A Novel Fibroblast Activation Protein-Based Algorithm to Assess Fibrosis in Metabolic Dysfunction–Associated Steatotic Liver Disease

Abstract

Background: Noninvasive fibrosis testing is crucial for metabolic dysfunction–associated steatotic liver disease (MASLD) management. This study evaluated a marker of activated mesenchymal fibrogenic cells, circulating fibroblast activation protein (cFAP), in a novel diagnostic algorithm, FAP Index, for patients with MASLD. Methods: Two retrospective cohorts recruited from tertiary hepatology clinics were studied as training (n = 160) and external validation cohorts (n = 332), with prevalence of histologic advanced fibrosis (F3–F4) of 20% and 11%, respectively. cFAP was measured using our rapid single-step FAP-specific microplate enzyme assay. A predictive model, FAP Index, containing age, type 2 diabetes, alanine transaminase, and ordinal cFAP was developed using logistic regression; then, its diagnostic accuracy was evaluated. Results: FAP Index AUROC for advanced fibrosis was 0.875 (95% CI: 0.813–0.938) in the training cohort and 0.841 (95% CI: 0.776–0.906) in the validation cohort. Low cutoff 0.157 (sensitivity 84.3%, negative predictive value 95%) and high cutoff 0.695 (specificity 99.2%, positive predictive value 92.9%) values excluded and predicted advanced fibrosis, respectively. FAP Index following FIB-4 reduced the frequency of indeterminate results by more than one-third compared to FIB-4 alone. FAP Index following NFS (NAFLD Fibrosis Score) reduced the frequency of indeterminate results by ~70% compared to NFS alone. Conclusion: Without a need for elastography, applying FAP Index following FIB-4 or NFS can facilitate accurate risk stratification of patients by greatly reducing the frequency of indeterminate results compared to FIB-4 or NFS alone, without compromising negative predictive value. Thus, FAP Index is a novel, fibrogenesis-relevant, rapid, robust diagnostic tool suited to increasing the efficiency of liver fibrosis triage in primary care.