A new generation of non-invasive tests of liver fibrosis with improved accuracy in MASLD

Abstract

Background & aims: The accuracy of non-invasive tests (NITs) should be ≥80% (EASL recommendation). We aimed to compare the accuracies of the recommended NITs for advanced fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD) and to develop NITs with improved accuracy.

Methods: A total of 1,051 patients with MASLD were allocated to derivation (n = 637) and validation (n = 414) sets. The main outcome (Kleiner F3+F4) was primarily evaluated by accuracy. Recommended NITs included: FIB-4, Fibrotest, FibroMeter, liver stiffness measurement (LSM by Fibroscan), Elasto-FibroMeter (FibroMeter-LSM combination), and ELF (enhanced liver fibrosis) in 396 patients. We used machine learning-optimized multitargeting to develop new NITs: FIB-9 (including nine common biomarkers), FIB-11 (adding two specialized blood markers) and FIB-12 (adding LSM).

Results: In the whole population, the accuracies of recommended NITs were insufficient: Fibrotest, 68.0%; FIB-4, 71.2%; FibroMeter, 75.1%; LSM, 75.9%; Elasto-FibroMeter, 78.6%. Therefore, new NITs (FIB-9, FIB-11, FIB-12) were developed in the derivation set. In the validation set, AUROCs were: FIB-4, 0.757; Fibrotest, 0.766; FibroMeter, 0.850; LSM, 0.852; FIB-9, 0.863; FIB-11, 0.880; Elasto-FibroMeter, 0.894; FIB-12, 0.912 (p <0.001). The FIB-12 AUROC was superior to the ELF AUROC (0.906 vs. 0.865, p = 0.039). Accuracies were: FIB-4, 68.8%; Fibrotest, 68.6%; LSM, 75.4%; FibroMeter, 76.3%; FIB-9, 78.7%; Elasto-FibroMeter, 79.7%; FIB-11, 80.2%; FIB-12, 83.3% (p <0.001 between all NITs). Scores were segmented by ≥90% sensitivity and specificity cut-offs or NIT match, which individualized subgroups with NIT accuracies ≥80%, e.g. for FIB-9: 85.8% in 68.1% of patients using two cut-offs and 83.2% in 71.7% of patients where FIB-9 agreed with FIB-4.

Conclusions: Recommended NITs had accuracies <80% for advanced fibrosis in MASLD. Several NIT segmentations individualized subgroups with accuracies ≥80%. New NITs further improved accuracy. The simple FIB-9 (available via a free calculator) provided accuracy equaling or surpassing recommended NITs. FIB-12 outperformed other NITs.

Impact and implications: Currently recommended non-invasive tests (NITs) have insufficient accuracy (<80%) for the diagnosis of advanced fibrosis in metabolic dysfunction-associated steatotic liver disease (MASLD). Therefore, we developed three new NITs with new statistical techniques. Thus, FIB-9 (available via a free calculator), including nine common blood markers, equaled the performance of patented NITs. FIB-11, adding two specialized blood markers, and FIB-12, adding liver stiffness, had accuracy >80%. FIB-12 outperformed all other NITs. FIB-9 is suitable for screening and FIB-11 or FIB-12 for diagnosis.

Keywords: Liver fibrosis; MASLD; NAFLD; blood test; diagnosis; elastometry; non-invasive test.