Two-step care pathways for advanced MASLD in primary and hospital care: A multicenter study

Background: Early diagnosis of metabolic dysfunction–associated steatotic liver disease (MASLD) fibrosis may prevent liver-related morbidity and mortality. We investigated the effectiveness of multiple 2-step approaches for detecting at-risk advanced MASLD fibrosis, defined as a hierarchical clinical score comprising liver histology and VCTE depending on availability, in primary and hospital outpatient care. Methods: Patients at risk for MASLD were recruited from general practices and regional and tertiary internal medicine clinics, after excluding other liver diseases. Simultaneous measurement of non-invasive tests (NITs), including fibrosis-4 score (FIB4), metabolic dysfunction–associated fibrosis-5 score (MAF5), NAFLD fibrosis score (NFS), enhanced liver fibrosis (ELF) test, procollagen type III N-terminal propeptide (PRO-C3), procollagen type VI N-terminal propeptide (PRO-C6), and vibration-controlled transient elastography (VCTE), allowed testing of 2-step referral pathways. Referral patterns were compared with regular care between 2016 and 2024 using a predefined reference standard. Results: Among 595 participants, 9.4% were at-risk of advanced MASLD fibrosis. A care pathway consisting of FIB4 (≥1.30) followed by VCTE yielded the greatest improvement, increasing the correct referral rate 5.0-fold (95% CI: 2.4–10.1) compared with regular care. However, care pathways incorporating MAF5 (≥1.0) or NFS (≥−1.455) followed by VCTE demonstrated markedly higher sensitivity at comparable increases in detection (both >4.5-fold). Among other second-step NITs, PRO-C3 outperformed ELF, PRO-C6, and ADAPT, resulting in a 2.2-fold (95% CI: 1.1–4.4) increase in correct referrals when used after FIB4 (≥1.30). Conclusion: Two-step care pathways substantially improve the detection of at-risk advanced MASLD fibrosis across care settings. Pathways using FIB4, MAF5, or NFS followed by VCTE offer the best performance overall, while PRO-C3 is the most effective alternative blood-based second-step test.