标题：Nrf2/ARE信号通路关键因子与 ICP孕妇肝功能和预后的关联性

      作者：张全华，管文莉，郭芳，徐雪，任艳芳    张全华，管文莉，郭芳，徐雪，任艳芳新乡医学院第一附属医院产科二病区，河南 新乡 453100

      卷次： 2024年35卷13期

      【摘要】 目的 探讨核因子相关因子2/抗氧化反应元件(Nrf2/ARE)信号通路关键因子与妊娠期肝内胆汁淤积症(ICP)孕妇肝功能和预后的关联性。方法 选取2020年1月至2023年6月新乡医学院第一附属医院收治的89例ICP孕妇作为研究组，另按照1∶1配对原则选择孕周、年龄等因素匹配的正常妊娠期女性作为对照组。统计两组孕妇入院当天Nrf2/ARE信号通路关键因子[Nrf2蛋白、血红素加氧酶-1 (HO-1)蛋白、醌氧化还原酶 1 (NQO1)蛋白]、肝功能指标[总胆红素(TBIL)、天冬氨酸氨基转氨酶(AST)、总胆汁酸(TBA)]，采用Spearman分析Nrf2/ARE信号通路关键因子与 ICP孕妇肝功能指标相关性，同时以不良母婴结局为预后判定标准，比较预后良好和不良孕妇Nrf2/ARE信号通路关键因子、肝功能指标，采用受试者工作特征(ROC)曲线及曲线下面积(AUC)、净重新分类指数(NRI)、整体鉴别指数(IDI)分析上述指标单一及联合预测预后效能。结果 研究组孕妇的Nrf2、HO-1、NQO1蛋白表达及TBIL、AST、TBA含量明显高于对照组，差异均有统计学意义(P<0.05)；ICP孕妇Nrf2、HO-1、NQO1蛋白表达与TBIL、AST、TBA呈正相关(r1=0.592、0.587、0.624，r2=0.571、0.599、0.611，r3=0.566、0.576、0.598，P<0.05)；预后不良组孕妇的Nrf2、HO-1、NQO1蛋白表达及TBIL、AST、TBA含量分别为 1.70±0.39、1.59±0.33、1.75±0.44、(24.46±7.34) μmol/L、(50.51±16.11) U/L、(61.77±13.38) μmol/L，明显高于预后不良组 1.40±0.33、1.35±0.30、1.34±0.36、(16.24±4.88) μmol/L、(41.24±12.34) U/L、(49.68±8.89) μmol/L，差异均有统计学意义(P<0.05)；Nrf2+HO-1+NQO1蛋白预测 ICP孕妇预后效能近似TBIL+AST+TBA (AUC：0.924 vs 0.929)；Nrf2+HO-1+NQO1蛋白、TBIL+AST+TBA较单一指标可显著提升 ICP孕妇预后预测能力，IDI分别为 0.714 (0.448~0.970)、0.709 (0.423~1.457)、NRI分别为0.077 (0.021~0.119)、0.089 (0.018~0.027)。结论 Nrf2/ARE信号通路关键因子与 ICP孕妇肝功能密切相关，三者联合检测有助于提高预后预测效能，为本病鉴别诊治提供依据。
      【关键词】 妊娠期肝内胆汁淤积症；肝功能；核因子相关因子2；抗氧化反应元件；预后；相关性
      【中图分类号】 R714.255 【文献标识码】 A 【文章编号】 1003—6350（2024）13—1825—05

Correlation between key factors of nuclear factor-related factor 2/antioxidant response element signalingpathway and liver function and prognosis of pregnant women with intrahepatic cholestasis of pregnancy.
ZHANGQuan-hua, GUAN Wen-li, GUO Fang, XU Xue, REN Yan-fang. Ward Ⅱ, Department of Obstetrics, the First AffiliatedHospital of Xinxiang Medical University, Xinxiang 453100, Henan, CHINA
【Abstract】 Objective To investigate the correlation between key factors of the nuclear factor-related factor 2/antioxidant response element (Nrf2/ARE) signaling pathway and liver function and prognosis in pregnant women withintrahepatic cholestasis of pregnancy (ICP). Methods A total of 89 pregnant women with ICP who were admitted tothe First Affiliated Hospital of Xinxiang Medical University from January 2020 to June 2023 were selected as the studygroup. In addition, 89 normal pregnant women with matching gestational age and age were selected as the control group.The key factors of the Nrf2/ARE signaling pathway [Nrf2 protein, heme oxygenase-1 (HO-1) protein, NAD(P)H: qui-none oxidoreductase 1 (NQO1) protein], liver function indicators [total bilirubin (TBIL), aspartate aminotransferase(AST), total bile acid (TBA)] were statistically analyzed on the day of admission. Spearman analysis was used to analyzethe correlation between the key factors of the Nrf2/ARE signaling pathway and liver function indicators in pregnantwomen with ICP. At the same time, the adverse maternal and infant outcomes were used as the prognostic criteria, andthe key factors of the Nrf2/ARE signaling pathway and liver function indicators were compared between pregnant wom-en with poor and good prognosis. The receiver operating characteristic (ROC) curve, area under the curve (AUC), net re-classification improvement (NRI), and integrated discrimination improvement (IDI) were used to analyze the predictiveefficacy of these indicators alone and in combination for prognosis. Results The expression of Nrf2, HO-1, and NQO1proteins and the levels of TBIL, AST, and TBA in the study group were significantly higher than those in the controlgroup (P<0.05). The expression of Nrf2, HO-1, and NQO1 protein in ICP pregnant women was positively correlatedwith TBIL, AST, and TBA (r1=0.592, 0.587, 0.624; r2=0.571, 0.599, 0.611; r3=0.566, 0.576, 0.598; P<0.05). The expres-sion of Nrf2, HO-1, and NQO1 proteins and the levels of TBIL, AST, and TBA in the subgroup with poor prognosiswere 1.70±0.39, 1.59±0.33, 1.75±0.44, (24.46±7.34) μmol/L, (50.51±16.11) U/L, and (61.77±13.38) μmol/L, respective-ly, which were significantly higher than 1.40±0.33, 1.35±0.30, 1.34±0.36, (16.24±4.88) μmol/L, (41.24±12.34) U/L, and(49.68±8.89) μmol/L in the subgroup with poor prognosis (P<0.05). The predictive efficacy of Nrf2+HO-1+NQO1 pro-tein for predicting the prognosis of pregnant women with ICP was similar to that of TBIL+AST+TBA (AUC: 0.924 vs0.929). Compared with each indicator alone, Nrf2+HO-1+NQO1 protein and TBIL+AST+TBA can significantly im-prove the predictive efficacy for the prognosis of pregnant women with ICP, with IDI of 0.714 (0.448-0.970) and 0.709(0.423-1.457), and NRI of 0.077 (0.021-0.119) and 0.089 (0.018-0.027), respectively. Conclusion The key factors ofNrf2/ARE signaling pathway are closely related to the liver function of pregnant women with ICP. The combined detec-tion of the three factors can help improve the predictive efficacy for prognosis and provide a basis for the differential di-agnosis and treatment of this disease.
      【Key words】 Intrahepatic cholestasis of pregnancy; Liver function; Nuclear factor related factor 2 (Nrf2); Anti-oxidant reaction elements (ARE); Prognosis; Correlation