Sequential FIB-4–based testing limits detection of fibrotic MASLD despite optimized ELF thresholds

Abstract

Background: Societal guidance recommends sequential noninvasive testing for metabolic dysfunction–associated steatotic liver disease (MASLD), using Fibrosis-4 (FIB-4) ≥1.3 as a gatekeeper before second-line assessment with the Enhanced Liver Fibrosis (ELF) score (<7.7 as a rule-out). The impact of this pathway design on the detection of fibrotic MASH remains uncertain. We aimed to evaluate the performance of guideline-endorsed sequential testing and to determine optimized ELF thresholds within alternative strategies. Methods: In this prospective study, patients with or at risk for MASLD underwent FIB-4, ELF testing, magnetic resonance elastography (MRE), and liver biopsy within 1 month. Fibrotic MASLD was defined as fibrosis stage ≥2 on histology or liver stiffness ≥3.1 kPa on MRE. Diagnostic performance of ELF was assessed, and sequential (ELF applied after FIB-4 ≥1.3) and concurrent (either test positive) testing strategies were compared. Results: Among 186 participants (median age 51 years; 69% women), fibrotic MASLD was present in 71 (38%). ELF demonstrated AUROC 0.77 (95% CI 0.70–0.84); the cohort-derived cutoff was 9.4 (80% sensitivity, 65% specificity). Lower cutoffs (8.7 and 7.7) increased sensitivity (≥90% and 100%) but low specificity (34% and 4%). FIB-4 ≥1.3 showed limited sensitivity (57%), resulting in 43% of fibrotic MASH cases being excluded from second-line testing. Sequential application of ELF, therefore, failed to overcome this sensitivity ceiling. A concurrent strategy using FIB-4 ≥1.3 or ELF ≥9.4 improved sensitivity to 87% with 64% specificity. Conclusions: Sequential FIB-4–based testing substantially limits the detection of fibrotic MASLD due to gatekeeping sensitivity constraints. Concurrent first-line testing with FIB-4 and ELF improves case identification, underscoring the importance of pathway design in optimizing noninvasive fibrosis assessment.