Defining Noninvasive Criteria for Indicating Drug Therapy in Metabolic dysfunction-associated Steatotic Liver Disease in Clinical Practice

Abstract

Background & aims: Resmetirom is the first Food and Drug Administration-approved drug for metabolic dysfunction-associated liver disease (MASLD) in F2 and F3 patients with steatohepatitis. Noninvasive criteria have been proposed for initiating treatment; however, these have not been validated in clinical practice. We validated the proposed criteria and established new guidelines for initiating resmetirom treatment in clinical practice.

Methods: This was a cross-sectional study of 1281 MASLD patients from the HEPAmet registry with biopsy, comorbidity assessment, analytical profile, and elastography. Identification of MASLD with F2 and F3 was the main endpoint. A comprehensive review of international guidelines and expert consensus up to November 2024, focusing on therapeutic indications, was conducted.

Results: A total of 38% (n = 486 of 1281) of patients were diagnosed with MASLD F2 and F3 based on biopsy. However, only 39% and 56% of them met treatment eligibility criteria according to the Expert Panel Criteria and the American Association for the Study of Liver Diseases Practice Guidance, respectively. They included 45% of patients with early-stage fibrosis. False positive and false negative rates ranged from 23% to 41% and 44% to 60%, respectively, with area under the receiver-operating characteristic curve values below 0.60.These findings were validated in an external cohort. A two-step strategy, first selecting patients with Fibrosis-4 (FIB-4) ≥1.30, or with diabetes and overweight if FIB-4 <1.30, followed by a liver stiffness between 8 and 25 kPa, demonstrated higher positive (55%) and negative predictive values (77%) and higher area under the receiver-operating characteristic curve (0.67).This approach successfully identified 74% of the target population.

Conclusions: The diagnostic performance and reliability of the proposed noninvasive criteria for initiating resmetirom treatment were suboptimal. About the half of patients with indication would not receive treatment under these criteria. A new strategy, using FIB-4, the presence of diabetes and overweight, and liver stiffness improved the identification of MASLD patients with F2 and F3.

Keywords: MASH; MASLD; guidelines; resmetiron; steatohepatitis.