Development and validation of a novel circulating fibroblast activation protein - based predictive model to improve fibrosis risk stratification in metabolic liver disease population

ObjectiveMetabolic fatty liver disease drives chronic liver injury leading to fibrosis. This study aimed to establish a model utilising serum circulating fibroblast activation protein (cFAP) to diagnose advanced fibrosis in patients with fatty liver disease. DesignTwo retrospective cohorts recruited from tertiary hepatology clinics were studied as training (n=160) and external validation cohorts (n=342), with prevalence of histologic advanced fibrosis (F3-F4) of 20% and 11%, respectively. A marker of activated mesenchymal fibrogenic cells, cFAP, was measured using our single-step enzyme assay. A predictive model, FAP Index, containing age, type 2 diabetes, alanine transaminase and ordinal cFAP was developed using logistic regression. Diagnostic accuracy of FAP Index was assessed on a single and then sequential basis. ResultsFAP Index AUROC 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 cut-off -1.68 (Sensitivity 80.0%, negative predictive value 95.5%) and high cut-off +0.953 values (Specificity 97.7%, positive predictive value 88.9%) excluded and diagnosed advanced fibrosis, respectively. In the validation cohort, FAP Index then FIB-4 reduced indeterminate results by one-third compared to FIB-4 alone. Whereas FAP Index followed by NFS (NAFLD Fibrosis Score) resulted in a reduction of indeterminate results by 70% compared to NFS alone. ConclusionFAP Index is a novel, rapid, robust, inexpensive diagnostic tool for advanced fibrosis in metabolic fatty liver disease. Applying FAP Index followed by FIB-4 or NFS facilitates 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. What is already known on this topicFatty liver disease affects one quarter of the global population. Current screening algorithms to triage those at high risk of advanced fibrosis use a dual cut-off approach that results in a proportion of patients that cannot be classified (indeterminate result) and hence need further and more costly testing. What this study addsWe have developed the FAP Index, which is a model using a simple circulating fibroblast activation protein enzyme assay and routinely available clinical variables. Using FAP Index as a first-line test followed by the current recommended screening tests (FIB-4 and NFS [NAFLD Fibrosis Score]) can reduce indeterminate results by up to 70% compared to the current first-line standard of care tests alone, without compromising diagnostic accuracy. How this study might affect research, practice or policyWith recently approved pharmacotherapy for fatty liver disease, improved tools for triaging people with metabolic fatty liver disease has increasing urgency. Use of FAP Index could have a dramatic effect on screening for advanced fibrosis by reducing fruitless referrals to tertiary care and/or further testing. Furthermore, our single-step enzymatic cFAP assay can be adapted to point of care or reflex testing settings, allowing for low-cost and high throughput FAP Index screening.