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.