Dynamic FIB‑4 Score Changes and HCC Risk in Patients with MASLD and Elevated Liver Enzymes: A Nationwide Cohort Study

Introduction: Hepatocellular carcinoma (HCC) can develop in individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) without cirrhosis, especially those with elevated liver enzymes. However, there is currently no low-cost, scalable screening tool for this population. To address this need, we investigated the association between serial changes in FIB-4 (fibrosis-4) scores over a three-year period and the risk of developing HCC in a large, diverse cohort of patients with MASLD without cirrhosis. Methods: This study utilized a nationwide cohort from the National Health Insurance Research Database (NHIRD), including 810,698 patients with MASLD who had demographic and laboratory data at baseline and at least 3 years of follow-up. FIB-4 scores were analyzed to assess transitions between low- (2.67) categories over time. Competing risks for HCC and mortality were modeled to estimate the sub-distribution hazard ratios (SHRs). Results: Changes in FIB-4 scores over time provided superior predictive accuracy compared to one-time measurement. Individuals with persistent high FIB-4 (high-to-high group) had a 14-fold higher risk of developing HCC (adjusted SHR aSHR 13.91, 95% CI 11.94-16.20) compared to those with stable low FIB-4 (low-to-low group), while those with improved scores (high-to-low and high-to-indeterminate groups) had a lower risk compared to the high-to-high group. Worsening FIB-4 scores, as shown in the low-to-indeterminate group (aSHR 2.22, 95% CI 1.93-2.57 or the low-to-high group (aSHR 4.75, 95% CI 3.38-6.68), were associated with progressively increased risks of HCC, compared to the low-to-low group. In contrast, when compared to the high-to-high group, those with improved FIB-4 scores, including the high-to-indeterminate group (aSHR 0.41, 95% CI 0.35-0.48) and the high-to-low group (aSHR 0.25, 95% CI 0.15-0.42), exhibited reduced HCC risks. Conclusion: Serial FIB-4 measurements offer greater accuracy in identifying individuals at high risk for HCC in non-cirrhotic MASLD Asians, with HCC surveillance warranted in high-risk groups.