VALIDATION OF NONINVASIVE CLINICAL PATHWAYS TO IDENTIFY ADVANCED

Abstract

Introduction and Objectives

Limited data exist on non-invasive clinical algorithms for MetALD and ALD. We aimed to (1) quantify the false-negative rate of standard algorithms combining Fibrosis-4 index (FIB-4) and vibration-controlled transient elastography (VCTE) for detecting advanced fibrosis in MetALD and ALD, and (2) evaluate the diagnostic accuracy of FIB-4 for advanced fibrosis in MetALD.

Materials and Methods

Retrospective cohort including 764 well-characterized adults with MetALD (n=334, 43.7%) or ALD (n=430, 56.3%) from 14 countries (2003–2025) according to the 2023 criteria; other concomitant liver diseases were excluded. All underwent VCTE (>8 kPa considered elevated); 244 (31.9%) also had liver biopsy. FIB-4 was categorized as low risk <1.3, indeterminate 1.3–2.67 (2.0–2.67 if ≥65 years), and high risk >2.67. Analysis included AUROC curves.

Results

Mean age was 49.5 years (IQR 41–59); 73.1% were male; mean BMI 28.0 kg/m² (IQR 24.1–31.6); 32.2% had diabetes. Median FIB-4 was 1.57 (IQR 0.92–3.29); median LSM 8.6 kPa (IQR 5.9–22.3). Among those biopsied (n=244), 14.3% had F3 and 11.9% had cirrhosis (F4). Of the low FIB-4 group, 28.1% had elevated VCTE (32.0% MetALD; 24.9% ALD). Sixteen participants classified as low-risk by both FIB-4 and LSM had ≥F3 fibrosis on biopsy—false-negative rate 6.6% overall (5.7% MetALD; 7.4% ALD) (Figure). In MetALD, FIB-4 yielded an AUROC of 0.736 (95%CI:0.610–0.863) for ≥F3 fibrosis; the optimal cut-point was ≥1.65 (sensitivity 74%, specificity 73%). Applying ≥1.65 to participants over 65 years with MetALD reduced the false-negative rate to 2.0%, while the referral rate rose only from 30.3% to 33.6%.

Conclusions

Standard noninvasive pathways combining FIB-4 and VCTE had low false-negative rates for advanced fibrosis in MetALD and ALD. In patients with MetALD aged +65 years, lowering the FIB-4 threshold to ≥1.65 may improve advanced fibrosis detection.