SAFE vs. FIB-4: diagnostic accuracy for clinically significant fibrosis in U.S. adults with cardiometabolic risk factors – a NHANES 2017–2020 analysis

BACKGROUND: Steatotic liver disease (SLD), largely driven by cardiometabolic dysfunction, affects nearly one-third of the global population and may progress to advanced fibrosis. Although liver biopsy remains the gold standard for fibrosis assessment, noninvasive tools such as the Fibrosis-4 (FIB-4) and the recently developed steatosis-associated fibrosis estimator (SAFE) score are used risk stratification. We compared the diagnostic accuracy of FIB-4 and SAFE for detecting clinically significant fibrosis in adults with cardiometabolic risk factors. METHODS: We conducted a cross-sectional analysis of 2196 adults aged 18-80 years from the National Health and Nutrition Examination Survey (2017-2020) with valid liver stiffness measurements (LSM) by FibroScan. Individuals with known chronic liver disease, excessive alcohol use, or missing data were excluded. Clinically significant fibrosis was defined as LSM ≥ 8.0 kPa. Diagnostic performance was evaluated using sensitivity, specificity, predictive values, and area under the receiver operating characteristic curve (AUC). RESULTS: SAFE demonstrated superior discrimination compared with FIB-4 (AUC 0.719 vs. 0.578; P < 0.001). As a rule-out test, SAFE showed higher sensitivity (78% vs. 41%) and negative predictive value (95% vs. 91%). FIB-4 missed 58.6% of patients with significant fibrosis, whereas SAFE missed 22%. SAFE consistently outperformed FIB-4 across age, sex, MASLD status, and glycemic control subgroups. CONCLUSION: These findings support the use of SAFE over FIB-4 as a noninvasive screening tool for significant fibrosis in patients with cardiometabolic risk factors.