BACKGROUND & AIMS:Noninvasive tests (NITs) are widely used to risk-stratify patients with metabolic dysfunction-associated steatotic liver disease (MASLD); however, their performance may vary according to patient characteristics. We evaluated the accuracy of NITs in a large, multinational MASLD cohort across select subpopulations. METHODS:We analyzed 18,759 adults with biopsy-confirmed MASLD from 41 countries. NITs included FIB-4, liver stiffness measurement (LSM), and Agile-3+. Diagnostic performance for advanced fibrosis (F3-F4) was measured using areas under the curve (AUCs) across subgroups defined by age, sex, type 2 diabetes (T2D), obesity, and alcohol use. Subgroup-specific cutoffs were derived. RESULTS:Advanced fibrosis was present in 37% of patients. Pooled AUCs were 0.79 for FIB-4, 0.83 for LSM, and 0.86 for Agile-3+. FIB-4 accuracy declined with age (AUC 0.70 in ≥65 years vs 0.79 in <65 years, P < .0001) and in middle-aged patients with T2D. The LSM performance remained stable across T2D status but was moderately reduced in patients with obesity and, more profoundly, morbid obesity (body mass index [BMI] >35 kg/m2). Sex and alcohol use had minimal impact on AUCs. Age- and T2D-specific FIB-4 cutoffs varied substantially to maintain predefined accuracy (sensitivity or specificity). The cutoffs for LSM also differed based on patients' BMI, with lower diagnostic cutoffs for advanced fibrosis required in nonobese MASLD (sensitivity 80%: 8.8 kPa in lean, 9.0 kPa overweight, 9.6 kPa in obesity, 11.0 kPa in morbid obesity). CONCLUSIONS:Accuracy of NITs for advanced fibrosis in MASLD is influenced by age, T2D, and obesity. Age-adjusted FIB-4 thresholds may enhance risk stratification. Imaging-based and composite NITs (LSM and Agile-3+) provide more consistent performance across MASLD subpopulations.
INTRODUCTION AND OBJECTIVES:Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease but remains widely under-recognized in primary care. The 2023 shift from "nonalcoholic fatty liver disease" to MASLD emphasized metabolic dysfunction as a driver of disease but introduced new communication and educational challenges for primary care providers (PCPs). We aimed to assess PCPs' awareness, risk assessment, and management practices related to MASLD in the four most populous U.S. cities. MATERIALS AND METHODS:A cross-sectional online survey was conducted from 5 to 13 September 2024 among 800 primary care providers (PCPs; n = 200 per city) in New York City, Los Angeles, Chicago, and Houston. Participants included physicians, physician assistants, nurse practitioners, and other primary care professionals. The survey assessed awareness of "MASLD" and "fatty liver disease", risk assessment practices for high-risk groups, patient discussions, management strategies, and the use of patient-reported outcomes (PROs). Descriptive statistics characterized sample responses, and logistic regression models identified correlates of awareness. RESULTS:Overall, 54.7% of PCPs reported awareness of MASLD and 86.6% were aware of fatty liver disease. Awareness of MASLD was highest among physicians (81.3%) and hospital-based practitioners (odds ratio [OR] = 2.02, 95% confidence interval [CI] 1.02-4.02) and lowest among nurse practitioners (OR = 0.21, 95% CI 0.09-0.49). Awareness of fatty liver disease increased with provider age (OR = 1.04, 95% CI 1.00-1.08). Lifestyle modification was the most recommended management approach (41.3-65.5%), while referral rates to specialists and PRO use varied substantially across cities, and 48.5% were aware of the FIB-4 Index. CONCLUSIONS:Only half of PCPs recognized the term MASLD, highlighting gaps in awareness and clinical practice following the mid-2023 terminology change. Targeted educational initiatives and standardized implementation of MASLD guidelines in primary care are needed to improve timely detection and management of this highly prevalent condition.
Metabolic dysfunction associated steatotic liver disease (MASLD) affects nearly one-third of adults worldwide, particularly among individuals with obesity or type 2 diabetes, and in 10-30% progresses to metabolic dysfunction associated steatohepatitis (MASH) or fibrosis. Resmetirom, a selective thyroid hormone receptor-β (THR-β) agonist, became the first therapy to demonstrate both MASH resolution and fibrosis improvement, leading to accelerated food and drug administration (FDA) approval in 2024 and conditional European Medicine Agency (EMA) approval in 2025 in the treatment of fibrotic MASH. Resmetirom is a liver-specific drug that simulates the effect of T3 and thereby reduces intrahepatic fat. It is safe and generally well tolerated. Current clinical guidance recommends treating patients with non-cirrhotic fibrotic MASH (typically those with LSM-VCTE 10-20 kPa or MRE 3.1-4.4 kPa), while excluding patients with cirrhosis, active liver disease, significant alcohol use, or untreated thyroid disorders. Treatment monitoring focuses on hepatic safety, thyroid function in selected patients, and assessment of response using non-invasive tests and ALT after 6-12 months. Real-world data indicate rapid adoption of non-invasive eligibility assessments, early improvements in liver stiffness, and frequent concomitant GLP-1 receptor agonist use, with treatment response appearing independent of weight-loss therapy. As semaglutide has now also gained regulatory approval for fibrotic MASH, optimal positioning of resmetirom within treatment algorithms, combination strategies with GLP-1 receptor agonists, and the long-term impact on liver-related and cardiometabolic outcomes remain key priorities. This review discusses the evidence supporting conditional approval of resmetirom, outlines current clinical recommendations, early real-world experiences, and highlights ongoing challenges and future directions in the management of fibrotic MASH.
BACKGROUND & AIMS:Metabolic dysfunction-associated steatotic liver disease with increased alcohol intake is a distinct clinical entity characterized by hepatic steatosis driven by both metabolic syndrome and alcohol use. This study aimed to characterize the clinical presentation and evaluate major liver outcomes and all-cause mortality in patients with lean vs nonlean metabolic dysfunction-associated steatotic liver disease with increased alcohol intake. METHODS:We conducted a retrospective cohort study using data from the Veterans Analysis of Liver Disease (VALID) cohort. Lean metabolic dysfunction-associated steatotic liver disease with increased alcohol intake was defined as metabolic dysfunction-associated steatotic liver disease with increased alcohol intake in individuals with a body mass index <25 kg/m2 (<23 kg/m2 in Asians). We used a multivariable Fine and Gray competing risk model to assess the association between lean metabolic dysfunction-associated steatotic liver disease with increased alcohol intake and major liver outcomes and all-cause mortality. RESULTS:A total of 98,076 veterans with metabolic dysfunction-associated steatotic liver disease with increased alcohol intake were included, of whom 12,613 met criteria for lean metabolic dysfunction-associated steatotic liver disease with increased alcohol intake, between January 1, 2011, and December 31, 2022, with follow-up through May 31, 2023. Patients with lean metabolic dysfunction-associated steatotic liver disease with increased alcohol intake had a higher Alcohol Use Disorders Identification Test-Concise score, and higher aspartate aminotransferase to alanine aminotransferase ratio (aspartate aminotransferase > alanine aminotransferase; 42.9 vs 37.9 IU/mL), whereas patients with nonlean metabolic dysfunction-associated steatotic liver disease with increased alcohol intake had more cardiometabolic risk factors and aspartate aminotransferase < alanine aminotransferase (38.1 vs 49.3 IU/mL). Lean metabolic dysfunction-associated steatotic liver disease with increased alcohol intake was independently associated with a 28% higher risk of major liver outcomes (adjusted hazard ratio, 1.28; 95% confidence interval, 1.18-1.38) and a 82% higher risk of all-cause mortality (adjusted hazard ratio, 1.82; 95% confidence interval, 1.74-1.91) compared with nonlean metabolic dysfunction-associated steatotic liver disease with increased alcohol intake. CONCLUSIONS:Patients with lean metabolic dysfunction-associated steatotic liver disease with increased alcohol intake displayed clinical features more consistent with alcohol-associated liver disease, whereas patients with nonlean metabolic dysfunction-associated steatotic liver disease with increased alcohol intake were clinically more similar to metabolic dysfunction-associated steatotic liver disease. Lean metabolic dysfunction-associated steatotic liver disease with increased alcohol intake is associated with significantly increased risks of liver-related complications and mortality, reinforcing the need for tailored management strategies targeting alcohol use disorder for this high-risk subgroup.
