Loglio Alessandro, Iavarone Massimo, Facchetti Floriana, Di Paolo Dhanai, Perbellini Riccardo, Lunghi Giovanna, Ceriotti Ferruccio, Galli Claudio, Sandri Maria T, Viganò Mauro, Sangiovanni Angelo, Colombo Massimo, Lampertico Pietro
Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Division of Gastroenterology and Hepatology, CRC "A. M. and A. Migliavacca" Center for Liver Disease, Milan, Italy.
Foundation IRCCS Ca' Granda Ospedale Maggiore Policlinico, Virology Unit, Milan, Italy.
Liver Int. 2020 Aug;40(8):1987-1996. doi: 10.1111/liv.14475. Epub 2020 May 23.
BACKGROUND & AIMS: Protein induced by vitamin K absence or antagonist-II (PIVKA-II) has been suggested as a serum biomarker for hepatocellular carcinoma (HCC) in Asian hepatitis B virus (HBV)-treated subjects but no studies tested it in Caucasian cirrhotics long-term nucleos(t)ide analogues (NUCs)-treated. We assessed the detection accuracy of PIVKA-II alone or in combination with alpha-foetoprotein (AFP) in patients under surveillance.
This cross-sectional, single centre case-control study was conducted in 212 NUC-treated cirrhotics: 64 HCC and 148 HCC-free controls for 84 (60-107) months. PIVKA-II was determined by a CMIA immunoassay (Abbott; limit of quantification: 8.2 mAU/mL).
Protein induced by vitamin K absence or agonist II (PIVKA-II) and AFP levels were significantly higher in HCC patients [Barcelona Clinic Liver Cancer staging system stage 0/A in 91%, diameter 20 (6-50) mm] compared to controls: 109 (17-12 157) vs 31 (13-82) mAU/mL and 5 (1-1163) vs 2 (1-7) ng/mL (P < .001 for both markers), with a cut-off of 48 mAU/mL and 4.2 ng/mL by AUROC analysis. The PIVKA-II 82 mAU/mL and AFP 7 ng/mL cut-offs showed 100% specificity, with the former more sensitive (54% vs 42%), accurate (86% vs 83%), with higher negative predictive value (80% vs 76%) compared to AFP for HCC detection. PIVKA-II more frequently than AFP levels exceeded the cut-off 6-18 months before HCC diagnosis. Combining PIVKA-II with AFP increased sensitivity, accuracy and negative predictive values to 67%, 90% and 85%, preserving 100% specificity. PIVKA-II was associated with lesions >20 mm or neoplastic thrombosis.
Combination of PIVKA-II and AFP increases the detection rate for HCC in NUC-treated HBV Caucasian cirrhotics, a potential new approach for surveillance.
维生素K缺乏或拮抗剂-II诱导蛋白（PIVKA-II）已被提议作为亚洲乙型肝炎病毒（HBV）感染受试者肝细胞癌（HCC）的血清生物标志物，但尚无研究在接受长期核苷（酸）类似物（NUC）治疗的白种人肝硬化患者中对其进行检测。我们评估了单独使用PIVKA-II或联合甲胎蛋白（AFP）在监测患者中的检测准确性。
这项横断面、单中心病例对照研究纳入了212例接受NUC治疗的肝硬化患者：64例HCC患者和148例无HCC的对照，随访时间为84（60 - 107）个月。采用化学发光微粒子免疫分析（CMIA）法（雅培；定量下限：8.2 mAU/mL）检测PIVKA-II。
与对照组相比，HCC患者[巴塞罗那临床肝癌分期系统0/A期占91%，直径20（6 - 50）mm]的维生素K缺乏或激动剂II诱导蛋白（PIVKA-II）和AFP水平显著更高：分别为109（17 - 12157）mAU/mL对31（13 - 82）mAU/mL以及5（1 - 1163）ng/mL对2（1 - 7）ng/mL（两种标志物P均<0.001），通过AUROC分析，其临界值分别为48 mAU/mL和4.2 ng/mL。PIVKA-II 82 mAU/mL和AFP 7 ng/mL的临界值显示出100%的特异性，前者在HCC检测中更敏感（54%对42%）、更准确（86%对83%），阴性预测值更高（80%对76%）。在HCC诊断前6 - 18个月，PIVKA-II超过临界值的频率高于AFP水平。联合使用PIVKA-II和AFP可将敏感性、准确性和阴性预测值分别提高至67%、90%和85%，同时保持100%的特异性。PIVKA-II与直径>20 mm的病变或肿瘤性血栓相关。
联合使用PIVKA-II和AFP可提高接受NUC治疗的HBV感染白种人肝硬化患者中HCC的检出率，这是一种潜在的新监测方法。
