Effect of magnesium isoglycyrrhizinate on concanavalin A-induced acute liver failure in mice
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摘要:
目的研究异甘草酸镁(Mg IG)对刀豆蛋白A(Con A)诱导的急性肝衰竭小鼠模型的作用及机制。方法选取健康BALB/C小鼠90只,随机分为4组,分别为对照组、Mg IG对照组,每组各10只; Con A模型组、Mg IG+Con A预处理组,每组各35只(其中15只用来计算总生存率)。提取小鼠肝脏及外周血,测定生存率、血清转氨酶水平,肝组织HE染色评价小鼠肝损伤程度,TUNEL荧光染色及caspase-3蛋白活性检测评价小鼠肝细胞凋亡水平,液相芯片法检测小鼠血清炎症细胞因子IL-1β和TNFα含量。计量资料多组间比较采用单因素方差分析,进一步两两比较采用LSD-t检验。结果 Con A模型组小鼠总生存率为40%,Mg IG+Con A预处理组小鼠总生存率为80%。Con A模型组血清ALT与AST水平较对照组均显著上升(P值均<0. 01),Mg IG+Con A预处理组血清ALT与AST水平较Con A模型组均显著降低(P值均<0. 01)。对照组、Mg IG对照组、Con A模型组及Mg IG+Con A预处理组病理评分分别为1. 0±0. 2、1. 2±0. 3、3...
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关键词:
- 肝功能衰竭,急性 /
- 甘草酸 /
- 小鼠,近交BALB C
Abstract:Objective To investigate the effect of magnesium isoglycyrrhizinate(MgIG) on concanavalin A(ConA)-induced acute liver failure in mice and its mechanism. Methods A total of 60 healthy BALB/C mice were randomly divided into control group with 10 mice,MgIG control group with 10 mice,ConA model group with 20 mice,and MgIG-ConA pretreatment group with 20 mice. The liver and peripheral blood were collected to evaluate survival rate,serum levels of aminotransferases,and degree of liver injury by HE staining of liver tissue; TUNEL fluorescence staining and activity of caspase-3 protein were used to evaluate the apoptosis of hepatocytes; the liquid chip method was used to measure the serum levels of the inflammatory cytokines interleukin-1β(IL-1β) and tumor necrosis factor α(TNFα).A one-way analysis of variance was used for comparison of continuous data between multiple groups,and the least significant difference t-test was used for further comparison between two groups. Results The overall survival rate of mice was 40% in the ConA model group and80% in the MgIG-ConA pretreatment group. The ConA model group had significantly increased serum levels of alanine aminotransferase( ALT) and aspartate aminotransferase( AST) compared with the control group( both P < 0. 01),while the MgIG + ConA pretreatment group had significantly reduced serum levels of ALT and AST compared with the ConA model group( both P < 0. 01). The control group,the MgIG control group,the ConA model group,and the MgIG-ConA pretreatment group had a pathological score of 1. 0 ± 0. 2,1. 2 ± 0. 3,3. 7 ±0. 6,and 2. 3 ± 0. 5,respectively,and there was a significant difference between groups( F = 2. 7,P < 0. 05); the apoptotic cells/100 cells ratio was 0. 2 ± 0. 1,0. 1 ± 0. 1,7. 8 ± 1. 3,and 2. 2 ± 0. 4,respectively,in these four groups,and there was a significant difference between groups( F = 27. 6,P < 0. 001); the activity of caspase-3 protein was 0. 813 ± 0. 022,0. 930 ± 0. 033,1. 347 ± 0. 042,and1. 060 ± 0. 053,respectively,in these four groups,and there was a significant difference between groups( F = 51. 072,P < 0. 001).Compared with the control group,the Con A model group had significant increases in serum levels of IL-1β and TNFα( both P < 0. 05);compared with the Con A model group,the Mg IG + Con A pretreatment group had significant reductions in serum levels of IL-1β and TNFα( both P < 0. 05). Conclusion Mg IG exerts a marked protective effect against Con A-induced acute liver failure in mice and can alleviate liver injury possibly by reducing hepatocyte apoptosis and alleviating liver inflammatory response caused by IL-1β and TNFα.
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Key words:
- liver failure,acute /
- glycyrrhizic acid /
- mice,inbred BALB C
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尽管药物和内镜治疗是门静脉高压症导致的食管胃静脉曲张破裂出血的首选治疗,但在内镜下止血失败,同时不能进行下一步治疗的情况下,脾切除门奇静脉断流术仍然是治疗食管胃底静脉曲张破裂出血的主要方式之一[1],脾切除门奇静脉断流术后肝脏血流动力学改变是研究热点之一,术后早期血流动力学研究较多[2],而对于术后血流动力学的长期、动态变化规律未见报道,本研究对术后患者进行长期随访,观察肝固有动脉及门静脉血流动力学的动态变化特点,分析肝脏血流动力学变化规律,为进一步了解脾切除门奇静脉断流术后肝功能、肝硬化等变化提供血流动力学方面的支持。
1. 资料与方法
1.1 研究对象
收集2014年4月—2019年2月首都医科大学附属北京佑安医院普外中心103例门静脉高压行脾切断流术患者的临床资料。
1.2 纳入和排除标准
纳入标准:(1)各种原因引起的肝硬化;(2)行脾切断流术;(3)有上消化道出血史或胃镜提示食管胃底静脉重度曲张,红色征阳性。排除标准:(1)合并肝癌或其他恶性肿瘤;(2)布加综合征、血液系统疾病、冠心病及其他需长期服用抗凝药物的疾病;(3)术后门静脉系统血栓形成。
1.3 术后抗凝治疗方案
所有行脾切断流术患者均于术后48~72 h开始给予低分子肝素皮下注射,0.3 mL/12 h,应用3~5 d,并口服华法林抗凝治疗,维持国际标准化比值(INR)在1.25~1.5,血小板计数>100×109/L时加用阿司匹林肠溶片100 mg/d,当血小板计数>300×109/L时加用噻氯匹定0.25 g/d抗血小板凝聚,直至血小板降至正常水平。术后2周内,每周常规行2次彩色多普勒超声监测肝脏血流变化。对于上述预防治疗后仍发生门静脉血栓患者给予静脉溶栓治疗,溶栓方案为:尿激酶持续泵入,200 000 U/30 min,维持量30 000~50 000 U/h,应用3~5 d,尿激酶停用后,继续抗凝治疗。
1.4 随访
随访截止到2021年2月,随访时间为24~82个月,中位随访时间42个月,随访数据来自门诊及住院病历记录以及电话随访。患者术后1~2周出院,术后2周至3个月,每2~4周检测1次血常规、PT、INR、门静脉血流超声(包括门静脉内径、流量、门静脉最大流速、门静脉平均流速、肝固有动脉内径、流量、最大流速、最小流速等),术后3个月至6个月,1~3个月完善1次上述检查;6个月后,每6个月完善1次上述检查。
1.5 统计学方法
采用SPSS 21.0软件行数据分析,计量资料以x±s表示,符合正态分布时采用配对样本t检验分析术前、术后指标的差异。P<0.05为差异有统计学意义。
2. 结果
2.1 一般资料
103例患者,随访96例,失访7例,随访率93.2%,其中男67例,女29例,年龄27~74岁,平均(47.6±9.4)岁,其中乙型肝炎肝硬化66例、丙型肝炎肝硬化12例、酒精性肝硬化11例、原发性胆汁性胆管炎5例、自身免疫性肝硬化2例(表 1)。术后门静脉压力较术前明显降低(P<0.001),而术后Child-Pugh分级较术前无明显变化(表 2)。
表 1 患者术前一般资料Table 1. Patient demographic and baseline characteristics项目 数值 年龄(岁) 47.6±9.4 性别(例) 男 67 女 29 病因(例) 乙型肝炎肝硬化 66 丙型肝炎肝硬化 12 酒精性肝硬化 11 原发性胆汁性胆管炎 5 自身免疫性肝病 2 Child-Pugh分级(例) A 68 B 24 C 4 表 2 术前、术后门静脉压力及肝功能变化Table 2. Comparison of portal vein pressure and liver function at baseline and postoperatively in liver cirrhosis patients项目 术前 术后 统计值 P值 门静脉压力(cmH2O) 36.1±4.1 23.9±3.9 t=14.99 < 0.001 TBil (μmol/L) 21.5±9.2 15.2±6.6 t=5.33 < 0.001 Alb (g/L) 36.9±3.7 35.5±1.8 t=2.20 0.027 PT (s) 13.9±2.0 16.2±5.7 t=-6.70 < 0.001 Child-Pugh分级(A/B/C) 68/24/4 69/24/3 χ2=4.00 0.407 2.2 术后1周肝血流情况
患者门静脉内径、门静脉流量、门静脉最大流速及门静脉平均流速均较术前显著减低(P值均<0.05)。肝固有动脉内径、流量、最大流速及最小流速均较术前明显升高(P值均<0.05)(表 3)。
表 3 术前和术后1周肝血流情况比较Table 3. Comparison of hepatic hemodynamics at baseline and 1 week postoperation in liver cirrhosis patients项目 例数 术前 术后1周 t值 P值 门静脉内径(mm) 89 12.79±1.50 12.19±1.60 3.13 0.003 门静脉流量(mL) 89 1 533.01±125.48 1 088.15±136.65 6.16 <0.001 门静脉最大流速(cm/s) 89 24.65±4.33 18.92±4.67 4.62 <0.001 门静脉平均流速(cm/s) 89 19.50±6.30 15.19±4.32 5.08 <0.001 肝动脉内径(mm) 89 3.76±0.48 3.93±0.85 -2.35 0.019 肝动脉流量(mL) 89 230.01±37.13 358.52±76.20 -4.23 <0.001 肝动脉最大流速(cm/s) 89 62.32±18.47 94.30±22.16 -5.84 <0.001 肝动脉最小流速(cm/s) 89 17.96±6.14 31.36±6.70 -5.78 <0.001 2.3 术后1个月肝血流情况
患者门静脉流量、门静脉最大流速及门静脉平均流速均较术前显著减低(P值均<0.05)。肝固有动脉流量、最大流速及最小流速均较术前明显升高(P值均<0.05)。门静脉内径、肝固有动脉内径较术前无明显差异(P值均>0.05)(表 4)。
表 4 术前和术后1个月肝血流情况比较Table 4. Comparison of hepatic hemodynamics at baseline and 1 month postoperation in liver cirrhosis patients项目 例数 术前 术后1个月 t值 P值 门静脉内径(mm) 81 12.77±1.53 12.37±2.09 1.499 0.141 门静脉流量(mL) 81 1 577.28±190.48 940.82±142.27 5.514 <0.001 门静脉最大流速(cm/s) 81 25.49±8.96 16.58±5.43 5.490 <0.001 门静脉平均流速(cm/s) 81 19.84±3.96 13.61±5.01 4.870 <0.001 肝动脉内径(mm) 81 3.76±0.47 3.87±0.45 -1.055 0.298 肝动脉流量(mL) 81 230.34±59.97 276.48±66.07 -2.691 0.028 肝动脉最大流速(cm/s) 81 62.51±19.66 71.62±12.84 -2.199 0.042 肝动脉最小流速(cm/s) 81 18.25±6.05 23.18±4.28 -3.393 0.002 2.4 术后3个月肝血流情况
患者门静脉内径、门静脉流量、门静脉最大流速及门静脉平均流速均较术前显著减低(P值均<0.05)。肝固有动脉内径、肝动脉流量、最大流速及最小流速均较术前无显著差异(P值均>0.05)(表 5)。
表 5 术前、术后3个月肝血流情况比较Table 5. Comparison of hepatic hemodynamics at baseline and 3 month postoperation in liver cirrhosis patients项目 例数 术前 术后3个月 t值 P值 门静脉内径(mm) 79 12.88±1.62 12.16±1.71 2.55 0.016 门静脉流量(mL) 79 1 497.90±161.76 1 030.76±174.13 3.70 0.001 门静脉最大流速(cm/s) 79 23.27±4.12 16.99±4.97 4.25 <0.001 门静脉平均流速(cm/s) 79 18.15±4.85 14.27±4.67 -3.23 0.003 肝动脉内径(mm) 79 3.79±0.47 3.85±0.43 -0.68 0.502 肝动脉流量(mL) 79 230.90±47.13 201.68±36.45 1.27 0.213 肝动脉最大流速(cm/s) 79 61.10±18.07 58.51±16.63 0.62 0.535 肝动脉最小流速(cm/s) 79 18.60±6.36 17.09±5.29 1.07 0.292 2.5 术后6个月肝血流情况
患者门静脉内径、门静脉流量、门静脉最大流速及门静脉平均流速均较术前显著减低(P值均<0.05)。肝固有动脉内径较术前显著增加(P<0.05)。肝动脉流量、最大流速及最小流速均较术前无统计学差异(P值均>0.05)(表 6)。
表 6 术前、术后6个月肝血流情况比较Table 6. Comparison of hepatic hemodynamics at baseline and 6 month postoperation in liver cirrhosis patients项目 例数 术前 术后6个月 t值 P值 门静脉内径(mm) 77 12.89±1.49 12.09±1.87 2.59 0.015 门静脉流量(mL) 77 1 568.64±220.48 933.00±182.94 4.17 0.002 门静脉最大流速(cm/s) 77 23.92±7.21 17.73±5.39 3.83 0.001 门静脉平均流速(cm/s) 77 18.91±7.21 14.75±4.72 2.92 0.006 肝动脉内径(mm) 77 3.65±0.47 3.95±0.49 -2.69 0.012 肝动脉流量(mL) 77 218.33±17.13 219.05±46.11 -0.04 0.962 肝动脉最大流速(cm/s) 77 63.15±8.50 66.86±20.83 -0.74 0.460 肝动脉最小流速(cm/s) 77 17.82±5.65 18.90±7.92 -0.65 0.519 2.6 术后12个月肝血流情况
患者门静脉内径、门静脉流量、门静脉最大流速及门静脉平均流速均较术前显著减低(P值均<0.05)。肝固有动脉内径、流量、最大流速及最小流速均较术前无明显差异(P值均>0.05)(表 7)。
表 7 术前、术后12个月肝血流情况比较Table 7. Comparison of hepatic hemodynamics at baseline and 12 month postoperation in liver cirrhosis patients项目 例数 术前 术后12个月 t值 P值 门静脉内径(mm) 64 12.83±1.62 11.96±1.10 3.11 0.004 门静脉流量(mL) 64 1 649.60±123.48 937.64±181.42 4.32 <0.001 门静脉最大流速(cm/s) 64 25.63±4.17 18.19±4.73 4.14 <0.001 门静脉平均流速(cm/s) 64 19.84±3.78 15.45±4.13 3.09 0.005 肝动脉内径(mm) 64 3.71±0.44 3.73±0.50 -0.13 0.895 肝动脉流量(mL) 64 210.82±55.06 202.97±71.50 0.35 0.729 肝动脉最大流速(cm/s) 64 60.89±10.22 64.19±11.92 -0.88 0.386 肝动脉最小流速(cm/s) 64 17.90±4.26 17.16±5.21 0.511 0.613 2.7 术后24个月肝血流情况
患者门静脉内径、门静脉流量、门静脉最大流速及门静脉平均流速均较术前显著减低(P值均<0.05)。肝固有动脉内径、流量、最大流速及最小流速均较术前无明显差异(P值均>0.05)(表 8)。
表 8 术前、术后24个月肝血流情况比较Table 8. Comparison of hepatic hemodynamics at baseline and 24 month postoperation in liver cirrhosis patients项目 例数 术前 术后24个月 t值 P值 门静脉内径(mm) 60 12.72±1.23 11.23±1.44 2.44 0.016 门静脉流量(mL) 60 1 554.73±171.48 910.47±122.28 2.47 0.015 门静脉最大流速(cm/s) 60 21.22±4.96 15.21±3.73 3.32 0.001 门静脉平均流速(cm/s) 60 19.16±3.08 14.55±3.23 2.82 0.006 肝动脉内径(mm) 60 3.70±0.45 3.66±0.44 0.12 0.906 肝动脉流量(mL) 60 224.91±17.70 219.33±16.33 -0.08 0.934 肝动脉最大流速(cm/s) 60 63.98±10.68 64.58±19.00 -0.37 0.706 肝动脉最小流速(cm/s) 60 19.40±6.78 18.09±7.42 -0.46 0.651 3. 讨论
肝硬化通常合并门静脉高压症,这是门静脉血流阻力增加和门静脉流入增加的结果[3],由于肝脏是肝固有动脉和门静脉双重供血,同时肝固有动脉和脾动脉均由腹腔干发出,因此肝固有动脉、门静脉、脾动脉的血流动力学之间存在密切联系。门静脉高压症患者的内脏血流动力学紊乱已经得到证实,Zeng等[4]报道肝硬化门静脉高压症患者脾动脉/肝固有动脉内径比值异常的发生率较高,可作为内脏血流动力学紊乱的重要指标。而脾动脉半径和门静脉压力以及脾切除术后门静脉压力降低的程度之间存在关联[5],长时间的门静脉压力升高,可能引起上消化出血,显著减低患者生存率,部分患者会出现门静脉系统血栓,进一步加重门静脉高压症,使肝功能恶化,甚至死亡[6-7],而脾切除门奇静脉断流术是治疗门静脉高压导致食管胃曲张静脉出血的主要选择之一[8]。
在我国脾切除门奇静脉断流术多是限期或者急诊手术[9],术后并发症低,而且对肝功能有改善作用[10]。本研究中有4例术前Child-Pugh C级患者,均为因门静脉高压症导致的食管胃底曲张静脉破裂出血而行急诊手术,术前肝功能较差,而患者术后Child-Pugh评分恢复至A级或B级。此外术后患者外周血中透明质酸升高,Ⅲ型前胶原氨基末端前肽、Ⅳ型胶原降低也提示肝硬化门静脉高压症患者在脾切除门奇静脉断流术后肝硬化得到了逆转[2, 11],同时门静脉流量减少以及肝动脉流量增加也是术后内脏血流动力学改变之一[12],但由于数据量少且缺少长期随访,对于其动态变化并不了解,本研究观察脾切除门奇静脉断流患者术前以及术后短期、长期的肝固有动脉及门静脉内径、流量、流速的改变,从而了解肝脏内血流的动态变化。
Huang等[2]发现与健康对照组相比,因门静脉高压症行脾切除门奇静脉断流术患者术后1周其门静脉内径、流量均明显高于健康对照组,门静脉最大流速较低,而与术前相比,肝固有动脉的最大流速和血流量均较术前显著升高,与其不同的是,本研究对比行脾切除门奇静脉断流术患者术前及术后的内脏血流改变,而非与健康对照组比较,更有利于了解术后和术前的血流变化差异,在术后1周时,也发现肝固有动脉的内径、流量、最大流速及最小流速均较术前显著增加,这种变化仅仅维持到术后1个月,而到术后3个月后,肝固有动脉的流量、最大流速及最小流速则恢复至术前水平,该结果在其他研究中未见报道。
曾道炳团队等[4, 13]也发现脾切除门奇静脉断流术能够降低门静脉血流量和门静脉压力,伴有肝固有动脉流速、流量增加,此外,与健康人群的脾动脉内径/肝固有动脉内径(脾动脉/肝固有动脉)的比值相比,门静脉高压症患者的比值明显升高,证实存在内脏动力学紊乱,同时也对门静脉高压症的并发症有预测作用,研究结果还显示脾切除术后肝功能改善,而这一改变可能与术后血流动力学改变有关。本研究结果显示肝固有动脉的血流动力学改变比较短暂,而门静脉血流改变很持久,门静脉流量、流速以及内径等指标在术后1周开始就明显降低,之后持续保持在较低的水平。
本研究动态显示了行脾切除门奇静脉断流患者手术前、后肝固有动脉及门静脉的血流动力学变化,以患者术前的结果作为参考,比较术后血流变化,不仅呈现术后早期的及变化特点,而且发现了长期的变化规律,尤其是肝固有动脉的血流变化仅仅维持1个月,而在术后3个月后则恢复至术前水平,这一变化与术后门静脉血流量和流速持续降低不同,这种变化为临床更好的研究脾切除门奇静脉断流术后的肝功能变化、肝硬度变化、门静脉系统血栓形成等方面提供了血流动力学方面的支持,为提高患者生活质量、改善预后提供帮助。
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1. 李芷西,黄少坚,贺卓,黄嘉明,张起帆,周杰,王恺. 乙肝肝硬化门静脉高压症脾切除术后腹腔积液预测模型. 肝胆胰外科杂志. 2023(12): 736-741+746 . 百度学术
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