Obesity Modifies the Performance of Fibrosis Biomarkers in Nonalcoholic Fatty Liver Disease

Context: Guidelines recommend blood-based fibrosis biomarkers to identify advanced nonalcoholic fatty liver disease (NAFLD), which is particularly prevalent in patients with obesity. Objective: To study whether the degree of obesity affects the performance of liver fibrosis biomarkers in NAFLD. Design: Cross-sectional cohort study comparing simple fibrosis scores (FIB-4, NFS, APRI, BARD, HFS) and newer scores incorporating neo-epitope biomarkers PRO-C3 (ADAPT, FIBC3) or CK-18 (MACK-3). Setting: Tertiary referral center. Patients: We recruited overweight/obese patients from endocrinology (n=307) and hepatology (n=71) clinics undergoing a liver biopsy (median BMI 40.3 [IQR 36.0-44.7] kg/m 2). Additionally, we studied 859 less obese patients with biopsy-proven NAFLD to derive BMI-adjusted cut-offs for NFS. Main outcome measures: Biomarker AUROC, sensitivity, specificity, and predictive values to identify histological stage ≥F3 fibrosis or nonalcoholic steatohepatitis with ≥F2 fibrosis (fibrotic NASH). Results: The scores with an AUROC >0.85 to identify ≥F3 fibrosis were ADAPT, FIB-4, FIBC3, and HFS. For fibrotic NASH, the best predictors were MACK-3 and ADAPT. The specificities of NFS, BARD, and FIBC3 deteriorated as a function of BMI. We derived and validated new cut-offs for NFS to rule in/out ≥F3 fibrosis in groups with BMIs <30.0, 30.0-39.9, and ≥40.0 kg/m 2. This optimized its performance at all levels of BMI. Sequentially combining FIB-4 with ADAPT or FIBC3 increased specificity to diagnose ≥F3 fibrosis. Conclusions: In obese patients, the best-performing fibrosis biomarkers are ADAPT and the inexpensive FIB-4, which are unaffected by BMI. The widely used NFS loses specificity in obese individuals, which may be corrected with BMI-adjusted cut-offs.