Espelund Ulrick, Grønbæk Henning, Villadsen Gerda Elisabeth, Simonsen Kira, Vestergaard Poul Frølund, Jørgensen Jens Otto Lunde, Flyvbjerg Allan, Vilstrup Hendrik, Frystyk Jan
Medical Research Laboratory, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark; Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Aarhus, Denmark.
Department of Hepatology & Gastroenterology, Aarhus University Hospital and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Growth Horm IGF Res. 2015 Aug;25(4):174-81. doi: 10.1016/j.ghir.2015.05.002. Epub 2015 May 31.
Previous studies have demonstrated an elevated IGF-II mRNA expression and protein levels in tumors and blood from patients with hepatocellular carcinoma (HCC), hereby suggesting a role of IGF-II as a pathogenic marker of HCC. We hypothesized that in HCC, an increased IGF-II secretion would translate into an elevated circulating IGF bioactivity, which would normalize following treatment.
Patients with HCC (n=39) were studied before and after radio-frequency ablation and/or transarterial chemo-embolization. Baseline data were compared to healthy subjects (n=150) and patients with liver cirrhosis (n=41). Serum levels of IGF ligands and IGF binding proteins (IGFBPs) were determined using gold standard methods as well as novel assays and compared to liver function tests and HCC treatment status.
At baseline, HCC patients differed from cirrhosis patients and healthy controls regarding IGF-I (29 [23-37] vs. 12 [7-19] vs. 109 [103-116] μg/l), IGF-II (254 [224-288] vs. 118 [102-137] vs. 545 [525-566] μg/l) and IGF bioactivity (0.53 [0.41-0.68] vs. 0.29 [0.24-0.34] vs. 1.43 [1.33-1.53] μg/l) (mean [95% confidence interval], all age-adjusted P<0.001). All variables but IGFBP-2 were strongly associated with liver status (MELD score), and accordingly, differences were either attenuated or disappeared when adjusted for MELD score. There was no effect of treatment on any IGF variables.
The marked differences in IGF and IGFBP levels between patients with HCC, liver cirrhosis and healthy subjects are mainly explained by variations in liver status. Therefore, this study questions the clinical utility of circulating IGF variables as markers of HCC.
既往研究表明，肝细胞癌（HCC）患者肿瘤组织及血液中IGF-II mRNA表达和蛋白水平升高，提示IGF-II可能作为HCC的致病标志物。我们推测，在HCC中，IGF-II分泌增加会导致循环中IGF生物活性升高，而治疗后该活性会恢复正常。
对39例HCC患者在射频消融和/或经动脉化疗栓塞前后进行研究。将基线数据与150例健康受试者及41例肝硬化患者进行比较。采用金标准方法及新检测方法测定血清中IGF配体和IGF结合蛋白（IGFBP）水平，并与肝功能检查及HCC治疗状态进行比较。
基线时，HCC患者与肝硬化患者及健康对照相比，IGF-I水平（29 [23 - 37] vs. 12 [7 - 19] vs. 109 [103 - 116] μg/l）、IGF-II水平（254 [224 - 288] vs. 118 [102 - 137] vs. 545 [525 - 566] μg/l）及IGF生物活性（0.53 [0.41 - 0.68] vs. 0.29 [0.24 - 0.34] vs. 1.43 [1.33 - 1.53] μg/l）存在差异（均值[95%置信区间]，均经年龄校正，P<0.001）。除IGFBP-2外，所有变量均与肝脏状态（MELD评分）密切相关，因此，经MELD评分校正后，差异要么减弱要么消失。治疗对任何IGF变量均无影响。
HCC患者、肝硬化患者及健康受试者之间IGF和IGFBP水平存在显著差异，主要原因是肝脏状态不同。因此，本研究对循环IGF变量作为HCC标志物的临床实用性提出质疑。
