Circulating Fibroblast Growth Factor 21 (FGF21) as a Prognostic and Diagnostic Biomarker in Hepatocellular Carcinoma

Fibroblast growth factor 21 (FGF21) is a hormone synthesized and released by liver cells. Deficiency in FGF21 has been shown to be associated with steatosis, inflammation, fibrosis, and increased risk of hepatocellular carcinoma (HCC) development. Moreover, recent evidence suggests that elevated FGF21 levels may paradoxically correlate with worse outcomes in HCC. We aimed to evaluate the association between serum FGF21 levels, clinicopathological parameters, and overall survival (OS) in HCC patients.

From 2001 to 2014, newly diagnosed HCC patients were recruited as part of an IRB-approved protocol. Blood samples were prospectively collected and a CLIA-certified lab measured serum FGF21 concentrations. Using FGF21 median as a cutoff point, all patients were categorized into subjects with low and high levels. The primary endpoint was OS.

A total of 767 HCC patients were analyzed. Mean age was 65 years, and 74% were male. Median FGF21 value was 0.41 ng/mL. Our data showed that patients with advanced HCC including those with multinodular tumors, vascular invasion, distant metastasis, a higher Child-Pugh score, CLIP, BCLC, TNM, and ECOG stage had significantly increased FGF21 serum levels (p < 0.05 for all parameters). OS was significantly shorter in patients with high FGF21 compared to those with low FGF21 (24 months OS 28% vs 43%; p < 0.001). On multivariate analysis, high FGF21 was significantly associated with worse OS (HR: 1.422; 95% CI: 1.180-1.714; p < 0.001).

Elevated circulating FGF21 levels correlate with advanced clinicopathologic features and poor OS in HCC patients. Because elevated FGF21 during liver stress may indicate significant metabolic disruption, our data provides strong evidence that FGF21 may represent a valuable prognostic and potentially therapeutic biomarker in HCC. Future independent studies are required to validate our results.