传统炎性标志物对妊娠期肝内胆汁淤积症的诊断及预后预测价值

Diagnostic and prognostic value of blood routine inflammatory markers in intrahepatic cholestasis of pregnancy

目的探讨传统炎性标志物对妊娠期肝内胆汁淤积症(ICP)的诊断及预后预测价值。方法选择2009年1月至2019年1月,于厦门大学附属中山医院消化内科和妇产科确诊的130例ICP患者为研究对象,并纳入ICP组,其中,初产妇为86例,经产妇为44例。根据ICP严重程度,进一步将其分为重度ICP亚组(n=29)和轻度ICP亚组(n=101)。选择同期在本院就诊的80例健康孕妇纳入对照组。按照86例初产妇的分娩孕龄,进一步分为ICP早产亚组(n=37)和ICP足月亚组(n=49)。采集受试者一般临床资料(年龄、孕龄等),天冬氨酸氨基转氨酶(AST)、丙氨酸转氨酶(ALT)、碱性磷酸酶(ALP)、γ-谷氨酰转肽酶(GGT)、白细胞计数、中性粒细胞计数、淋巴细胞计数、血小板计数、红细胞分布宽度(RDW)、血红蛋白(Hb)、平均血小板体积(MPV)、血细胞比容(HCT)、中性粒细胞与淋巴细胞比值(NLR)、血小板与淋巴细胞比值(PLR)和血清总胆汁酸(sTBA)等。本研究经过厦门大学附属中山医院伦理委员会批准(审批文号:2019076),与所有患者签署临床研究知情同意书。结果①ICP组和对照组孕妇年龄、中性粒细胞计数、淋巴细胞计数、血小板计数、MPV、ALP、AST、NLR和sTBA比较,差异均有统计学意义(P<0.05)。2组孕妇孕龄、白细胞计数、HCT、Hb、GGT、ALT和PLR比较,差异无统计学意义(P>0.05)。②轻度ICP亚组患者的孕龄大于重度ICP亚组,而轻度ICP亚组患者sTBA浓度低于重度ICP亚组,2组比较,差异均有统计学意义(P<0.05)。此外,2组患者年龄、白细胞计数、中性粒细胞计数、淋巴细胞计数、MPV、HCT、血小板计数、Hb、GGT、ALP、ALT、AST、NLR和PLR比较,差异均无统计学意义(P>0.05)。③NLR、血小板计数和MPV诊断ICP的受试者工作特征曲线(ROC)分析结果:NLR、血小板计数和MPV诊断ICP的曲线下面积(AUC)分别为0.802(95%CI:0.737~0.867,P<0.001),0.642(95%CI:0.560~0.724,P<0.001)和0.947(95%CI:0.920~0.974,P<0.001);根据约登指数最大原则,NLR、血小板计数和MPV诊断ICP的最佳临界值分别为2.831、254×109/L和9.662 fL,此时其诊断ICP的敏感度分别为71.4%、64.7%和72.2%,特异度分别为81.3%、71.2%和82.5%。④ICP早产亚组与ICP足月分娩亚组孕妇ALT、AST和sTBA水平比较,差异均有统计学意义(P<0.05);而2组孕妇年龄、白细胞计数、中性粒细胞计数、淋巴细胞计数、血小板计数、MPV、PDW、NLR和PLR比较,差异均无统计学意义(P>0.05)。⑤sTBA、ALT、AST预测ICP所致早产的ROC分析结果:sTBA、ALT和AST预测ICP所致早产的AUC分别为0.634(95%CI:0.513~0.751,P<0.05),0.672(95%CI:0.563~0.784,P<0.001)和0.692(95%CI:0.544~0.793,P<0.001);根据约登指数最大原则,sTBA、ALT和AST预测ICP所致早产的最佳临界值分别为48μmol/L、56 U/L和37 U/L,此时其预测ICP所致早产的敏感度分别为67.2%、62.2%和63.2%,特异度分别为59.6%、41.3%和49.6%。结论传统炎性标志物NLR、血小板计数、MPV对诊断ICP具有良好准确度,而目前发现的传统炎性标志物对ICP严重程度评估均无价值,sTBA、ALT和AST水平可能对ICP所致早产具有一定预测价值。

Objective To investigate the diagnostic and prognostic value of blood routine inflammatory markers in intrahepatic cholestasis of pregnancy(ICP).Methods From January 2009 to January 2019,a total of 130 pregnant women with ICP diagnosed at the Department of Gastroenterology and Department of Obstetrics and Gynecology,Zhongshan Hospital,Affiliated to Xiamen University were selected into this study(ICP group),including 86 primiparae and 44 pluriparae.According to the severity of ICP,they were further divided into severe ICP subgroup(n=29)and mild ICP subgroup(n=101).Meanwhile,another 80 healthy pregnant women who visited the same hospital during same period were included into control group.In addition,those 86 primiparae were further divided into premature subgroup(n=37)and full-term subgroup(n=49).General clinical data(age,gestational age),aspartate transaminase(AST),alanine transaminase(ALT),alkaline phosphatase(ALP),γ-glutamyltranspeptidase(GGT),leukocyte count,neutrophil count,lymphocyte count,platelet count,red blood cell distribution width(RDW),hemoglobin(Hb),mean platelet volume(MPV),hematocrit(HCT),neutrophil-to-lymphocyte ratio(NLR),platelet-to-lymphocyte ratio(PLR)and serum total bile acid(sTBA)were collected.This study followed the ethical standards formulated by the Ethics Committee of Zhongshan Hospital,Affiliated to Xiamen University,and was approved(Approval No.2019076).Informed concent was obtained from each participate.Results①There were significant differences between ICP group and control group in age,neutrophil count,lymphocyte count,platelet count,MPV,ALP,AST,NLR and sTBA(P<0.05).There were no significant differences between ICP group and control group in gestational age,white blood cell count,HCT,Hb,GGT,ALT and PLR(P>0.05).②The gestational age in mild ICP subgroup was higher than that in severe ICP subgroup,while the sTBA concentration in mild ICP subgroup was lower than that in severe ICP subgroup,and the differences were statistically significant(P<0.05).In addition,there were no significant differences in age,white blood cell count,neutrophil count,lymphocyte count,MPV,HCT,platelet count,Hb,GGT,ALP,ALT,AST,NLR and PLR between two groups(P>0.05).③Receiver operating characteristic curve(ROC)analysis showed that area under curve(AUC)of NLR,platelet count,MPV for diagnosing ICP were 0.802(95%CI:0.737-0.867,P<0.001),0.642(95%CI:0.560-0.724,P<0.001)and 0.947(95%CI:0.920-0.974,P<0.001).According to the principle of maximum Youden index,the optimal cut-off value for NLR,platelet count,MPV to diagnose ICP were 2.831,254×109/L and 9.662 fL,the sensitivity were 71.4%,64.7%and 72.2%,respectively,and the specificity were 81.3%,71.2%and 82.5%,respectively.④There were significant differences in ALT,AST and sTBA levels between preterm subgroup and full-term subgroup(P<0.05),but there were no significant differences in age,white blood cell count,neutrophil count,lymphocyte count,platelet count,MPV,PDW,NLR and PLR between two groups(P>0.05).⑤ROC analysis showed that AUC of sTBA,ALT and AST for predicting premature birth caused by ICP were 0.634(95%CI:0.513-0.751,P<0.05),0.672(95%CI:0.563-0.784,P<0.001)and 0.692(95%CI:0.544-0.793,P<0.001).According to the principle of maximum Youden index,the optimal cut-off value for sTBA,ALT and AST to predicting premature birth caused by ICP were 48μmol/L,56 U/L and 37 U/L,the sensitivity were 67.2%,62.2%and 63.2%,respectively;and the specificity were 59.6%,41.3%and 49.6%,respectively.Conclusions NLR,platelet count and MPV have good accuracy in diagnosis of ICP,but the blood routine inflammatory markers have no value in the evaluation of the severity of ICP,and ALT,AST and sTBA may have certain predictive value in predicting the preterm birth caused by ICP.