Transcriptomics Identify Thrombospondin-2 as a Biomarker for NASH and Advanced Liver Fibrosis.
Transcriptomics Identify Thrombospondin-2 as a Biomarker for NASH and Advanced Liver Fibrosis.
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DOI：
10.1002/hep.31995
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发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Takehara T
中科院分区：
文献类型：
--
作者：
Kozumi K;Kodama T;Murai H;Sakane S;Govaere O;Cockell S;Motooka D;Kakita N;Yamada Y;Kondo Y;Tahata Y;Yamada R;Hikita H;Sakamori R;Kamada Y;Daly AK;Anstee QM;Tatsumi T;Morii E;Takehara T
非酒精性脂肪性肝病（NAFLD）是全球最常见的肝脏疾病。非酒精性脂肪性肝炎（NASH）是NAFLD的进展形式，晚期肝纤维化与不良预后相关。我们寻找它们的非侵入性生物标志物。
对98例经活检证实为NAFLD的患者的肝组织进行了全基因组RNA测序。无监督层次聚类很好地区分了NASH和非酒精性脂肪肝（NAFL），NASH患者表现出反映其病理特征的分子异常。转录组分析确定了在NASH和/或晚期纤维化（F3 - F4期）中上调的蛋白质，包括由血小板反应蛋白2（THBS2）基因编码的基质细胞糖蛋白血小板反应蛋白 - 2（TSP - 2）。肝内THBS2表达水平在诊断NASH和晚期纤维化时，受试者工作特征曲线下面积（AUROC）分别高达0.915和0.957。根据NAFLD活动评分、血清天冬氨酸氨基转移酶和透明质酸（HA）水平以及NAFLD纤维化评分（NFS），THBS2与炎症和气球样变呈正相关。THBS2与细胞外基质和胶原生物合成、血小板激活、半胱天冬酶介导的细胞骨架蛋白裂解以及免疫细胞浸润有关。对213例经活检证实为NAFLD的患者测量了血清TSP - 2表达，NASH患者的血清TSP - 2表达明显高于NAFL患者，且与纤维化分期平行升高。预测NASH和晚期纤维化的AUROC分别为0.776和0.856，在晚期纤维化诊断中与Fibrosis - 4指数、血清HA水平和NFS相当。血清TSP - 2水平和血小板计数是NASH和晚期纤维化的独立预测因子。血清TSP - 2水平可根据包括肝癌和失代偿性肝硬化事件在内的肝脏并发症风险对NAFLD患者进行分层。
TSP - 2可能是NAFLD患者NASH和晚期纤维化诊断的有用生物标志物。
NAFLD is the most common liver disease worldwide. NASH, the progressive form of NAFLD, and advanced fibrosis are associated with poor outcomes. We searched for their noninvasive biomarkers. Global RNA sequencing of liver tissue from 98 patients with biopsy‐proven NAFLD was performed. Unsupervised hierarchical clustering well distinguished NASH from nonalcoholic fatty liver (NAFL), and patients with NASH exhibited molecular abnormalities reflecting their pathological features. Transcriptomic analysis identified proteins up‐regulated in NASH and/or advanced fibrosis (stage F3‐F4), including matricellular glycoprotein thrombospondin‐2 (TSP‐2), encoded by the thrombospondin 2 (THBS2) gene. The intrahepatic THBS2 expression level showed the highest areas under the receiver operating characteristic curves (AUROCs) of 0.915 and 0.957 for diagnosing NASH and advanced fibrosis, respectively. THBS2 positively correlated with inflammation and ballooning according to NAFLD activity score, serum aspartate aminotransferase and hyaluronic acid (HA) levels, and NAFLD Fibrosis Score (NFS). THBS2 was associated with extracellular matrix and collagen biosynthesis, platelet activation, caspase‐mediated cleavage of cytoskeletal proteins, and immune cell infiltration. Serum TSP‐2 expression was measured in 213 patients with biopsy‐proven NAFLD, was significantly higher in NASH than in NAFL, and increased parallel to fibrosis stage. The AUROCs for predicting NASH and advanced fibrosis were 0.776 and 0.856, respectively, which were comparable to Fibrosis‐4 index, serum HA level, and NFS in advanced fibrosis diagnosis. Serum TSP‐2 level and platelet count were independent predictors of NASH and advanced fibrosis. Serum TSP‐2 levels could stratify patients with NAFLD according to the risk of hepatic complications, including liver cancer and decompensated cirrhotic events. TSP‐2 may be a useful biomarker for NASH and advanced fibrosis diagnosis in patients with NAFLD.
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通讯作者：
Bendtsen F