Staufer Katharina, Huber Heidemarie, Zessner-Spitzenberg Jasmin, Stauber Rudolf, Finkenstedt Armin, Bantel Heike, Weiss Thomas S, Huber Markus, Starlinger Patrick, Gruenberger Thomas, Reiberger Thomas, Sebens Susanne, McIntyre Gail, Tabibiazar Ray, Giaccia Amato, Zoller Heinz, Trauner Michael, Mikulits Wolfgang
Department of General Surgery, Division of Transplantation, Medical University of Vienna, Vienna, Austria.
Department of Internal Medicine III, Division of Gastroenterology & Hepatology, Medical University of Vienna, Vienna, Austria.
Cell Death Discov. 2023 Aug 2;9(1):282. doi: 10.1038/s41420-023-01551-6.
The expression of the receptor tyrosine kinase Axl and its cleavage product soluble Axl (sAxl) is increased in liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). In this multicenter study, we evaluated the diagnostic value of Gas6, the high-affinity ligand of Axl, in patients with chronic liver disease. Levels of sAxl and Gas6, and their albumin (alb) ratios were analyzed in serum samples of patients with biopsy-proven liver fibrosis, end-stage liver disease, HCC, and healthy controls, and were compared to Fibrosis-4 (FIB-4), enhanced liver fibrosis (ELF™) test, Child-Pugh score (CPS), model of end-stage liver disease (MELD) score, hepatic venous pressure gradient, and α-fetoprotein, respectively. A total of 1111 patients (median age 57.8 y, 67.3% male) was analyzed. Gas6/alb showed high diagnostic accuracy for the detection of significant (≥F2: AUC 0.805) to advanced fibrosis (≥F3: AUC 0.818), and was superior to Fib-4 for the detection of cirrhosis (F4: AUC 0.897 vs. 0.878). In addition, Gas6/alb was highly predictive of liver disease severity (Odds ratios for CPS B/C, MELD ≥ 15, and clinically significant portal hypertension (CSPH) were 16.534, 10.258, and 12.115), and was associated with transplant-free survival (Hazard ratio 1.031). Although Gas6 and Gas6/alb showed high diagnostic accuracy for the detection of HCC in comparison to chronic liver disease patients without cirrhosis (AUC 0.852, 0.868), they failed to discriminate between HCC in cirrhosis versus cirrhosis only. In conclusion, Gas6/alb shows a high accuracy to detect significant to advanced fibrosis and cirrhosis, and predicts severity of liver disease including CSPH.
受体酪氨酸激酶Axl及其裂解产物可溶性Axl（sAxl）在肝纤维化、肝硬化和肝细胞癌（HCC）中表达增加。在这项多中心研究中，我们评估了Axl的高亲和力配体Gas6在慢性肝病患者中的诊断价值。分析了经活检证实的肝纤维化、终末期肝病、HCC患者及健康对照者血清样本中sAxl和Gas6的水平及其与白蛋白（alb）的比值，并分别与纤维化-4（FIB-4）、增强肝纤维化（ELF™）检测、Child-Pugh评分（CPS）、终末期肝病模型（MELD）评分、肝静脉压力梯度和甲胎蛋白进行比较。共分析了1111例患者（中位年龄57.8岁，67.3%为男性）。Gas6/alb在检测显著（≥F2：AUC 0.805）至晚期纤维化（≥F3：AUC 0.818）方面显示出较高的诊断准确性，在检测肝硬化（F4：AUC 0.897对0.878）方面优于Fib-4。此外，Gas6/alb对肝病严重程度具有高度预测性（CPS B/C、MELD≥15和临床显著门静脉高压（CSPH）的比值比分别为16.534、10.258和12.115），并与无移植生存率相关（风险比1.031）。尽管与无肝硬化的慢性肝病患者相比，Gas6和Gas6/alb在检测HCC方面显示出较高的诊断准确性（AUC 0.852，0.868），但它们无法区分肝硬化中的HCC与仅肝硬化。总之，Gas6/alb在检测显著至晚期纤维化和肝硬化方面具有较高的准确性，并可预测包括CSPH在内的肝病严重程度。
