mean GLOBE (Global Assessment of Liver Outcomes) score changes at three months and one year for patients on seladelpar were –0.38 (0.21) and –0.34 (0.39), respectively, compared with –0.07 (0.28) and –0.01 (0.32) for patients who received placebo. After a year, patients receiving placebo could cross over to seladelpar. After two years, the GLOBE score changes were –0.39 (0.33) and –0.42 (0.50) for patients who continued seladelpar or switched from placebo, respectively. Another abstract presented at EASL that also analyzed findings from RESPONSE and ASSURE showed that seladelpar significantly improved itching, said Cynthia Levy, MD, the Arthur Hertz Chair in Liver Disease and associate director of the Schiff Center for Liver Diseases at the University of Miami Miller School of Medicine. Across the two studies, 126 patients with moderate to severe pruritus received either 10 mg of seladelpar (n=76) or placebo (n=50) (abstract THU-294). The researchers found significant improvements across three measures of itch, Dr. Levy said. For instance, the numerical rating scale went down by 3.1 points in patients taking seladelpar, compared with 2.09 points in patients on placebo. A related study found a 3-point improvement in the pruritus numerical rating scale is the minimum meaningful change for patients (abstract THU-291). “This is exciting news,” said Dr. Levy, who was involved in the two studies. “Having a therapy that can both help prevent progression of disease and mitigate symptoms is certainly desirable.” Fewer studies at EASL looked at elafibranor’s impact on pruritus, but research published so far

suggests that elafibranor does not seem to exacerbate itching, Dr. Aseem said. In one study of elafibranor presented at the conference, fatigue and pruritus were not strongly associated at baseline. This finding indicated that pruritus was not driving fatigue in the study participants and that the observed improvements in itching and fatigue scores for patients taking elafibranor were independent from one another, said Dr. Levy, a co-researcher on the study (abstract LBP-027).

‘ The past year and a half have been a time of monumental change for patients with primary biliary cholangitis and their caregivers.’ —John E. Eaton, MD Mayo Clinic, Rochester, Minnesota

These findings show that “now we have treatment options that can both treat the disease and improve patients’ quality of life,” Dr. Eaton said.

Volixibat and Linerixibat Volixibat and linerixibat are part of a novel drug class of ileal bile acid transport inhibitors. The two drugs work by blocking the reabsorption of bile acids and are being investigated for PBC-related itching. Bile acids are believed to play an indirect role in pruritus, but the exact mechanism is unknown, Dr. Aseem said. In one abstract, Dr. Eaton and his co-researchers shared interim results of a phase 2b, randomized, multicenter, double-blind, placebo-controlled study of volixibat (abstract OS-059), in which patients with moderate to severe pruritus received either 20 mg of volixibat (n=10), 80 mg of volixibat (n=10), or placebo (n=11). Over 28 weeks, the combined volixibat dose group had a statistically significant 3.78-point reduction from their baseline Itch Reported Outcome score (P<0.0001) and a placeboadjusted response of –2.51 (P=0.0004). In another phase 3, double-blind study of linerixibat, investigators treated 238 patients with 40 mg of linerixibat or placebo twice daily for 24 weeks, (abstract GS-011). A greater proportion of the patients who received linerixibat than those taking placebo said their pruritus was see PPARs, page 17

Hepatology Insights

2026

Machine Learning Model Predicts Inpatient Cirrhosis Mortality

achine learning strategies outperformed traditional methods of predicting

inpatient cirrhosis mortality, enabling easier identification of at-risk patients who need extra attention at the hospital, according to newly published research.

“It’s very easy to be a Monday morning quarterback and say, ‘This patient went to the ICU while they were in the hospital. This patient had dialysis while they were in the hospital.’ Literally everyone would know that patient is not going to do well. What we want is for clinicians to know on the day of admission, … What we want is for clinicians to know on the day of what is the likelihood that this patient admission, … what is the likelihood that this patient is is going to get better?” said Jasmohan S. going to get better? Bajaj, MD, MS, a professor of medicine —Jasmohan S. Bajaj, MD, MS at Virginia Commonwealth University, Virginia Commonwealth University, Richmond in Richmond, and the study’s lead investigator. The new machine learning approach was developed using the global CLEARED Consortium, which includes a cohort of 7,239 inpatients with cirrhosis (64% men; mean age, 56±13 years; median Model of End-Stage Liver Disease-Na score, 25). Participants were from 115 health centers in every populated continent of the world, in countries of varying income levels. A total of 808 patients (11.1%) died while in the hospital.

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Hepatology Insights

2026

The investigators evaluated 69 variables including clinical variables such as history of hepatic encephalopathy or an acute kidney injury when arriving at the hospital, as well as hemoglobin, white blood cell and platelet levels. They also tracked whether people had been hospitalized for any reason in the six months prior to admission for cirrhosis and whether they had an infection in those six months, among other pre-admission variables. All variables were input into different predictive models that were then compared (Gastroenterology 2025 Jul 23. doi:10.1053/j. gastro.2025.07.015). The investigators explored which model most effectively predicted inpatient death from cirrhosis. Machine learning outperformed the traditional approach of logistic regression at predicting inpatient cirrhosis mortality. The area under the curve for machine learning was 0.815 (95% CI, 0.785-0.844), compared with 0.773 (95% CI, 0.738-0.807) for logistic regression. This represented a 4.2-point advantage (P<0.001) for machine learning, which was a better predictor regardless of where someone lived. “The machine leaning model is very easy to use and is freely available,” Dr. Bajaj said. The researchers validated the model in 28,670 U.S. veterans with cirrhosis, of whom 4% (n=1,158) died in the hospital. In this cohort, machine learning again outperformed other predictive models, even when using just 15 variables rather than the 69 variables used in the CLEARED cohort. Those 15 variables are included in a freely available tool (silveys.shinyapps.io/app_cleared/). Dr. Bajaj noted that the mortality rates in both cohorts were lower than those seen in other studies of patients with cirrhosis, but he added that the CLEARED data more accurately reflect real-world clinical experience. “Prior studies have very selected, very highmortality patients with cirrhosis,” Dr. Bajaj explained. But if the machine learning model identifies someone at lower risk who nonetheless could still die in the hospital, clinicians can use that information to prioritize care for those most at risk. With this approach, he said, “there is a hope that you can do something more,” Dr. Bajaj said.

Room for Improvement “[The researchers] identified some common factors in the various countries and income groups that lead to higher inpatient mortality from cirrhosis,” such as acute kidney injury and hepatic encephalopathy, said Mark Russo, MD, MPH, a transplant hepatologist at Advocate Health in Charlotte, North Carolina. “That’s pretty unique to this study, to identify those common factors in inpatient mortality across many countries,” added Dr. Russo, who was not involved in the study. He called the research a “tremendous effort,” given the number of patients evaluated by machine learning and the breadth of countries included.

With additional data not collected in this study, such as what proportion of patients died within seven days of admission and what they died from, clinical management could be even more precise. —Mark Russo, MD, MPH Advocate Health, Charlotte, North Carolina

“This data suggest maybe this patient requires more frequent monitoring, or we should move them into intensive care because they’re really at high risk for dying,” Dr. Russo said. In the most concerning cases, he noted, the model might inform conversations with patients and their loved ones about transitioning to palliative or hospice care. With additional data not collected in this study, such as what proportion of patients died within seven days of admission and what they died from, clinical management could be even more precise, Dr. Russo added. “I think those are the next steps,” he said. For example, he explained, data could indicate that people with cirrhosis die of sepsis in the hospital more than expected. If that is the case, clinicians could order more blood cultures and monitor for signs of sepsis more intensively. These two variables—death within seven days and cause of death—would be applicable to all the countries in the study, Dr. Russo said, adding that it also would be helpful to know which patients were saved by a liver transplant in countries where such transplants are available. —Marcus A. Banks Drs. Bajaj and Russo reported no relevant financial disclosures.

Hepatology Insights

2026

Liver Stiffness Emerges as Key Predictor Of Outcomes in MASLD Patients

esults of a new study support the use of liver stiffness

measurements to stratify risk in patients with metabolic

dysfunction–associated steatotic liver disease. “Liver biopsy remains the gold standard for assessing liver fibrosis, [but] it is an invasive procedure that carries risks and involves high costs related to specialized staff, equipment, and procedural time,” said investigator Antonio Liguori, MD, PhD, a hepatologist at Fondazione Policlinico Universitario Agostino Gemelli IRCCS, in Rome. Measuring liver stiffness through elastography (FibroScan, Echosens) is emerging as a less invasive, cost-effective option, he said. In addition, “it can be easily repeated over time, which is not easily feasible with liver biopsy.” Given the ease of noninvasive testing, In the study, prestudies like this one are needed to help sented at the 2025 EASL clinicians manage patients with MASLD. Congress, Dr. Liguori —Richard Sterling, MD and his co-investigators Virginia Commonwealth University, Richmond followed 389 patients with MASLD who had undergone LSM at least twice spaced at least six months apart between January 2011 and December 2023 (abstract TOP-380-YI). The patients were categorized into three risk groups based on their baseline LSM: low (<10 kPa), intermediate (10-20 kPa), and high (>20 kPa). The researchers then assessed whether baseline liver stiffness and its changes over time could predict the risk of developing adverse liver-related

‘

’

Hepatology Insights

events, such as disease decompensation, liver cancer, and the need for liver transplantation. Over a median follow-up period of 28 months, 29 patients (7.5%) experienced one of these adverse outcomes. Individuals with liver-related adverse events had a higher baseline LSM consistent with cirrhosis than those who did not (23.3 vs. 6.2 kPa; P<0.01). They also showed worsening liver stiffness over time. Compared with patients in the low-risk group, those with intermediate stiffness values had nearly a 10-fold higher risk for negative outcomes (hazard ratio [HR], 9.7; 95% CI, 2.05-45.79; P≤0.01), while high-risk patients faced a more than 55-fold increased risk (HR, 55.63; 95% CI, 12.15-254.74; P≤0.01). “Our findings showed that not only the baseline liver stiffness value could stratify risk, but also that longitudinal changes added significant prognostic value,” Dr. Liguori said. “Specifically, patients who achieved a reduction in liver stiffness over time—thanks to therapies or lifestyle improvements—were able to reduce their risk of adverse outcomes, even if they initially started at medium or high risk.” Specifically, patients whose stiffness improved had an adverse event rate of 15.5 per 1,000 person-years, compared with 19.7 in stable patients and 81.4 in those whose LSM worsened.

2026

“This dynamic assessment allows us to monitor how patients respond to dietary, pharmacologic, or surgical interventions, while also identifying those who are progressing and may require more intensive treatments,” Dr. Liguori said. The study has several important limitations, including its small sample size and having been conducted at a single center, and, thus, the results may not be generalizable, noted Richard Sterling, MD, a hepatologist and professor of medicine at Virginia Commonwealth University, in Richmond. In addition, Dr. Sterling noted that although the investigators “adjusted for comorbidities that might impact liver-related events,” the EASL abstract did not include demographic information about the cohort. “Furthermore, they do not mention if any of the subjects had undergone liver biopsy to confirm the diagnosis, had any liverdirected therapies, lost weight, or had any alcohol use,” he said. “However, these data do support the use of LSM both at baseline and to monitor patients with MASLD to help identify those at risk for liver-related events,” Dr. Sterling noted. “Given

the ease of noninvasive testing, studies like this one are needed to help clinicians manage patients with MASLD. With new treatments now available for [patients with] MASLD, particularly those with moderate fibrosis (F2-F3), using dynamic noninvasive tests will be increasingly important.”

PPARs continued from page 13

Dr. Aseem. However, he said, several of the EASL studies had good designs to account for the subjectivity of selfreported outcomes. Longer-term studies This is exciting news. Having a therapy are needed of all four that can both help prevent progression of drugs, Dr. Aseem concluded, adding that, evendisease and mitigate symptoms is certainly tually, experts will need to desirable. provide guidance on how —Cynthia Levy, MD these medications can University of Miami Miller School of Medicine be used together to treat both PBC and pruritus.

very much improved (55% vs. 37%) or absent (21% vs. 9%) at week 24. The researchers found linerixibat significantly improved pruritus over the study period compared with placebo (least-squares [LS] mean change, –2.86 vs. –2.15; adjusted mean difference, –0.72; P=0.001). The drug appeared to work quickly, with patients experiencing relief at week 2 of the study (LS mean change, –1.78 vs. –1.07; adjusted mean difference, –0.71; P<0.001). In both studies, gastrointestinal symptoms (particularly diarrhea) were the most common side effects. Because researchers have not identified the biochemical markers of itch, they rely on patient-reported outcomes, potentially affecting the results of pruritus studies, said

‘ Our findings showed that not only the baseline liver stiffness value

could stratify risk, but also that longitudinal changes added significant prognostic value.

’

—Antonio Liguori, MD, PhD Università Cattolica del Sacro Cuore, Rome

Although larger cohort studies with fixed intervals are needed, the findings are promising, Dr. Liguori said. “Combined with other evidence,” he added, “they could pave the way for incorporating repeated liver stiffness measurements into international guidelines, both for their prognostic value and as a tool to interpret treatment efficacy over time.” —Ashley Welch Drs. Liguori and Sterling reported no relevant financial disclosures.

‘

’

—Jillian Mock Dr. Aseem reported financial relationships with the Gilead Advisory Board and PSC Partners Seeking a Cure, and he is a site investigator for ELFINITY (phase 4 study of elafibranor). Dr. Eaton reported no relevant financial disclosures. Dr. Levy reported financial relationships with CymaBay, Gilead, GSK, Intercept, Ipsen, Kowa, Mirium, and Zydus.

Hepatology Insights

When accuracy, credibility, DQG FRQƓGHQFH PDWWHUŋ choose the technology that GHƓQHV WKH VWDQGDUG. For more than 25 years, FibroScan has set the global standard in the non-invasive assessment of liver and metabolic health. ®

VCTE™ and CAP™ technologiesŋ FUHDWHG YDOLGDWHG DQG RZQHG E\ (FKRVHQVŋ continue to elevate care. When VCTE™ or CAP™ DUH PHQWLRQHG LQ UHsearch r or clinical rch RJLHV WKDW VKDSHG PRGHUQ practice, they refer to the FibroScan® WHFKQRORJLHV WKDW VKDSHG PRGHUQ d by other methods. OLYHU FDUHŋprecision that can’t be replicated

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Validated. Proven. Exclusively: For more information, scan or visit echosens.com

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The FibroScan® device (Models: 502 Touch, 530 Compact, 430 Mini+, 230, and 630) is intended to measure liver stiffness (E) using Vibration Controlled Transient Elastography (VCTETM) at 50 Hz shear wave frequency and liver ultrasound attenuation coefficient (CAPTM)* at 3.5 MHz. FibroScan® 630 Expert is also intended to measure spleen stiffness using VCTETM at 100 Hz shear wave frequency. FibroScan® liver stiffness measurements (LSM) by VCTETM may aid the physician in determining the likelihood of cirrhosis and may be used, taken in context with other clinical and laboratory data, as an aid in the assessment of liver fibrosis. FibroScan® CAPTM measurements may be used, taken in context with other clinical and laboratory data, as an aid in the assessment of hepatic steatosis. FibroScan® is indicated as a non-invasive aid for the clinical management, diagnosis, and monitoring of adult and pediatric patients with confirmed or suspected liver disease, as part of an overall assessment of the liver. Results in the pediatric population should be interpreted while considering the clinical condition and the overall patient profile. The FibroScan® device is intended for use by healthcare professionals in hospitals, clinics or any facility where healthcare is provided. *CAPTM refers to ultrasound attenuation coefficient (originally defined as Controlled Attenuation Parameter). CAPTM on S+ probe is only available with SmartExam capability. © 2025 Echosens, All rights reserved. EchosensTM, FibroScan®, among others, are trademarks and/or service mark of Echosens Group and are registered in the U.S. and/or other countries. US V1 202511

2026

In Lieu of Biopsy: A Review Of Noninvasive Liver Disease Assessments MICHAEL J. EISWERTH, DO JOHN T. GRADY, MD TAMOORE ARSHAD, MD

RICHARD STERLING, MD, MSC

Division of Gastroenterology, Hepatology and Nutrition Virginia Commonwealth University Richmond, Virginia

Division of Gastroenterology, Hepatology and Nutrition Stravitz-Sanyal Institute for Liver Disease and Metabolic Health Virginia Commonwealth University Richmond, Virginia

o address the diagnostic challenges of fibrosis staging in chronic liver disease (CLD), blood-based biomarkers and imaging-based modalities, collectively termed noninvasive liver disease assessments (NILDAs),

have been developed to evaluate for the presence and degree of hepatic fibrosis, steatosis, and clinically significant portal hypertension.

Hepatology Insights

2026

Hepatic fibrosis is a significant disease threshold in chronic liver disease because most clinically relevant liver-related morbidity and mortality occurs in patients with advanced fibrosis (AF) or cirrhosis.1 In patients with fibrosis, hepatic decompensation and complications from portal hypertension drive poor outcomes. Fibrosis assessment is associated with prognosis and used to direct treatment strategies for hepatitis B virus (HBV), hepatitis C virus (HCV), and metabolic dysfunction–associated steatotic liver disease (MASLD). Therefore, fibrosis assessment to identify patients with moderate to AF and cirrhosis is crucial in the management of CLD. Fibrosis stage classification ranges from F0 to F4, with fibrosis percentage increasing from F0 (normal) to F4 (cirrhosis).2 Degrees of fibrosis are stratified as at least significant fibrosis (≥F2), at least AF (≥F3), and cirrhosis (≥F4).2-4 However, fibrosis staging is challenging because it is a nonlinear, dynamic process that is neither static nor necessarily progressive. Traditionally, the diagnosis of CLD and fibrosis staging has relied on histologic evaluation by liver biopsy, but this approach has limitations. Liver biopsy is not only expensive and invasive but also is associated with adverse events, such as pain, bleeding, perforation of hollow viscus, and, rarely, death.5 Although liver biopsy is considered the gold standard in diagnosis of CLD, it can lead to incorrect fibrosis staging in up to 25% of cases due

to length, number, and type of biopsies performed and etiology of liver disease.5 To address the diagnostic challenges in CLD, NILDAs have been developed to evaluate for the presence and degree of hepatic fibrosis, steatosis, and clinically significant portal hypertension.2 The American Association for the Study of Liver Diseases (AASLD) recently developed guidelines based on systematic reviews on the use of NILDAs to detect significant fibrosis, AF, and cirrhosis.2,6-9 NILDAs can be classified as either blood-based or imaging-based, and there is a wide array of available biomarkers. Blood-based NILDAs include routine tests, algorithms, and proprietary and patented tests and algorithms. They can be further broken down into simple, nonproprietary tests and more complex, proprietary tests (Table 1). Imaging-based NILDAs, based on elastography principles to assess liver stiffness, can be further stratified by their modality (Table 1). Interpreting both blood- and imaging-based NILDAs requires understanding several confounding factors. Specifically, bloodbased NILDAs can be affected by age, splenectomy, gastrectomy, thrombocytopenia not related to portal hypertension, alcohol use, abnormal aspartate aminotransferase (AST) or alanine transaminase (ALT) values due to hepatic ischemia or acute liver injury, chronic kidney disease, malnutrition, inflammatory

Table 1. Available Biomarkers for the Evaluation Of Fibrosis in CLD

Table 2. Components of Noninvasive Assessments of Liver Fibrosis

Blood-based

Model

Components

APRI

AST, PLT

FIB-4

AST, ALT, age, PLT

NFS

AST, ALT, age, PLT, BMI, albumin

ELF

Age, TIMP1, PIIINP, HA

FibroTest/ FibroSURE

Alpha2-macroglobulin, apolipoprotein A1, haptoglobin, bilirubin, GGT

VCTE

Liver stiffness

Imaging-based

Simple, nonproprietary

Complex, proprietary

APRI

FibroTest/ FibroSURE

VCTE

FibroSpec II

Acoustic radial force imaging

FIB-4

NFS

Hepascore

SWE MRE

FibroIndex

FibroMeter

SWE

Liver stiffness

King’s Score

ELF

MRE

Liver stiffness

Easy Liver Fibrosis Test

OWLiver

ALT, alanine transaminase; APRI, aspartate aminotransferase-toplatelet ratio index; AST, aspartate aminotransferase; BMI, body mass index; ELF, Enhanced Liver Fibrosis; FIB-4, Fibrosis-4 Index; GGT, gamma-glutamyl transpeptidase; HA, hyaluronic acid; MRE, magnetic resonance elastography; PLT, platelets; PIIINP, procollagen type III amino-terminal propeptide; SWE, shear wave elastography; TIMP1, tissue inhibitor of metalloproteinase 1; VCTE, vibrationcontrolled transient elastography.

APRI, aspartate aminotransferase-to-platelet ratio index; CLD, chronic liver disease; ELF, Enhanced Liver Fibrosis; FIB-4, Fibrosis-4 Index; MRE, magnetic resonance elastography; SWE, shear wave elastography; VCTE, vibration-controlled transient elastography.

Hepatology Insights

2026

disorders, hemolysis, cholestatic diseases, postprandial hyperglycemia, extrahepatic fibrosing conditions, and auto–sickle cell crisis.2,10-19 Liver stiffness measurement (LSM) also can be affected by deposition diseases, such as amyloidosis, hepatic congestion in the setting of congestive heart failure or valvopathies, and hepatic infiltration in conditions such as leukemia.6 In the AASLD guidelines on NILDAs, the panel reviewed 9,447 articles published through April 2022. Among these studies, 286 addressed blood-based NILDAs2 and 240 addressed imaging-based NILDAs.6 Using the patient, intervention, comparison, and outcome method, the authors generated 21 guidance statements.2,6 Diagnostic performance is an important consideration in the use of NILDAs, and the application of standard statistical principles including sensitivity and specificity, both of which are independent of disease prevalence, is essential. Noninvasive tests historically have had a much higher sensitivity than specificity, marking their utility in ruling out a condition.

Table 3a. Performance of Blood-Based NILDA Modalities in Detecting AF (F3-F4) Test

Disease

Cutoff

Sensitivity

Specificity

FIB-4

HCV

1.45

0.86

0.70

3.25

0.55

0.90

1.45

0.67

0.69

3.25

0.26

0.96

1.3

0.82

0.64

HBV

MASH

APRI

Table 3b. Performance of Imaging-Based NILDA Modalities in Detecting AF (F3-F4) Disease

Cutoff (kPa)

Sensitivity

Specificity

HCV

8.7

0.97

0.85

2.67

0.36

0.95

Test

HCV

0.5

0.82

0.60

SWE

HBV

0.5

0.77

0.69

HBV

8.3

0.90

0.77

0.5

0.78

0.65

MASH

1.64

1.0

0.80

0.32

0.87

0.62

HCV

0.89

0.90

0.58

0.75

0.74

HBV

0.82

0.83

MASH

0.80

0.78

HCV

—

HBV

5.5

1.0

MASH

3.7

0.9

0.94

MASH FibroTest/ FibroSURE

For many NILDAs, a low threshold has a higher sensitivity, and a higher threshold has a higher specificity. Conversely, both positive predictive value (PPV) and negative predictive value (NPV) are affected by disease prevalence, which is relevant, given factors such as patient selection in clinical practice because AF is less common in general practice than in hepatology practice, with estimates greater than 30% in the latter setting.2 To assess the accuracy of NILDAs across populations with varying prevalence, clinicians should use the diagnostic odds ratio. This ratio summarizes the odds of fibrosis in those with a positive test relative to that in those with a negative test2 and is a reliable estimate of a test’s accuracy, independent of the prevalence of the condition being tested. Overall, careful interpretation of NILDAs is required to apply results correctly in clinical practice. A useful NILDA should have both a low threshold to rule out AF and a high threshold to rule in AF. Furthermore, when analyzing a NILDA, any result should be followed by assessing the test’s PPV and NPV in the population of interest before interpreting it or using the diagnostic odds ratio to assess its accuracy. Both blood- and imaging-based NILDAs have limitations in their application, and the application of these tests is not uniform. The assessments were developed primarily to identify either AF or cirrhosis, not to assess significant fibrosis (≥F2). Furthermore, many of these tests have up to 50% indeterminate results and

HCV

ELF

HCV

9.13-9.49 0.92

0.66

Hepascore

HCV

0.5-0.6

0.79

0.76

NFS

MASH

–1.455

0.75

—

0.676

—

0.96

VCTE

MRE

AF, advanced fibrosis; APRI, aspartate aminotransferase-to-platelet ratio index; ELF, Enhanced Liver Fibrosis; FIB-4, Fibrosis-4 Index; HBV, hepatitis B virus; HCV, hepatitis C virus; MASH, metabolic dysfunction–associated steatohepatitis; NFS, NAFLD fibrosis score; NILDA, noninvasive liver disease assessment.

AF, advanced fibrosis; HBV, hepatitis B virus; HCV, hepatitis C virus; MASH, metabolic dysfunction–associated steatohepatitis; MRE, magnetic resonance elastography; SWE, shear wave elastography; VCTE, vibration-controlled transient elastography.

Based on reference 8.

Based on reference 6.

Hepatology Insights

2026

are most accurate at the ends of the fibrosis spectrum, either F0 or F4. In addition, both blood- and imaging-based NILDAs were not developed to differentiate between adjacent fibrosis strata (eg, F2 from F3).2,6 Also, there are limited data and a lack of validation for using these tests as a measure to show improvement of fibrosis after disease-specific treatment. Further comparative and collaborative studies in these areas are needed.

Blood-Based NILDAs Numerous blood-based noninvasive tests have emerged over the past 2 decades (Table 1). Perhaps the 2 most studied are the AST-to-platelet ratio index (APRI) and Fibrosis-4 Index (FIB-4).20-21 These NILDAs incorporate simple laboratory and demographic parameters; APRI is composed of AST and platelet count, whereas the FIB-4 also adds ALT and age (Table 2). Subsequent simple, noninvasive tests have been developed that often contain these core parameters and add additional metabolic parameters. These tests use readily accessible inputs and are easily computed with online calculators. However, simple scores can be misleading in patients at extremes of age or who have confounding explanations for abnormal laboratory inputs, such as acute hepatitis or an alternative cause of thrombocytopenia. More complex, proprietary tests have been developed that often include direct molecular markers of fibrosis but are more costly and less accessible. The 2025 AASLD guidelines on blood-based NILDAs recommend using simple blood-based noninvasive scores, such as APRI or FIB-4, over proprietary tests as an initial test to

identify fibrosis stage in patients with chronic viral hepatitis.2 In the AASLD guideline and systematic review, FIB-4 cutoffs of 1.45/3.25 had a sensitivity/specificity of 0.86/0.70 and 0.55/0.90, respectively, for the detection of AF in HCV (Table 3a). 2,8 In chronic HBV, the FIB-4 had decreased sensitivity (0.67) for the diagnosis of AF at the lower cutoff of 1.45 but maintained high specificity (0.96) at the upper cutoff of 3.25. All noninvasive tests should be used prior to initiating therapy in patients with chronic HCV or chronic HBV because there are no validated NILDA cutoffs that correlate with fibrosis stage after sustained virologic response in HCV or viral suppression in HBV. Treatments of the underlying liver disease improve AST and ALT values, resulting in underestimation of fibrosis stage by bloodbased NILDAs. In patients with MASLD, the guidelines also recommend using simple blood-based noninvasive tests over complex, proprietary tests to detect AF (F3-F4). A systematic review of 32 studies evaluating the FIB-4 found a pooled specificity of 0.94 for upper cutoffs (FIB-4 ≥2.67 and ≥3.25 in diagnosing AF and cirrhosis) (Tables 3a and 4a).2 The NAFLD fibrosis score (NFS) is a simple blood-based NILDA that incorporates body mass index (BMI), diabetes status, and albumin in addition to the FIB-4 parameters.22 In the guideline panel’s review of available studies evaluating NFS, a cutoff of less than –1.455 yielded a sensitivity of 0.75 (95% CI, 0.61-0.81) for ruling out AF, while a cutoff of greater than 0.676 had a specificity of 0.96 (95% CI, 0.93-0.98) for diagnosis of AF. However, 33.5% of patients fell within the indeterminate range.

No Advanced Fibrosis

Indeterminate Result

Advanced Fibrosis

Non-MASLD FIB-4 <1.45 MASLD FIB-4 <1.3 or NFS <–1.455

Non-MASLD FIB-4 1.45-3.25 MASLD FIB-4 1.3-2.67 or NFS –1.455 to 0.676

Non-MASLD FIB-4 >3.25 MASLD FIB-4 >2.67 or NFS >0.676

F0-F2

Confirmatory Testing

F3-F4

Figure i 1. Blood-based NILDA algorithm for staging i fibrosis. i i FIB-4, Fibrosis-4 Index; MASLD, metabolic dysfunction–associated steatotic liver disease; NFS, NAFLD fibrosis score; NILDA, noninvasive liver disease assessment. Adapted from reference 2.

Hepatology Insights

2026

Figure 1 and Table 3a highlight the FIB-4 and NFS thresholds proposed by the AASLD guideline panel for fibrosis staging.2 To identify AF in MASLD, the guideline panel suggests that a sequential combination of blood-based NILDAs may be considered rather than a single test, although the quality of evidence is low. They further note that blood-based biomarkers should not be used to assess steatosis in MASLD patients. Most NILDA studies have been performed in patients with viral hepatitis or MASLD. There was insufficient evidence for the guideline panel to recommend blood-based NILDAs for fibrosis assessment in patients with alcohol-associated liver disease or cholestatic liver disease. In pediatric patients with CLD, the guideline panel suggests that simple blood-based NILDAs, such as APRI or FIB-4, should be used for the diagnosis of AF. They note that blood-based NILDAs are not suitable to discriminate earlier stages of fibrosis and that and blood-based NILDAs incorporating age as a parameter, including FIB-4, do not perform as well in children as adults. Given the frequency of indeterminate results with bloodbased NILDAs, the panel suggests that a combination of noninvasive tests performed sequentially may perform better than a single test for diagnosing significant fibrosis or cirrhosis. Blood-based NILDAs have high sensitivity for ruling out AF but can have limited PPV for confident diagnoses. In

Table 4a. Performance of Blood-Based NILDA Modalities in Detecting Cirrhosis (F4)

addition, blood-based noninvasive models frequently categorize patients into indeterminate ranges, which necessitates additional testing to assess fibrosis stage. NILDAs have difficulty differentiating between adjacent stages of disease, which limits their use in tracking longitudinal changes in fibrosis. Thus, the AASLD advises against using blood-based noninvasive tests to follow progression, stability, or regression in histologic stage in patients with CLD.

Imaging-Based NILDAs Broadly speaking, there are 3 imaging-based NILDA techniques available for widespread use (Table 1). These include vibration-controlled transient elastography (VCTE), shear wave elastography (SWE), and magnetic resonance elastography (MRE). A key advantage of imaging-based NILDAs over bloodbased NILDAs is that in addition to detecting fibrosis, these modalities also enable the quantification of hepatic steatosis. Among the 3 techniques, VCTE is the best validated, most widely available, and most used modality in clinical practice, followed by SWE and MRE. VCTE and SWE are ultrasound-based techniques that detect liver stiffness by measuring the speed with which shear waves transit through the parenchyma.23 The key difference in technique between the 2 is the method used to generate shear

Table 4b. Performance of Imaging-Based NILDA Modalities in Detecting Cirrhosis (F4)

Test

Disease

Cutoff (kPa)

Sensitivity

Specificity

Test

Disease

Cutoff (kPa)

Sensitivity

Specificity

FIB-4

HCV

1.45

0.88

0.63

SWE

HCV

10.3

0.88

0.96

3.25

0.73

0.79

HBV

8.3

0.90

0.77

1.45

0.76

0.72

MASH

—

3.25

0.46

0.92

HCV

0.93

0.80

MASH

0.92-2.2 0.88

0.77

HBV

0.97

0.92

HCV

0.41

0.94

MASH

0.90

0.88

HBV

0.21

0.92

HCV

—

Hepascore HCV

0.75

0.61

0.86

HBV

6.87

1.0

0.99

HCV

0.84

0.87

0.86

MASH

4.67

0.8

0.94

HBV

APRI

VCTE

MRE

APRI, aspartate aminotransferase-to-platelet ratio index; FIB-4, Fibrosis-4 Index; HBV, hepatitis B virus; HCV, hepatitis C virus; MASH, metabolic dysfunction–associated steatohepatitis; NFS, NAFLD fibrosis score.

HBV, hepatitis B virus; HCV, hepatitis C virus; MASH, metabolic dysfunction–associated steatohepatitis; MRE, magnetic resonance elastography; SWE, shear wave elastography; VCTE, vibration-controlled transient elastography.

Based on reference 8.

Based on reference 6.

Hepatology Insights

2026

Imaging-based fibrosis (kPa)

Blood-based fibrosis

Assess Fibrosis Stage

Non-MASLD: FIB-4 <1.45 MASLD: FIB-4 <1.3 or NFS <1.455

LSM US <5 MRE <2.5

F0-F1

LSM US <5 MRE <2.5

Non-MASLD: FIB-4 1.45-3.25 MASLD: FIB-4 1.3-2.67 or NFS –1.455 to 0.676

LSM US <8 MRE <3.1

Follow-up vs liver biopsy

Non-MASLD: FIB-4 >3.25 MASLD: FIB-4 >2.67 or NFS >0.676

LSM US 8-11 MRE 3.1-3.5

LSM US 12-14 MRE 3.6-4.6

LSM US ≥15 MRE ≥4.7

F2-F3

LSM US <12 MRE <3.6

LSM US 12-14 MRE 3.6-4.6

LSM US ≥15 MRE ≥4.7

LSM US ≥25

Follow-up vs liver biopsy

F2-F3

CSPH

Identify Presence of Steatosis MR-PDFF ≥6.4% or TE-CAP ≥275 dB/m Yes

Steatosis present

No steatosis

Figure 2. Simplified NILDA algorithm for the clinician. CSPH, clinically significant portal hypertension; FIB-4, Fibrosis-4 Index; MASLD, metabolic dysfunction–associated liver disease; LSM, liver stiffness measurement; MRE, magnetic resonance elastography; MR-PDFF, magnetic resonance–proton density fat fraction; NFS, NAFLD fibrosis score; NILDA, noninvasive liver disease assessment; TE-CAP, transient elastography–controlled attenuation parameter; US, ultrasound. Adapted from reference 8.

waves. VCTE uses vibration to generate shear waves, whereas in SWE, the absorption of an acoustic pulse by tissue results in generation of shear waves.24 MRE uses mechanical shear waves generated by a plastic disc placed over the patient’s right upper quadrant and connected to an external wave generator, referred to as an active driver.25 The speed at which this generates shear waves across the liver is then detected using MRI techniques, allowing for the evaluation of cross-sectional imaging as well as an assessment of liver stiffness. The 2025 AASLD guidelines recommend use of imagingbased NILDAs across the entire spectrum of chronic liver diseases to detect significant fibrosis (F2-F4), AF (F3-F4), and

cirrhosis (F4). Imaging-based NILDAs have excellent sensitivity and specificity to assess for AF (Table 3b) and cirrhosis (Table 4b).6 The guidelines also recommend the use of imaging-based NILDA to detect AF and cirrhosis in patients with alcohol-associated liver disease and chronic cholestatic liver diseases.6 Of note, much of the data on viral hepatitis were collected from viremic patients and, as such, the appropriate use of NILDAs for patients who have completed antiviral therapy is poorly defined. 6 Overall, evidence for the use of imaging-based NILDAs is not as robust in these disease states. The guidelines further specify that either ultrasoundbased elastography (VCTE or SWE) or MRE can be used for

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noninvasive detection of fibrosis. Choice of imaging modality should be based on local availability, expertise, need for crosssectional imaging, and patient factors that may confound the accuracy of ultrasound-based testing and, thus, should be considered in this diagnostic decision. 6 Patient factors such as ascites and obesity have the greatest effect on LSM accuracy in VCTE, followed by SWE,6,26 which may support use of MRE in these contexts. The XL VCTE probe can counter VCTE-LSM failure in many cases of obesity, but in patients with extreme obesity (BMI ≥40 kg/m2), the XL probe may still produce inaccurate results. The totality of the available data shows that imaging-based NILDAs generally outperform blood-based diagnostics. 6 On these grounds, the AASLD panel recommends that, if available, imaging-based techniques be incorporated into the initial fibrosis staging of adults with CLD. Although imaging-based techniques are considered superior, the guidelines support either concomitant or sequential combination of blood- and imaging-based techniques to improve the accuracy of noninvasive fibrosis detection. 6 This strategy was implemented into the 2023 AASLD practice guidance on the clinical assessment and management of MASLD, which recommends the use of FIB-4 as a primary risk assessment, followed by VCTE.27 The easy accessibility of most blood-based NILDAs allows for convenient implementation as an initial screening tool across a variety of clinical settings. The AASLD does not recommend stand-alone imaging-based NILDAs for longitudinal monitoring of regression or progression of fibrosis. It also is important to understand the effect that patient factors—such as obesity, alcohol use, viremia, and more—have on LSM when interpreting these results. For example, LSM is less reliable when ALT or AST are greater than 100 U/mL, which can be important when evaluating patients in acute or acute-on-chronic disease states, such as in the setting of acute alcohol– associated hepatitis.28 Although there are promising data on the use of imaging-based NILDAs to track changes in fibrosis longitudinally, the evidence remains insufficient to broadly support the practice.6 In the detection of steatosis, blood-based NILDAs do not perform as well as imaging-based NILDAs. Transient elastography–controlled attenuation parameter (TE-CAP) has good diagnostic accuracy to grade steatosis and typically is used first-line in screening for steatosis given its wide availability and convenience as a point-of-care test.6 MRI proton density fat fraction has superior accuracy to TE-CAP, but it is more expensive and less widely available than its ultrasound-based counterparts.6 Within the pediatrics population, there is insufficient evidence to recommend one imaging-based NILDA over

another. There are still limited data evaluating imaging-based NILDAs in the pediatric population, but in practice, clinicians use both MRE and VCTE to quantify steatosis in children with both MASH and cystic fibrosis.

Conclusion With the advent of NILDAs, clinicians now have less expensive and safer alternatives to liver biopsy for the evaluation of CLD.6 The 2025 AASLD guidelines on blood-based and imaging-based NILDAs provide a formal roadmap for their implementation based on 21 guidance statements. As depicted in Figure 2, clinicians can use a sequential approach to accurately assess the degree of fibrosis and reduce the pool of patients who, ultimately, will require liver biopsy. FIB-4 and NFS have good specificity for AF and serve as initial “rule-out” tests. Since these are calculated using commonly accessible parameters, they are universally accessible across all clinical settings. Imaging-based NILDAs can then be implemented to further stratify patients by their degree of fibrosis. The use of ultrasound- and MRI-based techniques also allows for the quantification of steatosis. Despite their utility, NILDAs are imperfect. There remains a subset of patients who require liver biopsy for diagnosis due to indeterminant results, although this subset of patients is much smaller now that NILDA use is more widespread. There are also limited data to correlate these assessments with post-treatment disease states (eg, HCV after direct-acting antivirals, HBV with suppression, and autoimmune hepatitis after therapy). Access to imagingbased NILDAs, both in local availability of equipment as well as the expertise to operate it, remains limited. Ultrasound-based modalities, specifically, can be quite operatordependent, despite being the most used imaging-based NILDA. The population most coveted for clinical trials remains those with F2-F3 because these patients can be treated most effectively with pharmacotherapeutics. NILDAs, like most biomarkers, are designed to detect the extremes of disease and, as such, play a limited role in capturing moderate fibrosis. A tremendous amount of progress has been made in the field to develop effective modes of noninvasive evaluation of liver disease. There are newer models moving beyond the NILDAs covered in the AASLD guidelines that may address these limitations.29 The future continues to hold a great deal of promise, from artificial intelligence and machine learning technologies that may further improve diagnostic techniques, to advances in hardware and software efficiencies to facilitate easier access and implementation of existing NILDAs.6

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References 1.

Hagström H, Nasr P, Ekstedt M, et al. Fibrosis stage but not NASH predicts mortality and time to development of severe liver disease in biopsy-proven NAFLD. J Hepatol. 2017;67(6):1265-1273.

Sterling RK, Patel K, Duarte-Rojo A, et al. AASLD Practice Guideline on blood-based non-invasive liver disease assessments of hepatic ﬁbrosis and steatosis. Hepatology. 2025;81(1):321-357.

Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41(6):1313-1321.

Brunt EM, Janney CG, Di Bisceglie AM, et al. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94(9):2467-2474.

Rockey DC, Caldwell SH, Goodman ZD, et al. Liver biopsy. Hepatology. 2008;49(3):1017-1044.

Sterling RK, Duarte-Rojo A, Patel K, et al. AASLD Practice Guideline on imaging-based non-invasive liver disease assessments of hepatic ﬁbrosis and steatosis. Hepatology. 2025;81(2):672-724.

Sterling RK, Asrani SK, Levine D, et al. AASLD Practice Guideline on non-invasive liver disease assessments of portal hypertension. Hepatology. 2025;81(3):1060-1085.

Patel K, Asrani SK, Fiel MI, et al. Accuracy of blood-based biomarkers for staging liver ﬁbrosis in chronic liver disease: a systematic review supporting the AASLD Practice Guideline. Hepatology. 2025;81(1):358-379. Duarte-Rojo A, Taouli B, Leung DH, et al. Imaging-based noninvasive liver disease assessment for staging liver ﬁbrosis in chronic liver disease: a systematic review supporting the AASLD Practice Guideline. Hepatology. 2025;81(2):725-748.

10.

Nguyen-Khac E, Thiele M, Voican C, et al. Non-invasive diagnosis of liver ﬁbrosis in patients with alcohol-related liver disease by transient elastography: an individual patient data metaanalysis. Lancet Gastroenterol Hepatol. 2018;3(9):614-625.

11.

Petta S, Wong VWS, Bugianesi E, et al. Impact of obesity and alanine aminotransferase levels on the diagnostic accuracy for advanced liver ﬁbrosis of noninvasive tools in patients with nonalcoholic fatty liver disease. Am J Gastroenterol. 2019;114(6):916-928.

hepatitis C and end-stage renal disease. Clin Gastroenterol Hepatol. 2020;18(10):2332-2339.e1. 16.

Vuppalanchi R, Weber R, Russell S, et al. Is fasting necessary for individuals with nonalcoholic fatty liver disease to undergo vibration-controlled transient elastography? Am J Gastroenterol. 2019;114(6):995-997.

17.

Murawaki Y, Idobe Y, Ikuta Y, et al. Inﬂuence of a history of gastrectomy for gastric cancer on serum hyaluronan concentration in normal individuals and patients with chronic liver disease. Hepatol Res. 1998;10(3):248-254.

18.

Su Y, Gu H, Weng D, et al. Association of serum levels of laminin, type IV collagen, procollagen III N-terminal peptide, and hyaluronic acid with the progression of interstitial lung disease. Medicine. 2017;96(18):e6617e6617.

19.

Koh C, Turner T, Zhao X, et al. Liver stiffness increases acutely during sickle cell vaso-occlusive crisis. Am J Hematol. 2013;88(11):E250-E254.

20. Wai CT, Greenson JL, Fontana RJ, et al. A simple non-invasive index can predict both signiﬁcant ﬁbrosis and cirrhosis in patients with chronic hepatitis C. Hepatology. 2003;38(2):518-526. 21.

Sterling RK, Lissen E, Clumeck N, et al. Development of a simple noninvasive index to predict signiﬁcant ﬁbrosis in patients with HIV/HCV coinfection. Hepatology. 2006;43(6):1317-1325.

22. Angulo P, Hui JM, Marchesini G, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology. 2007;45(4):846-854. 23. Wong VWS, Vergniol J, Wong GLH, et al. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology. 2010;51(2):454-462. 24. Kennedy P, Wagner M, Castéra L, et al. Quantitative elastography methods in liver disease: current evidence and future directions. Radiology. 2018;286(3):738-763. 25. Akkaya HE, Erden A, Kuru Öz D, et al. Magnetic resonance elastography: basic principles, technique, and clinical applications in the liver. Diagn Interv Radiol. 2018;24(6):328-335. 26. Sigrist RMS, Liau J, Kaffas AE, et al. Ultrasound elastography: review of techniques and clinical applications. Theranostics. 2017;7(5):1303-1329.

12.

Wong GL, Wong VW, Choi PC, et al. Increased liver stiffness measurement by transient elastography in severe acute exacerbation of chronic hepatitis B. J Gastroenterol Hepatol. 2009;24(6):1002-1007.

27.

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Liu CH, Liang CC, Huang KW, et al. Transient elastography to assess hepatic ﬁbrosis in hemodialysis chronic hepatitis C patients. Clin J Am Soc Nephrol. 2011;6(5):1057-1065.

28. Altamirano J, Qi Q, Choudhry S, et al. Non-invasive diagnosis: non-alcoholic fatty liver disease and alcoholic liver disease. Transl Gastroenterol Hepatol. 2020;5:31.

14.

Taneja S, Borkakoty A, Rathi S, et al. Assessment of liver ﬁbrosis by transient elastography should be done after hemodialysis in end stage renal disease patients with liver disease. Dig Dis Sci. 2017;62(11):31863192.

29. Grady JT, Cyrus JW, Sterling RK. Novel noninvasive tests for liver ﬁbrosis: moving beyond simple tests in metabolic dysfunction-associated steatotic liver disease. Clin Gastroenterol Hepatol. Published online May 30, 2025. doi:10.1016/j.cgh.2025.02.035

15.

Schmoyer CJ, Kumar D, Gupta G, et al. Diagnostic accuracy of noninvasive tests to detect advanced hepatic ﬁbrosis in patients with

Rinella ME, Neuschwander-Tetri BA, Siddiqui MS, et al. AASLD Practice Guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023;77(5):1797-1835.

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First Reports From The Liver Meeting

MASLD, Pruritus in PBC, and More

WASHINGTON—Hepatologists from around the world recently gathered in the nation’s capital for five days of new research, continuing education, and networking opportunities. Topics highlighted during the conference included an array of potential new therapies for and diagnostic approaches to metabolic dysfunction–associated steatotic liver disease and metabolic dysfunction–associated steatohepatitis, as well as new data on primary biliary cholangitis, alcohol-related hepatitis, hepatocellular carcinoma, and more. Below are some early reports, and stay tuned for our continued coverage of important research from the conference.

Cholesterol Ratio Has Potential Role as Biomarker for MASLD Risk There is a strong association between the ratio of non–high-density lipoprotein cholesterol to high-density lipoprotein cholesterol (NHHR) and the incidence and severity of MASLD, according to data presented at the meeting. Building on prior studies of lipid metabolism and the pathogenesis of MASLD, researchers at the Center of Liver Diseases at Beijing Ditan Hospital, in China, conducted an observational study of 1,648 participants from the 2019 to 2020 National Health and Nutrition Examination Survey, using logistic regression analysis to evaluate the relationship between NHHR and the risk for MASLD development (abstract 2127). In addition to evaluating the association between NHHR and MASLD, they looked at differences between pure MASLD and

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metabolic and alcohol–associated liver disease (MetALD). They found a positive relationship between NHHR and MASLD overall (odds ratio [OR], 14.11; 95% CI, 5.37-37.07). Furthermore, NHHR was associated with risk for pure MASLD (OR, 5.41; 95% CI, 2.91-10.04) and MetALD (OR, 5.05; 95% CI, 1.06-24.07). The investigators found a linear relationship between NHHR and MASLD (P<0.001).

In addition, the receiver operating characteristic curve indicated that NHHR is more accurate than traditional lipid metrics for predicting MASLD (area under the curve, 0.586; 95% CI, 0.557-0.616). These findings suggest that NHHR has potential as a novel biomarker for risk evaluation and early detection of MASLD and underscore the need for lipid monitoring in patients who are predisposed to metabolic disease.

Elafibranor Eases Fatigue in PBC Elafibranor, indicated as a second-line treatment for primary biliary cholangitis for its ability to reduce markers of liver damage, also may help improve the debilitating fatigue associated with PBC, according to new research presented at TLM 2025. To evaluate the role of elafibranor (Iqirvo, Ipsen) in protein changes associated with fatigue, researchers collected serum samples from patients in the phase 3 ELATIVE trial, which compared the drug with placebo, and analyzed the samples using the Olink Explore HT proteomic panel, an assay that measures more than 5,000 proteins per sample (abstract 5030). “We found 62 proteins that had significant changes in those patients with a biochemical response to elafibranor treatment,” said Mark Swain, MD, the chair of hepatology at the University of Calgary’s Cumming School of Medicine, in Alberta. Those proteins fell into different groups with pathways relevant to PBC, such as pruritus, inflammation and immune function, fibrosis, bile acid metabolism, lipoproteins, fatigue, and mitochondrial function. Many diseases associated with chronic fatigue, such as long COVID and chronic fatigue syndrome, are associated with changes in blood that indicate impaired mitochondrial activity. “Those changes correlate with alterations in their brain that drive fatigue,” Dr. Swain said. “We’ve found a pattern of changes in proteins in the blood that suggest mitochondria are not working normally in people with PBC and fatigue.”

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About half of the patients treated with elafibranor reported moderate to severe fatigue at baseline, and fatigue scores in this group correlated with changes in blood proteins associated with mitochondrial dysfunction. Those abnormal blood mitochondrial protein patterns normalized with elafibranor treatment by week 52, which corresponded with a reported improvement in fatigue symptoms on patient questionnaires, Dr. Swain said. “What this suggests is that mitochondrial dysfunction in PBC may be associated with changes in the brain that drive fatigue, and when you treat with this medication that activates alpha and delta [peroxisome proliferator–activated receptors], you get a shift towards normalization of those mitochondrial changes that is linked to an improvement in their symptoms of fatigue.” Dr. Swain explained he considers these findings encouraging for two reasons. The study suggests an objective way to measure something in the blood linked to a common symptom in PBC that’s often considered to be subjective in nature, giving physicians and patients something tangible and recognizable. This recognition can be especially validating to patients, he said. Second, the findings indicate that PBC-related fatigue can potentially be treated with medication, Dr. Swain said. “It’s a very exciting opportunity to have a dialogue with our PBC patients about a treatment that improves measures of liver injury but may also help them with regards to their fatigue.” see TLM First Reports, page 30

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TLM First Reports continued from page 28 Less Is More? A Data-Based Argument For Narrowing MASLD Screening Indicators Current guidelines suggest 60% to 76% of the U.S. population should be screened for MASLD, but refined criteria reducing the target screening population to about 22% would be safe and likely more practical, according to an analysis presented at the meeting.

would include adults with diabetes, normal alanine aminotransferase (ALT) levels (<30 IU/L), and no obesity, as well as those with obesity class 1 or 2, no diabetes, and normal ALT levels. Forgoing screening in these patient groups would allow for a more targeted, effec-

Table. Prevalence of MASLD Among Screening Subgroups T2D Weight status

No T2D

ALT ≥30

ALT ≤30

ALT ≥30

ALT ≤30

Healthy weight, %

2-4

Overweight, %

≤1

Overweight and ≥3 metabolic dysfunctions, %

2-3

Obesity class 1, %

14-17

1-3

Obesity class 1 and ≥3 metabolic dysfunctions, %

14-17

5-9

Obesity class 2, %

17-44

Obesity class 3, %

45-48

22-28

ALT, alanine aminotransferase; MASLD, metabolic dysfunction–associated steatotic liver dysfunction; T2D, type 2 diabetes.

In the study, investigators, led by Laurens van Kleef, MD, PhD, a postdoctoral researcher at Erasmus MC, in Rotterdam, Netherlands, looked at National Health and Nutrition Examination Survey data from 2017 to 2020 and identified 5,904 adults with a medical history indicating screening eligibility and a body mass index of at least 18.5 kg/m2 (abstract 2497). The investigators assessed the cohort for the presence of a liver stiffness measure (LSM) of at least 8 kPa and found that it was present in 8.9% of the population. They stratified this group of patients “across the full spectrum of current recommended screening indicators” and identified 80 potential subgroups, the Dr. van Kleef noted. Among the 24% to 40% of the general population who do not meet the screening guidelines, the rate of LSM of at least 8 kPa is around 2%, which is similar to that in some subgroups in the analysis who are eligible for screening, Dr. van Kleef said (Table). For example, this

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tive approach, according to the investigators. The current guidelines-based screening strategy has a positive predictive value (PPV) of 11.1% to 13.5% for an LSM of at least 8 kPa. A refined screening strategy comprising 22% of the U.S. population would improve PPV to 27.7% for an LSM of at least 8 kPa and would have a negative predictive value of 96.3%, according to the analysis. Dr. van Kleef acknowledged the irony of recommending screening fewer patients in a highly underdiagnosed disease but said underdiagnosis may be a clarion call to better stratify them and improve engagement of healthcare professionals in these targeted screening programs. “As it is, these patients are barely getting screened,” he told GEN Priority Report. “It’s important to be realistic and start with those at highest risk in our attempts to reach the patients who need diagnosis and treatment.” —Monica J. Smith and Katie Prince

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Expert Picks From EASL 2025 Corticosteroids in severe AH, identifying MASLD patients eligible for resmetirom, GLP-1s and MASLD cirrhosis, and more

n this installment of Expert Picks from EASL 2025, Ashwani Singal, MD, the medical director of liver

ttransplantation at the University of Louisville’s Trager

EXPERT PICKS

T Transplant Center and a professor of medicine at tthe University of Louisville School of Medicine, in K Kentucky, discusses five of his favorite abstracts ffrom the meeting.

Abstract OS-043-YI. Nonselective Beta-Blockers and Cirrhosis With AKI These results can reassure community gastroenterologists and hepatologists that hospitalized AKI patients ... are not more likely to have adverse outcome because of continued NSBBs.

Abstract OS-092-YI. Antibody-Mediated LT Rejection

Abstract OS-034. Corticosteroids are ineffective in individuals with severe alcohol-associated hepatitis and early spontaneous improvement: a multicenter randomized controlled trial (Moreno et al) Investigators conducted a randomized controlled trial at 10 hospitals in Belgium to evaluate the effect of corticosteroid treatment on mortality in patients with severe alcohol-associated hepatitis (AH) who had spontaneous improvement after hospital admission. Adult hospitalized patients were eligible if they had severe AH (Maddrey discriminant function [mDF], ≥32), as indicated by biopsy, and recent-onset jaundice with spontaneous improvement,

defined as more than a 10% decrease in serum bilirubin within five to 10 days after admission. Participants were randomized to either 32 mg of methylprednisolone per day (n=38) or placebo (n=31) for 28 days. The primary end point was three-month mortality, with secondary end points of one-month mortality and infection rate. At baseline, patients in the corticosteroid and placebo groups had similar age (52 vs. 51 years), sex distribution (76% vs. 63%

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This study can remind gastroenterologists that the diagnosis of antibody-mediated rejection is supported by DSAs in the serum, but that alone should not be enough to make that diagnosis.

Abstract SAT406. GLP-1s and MASLD Cirrhosis This is an important study, as data are emerging that GLP1s, at least in compensated cirrhosis patients, are safe. … It would be relevant to have a study of GLP-1 agonists in patients with cirrhosis assessing muscle density and sarcopenia.

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male), total bilirubin (7.4 vs. 9.3 mg/dL), international normalized ratio (INR) (1.64 vs. 1.70), mDF (44 vs. 45), Model for End-Stage Liver Disease (MELD) score (21 vs. 21), and decrease in bilirubin from admission (31% vs. 27%). At three months, the probability of survival was similar in the corticosteroid and placebo groups (83% vs. 82%). Similarly, the probability of survival at one month was comparable between the treatment groups (95% vs. 94%). Among those in the corticosteroid group, 48% had an infection during the study period, compared with 36% in the placebo group (P=0.41). The investigators noted that despite the study being “prematurely interrupted due to a low recruitment rate,” the results indicate that “it is unlikely that corticosteroids provide a survival benefit when bilirubin level spontaneously decreases by at least 10%.” Thus, “waiting five days after admission before deciding to start steroids seems to be a reasonable strategy.”

Dr. Singal: When patients are hospitalized with severe AH, residents, fellows, and hospitalists often think about giving steroids as the first thing and as an urgent decision. It should be recognized that corticosteroids are recommended, but they are not perfect drugs. They have side effects, so take your time to screen your population, make sure they have no infection, get cultures, give it time. In most randomized trials, the median time to starting steroids has been four to five days because it takes time for the cultures to come back. And in that time, the body’s regenerative and hepatic immune system can result in spontaneous improvement. In that case, there may be no need to start the treatment, and you can avoid making the patient more susceptible to infections. This is an important study because it is randomized and confirms the practice of avoiding steroid use in patients with severe AH who have spontaneous improvement of liver disease and serum bilirubin.

Abstract OS-043-YI. Clinical impact of non selective beta-blockers in patients with cirrhosis and acute kidney injury: a post hoc analysis of the international club of ascites GLOBAL-AKI study (Incicco et al) In a post hoc analysis of the GLOBAL-AKI study, investigators evaluated the effect of treatment with nonselective beta-blockers (NSBBs) on the outcomes of patients with acute kidney injury (AKI). The prospective GLOBAL-AKI study included patients who were hospitalized between July 2022 and May 2023 with acute decompensation of cirrhosis. Outcomes were compared between AKI patients who were taking NSBBs at diagnosis and those who were not. In addition, where data were available, outcomes were compared between those who continued NSBBs during hospitalization and those who tapered or discontinued these agents. The investigators used propensity score matching to balance the NSBB and no-NSBB groups by age, sex, sodium-adjusted model for end-stage liver disease (MELD-Na) score, mean arterial pressure (MAP), ascites, hepatic encephalopathy, AKI stage, acute-on-chronic liver failure (ACLF) grade at AKI diagnosis, and whether patients were from low- or middle-income countries. Among 1,238 patients with AKI, 503 were taking NSBBs at diagnosis (55% propranolol, 45% carvedilol). These patients had lower odds of AKI non-resolution (odds ratio [OR], 0.65; P=0.001) and lower hazard of 28-day mortality (subdistribution hazard ratio [sHR], 0.68; P=0.005) than patients who were not

taking NSBBs at AKI diagnosis. When assessing the association of continuing (n=123) versus tapering or withdrawing from NSBBs (n=350) during hospitalization, the investigators found that there was no statistically significant difference in the odds of AKI non-resolution (OR, 1.00; P=0.999) or the hazard of 28-day mortality (sHR, 0.56; P=0.190) between groups. These results were consistent in subgroup analyses of patients with MAP under 70 mm Hg, serum Na under 130 mmol/L, and ACLF. Based on these results, the investigators concluded, “Continuation of treatment with NSBBs in patients with cirrhosis and AKI does not seem to be harmful.” Dr. Singal: This is an important study for two reasons. First, patients with cirrhosis who are on NSBBs have better outcomes when hospitalized. Second, if NSBBs are continued during the hospitalization in patients with AKI, the outcomes are unaffected. Hence, patients can continue taking these NSBBs without negatively affecting their AKI outcomes while they’re hospitalized. These results can reassure community gastroenterologists and hepatologists that the hospitalized AKI patients they see are not more likely to have adverse outcomes because of continued NSBBs.

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Abstract OS-092-YI. The transcriptomic profile of antibody-mediated rejection is independent from the presence of donor specific antibodies (Engel et al) A multicenter team of researchers assessed the transcriptomic signature of liver biopsies in patients who underwent liver transplantation (LT) to look for differences in gene expression in cases of chronic antibody mediated rejection (cABMR), cABMR with absence of donor-specific antibodies (cABMR-DSAneg), and no histologic rejection (NHR). Liver biopsies performed from 2018 to 2022 at the Hannover Medical School, in Germany, were evaluated for inclusion. Of 21 biopsies meeting cABMR criteria, per Banff 2016 criteria, and with enough tissue for RNA extraction, 15 were cABMR-DSAneg. In addition, 20 biopsies with NHR were used as controls. Patients with cABMR (n=6) and cABMR-DSAneg (n=15) had similar age at LT (47 vs. 40 years; P=0.88) and time since LT (149 vs. 158 months; P=0.88), with most cases found in surveillance biopsies, as opposed to indication biopsies (cABMR, 50%; cABMR-DSAneg, 67%). “The transcriptomic profile or cABMR was characterized by fibrogenesis, complement activation and TNF pathways,” the investigators concluded. They did not find any differences in gene expression in cABMR versus cABMR-DSAneg, “with no up- or

down-regulated genes that differ between the groups.” These results indicate that “the presence of DSA, as described in other solid organ transplants, is not necessary for the diagnosis of cABMR.” Dr. Singal: I think this is a very important study, because we see it all the time that just the presence of DSAs in the serum in a transplant recipient triggers plasmapheresis and treatment of antibody-mediated rejection. But this is not always appropriate because, first, antibody-mediated rejection in LT is a very rare event, and second, you have to take your time to make the diagnosis. Obviously, DSAs and the titers are important, but also you should have a biopsy and C4d staining and make sure that you have proper histology, so you’re not treating somebody for antibody-mediated rejection just because they have DSAs. This study makes that point and can remind gastroenterologists that here is a proper set of findings you need to see on biopsy to make the diagnosis of antibody-mediated rejection. It’s supported by DSAs in the serum, but that alone should not be enough to make that diagnosis.

Abstract OS-097. Evaluating noninvasive diagnostic pathways for identifying MASH patients eligible for resmetirom therapy: a real-world cohort analysis (Dunn et al) A team of researchers at six U.S. tertiary hepatology clinics compared the performance of several noninvasive tests (NITs) for diagnosis of metabolic dysfunction–associated steatohepatitis (MASH) with significant (F2) to advanced (F3) fibrosis and consideration for treatment with resmetirom (Rezdiffra, Madrigal). The investigators noted that such NITs can be used in primary care to “determine who needs referral to hepatology care.” Patients were included in this retrospective analysis if they were treated for metabolic dysfunction–associated steatotic liver disease (MASLD) with resmetirom between March and November 2024 at one of the six study centers and met at least one of the AASLD treatment consideration criteria (liver stiffness measurement [LSM] of 8-20 kPa, Enhanced Liver Fibrosis [ELF] test result of 9.2-11.3, or liver biopsy fibrosis stage 2 or 3). In total, 424 patients were evaluated for inclusion. Among 88.9% who underwent transient elastography, 69.8% met the AASLD LSM-based criteria. Among 13.2% who underwent ELF testing, 73.2% met the AASLD ELF-based criteria. Among 20.8% who underwent liver biopsy, 45.5% had F2 fibrosis and

46.6% had F3 fibrosis. Thus, 337 of the patients met AASLD criteria and were included in the analysis evaluating the NITs (FIB4, SAFE score, LiverRisk Score, and ALADDIN-F2-Lab score). The proportion of the 337 patients who met AASLD criteria but were characterized as low risk by the NITs ranged from 12.5% for ALADDIN-F2-Lab, 13.0% for SAFE, 45.8% for FIB-4, and 80.2% for LiverRisk Score. The investigators highlighted that “this real-world analysis highlights the limitations of current AASLD and EASL guidelines, which rely on FIB-4, in identifying MASH patients with significant fibrosis,” based on “nearly half ” of eligible patients being characterized as low risk based on FIB-4. “In contrast,” the investigators noted, “novel scoring systems like SAFE and ALADDIN-F2-Lab, leveraging routine laboratory data, identified the majority of patients as intermediate or high risk.” Dr. Singal: This study came up with a new machine learning model called ALLADIN-F2-Lab (Am J Gastroenterol 2025 Mar 27. doi:10.14309/ajg.0000000000003432), developed under the

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leadership of Dr. Winston Dunn, a transplant hepatologist at the University of Kansas Health System, which was shown to be better than the two-step strategy of FIB-4 followed by vibrationcontrolled transient elastography (VCTE) (FibroScan, EchoSens) for identifying F2/F3 patients. I think an important advantage of this model is that does not take VCTE into consideration, so community gastroenterologists and

hepatologists who do not have access to VCTE can use the ALADDIN model and be confident in picking F2 or F3 patients who may be candidates for resmetirom treatment for MASH. They can go to a website to get the probability of F2 or higher fibrosis by plugging in values for certain variables, including VCTE (aihepatology.shinyapps.io/ALADDIN1/) or excluding VCTE (aihepatology.shinyapps.io/ALADDIN2/).

Abstract SAT406. Role of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) in mortality reduction among patients with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD) cirrhosis: a global retrospective analysis (Aitharaju et al) Using data from TriNetX, researchers assessed the association of glucagon-like peptide-1 receptor agonist (GLP-1) use with mortality and hepatocellular carcinoma (HCC) incidence in a cohort of patients with MASLD complicated by cirrhosis. Data from 2004 to 2024 were examined, with patients split into those who were prescribed GLP-1s after diagnosis (users) and those who had never been prescribed a GLP-1 (nonusers). Patients who had cirrhosis from etiologies other than MASLD were excluded, as were patients with decompensated cirrhosis. Among 40,646 eligible patients, 4,328 were GLP-1 users. Propensity score matching resulted in inclusion of 3,846 users and 3,846 nonusers in analyses. The investigators found that GLP-1 users had a decreased hazard of five-year mortality (HR, 0.37; 95% CI, 0.27-0.50) and five-year incidence of HCC (HR, 0.57; 95% CI, 0.36-0.89), compared with nonusers. Secondary outcomes were also improved in GLP-1 users, including lower incidence of

Hepatology Insights

liver transplant (hazard ratio [HR], 0.45; 95% CI, 0.24-0.82), sepsis (HR, 0.52; 95% CI, 0.36-0.76), inpatient admissions (HR, 0.54; 95% CI, 0.47-0.62), obesity-associated malignancies (HR, 0.64; 95% CI, 0.54-0.76), and major adverse cardiovascular events (HR, 0.84; 95% CI, 0.72-0.98). Dr. Singal: This is an important study, as data are emerging that GLP-1s, at least in compensated cirrhosis patients, are safe. So, I think this is another example of reassuring data on GLP-1 safety and efficacy in a cirrhosis population. We know that 40% of weight loss that comes from GLP-1s is lean mass and not fat mass. But cirrhosis patients are prone to lean body mass loss due to nutritional deficiency and catabolic state. It would be relevant to have a study of GLP-1 agonists in patients with cirrhosis assessing muscle density and sarcopenia. —Compiled and written by Natasha Albaneze, MPH Dr. Singal is a member of the Gastroenterology & Endoscopy News editorial board.

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Reports From The Liver Meeting, Advanced ALD Review, New Resmetirom Analyses and More

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