Fibrosis‐4 Index as an Independent Predictor of Mortality and Liver‐Related Outcomes in NAFLD

Abstract

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, and its prevalence continues to rise. Fibrosis‐4 index (FIB‐4) has been shown to be a prognostic marker of liver‐related outcomes in patients with NAFLD. We analyzed data from TriNetX global federated research network, combining data on 30 million patients. Patients were categorized into three diagnostic groups: NAFLD, nonalcoholic steatohepatitis (NASH), and at risk of NASH. Primary outcome was all‐cause mortality, and secondary outcomes included progression to NASH, development of cirrhosis, end‐stage liver disease, hepatocellular carcinoma (HCC), and liver transplantation. A total of 442,277 subjects (1.5% of the cohort) were assessed, and 81,108 were retained for analysis. Median follow‐up was 34.8 months (interquartile range 12.2). FIB‐4 was < 1.3 in 52.3% patients and ≥ 2.67 in 11.4% patients. In multivariate analysis, FIB‐4 ≥ 2.67 was significantly and independently associated with all‐cause mortality (hazard ratio [HR] 2.49, 95% confidence interval [CI] 2.20‐2.82, P < 0.001) as well as with progression to NASH (HR 5.78, 95% CI 4.72‐7.07, P < 0.001), cirrhosis (HR 2.04, 95% CI 1.86‐2.24, P < 0.001), end‐stage liver disease (HR 1.86, 95% CI 1.68‐2.05, P < 0.001), HCC (HR 3.66, 95% CI 2.71‐4.94, P < 0.001), and liver transplantation (HR 7.98, 95% CI 4.62‐13.79, P < 0.001). Conclusion: In a real‐world nationwide database, FIB‐4 ≥ 2.67 was a strong predictor of both all‐cause mortality and liver‐related adverse outcomes independently of the baseline diagnostic group and common risk factors. Our findings indicate that FIB‐4 could play a role as a risk‐stratification tool for a population health approach. Significant underdiagnosis of both NAFLD/NASH and NASH cirrhosis in electronic medical records was observed.