Department of Medicine, Division of Gastroenterology and Hepatology, Shinshu University School of Medicine, Matsumoto, Japan.
Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA.
Liver Int. 2021 Mar;41(3):505-514. doi: 10.1111/liv.14776. Epub 2021 Jan 20.
Thrombospondins are a family of multidomain and secretory glycoproteins. Among them, thrombospondin 2 (TSP2) encoded by TSP2 gene has been reported to be involved in various functions such as collagen/fibrin formation, maintenance of normal blood vessel density and cell adhesion properties. Microarray analyses ranked TSP2 as one of the most highly up-regulated genes in the fibrotic liver in patients with non-alcoholic fatty liver disease (NAFLD). Since TSP2 possesses unique properties as a secretory protein, we hypothesized that hepatic TSP2 gene expression levels would be reflected in serum TSP2 levels. In this study, we examined the relationship between serum TSP2 concentrations and clinicopathological findings in NAFLD patients.
One hundred and thirty NAFLD patients who had undergone liver biopsy between 2009 and 2015 were retrospectively enrolled. Serum samples were collected at the time of biopsy, and TSP2 was measured by enzyme immunoassays.
Serum TSP2 levels moderately correlated with ballooning (r = 0.56, P < .001) and fibrosis stage (r = 0.53, P < .001). The AUC values of TSP2 for predicting mild fibrosis (≧F1), moderate fibrosis (≧F2) and severe fibrosis (≧F3) were 0.73, 0.76 and 0.82 respectively. Additionally, NAFLD activity score (NAS) correlated best with TSP2 (r = 0.52, P < .001) compared to conventional NAFLD-related biomarkers, such as cytokeratin 18 M30, hyaluronic acid, type IV collagen 7S, APRI and FIB-4 index.
Serum TSP2 levels reflected hepatocyte ballooning, fibrosis and NAS in NAFLD patients. For clinical application of serum TSP2 as a predictor of NAFLD histological activity, additional validation and mechanistic investigations are required.
血小板反应蛋白（Thrombospondin，TSP）是一组具有多种结构域和分泌功能的糖蛋白。其中，血小板反应蛋白 2（TSP2）由 TSP2 基因编码，据报道其参与多种功能，如胶原/纤维蛋白形成、维持正常血管密度和细胞黏附特性。微阵列分析将 TSP2 列为非酒精性脂肪性肝病（Non-alcoholic fatty liver disease，NAFLD）患者纤维化肝脏中上调最显著的基因之一。由于 TSP2 作为一种分泌蛋白具有独特的特性，我们假设肝 TSP2 基因表达水平将反映在血清 TSP2 水平中。在这项研究中，我们检查了血清 TSP2 浓度与 NAFLD 患者临床病理发现之间的关系。
回顾性纳入 2009 年至 2015 年间接受肝活检的 130 名 NAFLD 患者。在活检时采集血清样本，并通过酶免疫测定法测量 TSP2。
血清 TSP2 水平与气球样变（r=0.56，P<0.001）和纤维化分期（r=0.53，P<0.001）中度相关。TSP2 预测轻度纤维化（≧F1）、中度纤维化（≧F2）和重度纤维化（≧F3）的 AUC 值分别为 0.73、0.76 和 0.82。此外，与传统的 NAFLD 相关生物标志物（如细胞角蛋白 18 M30、透明质酸、IV 型胶原 7S、APRI 和 FIB-4 指数）相比，NAFLD 活动评分（NAS）与 TSP2 的相关性最佳（r=0.52，P<0.001）。
血清 TSP2 水平反映了 NAFLD 患者的肝细胞气球样变、纤维化和 NAS。为了将血清 TSP2 作为 NAFLD 组织学活动的预测因子在临床应用，需要进一步验证和机制研究。
