Liver Fibrosis Marker FIB-4 Is Associated With Hepatic and Extrahepatic Malignancy Risk in a Population-Based Cohort Study

Background and Aims: An association between Metabolic Dysfunction–Associated Steatotic Liver Disease (MASLD) and the development of extrahepatic malignancies has been demonstrated. However, the association of fibrosis with extrahepatic cancer is unclear. Our study aimed to test the long-term association between liver fibrosis marker and the incidence of hepatic and extrahepatic malignancies. Methods: A retrospective cohort study of a nationally representative sample, following 763 752 adult Clalit health services members without pre-existing liver-related diagnoses or malignancies for 14.67 years. The adjusted association between baseline liver Fibrosis-4 score (FIB-4; FIB-4 ≥ 2.67 indicated presumed advanced fibrosis), assessed from routine laboratory measurements, and incident cancer was assessed through multivariable Cox regression models. Results: The study included 763 752 people (mean age 54.3 ± 8.2 years, 43.9% males). Presumed advanced fibrosis was associated with a 16% greater risk for malignancy compared to the risk of those with no fibrosis (hazard ratio (HR) = 1.16; 95% CI, 1.10–1.22), adjusting for age, sex, ethnicity, socioeconomic status, peripherality index, baseline smoking, and obesity. The association of advanced fibrosis with malignancy was stronger when the age-specific FIB-4 cutoff was applied (HR = 1.40; 1.34–1.46) and in a subsample of subjects with MASLD diagnosis at baseline (HR = 1.43; 1.12–1.83). The association remained robust across sex, age, and ethnic groups. Both inconclusive fibrosis and fibrosis were strongly associated with malignancy of the liver or bile ducts [(HR = 1.41; 1.21–1.66) and (HR = 5.66; 4.19–7.64), respectively]. Conclusions: Liver fibrosis score is independently associated with malignancy occurrence and certain types of malignancies, and may serve as an indicator of high-risk cancer in the general population.