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血清壳多糖酶3样蛋白1(CHI3L1)对肝硬化患者发生失代偿事件风险的预测价值
DOI: 10.3969/j.issn.1001-5256.2023.07.011
伦理学声明：本研究方案于2021年10月13日经由天津市第二人民医院伦理委员会审批，批号：津二人民伦审字[2021]54号，患者均签署知情同意书。
利益冲突声明：本文不存在任何利益冲突。
作者贡献声明：李嘉、赵黎莉对研究的思路或设计有关键贡献；杨航、韩萍、文君、刘洁、程晓静参与了研究数据的获取、分析和解释过程；杨航、陈庆灵参与起草或修改文章的关键内容。
Value of serum chitinase-3-like protein 1 in predicting the risk of decompensation events in patients with liver cirrhosis
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摘要:
目的 预测失代偿事件以采取积极的预防措施，是提高肝硬化患者生存期的关键。本文旨在探索血清壳多糖酶3样蛋白1(CHI3L1)对肝硬化患者发生失代偿事件风险的预测价值。 方法 纳入2019年1月—2021年5月于天津市第二人民医院诊疗的305例肝硬化患者，进行病例对照研究。其中基线时处于代偿期肝硬化的患者200例，处于失代偿期肝硬化的患者105例。将305例肝硬化患者，以1年内是否发生失代偿事件进行分组，其中发生失代偿事件组79例，未发生失代偿事件组226例；将200例代偿期肝硬化患者，以1年内是否发生首次失代偿事件进行分组，其中发生首次失代偿事件组43例，未发生首次失代偿事件组157例。符合正态分布的计量资料两组间比较采用成组t检验或Mann-Whitney U检验；计数资料两组间比较采用Wilcoxon秩和检验或χ2检验。采用二分类Logistic回归分析各变量与失代偿事件之间的相关性；采用受试者工作特征曲线(ROC曲线)下面积(AUC)来评价各变量对失代偿事件的预测价值，采用约登指数最大值来确定最佳临界值。 结果 1年内发生失代偿事件患者的基线血清CHI3L1水平高于未发生患者[243.00(136.00~372.00)ng/mL vs 117.50(67.75~205.25)ng/mL，U=4 720.500，P＜0.001]；1年内发生首次失代偿事件患者的基线血清CHI3L1水平高于未发生患者[227.98(110.00~314.00)ng/mL vs 90.00(58.00~168.50)ng/mL，U=1 681.500，P＜0.001]。基线血清CHI3L1水平较高的肝硬化患者，1年内发生失代偿事件的风险增加(OR=1.004, 95%CI：1.002~1.006，P＜0.001)；基线血清CHI3L1水平较高的代偿期肝硬化患者，1年内发生首次失代偿事件的风险增加(OR=1.006, 95%CI：1.003~1.008，P＜0.001)。使用基线血清CHI3L1水平预测代偿期肝硬化患者发生首次失代偿事件风险的AUC为0.751，最佳临界值为95.5 ng/mL，敏感度和特异度分别为90.7%和55.4%；联合血清CHI3L1和Child-Pugh分级建立预测模型，AUC为0.809，约登指数最大时敏感度和特异度分别为72.1%和77.1%。 结论 血清CHI3L1可做为代偿期肝硬化患者发生首次失代偿事件风险的有效预测因子，且在联合Child-Pugh分级后具有更高的预测价值。 -
关键词:
- 肝硬化 /
- 壳多糖酶3样蛋白质1 /
- 危险因素
Abstract:Objective To investigate the value of serum chitinase-3-like protein 1 (CHI3L1) in predicting the risk of decompensation events in patients with liver cirrhosis, since prediction of decompensation events and adoption of active preventive measures are the key to improving the survival time of patients with liver cirrhosis. Methods A case-control study was conducted for 305 patients with liver cirrhosis who were diagnosed and treated in Tianjin Second People's Hospital from January 2019 to May 2021, among whom there were 200 patients with compensated liver cirrhosis and 105 patients with decompensated liver cirrhosis at baseline. According to whether decompensation events occurred within 1 year, the 305 patients with liver cirrhosis were divided into decompensation group with 79 patients and non-decompensation group with 226 patients; according to whether decompensation events occurred for the first time within 1 year, the 200 patients with compensated liver cirrhosis were divided into first-time decompensation group with 43 patients and non-first-time decompensation group with 157 patients. The independent samples t-test or the Mann-Whitney U test was used for comparison of normally distributed continuous data between groups, and the Wilcoxon rank-sum test or the chi-square test was used for comparison of categorical data between groups. The binary logistic regression analysis was used to investigate the association between each variable and decompensation events; the receiver operating characteristic (ROC) curve and the area under the ROC curve (AUC) were used to investigate the value of each variable in predicting decompensation events, and the maximum value of Youden index was used to determine the optimal cut-off value. Results The patients who experienced decompensation events within 1 year had a significantly higher baseline serum level of CHI3L1 than those who did not experience such events [243.00 (136.00-372.00) ng/mL vs 117.50 (67.75-205.25) ng/mL, U=4720.500, P < 0.001], and the patients who experienced decompensation events for the first time within 1 year had a significantly higher baseline serum level of CHI3L1 than those who did not experience such events [227.98 (110.00-314.00) ng/mL vs 90.00 (58.00-168.50) ng/mL, U=1 681.500, P < 0.001]. Patients with cirrhosis with higher baseline CHI3L1 levels had an increased risk of decompensation events within 1 year (OR=1.004, 95%CI: 1.002-1.006, P < 0.001); Patients with compensated cirrhosis with higher baseline serum CHI3L1 levels had an increased risk of first decompensated event within 1 year (OR=1.006, 95%CI: 1.003-1.008, P < 0.001). The baseline serum level of CHI3L1 had an AUC of 0.751 in predicting the risk of first-time decompensation events, with a sensitivity of 90.7% and a specificity of 55.4% at the optimal cut-off value of 95.5 ng/mL. The predictive model based on the combination of serum CHI3L1 level and Child-Pugh class had an AUC of 0.809, with a sensitivity of 72.1% and a specificity of 77.1% at the maximum value of Youden index. Conclusion Serum CHI3L1 level can be used as an effective predictive factor for the risk of first-time decompensation events in patients with compensated liver cirrhosis, and its combination with Child-Pugh class shows a higher predictive value. -
Key words:
- Liver Cirrhosis /
- Chitinase-3-Like Protein 1 /
- Risk Factors
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图 1 CHI3L1、Child-Pugh分级和预测模型的ROC曲线
注：a, 失代偿事件；b，首次失代偿事件。
Figure 1. ROC curve of CHI3L1, Child Pugh classification and the model for the prediction
表 1 发生与未发生失代偿事件患者基线人口学特征和临床资料的比较
Table 1. Comparison of baseline demographic characteristics and clinical data between decompensation and non-decompensation group
项目 发生失代偿事件组
(n=79)未发生失代偿事件组
(n=226)统计值 P值 男性[例(%)] 54(68.4) 122(54.0) χ2=4.954 0.026 年龄(岁) 58.24±11.57 54.01±11.06 t=-2.308 0.022 病因[例(%)] χ2=2.248 0.956 乙型肝炎 45(57.0) 115(50.9) 乙型肝炎合并NAFLD 8(10.1) 23(10.2) 丙型肝炎 9(11.4) 22(9.7) 丙型肝炎合并NAFLD 1(1.3) 6(2.7) 酒精性肝病 3(3.8) 8(3.5) 自身免疫性肝炎 2(2.5) 6(2.7) 原发性胆汁性胆管炎 1(1.3) 5(2.2) 其他 10(12.7) 41(18.1) Child-Pugh分级[例(%)] Z=-5.434 ＜0.001 A级 30(38.0) 169(74.8) B级 39 (49.4) 37 (16.4) C级 10(12.7) 20(8.8) MELD评分 9.53(7.92~12.54) 7.89(6.09~10.73) U=6 258.500 0.001 ALT(U/L) 19.55(15.10~28.00) 22.00(16.10~29.60) U=7 822.500 0.102 Alb(g/L) 34.40(29.10~39.90) 41.60(35.08~45.30) U=5 040.500 ＜0.001 TBil(μmol/L) 21.80(14.20~36.40) 17.65(13.30~28.03) U=7 521.000 0.037 CHI3L1(ng/mL) 243.00(136.00~372.00) 117.50(67.75~205.25) U=4 720.500 ＜0.001 INR 1.20(1.10~1.30) 1.00(1.00~1.20) U=5 438.000 ＜0.001 PLT (×109/L) 77.00(53.00~129.00) 103.50(63.75~163.00) U=6 700.500 0.001 注：NAFLD，非酒精性脂肪性肝病。 
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表 2 发生与未发生首次失代偿事件患者基线人口学特征和临床资料的比较
Table 2. Comparison of baseline demographic characteristics and clinical data between first-time decompensation and non-first-time decompensation group
项目 发生首次失代偿事件组
(n=43)未发生首次失代偿事件组
(n=157)统计值 P值 男性[例(%)] 27(62.8) 90(57.3) χ2=0.415 0.520 年龄(岁) 56.56±11.41 52.38±10.95 t=2.200 0.029 病因[例(%)] χ2=4.717 0.680 乙型肝炎 23(53.5) 87(55.4) 乙型肝炎合并NAFLD 3(7.0) 20(12.7) 丙型肝炎 3(7.0) 12(7.6) 丙型肝炎合并NAFLD 1(2.3) 7(4.5) 酒精性肝病 2(4.7) 4(2.5) 自身免疫性肝炎 1(2.3) 4(2.5) 原发性胆汁性胆管炎 0(0.0) 3(1.9) 其他 10(23.3) 20(12.7) Child-Pugh分级[例(%)] Z=-5.510 ＜0.001 A级 29(67.4) 151(96.2) B级 14(32.6) 5(3.2) C级 0(0.0) 1(0.6) MELD评分 9.39(7.47~12.30) 6.78(5.60~8.87) U=1 804.000 ＜0.001 ALT(U/L) 19.00(15.10~26.30) 22.00(16.00~28.40) U=2 873.000 0.135 Alb(g/L) 37.30(30.50~44.30) 43.30(39.75~46.30) U=1 898.000 ＜0.001 TBil(μmol/L) 27.53(14.70~35.00) 15.60(12.10~21.25) U=2 236.500 ＜0.001 CHI3L1(ng/mL) 227.98(110.00~314.00) 90.00(58.00~168.50) U=1 681.500 ＜0.001 INR 1.16(1.00~1.30) 1.00(0.90~1.10) U=1 716.500 ＜0.001 PLT(×109/L) 83.26(44.00~100.00) 123.00(85.00~174.50) U=1 631.000 ＜0.001
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表 3 肝硬化患者1年内发生失代偿事件的单因素分析
Table 3. Univariate analysis of factors associated with decompensated events in patients with cirrhosis
变量 OR(95%CI) P值 年龄 1.035(1.010~1.060) 0.005 性别 0.543(0.316~0.933) 0.027 Child-Pugh分级 2.328(1.608~3.372) ＜0.001 MELD评分 1.111(1.041~1.187) 0.002 ALT 0.983(0.960~1.007) 0.161 Alb 0.898(0.864~0.933) ＜0.001 TBil 1.003(0.994~1.012) 0.508 CHI3L1 1.005(1.003~1.007) ＜0.001 INR 15.077(4.035~56.336) ＜0.001 PLT 0.995(0.991~0.999) 0.026
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表 4 代偿期肝硬化患者1年内发生首次失代偿事件的单因素分析
Table 4. Univariate analysis of factors associated with first decompensated events in patients with compensatory cirrhosis
变量 OR(95%CI) P值 年龄 1.035(1.003~1.069) 0.031 性别 0.796(0.397~1.594) 0.520 Child-Pugh分级 8.831(3.284~23.746) ＜0.001 MELD评分 1.288(1.146~1.446) ＜0.001 ALT 0.972(0.935~1.010) 0.143 Alb 0.871(0.820~1.924) ＜0.001 TBil 1.027(1.006~1.049) 0.012 CHI3L1 1.006(1.003~1.009) ＜0.001 INR 192.611(17.328~2 140.935) ＜0.001 PLT 0.984(0.976~0.991) ＜0.001
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表 5 血清CHI3L1水平对各失代偿事件的预测价值
Table 5. Predictive value of serum CHI3L1 level for decompensated events in patients with cirrhosis
变量 AUC 95%CI 截断值(ng/mL) 敏感度(%) 特异度(%) 阳性预测值(%) 阴性预测值(%) 腹水 0.726 0.660~0.792 206.5 63.2 74.7 41.7 87.6 EVB 0.824 0.760~0.888 215.5 78.3 76.8 37.5 95.2 显性肝性脑病 0.515 0.394~0.576 102.5 100 61.1 2.1 100
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