Chronic HBV infection has been associated with an increased risk of HCC 12. Since HCC can develop even in patients with chronic HBV but without cirrhosis, it is clinically important to predict HCC onset on a patient-by-patient basis. In addition to disease progression to cirrhosis, several prognostic HCC factors have been reported to date, including high HBV DNA levels, high HBsAg levels, male gender, genotype C, and family history of HCC 13. With advances in HBV treatment, biomarkers for predicting HCC development that are useful during NA therapy are also of particular interest.
This study investigated serum TSP2 patterns in patients with hepatitis B in both cross-sectional and longitudinal under NA therapy settings to reveal 3 major findings. First, serum TSP2 did not correlate significantly with histopathological results, including liver fibrosis, in the cross-sectional cohort. Second, serum TSP2 levels were significantly decreased after 48 weeks of NA therapy. Third, patients with higher TSP2-48W were associated with HCC onset in patients receiving NA therapy. These results raise the novel possibility of TSP2 as a predictor of HCC development in NA therapy of HBV-infected patients.
Thrombospondins are glycoproteins that interact with other components of the extracellular matrix to facilitate angiogenesis, tissue healing, and connective tissue organization. 14. TSP2 is secreted from the fibrotic liver, and we have recently proposed serum TSP2 as a novel biomarker for detecting advanced fibrosis in NAFLD patients 6. Similar findings were reported from other groups, thus corroborating the ability of TSP2 to estimate disease activity and fibrosis stage in NAFLD 8 7. In addition, we earlier reported that serum TSP2 levels reflected fibrosis severity and disease activity in HCV-infected patients 5. Based on this accumulating evidence, we hypothesized that a correlation between TSP2 and liver disease activity could also be present in hepatitis B. However, no significant correlations were noted for pathological inflammation, fibrosis, and TSP2 levels in Study 1. The unknown role of TSP2 in liver inflammation and fibrosis makes the interpretation of those results difficult. The complexity of the unique natural history of hepatitis B, the imbalance between fibrosis and inflammation, and the limited sample size may have influenced our findings, and so future studies of larger cohorts are needed to clarify the relationship between TSP2 and the pathological features of hepatitis B.
In Study 2, the observations that NA reduced serum TSP2 levels and that high TSP2-48W could predict HCC development were noteworthy. Since patients with histopathological fibrosis are particularly susceptible to HBV-related HCC, it is important to accurately assess liver fibrosis and determine the appropriate therapeutic strategy for patients with HBV, including the optimal timing for antiviral therapy. Simple and reliable non-invasive methods to estimate liver fibrosis and HBV progression have been established, including fibrosis-4 (FIB-4) index and Wisteria floribunda agglutinin-positive human Mac-2 binding protein 15 16. However, the risk of HCC development independently of liver fibrosis has not been sufficiently investigated. In this context, serum TSP2 could represent a new predictive marker for HCC development in HBV patients.
This study had several limitations. First, it was conducted at a single center with a retrospective design. Second, the number of patients was relatively small, which precluded multivariate Cox regression analysis. Larger multi-center analyses are needed to elucidate the clinical utility of TSP2 in HBV.
In conclusion, higher TSP2-48W of ≥ 24 ng/mL may be a predictive biomarker of HCC occurrence in HBV patients receiving NA therapy. Following the quantitative changes in serum TSP2 may be of clinical benefit during NA treatment and warrants further study.