Eguchi Akiko, Iwasa Motoh, Tamai Yasuyuki, Yamada Minori, Okuno Koji, Shigefuku Ryuta, Yoshikawa Kyoko, Tempaku Mina, Sakaguchi Koji, Tanaka Hideaki, Sugimoto Kazushi, Kobayashi Yoshinao, Yamaguchi Tetsuji, Nakagawa Hayato
Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan.
Bio-Reagent Material Development, Bio-Diagnostic Reagent Technology Center, Sysmex Corporation, Kobe, Japan.
Front Oncol. 2022 Aug 23;12:993705. doi: 10.3389/fonc.2022.993705. eCollection 2022.
Fragmented cytokeratin 18 (fCK18) is released from damaged hepatocytes undergoing apoptosis and is recognized as a liver condition biomarker. We have developed a highly sensitive serum fCK18 CLEIA and reported that serum levels of this caspase-derived protein were significantly associated with hepatocyte ballooning, thus assisting in the accurate diagnosis of nonalcoholic steatohepatitis (NASH). We aim to investigate serum fCK18 levels in a variety of chronic liver diseases and to explore its potential as a prognostic marker of survival in hepatocellular carcinoma (HCC) patients.
Serum fCK18 levels were measured using a highly sensitive CLEIA in 497 chronic liver disease patients (297 outpatients and 200 hospitalized with HCC).
In 497 chronic liver disease patients, serum fCK18 levels were significantly correlated with overall liver condition, including ALT, FIB-4 index and albumin-bilirubin (ALBI) score and were significantly increased in patients with HCC. In 200 HCC patients, serum fCK18 levels were significantly correlated with alpha-fetoprotein (AFP) and des-gamma-carboxy prothrombin (DCP), and were significantly associated with HCC stage, whereas FIB-4 index and ALBI score were not changed based on HCC stage. The Survival group had significantly lower levels of serum fCK18, AFP, DCP, FIB-4 index and ALBI score. A ROC analysis yield area under the curve (AUC) value of 0.728 for serum fCK18 is a significantly high value when compared to AUC measurements for other factors. Notably, AUROC values for serum fCK18 levels were constant in the short- and long-term by time-dependent ROC analysis for the prediction of HCC patient survival. HCC patients with serum fCK18 measured at < 1.15 ng/mL, AFP < 7.7 ng/mL, DCP < 133 mAU/mL, ALBI score < -2.97 or FIB-4 index < 6.4 had significantly longer rates of survival when compared to patients with values exceeding these thresholds. Serum fCK18 (HR, 3.5; < 0.0001), DCP (HR, 3.2; < 0.0001) and Barcelona Clinic Liver Cancer (BCLC) (HR, 2.4; = 0.001) values were independent predictors of patient survival. [Conclusion] Serum fCK18 levels reflect overall liver function, the level of liver fibrosis and the progression of HCC, and are a potential predictor of survival in HCC patients.
细胞角蛋白18片段（fCK18）从经历凋亡的受损肝细胞中释放出来，被认为是一种肝脏疾病生物标志物。我们开发了一种高灵敏度的血清fCK18化学发光免疫分析方法（CLEIA），并报告这种半胱天冬酶衍生蛋白的血清水平与肝细胞气球样变显著相关，从而有助于非酒精性脂肪性肝炎（NASH）的准确诊断。我们旨在研究各种慢性肝病患者的血清fCK18水平，并探讨其作为肝细胞癌（HCC）患者生存预后标志物的潜力。
使用高灵敏度的CLEIA检测了497例慢性肝病患者（297例门诊患者和200例住院HCC患者）的血清fCK18水平。
在497例慢性肝病患者中，血清fCK18水平与整体肝脏状况显著相关，包括谷丙转氨酶（ALT）、FIB-4指数和白蛋白-胆红素（ALBI）评分，且在HCC患者中显著升高。在200例HCC患者中，血清fCK18水平与甲胎蛋白（AFP）和异常凝血酶原（DCP）显著相关，并与HCC分期显著相关，而FIB-4指数和ALBI评分在不同HCC分期中无变化。生存组的血清fCK18、AFP、DCP、FIB-4指数和ALBI评分水平显著较低。ROC分析得出血清fCK18的曲线下面积（AUC）值为0.728，与其他因素的AUC测量值相比是一个显著较高的值。值得注意的是，通过时间依赖性ROC分析预测HCC患者生存情况时，血清fCK18水平的AUROC值在短期和长期内保持不变。血清fCK18测量值<1.15 ng/mL、AFP<7.7 ng/mL、DCP<133 mAU/mL、ALBI评分<-2.97或FIB-4指数<6.4的HCC患者与超过这些阈值的患者相比，生存率显著更长。血清fCK18（风险比[HR]，3.5；P<0.0001）、DCP（HR，3.2；P<0.0001）和巴塞罗那临床肝癌（BCLC）分期（HR，2.4；P=0.001）是患者生存的独立预测因素。结论：血清fCK18水平反映整体肝功能、肝纤维化程度和HCC进展情况，是HCC患者生存的潜在预测指标。
