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中医药对肝硬化门静脉血栓的干预作用及用药特点分析
DOI: 10.3969/j.issn.1001-5256.2023.02.014
伦理学声明：本研究于2017年11月29日经由上海中医药大学附属曙光医院伦理委员会审批通过，批号：2017-560-43。患者均签署知情同意书。
利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。
作者贡献声明：郭亚楠负责资料收集分析，撰写论文；顾宏图、赵长青、慕永平、袁继丽、邢枫负责提供患者资料；吕靖负责指导撰写并修改论文；陶艳艳参与修改论文；刘成海负责课题设计，修改、审定论文。
Effect of traditional Chinese medicine on portal vein thrombosis in patients with liver cirrhosis and its medication characteristics
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摘要:
目的 探究中医药对肝硬化合并门静脉血栓(PVT)患者的干预作用及用药特点。 方法 回顾性选取于上海中医药大学附属曙光医院住院治疗的肝硬化合并PVT患者89例，根据是否联用中医药治疗分为中药组59例，对照组30例。收集两组患者人口学、实验室检查、影像学检查、胃镜检查、手术史、门静脉高压相关并发症、用药情况及随访资料。符合正态分布的计量资料两组间比较采用独立样本t检验；不符合正态分布的计量资料两组间比较采用Mann－ Whitney U秩和检验。计数资料采用χ2检验或Fisher精确概率法。多因素分析采用有序多分类Logistic回归分析。利用中医传承计算平台V3.0对中药干预处方进行药物效应聚类分析。 结果 多因素Logistic回归分析显示，食管胃底静脉曲张(OR=3.144，95%CI: 1.221~8.094)、PVT范围波及PV+SMV(OR=51.667，95%CI: 3.536~754.859)、PV+ SV+SMV(OR=13.271，95%CI: 2.290~76.928)、伴门静脉海绵样变性(OR=11.896，95%CI: 1.172~120.696)及中药干预(OR=0.348，95%CI: 0.129~0.938)是肝硬化PVT结局的影响因素(P值均＜0.05)。随访结果显示，中药组PVT进展率明显低于对照组(16.95% vs 56.67%，P＜0.001)。中药组静脉曲张破裂出血发生率明显低于对照组(8.47% vs 33.33%，P＜0.001)。使用频率较高的有效中药为补虚类359次(34.6%)、活血化瘀类202次(19.5%)、利水渗湿类180次(17.3%)等；使用频次较高的中药为黄芪57次(8.7%)、当归50次(7.6%)、水蛭48次(7.3%)等；使用频次较高的药对为黄芪+当归、黄芪+水蛭、当归+水蛭、黄芪+当归+水蛭等。 结论 黄芪、当归、水蛭等益气活血破血中药可促进肝硬化PVT的稳定或再通，减少门静脉高压出血的发生。 Abstract:Objective To investigate the therapeutic effect of traditional Chinese medicine (TCM) on portal vein thrombosis (PVT) in patients with liver cirrhosis and its medication characteristics. Methods A retrospective analysis was performed for 89 patients with liver cirrhosis and PVT who were hospitalized and treated in Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, and according to whether TCM treatment was applied in combination, they were divided into TCM group with 59 patients and control group with 30 patients. Related data were collected for the two groups, including demographic data, laboratory examination, radiological examination, gastroscopy, history of surgery, portal hypertension-related complications, medication, and follow-up data. The independent samples t-test was used for comparison of normally distributed continuous data between two groups, and the Mann-Whitney U rank sum test was used for comparison of non-normally distributed continuous data between two groups; the chi-square test or the Fisher's exact test was used for comparison of categorical data between two groups. An ordinal polytomous Logistic regression analysis was used for multivariate analysis. TCM Inheritance Computing Platform (V3.0) was used to perform a drug effect cluster analysis of TCM prescriptions. Results The multivariate logistic regression analysis showed that esophageal and gastric varices (odds ratio [OR]=3.144, 95% confidence interval [CI]: 1.221-8.094), PVT involving the portal vein (PV) and the superior mesenteric vein (SMV) (OR=51.667, 95%CI: 3.536-754.859), PVT involving PV+spleen vein (SV)+SMV (OR=13.271, 95% CI: 2.290-76.928), cavernous transformation of the portal vein (OR=11.896, 95%CI: 1.172-120.696), and TCM intervention (OR=0.348, 95%CI: 0.129-0.938) were influencing factors for the outcome of PVT in liver cirrhosis. Follow-up results showed that compared with the control group, the TCM group had a significantly lower progression rate (16.95% vs 56.67%, P < 0.001) and a significantly lower incidence rate of variceal rupture and bleeding (8.47% vs 33.33%, P < 0.001). Effective TCM drugs with a relatively high frequency of use included deficiency-tonifying drugs (359 times, 34.6%), blood-activating and stasis-resolving drugs (202 times, 19.5%), and diuresis-inducing and dampness-draining drugs (180 times, 17.3%); the TCM drugs with a relatively high frequency of use included Astragalus membranaceus (57 times, 8.7%), Angelica sinensis (50 times, 7.6%), and leech (48 times, 7.3%); TCM drug combinations with a relatively high frequency of use included Astragalus membranaceus+Angelica sinensis, Astragalus membranaceus+leech, Angelica sinensis+leech, and Astragalus membranaceus+Angelica sinensis+leech. Conclusion Qi-tonifying, blood-activating, and stasis-breaking drugs, such as Astragalus membranaceus, Angelica sinensis, and leech, can promote the stabilization or recanalization of PVT in liver cirrhosis and reduce the incidence rate of bleeding events due to portal hypertension. -
Key words:
- Liver Cirrhosis /
- Portal Vein Thrombosis /
- Pathogenests (TCM)
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图 1 两组患者PVT进展率比较
Figure 1. Comparison of the probability of PVT progression between the two groups
图 2 两组患者静脉曲张破裂出血发生率比较
Figure 2. Comparison of the incidence of decompensated portal hypertension events (variceal bleeding) between the two groups
表 1 PVT患者及中药组与对照组临床资料比较
Table 1. Baseline features of the entire study cohort and of patients who did and did not treated with traditional Chinese medicine
指标 PVT患者(n=89) 中药组(n=59) 对照组(n=30) 统计值 P值 年龄(岁) 59.96±11.63 59.92±11.61 60.03±11.88 t=0.045 0.964 男性[例(%)] 47(52.8) 28(47.5) 19(63.3) χ2=2.011 0.156 肝硬化病因[例(%)] χ2=0.699 0.983 病毒 45(50.6) 29(49.2) 16(53.3) 酒精 6(6.7) 4(6.8) 2(6.7) PSC/AIH 7(7.9) 5(8.5) 2(6.7) 血吸虫 7(7.9) 4(6.8) 3(10.0) 混合病因 6(6.7) 4(6.8) 2(6.7) 其他 18(20.2) 13(22.0) 5(16.7) Child-Pugh评分 7.82±2.09 7.95±2.19 7.57±1.89 t=0.714 0.475 Child-Pugh分级[例(%)] χ2=0.661 0.509 A级 24(27.0) 15(25.4) 9(30.0) B级 50(56.2) 33(55.9) 17(56.7) C级 15(16.9) 11(18.6) 4(13.3) MELD评分 11.05±4.50 11.11±4.29 10.93±4.97 t=0.169 0.866 PVT范围[例(%)] PV 38(42.7) 23(39.0) 15(50.0) χ2=0.987 0.321 PV+SV 7(7.9) 6(10.2) 1(3.3) χ2=0.513 0.474 PV+SMV 29(32.6) 18(30.5) 11(36.7) χ2=0.343 0.558 PV+SV+SMV 6(6.7) 5(8.5) 1(3.3) χ2=0.218 0.640 伴门静脉海绵样变性[例(%)] 9(10.1) 7(11.9) 2(6.7) χ2=0.158 0.691 静脉曲张出血[例(%)] 43(48.3) 26(44.1) 17(56.7) χ2=1.264 0.261 腹水[例(%)] 59(66.3) 43(72.9) 16(53.3) χ2=3.401 0.065 内镜下治疗史[例(%)] 40(44.9) 25(42.4) 15(50.0) χ2=0.468 0.494 脾切除术史[例(%)] 21(23.6) 12(20.3) 9(30.0) χ2=1.030 0.310 合并用药[例(%)] NSBB 47(52.8) 27(45.8) 20(66.7) χ2=3.487 0.062 抗凝药 33(37.1) 18(30.5) 15(50.0) χ2=3.239 0.072 利尿剂 58(65.2) 41(69.5) 17(56.7) χ2=1.441 0.230 EV[例(%)] 76(85.4) 51(86.4) 25(83.3) χ2=0.006 0.940 EV+GV[例(%)] 35(39.3) 22(37.3) 13(43.3) χ2=0.305 0.581 TBil(μmol/L) 26.50(18.25~39.81) 26.70(18.70~40.88) 24.60(17.80~36.05) Z=-0.848 0.397 Alb(g/L) 30.90±5.12 31.07±5.27 30.55±4.88 t=-0.449 0.655 ChE(KU/L) 3629.53±1583.20 3512.91±1535.24 3875.29±1681.77 t=0.997 0.321 Scr(μmol/L) 64.00(53.93~80.12) 62.00(49.52~80.12) 69.00(58.25~80.28) Z=-1.545 0.122 PT(s) 16.42±3.32 16.44±2.49 16.37±4.63 t=-0.095 0.925 INR 1.34(1.20~1.49) 1.36(1.20~1.51) 1.29(1.20~1.46) Z=0.117 0.907 D-二聚体(μg/mL) 2.88(1.26~5.51) 2.88(1.03~5.88) 2.83(1.76~5.77) Z=-0.540 0.589 抗凝血酶Ⅲ(%) 58.16±18.26 56.98±19.32 60.71±15.80 t=0.859 0.393 WBC(×109/L) 3.21(2.13~5.01) 3.27(2.18~5.29) 3.21(2.11~4.84) Z=-0.212 0.832 中性粒细胞百分比 58.67±16.38 60.43±15.10 55.01±18.52 t=-1.447 0.152 Hb(g/L) 101.00(81.00~121.00) 102.50(83.00~121.50) 89.50(78.65~120.50) Z=-1.018 0.312 PLT(×109/L) 63.00(40.00~114.00) 57.50(39.75~109.50) 71.00(41.00~126.50) Z=-1.022 0.307 降钙素原(ng/mL) 0.07(0.05~0.14) 0.08(0.06~0.16) 0.06(0.03~0.14) Z=-1.478 0.139 注：PSC，原发性胆汁性胆管炎；AIH，自身免疫性肝炎；PV，门静脉；SV，脾静脉；SMV，肠系膜上静脉；EV，食管静脉曲张；GV，胃静脉曲张。 
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表 2 PVT结局相关因素的多因素分析
Table 2. Multivariate analysis of factors associated with PVT outcome
指标 OR值 95%CI P值 MELD评分 0.932 0.842~1.031 0.172 腹水 1.158 0.443~3.026 0.764 EV+GV 3.144 1.221~8.094 0.018 PVT范围 PV 2.921 0.584~14.600 0.192 PV+SMV 51.667 3.536~754.859 0.004 PV+SV+SMV 13.271 2.290~76.928 0.004 伴门静脉海绵样变性 11.896 1.172~120.696 0.036 中药干预 0.348 0.129~0.938 0.037 抗凝药物使用 1.391 0.524~3.693 0.508 静脉曲张程度 G1 0.566 0.179~1.786 0.332 G2 1.080 0.241~4.849 0.920 G3 0.762 0.211~2.746 0.677
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表 3 高频中药种类分布
Table 3. Distribution of high-frequency drug types
种类 用药频次[次(%)] 常用药[次(%)] 补虚类 359(34.6) 黄芪57(8.7)、当归50(7.6)、白术43(6.6)、白芍38(5.8)、鳖甲25(3.8)、党参23(3.5)、山药13(2.0)、甘草13(2.0)、山茱萸12(1.8)、太子参12(1.8) 活血化瘀类 202(19.5) 水蛭48(7.3)、穿山甲43(6.6)、丹参21(3.2)、川芎21(3.2)、桃仁21(3.2)、莪术18(2.7)、三棱13(2.0)、地龙14(2.0) 利水渗湿类 180(17.3) 茯苓41(6.3)、泽泻27(4.1)、车前子21(3.2)、猪苓18(2.7)、泽兰17(2.6) 清热类 70(6.7) 地黄14(2.1)、赤芍14(2.1)、黄芩13(2.0)、茵陈12(1.8) 消食类 53(5.1) 炒麦芽24(3.7) 止血类 38(3.7) 三七13(2.0) 理气类 37(3.66) 陈皮13(2.0)
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表 4 中药干预PVT处方中药物关联规则
Table 4. Drug association rules in TCM intervention PVT prescriptions
序号 规则 置信度 1 水蛭→当归 0.92 2 白术，茯苓→黄芪 0.94 3 水蛭，白术→当归 0.91 4 白芍→白术 0.92 5 白术，白芍→黄芪 0.97 6 黄芪，白芍→白术 0.92 7 当归，白术→黄芪 1 8 水蛭，白芍→黄芪 1 9 当归，茯苓→黄芪 1 10 当归→黄芪 1 11 当归，水蛭，白术→黄芪 1 12 黄芪，水蛭，白术→当归 0.91 13 白术→黄芪 0.95 14 当归，白芍→黄芪 1 15 水蛭→黄芪 1 16 当归，水蛭→黄芪 1 17 黄芪，水蛭→当归 0.92 18 茯苓→黄芪 0.95 19 水蛭，白术→黄芪 1 20 白芍→黄芪 0.97 21 水蛭，茯苓→黄芪 1
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表 5 聚类药组分析结果
Table 5. Cluster arm analysis results
序号 常用药物 1 黄芪，当归，水蛭，女贞子，麦冬，白术 2 白术，泽泻，茯苓，白芍，黄芪，黄连 3 当归，黄芪，赤芍，三棱，泽泻，茯苓 4 黄芪，茯苓，当归，白术，白芍，泽泻 5 水蛭，黄芪，当归，鳖甲，白术，茯苓
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