Circulating thrombospondin 2 as a predictor of hepatocellular carcinoma in hepatitis B patients undergoing nucleos(t)ide analog therapy

Thrombospondin 2 (TSP2) plays a vital role in collagen/fibrin formation, bone growth, vascular density regulation, hemostasis, and cell adhesion. Close associations of serum TSP2 with histological severity in non-alcoholic fatty liver disease and chronic hepatitis C were reported. The present study investigated the significance of circulating TSP2 in chronic hepatitis B patients. Eighty-seven biopsy-proven chronic hepatitis B patients were analyzed in cross-sectional Study 1 to search for correlations between serum TSP2 levels prior to liver biopsy and clinicopathological parameters. In longitudinal Study 2, 51 chronic hepatitis B patients with long-term follow-up (mean: 7.5 years) were examined for changes in serum TSP2 levels during nucleos(t)ide analog (NA) therapy along with trends in hepatocarciongenesis. In Study 1, serum TSP2 levels were not significantly associated with portal inflammation or fibrosis. Study 2 revealed that serum TSP2 was significantly decreased after 48 weeks of NA therapy (P < 0.001). Notably, TSP2 levels at 48 weeks of NA administration (TSP2-48W) were significantly higher in the hepatocellular carcinoma (HCC) (+) group than in the HCC (-) group (P = 0.043). Kaplan-Meier analysis showed that higher TSP2-48W (≥ 24 ng/mL) was associated with future HCC development (P = 0.030). Serum TSP2 levels may be a potential predictor of HCC development in hepatitis B patients receiving NA therapy. Longitudinal prospective studies are necessary to validate our findings.