Wu, Hao

Background: Accurate identification of patients with metabolic dysfunction–associated steatohepatitis (MASH) at risk of disease progression (at-risk MASH) is critical for guiding resmetirom and semaglutide therapy. Inconsistent definitions of at-risk MASH complicate clinical risk classification and comparisons across studies. This study aimed to standardize the definition of at-risk MASH and propose optimized MRE-based liver stiffness (LS-MRE) cutoffs to improve noninvasive risk stratification and better guide pharmacotherapy. Methods: In this prospective study, 413 patients with suspected or diagnosed MASLD from two medical centers underwent liver biopsy and MRE. Results: A simplified definition of at-risk MASH (MASH with fibrosis stage≥2) identified a broader group of patients requiring clinical attention than a stricter definition requiring NAFLD Activity Score≥4 with ≥1 point in steatosis, inflammation, and ballooning (n=122 vs. 77). LS-MRE alone showed the highest diagnostic accuracy for identifying at-risk MASH using the simplified definition (AUC 0.91 [0.87, 0.95]) and cirrhosis (AUC 0.93 [0.88, 0.99]), compared with FIB-4 and individual laboratory parameters (AST, ALT, and platelet count) ( p <0.01 for all, paired DeLong tests). Optimized LS-MRE cutoffs (2.8–6.4 kPa) captured 25 additional biopsy-proven pharmacotherapy candidates (28% of all eligible patients) compared to AASLD guidelines–recommended cutoffs (3.1–4.4 kPa), improving sensitivity (80% vs. 50%) with acceptable specificity (73% vs. 88%). Conclusions: A simplified definition of at-risk MASH enables broader identification of treatment candidates. LS-MRE demonstrates excellent diagnostic performance and improves noninvasive risk stratification when paired with optimized cutoffs. These findings support the use of MRE to guide resmetirom and semaglutide eligibility and improve access to emerging therapies.

Background: Qualification of non-invasive tests (NITs) and blood biomarkers for fibrosis severity and risk assessment is an unmet need in clinical care for cirrhosis. The paucity of reproducibility data for imaging and blood biomarkers in cirrhosis hinders their application for longitudinal monitoring. The aim of this study was to evaluate the reproducibility of imaging and blood biomarkers in a prospective cohort of adults with cirrhosis. Methods: We prospectively enrolled adults with cirrhosis in an observational, longitudinal cohort study. Participants completed a research visit with vibration-controlled transient elastography (VCTE) with liver stiffness measurement (LSM) and controlled attenuation parameter (CAP) and blood testing, including AST, ALT, platelets, alpha-fetoprotein (AFP), and the Fibrosis-4 Index (FIB-4). Biomarkers were repeated a median of 3 months apart without any interim intervention. The primary outcome was the reproducibility of each biomarker as assessed by the reproducibility coefficient (RDC%), within-participant coefficient of variation (wCV), intraclass correlation coefficient (ICC), and Bland–Altman analysis. Results: In total, 40 participants (mean age 62, 60% female, mean BMI 28.6 kg/m 2 ) had VCTE/CAP, 38 AST/ALT, and 26 had AFP at both time points. The RDC% for VCTE-LSM was 54.4, wCV 0.19, and ICC 0.91. VCTE CAP had an RDC% of 56, a wCV of 0.30, and ICC 0.47. AFP had an RDC% of 58, a wCV of 0.21, and an ICC of 0.95. RDC% for AST, ALT, and FIB-4 ranged from 70% to 79%. On Bland–Altman analyses, VCTE-LSM demonstrated the lowest relative bias (0.4%). Conclusions: Prospective assessment of repeat biomarkers in adults with cirrhosis found that VCTE-LSM and CAP provide consistent assessments across individuals but may yield substantial within-individual variation. Blood-based biomarkers had poor reproducibility within individuals but were consistent in detecting between-patient variability. These data can inform ultrasound-based non-invasive testing qualification by defining thresholds that may reflect measurement variability rather than true biologic change over time.