Golgi protein-73: A biomarker for assessing cirrhosis and prognosis of liver disease patients
Golgi protein-73: A biomarker for assessing cirrhosis and prognosis of liver disease patients
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DOI：
10.3748/wjg.v26.i34.5130
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发表时间：
2020-09-14
影响因子：
4.3
通讯作者：
Dalekos, George N.
中科院分区：
文献类型：
--
作者：
Gatselis, Nikolaos K.;Tornai, Tamas;Dalekos, George N.
背景：目前缺乏肝硬化、肝细胞癌（HCC）或慢性肝病进展的可靠生物标志物。在这种背景下，高尔基蛋白-73 （GP73）也被称为高尔基磷酸化蛋白-2，最初被定义为在上皮细胞中表达的常驻高尔基II型跨膜蛋白。因此，GP73主要在胆道上皮细胞中表达，仅在肝细胞中少量检测到。然而，在急慢性肝病患者，特别是HCC患者中，GP73在肝细胞中的表达显著上调。到目前为止，很少有研究评估GP73作为肝纤维化和疾病进展的诊断或预后标志物。目的评估血清GP73作为肝硬化和/或HCC诊断标志物或肝病进展预测指标的有效性。方法采用一种新型的GP73 ELISA （QUANTA Lite(R)GP73, Inova Diagnostics, Inc.，仅供研究使用）对来自希腊Larissa （n= 366）和匈牙利Debrecen （n= 266）两个三级学术中心的连续632例慢性病毒性和非病毒性肝病患者的血清GP73水平进行回顾性检测。计算所有患者相关时间点的谷草转氨酶(AST)/血小板（PLT）比值指数（APRI）。慢性乙型肝炎203例，慢性丙型肝炎183例，酒精性肝病198例，自身免疫性胆汁淤积性肝病28例，自身免疫性肝炎15例，其他肝脏相关疾病5例。随访时间为50（57）个月[中位数（四分位数间距）]。根据国际公认的指南评估随访期间肝硬化、肝功能失代偿和/或HCC的发展情况。特别是，通过超声成像和甲胎蛋白（AFP）检测定期监测HCC的发展，肝硬化患者每6个月检测一次，非肝硬化患者每12个月检测一次。结果：632例患者中有277例（43.8%）在初始评估时检测到血清GP73水平升高（bbb20单位）。基线时gp73血清阳性与肝硬化（96.4%vs . s51.5%，P< 0.001）、肝硬化失代偿（60.3%vs . 35.5%，P< 0.001）、HCC （18.4%vs . 7.9%，P< 0.001）和晚期HCC （52.9%vs . 14.8%，P= 0.002）相关。与APRI评分相比，GP73对肝硬化的诊断准确率更高[曲线下面积（AUC） （95%CI）： 0.909 (0.885-0.934)vs0.849 (0.813-0.886)，P= 0.003]。与GP73 （AUC: 0.909，P= 0.005）或单独使用APRI （AUC: 0.849，P< 0.001）相比，GP73联合APRI进一步提高了准确度（AUC: 0.925）。HCC患者的GP73水平明显高于非HCC患者[22.5（29.2）对16（20.3）单位，P< 0.001]，并且与BCLC分期呈正相关[0期：13.9 (10.8)；阶段A: 17.1 (16.8)；B期：19.6 (22.3)；C期：32.2 (30.8)；D期：45.3（86.6）个单位，P< 0.001)，肿瘤大小：13.9 (10.8)；中级：19.6 (18.4)；advance: 29.1（33.6）个单位，P= 0.004]。然而，HCC诊断的鉴别能力相对较低[AUC (95%CI): 0.623(0.570-0.675)]。Kaplan-Meier分析显示，基线时代偿性肝硬化患者的GP73检测预示着随访期间较高的失代偿率（P= 0.036）、HCC发展（P= 0.08）和肝脏相关死亡（P< 0.001）。结论GP73单独检测肝硬化有效，且优于APRI检测。与APRI结合，可进一步提高其诊断性能。最重要的是，简单的GP73测量被证明有希望预测病毒性和非病毒性慢性肝病患者的较差结果。
BACKGROUND Reliable biomarkers of cirrhosis, hepatocellular carcinoma (HCC), or progression of chronic liver diseases are missing. In this context, Golgi protein-73 (GP73) also called Golgi phosphoprotein-2, was originally defined as a resident Golgi type II transmembrane protein expressed in epithelial cells. As a result, GP73 expression was found primarily in biliary epithelial cells, with only slight detection in hepatocytes. However, in patients with acute or chronic liver diseases and especially in HCC, the expression of GP73 is significantly up-regulated in hepatocytes. So far, few studies have assessed GP73 as a diagnostic or prognostic marker of liver fibrosis and disease progression. AIM To assess serum GP73 efficacy as a diagnostic marker of cirrhosis and/or HCC or as predictor of liver disease progression. METHODS GP73 serum levels were retrospectively determined by a novel GP73 ELISA (QUANTA Lite(R)GP73, Inova Diagnostics, Inc., Research Use Only) in a large cohort of 632 consecutive patients with chronic viral and non-viral liver diseases collected from two tertiary Academic centers in Larissa, Greece (n= 366) and Debrecen, Hungary (n= 266). Aspartate aminotransferase (AST)/Platelets (PLT) ratio index (APRI) was also calculated at the relevant time points in all patients. Two hundred and three patients had chronic hepatitis B, 183 chronic hepatitis C, 198 alcoholic liver disease, 28 autoimmune cholestatic liver diseases, 15 autoimmune hepatitis, and 5 with other liver-related disorders. The duration of follow-up was 50 (57) mo [median (interquartile range)]. The development of cirrhosis, liver decompensation and/or HCC during follow-up were assessed according to internationally accepted guidelines. In particular, the surveillance for the development of HCC was performed regularly with ultrasound imaging and alpha-fetoprotein (AFP) determination every 6 mo in cirrhotic and every 12 mo in non-cirrhotic patients. RESULTS Increased serum levels of GP73 (> 20 units) were detected at initial evaluation in 277 out of 632 patients (43.8%). GP73-seropositivity correlated at baseline with the presence of cirrhosis (96.4%vs51.5%,P< 0.001), decompensation of cirrhosis (60.3%vs35.5%,P< 0.001), presence of HCC (18.4%vs7.9%,P< 0.001) and advanced HCC stage (52.9%vs14.8%,P= 0.002). GP73 had higher diagnostic accuracy for the presence of cirrhosis compared to APRI score [Area under the curve (AUC) (95%CI): 0.909 (0.885-0.934)vs0.849 (0.813-0.886),P= 0.003]. Combination of GP73 with APRI improved further the accuracy (AUC: 0.925) compared to GP73 (AUC: 0.909,P= 0.005) or APRI alone (AUC: 0.849,P< 0.001). GP73 levels were significantly higher in HCC patients compared to non-HCC [22.5 (29.2)vs16 (20.3) units,P< 0.001) and positively associated with BCLC stage [stage 0: 13.9 (10.8); stage A: 17.1 (16.8); stage B: 19.6 (22.3); stage C: 32.2 (30.8); stage D: 45.3 (86.6) units,P< 0.001] and tumor dimensions [very early: 13.9 (10.8); intermediate: 19.6 (18.4); advanced: 29.1 (33.6) units,P= 0.004]. However, the discriminative ability for HCC diagnosis was relatively low [AUC (95%CI): 0.623 (0.570-0.675)]. Kaplan-Meier analysis showed that the detection of GP73 in patients with compensated cirrhosis at baseline, was prognostic of higher rates of decompensation (P= 0.036), HCC development (P= 0.08), and liver-related deaths (P< 0.001) during follow-up. CONCLUSION GP73 alone appears efficient for detecting cirrhosis and superior to APRI determination. In combination with APRI, its diagnostic performance can be further improved.Most importantly, the simple GP73 measurement proved promising for predicting a worse outcome of patients with both viral and non-viral chronic liver diseases.