Limitations of Guideline-Recommended Risk Stratification in Identifying MASLD Patients for Novel Drug Treatments

Current guidelines recommend FIB-4 and transient elastography for non-invasive risk stratification in metabolic dysfunction-associated steatotic liver disease (MASLD). These tests can predict the presence or absence of advanced fibrosis, but their accuracy for identifying significant fibrosis in MASLD patients eligible for novel drug treatments remains unclear. In a multicenter cohort of 458 biopsy-proven MASLD patients, we evaluated the suitability of FIB-4 for identifying MASLD with histologically significant fibrosis (≥ F2). In a subcohort of 291 patients, we further assessed the diagnostic performance of the guideline-based sequential use of FIB-4 and transient elastography. We demonstrate that the recommended risk stratification remains suboptimal for the identification of patients with significant fibrosis, resulting in remarkably high false-positive and false-negative rates for FIB-4 (43% and 26%, respectively). Consequently, guideline-based risk stratification may misclassify a significant proportion of patients, leading to inappropriate treatment decisions regarding novel MASLD therapies approved for F2/F3 fibrosis.