New CLA3+/4 scores predict outcomes in MASLD

Fibrosis is a major determinant of adverse outcomes in metabolic dysfunction-associated steatotic liver disease (MASLD). We developed and validated two probability scores for advanced fibrosis (≥F3) and cirrhosis (F4)-CLA3+ and CLA4-using controlled attenuation parameter (CAP), liver stiffness (LS) by vibration-controlled transient elastography (VCTE), and alanine aminotransferase (ALT), and evaluated their prognostic values for liver-related events (LREs).

In a 16-center multinational cohort, single-term fractional-polynomial logistic regression models derived CLA3+ and CLA4 probabilities. Prognostic performance was assessed using time-dependent area under the receiver operating characteristic curve (AUROC), Brier score, integrated discrimination improvement (IDI), and serial-change analyses.

The derivation cohort included 2,811 biopsied patients; validation included 11,196 patients with baseline VCTE, of whom 8,046 had serial assessments. Derivation AUROCs were 0.84 for CLA3+ and 0.89 for CLA4. In validation, both achieved the highest integrated AUROC (0.83) and lowest integrated Brier scores (0.0078-0.0081) among non-invasive tests, with good calibration. CLA3+ classified 83.1%/10.8%/6.1% as low/intermediate/high risk (5-year LRE 0.4%/1.5%/11.8%; sensitivity 0.72), whereas CLA4 classified 92.0%/3.6%/4.4% (0.5%/4.7%/13.0%; specificity 0.93), with the smallest intermediate-risk groups. IDI favored CLA3+ over Agile3+, whereas CLA4 performed similarly to Agile4. Serial risk categories remained stable in 86.7% for CLA3+ and 93.2% for CLA4, while ≥10-30% decreases were associated with lower LRE risk. Two-step testing reduced intermediate classifications to 3.9% with FIB-4→CLA3+ and 1.4% with FIB-4→CLA4, with a 5-year LRE rate of 8.3% in the rule-in group.

CLA3+ and CLA4 provide well-calibrated estimates for advanced fibrosis and cirrhosis using controlled attenuation parameter, liver stiffness, and alanine aminotransferase, with small intermediate-risk groups and prognostically informative serial changes. They may serve as second-line tests within Fibrosis-4 index-based two-step pathways.

Current MASLD care pathways use sequential non-invasive testing to identify patients at risk of advanced fibrosis and liver-related events, but existing composite scores often require multiple clinical inputs and leave substantial intermediate-risk groups. CLA 3+ and CLA 4 use CAP, liver stiffness, and ALT to achieve prognostic performance comparable to Agile scores, while yielding small intermediate-risk groups and informative serial changes. These findings support their potential use as simple second-line tools after FIB-4 and for longitudinal risk assessment in VCTE-based pathways, with relevance to clinical triage and future trial design.