Association Between High FIB-4 Score and the Risk of Malignancy Development and Mortality: A Retrospective Longitudinal Case–Control Study

Background: The Fibrosis 4 (FIB-4) score, a widely used non-invasive marker for liver fibrosis in chronic liver disease, has recently been linked to systemic inflammation, cardiovascular risk, and mortality. However, its potential role in predicting malignancy risk and long-term outcomes in patients without known chronic liver disease remains unclear. Methods: We conducted a retrospective case–control study analyzing 43,080 patients from Leumit Health Services in Israel between 2002 and 2023. Of them, 21,540 had high FIB-4 levels > 2.67 and the 21,540 controls had low FIB-4 < 1.5. Patients from both groups were matched 1:1 according to gender, socioeconomic status, and birth year. The study surveyed both the prevalence of malignancies in both groups at baseline and during a 10-year follow-up period. Results: At baseline, the high FIB-4 group showed strong associations with existing malignancies, particularly pancreatic cancer (odds ratio [OR] = 27.53), hepatocellular carcinoma (OR = 14), and metastatic stage of any cancer (OR = 17.47). During the 10-year follow-up, while odds ratios decreased, significant risk for developing new malignancies persisted, including hepatocellular carcinoma (OR = 13.63); pancreatic (OR = 5.16), breast (OR = 2.88), and colon cancers (OR = 2.75); and metastatic stage of any cancer (OR = 6.41). The cumulative incidence of solid tumors increased from 15.84% to 22.30% in the high FIB-4 group compared with 4.85% to 9.65% in controls (at baseline and after 10 years, respectively). Additionally, the mortality rate was more than doubled in the high FIB-4 group (20.15% versus 9.72%; OR = 2.34). Conclusions: An elevated FIB-4 score appears to be associated with both existing malignancies and an increased risk of future cancer development. These associations remain significant independently of traditional cardiovascular risk factors and body mass index (BMI). Our findings suggest that the FIB-4 score may have potential utility as a marker for cancer risk stratification and warrant further investigation in prospective studies.