目的  系统评价经颈静脉肝内门体分流术（transjugular intrahepatic portosystemic shunt，TIPS）术后患者肝性脑病（hepatic encephalopathy，HE）发生现状及其影响因素。

方法  计算机检索Cochrane Library、Embase、PubMed、Web of Science、CINAHL、中国知网、维普、万方和中国生物医学文献数据库，检索时限为建库起至2024年10月20日。采用Stata 14.0及RevMan 5.3软件进行Meta分析。

结果  共纳入40项研究，涉及8 509例患者。Meta分析结果表明，TIPS术后患者HE发生率为31%[95%CI（28%，34%）]。年龄[OR=1.22，95%CI（1.15，1.29）]、MELD评分[OR=1.46，95%CI（1.29，1.65）]、术前血肌酐[OR=1.27，95%CI（1.14，1.41）]、Child-Pugh分级[OR=2.83，95%CI（1.56，5.13）]、术前血氨[OR=1.25，95%CI（1.18，1.33）]、Child-Pugh评分[OR=1.21，95%CI（1.08，1.35）]、术前胆红素[OR=1.35，95%CI（1.11，1.65）]、术前血钠[OR=1.30，95%CI（1.16，1.45）]及术前HE史[OR=2.00，95%CI（1.06，3.76）]是TIPS术后患者发生HE的影响因素。

结论  TIPS术后患者HE发生率较高，临床医疗人员可参考其影响因素，早识别、早干预，尽可能降低或延缓TIPS术后患者HE的发生。

经颈静脉肝内门体分流术（transjugular intrahepatic portosystemic shunt，TIPS）指在影像介入引导下，在肝静脉与门静脉主干之间放置支架建立分流通道，有效降低门静脉压力、阻止食管胃底静脉曲张破裂出血及促进胸腹水的吸收，其具有操作创伤小、过程安全、术后效果显著及重复性高等优势，已在临床广泛应用及推广[1-2]。然而，TIPS术后主要并发症——肝性脑病（hepatic encephalopathy，HE）仍需临床重点关注且亟待解决[3]。HE是一种以神经精神系统并发症为主要症状的疾病总称，多发生于术后3个月，患者常出现性格变化、认知及意识功能障碍或神经系统肌肉功能障碍，如扑翼样震颤等[4]。相关指南报道，TIPS术后HE的发生率为5%~35%，1年累计发病率的中位数可达50%[5-6]，具有不可预测性及高发性，部分患者远期认知功能障碍易受严重影响，不仅显著降低患者的生活质量和生存率，同时也极大限制并阻碍了TIPS技术的发展[7]。探索TIPS术后HE的发生率及明确相关影响因素，可对患者和临床治疗方式选择及HE的早诊断、早治疗提供重要参考依据，进而提高TIPS的手术效果、改善临床患者的远期预后。既往国内外 已对TIPS术后发生HE的影响因素进行了较多研究 [8- 10]，如年龄、肝功能水平、终末期肝病模型（model for end-stage liver disease，MELD）评分等是HE的影响因素，但如既往HE史、并发症类型等部分影响因素仍存在一定争议[11-12]。因此，本研究对TIPS术后HE的发生率及其影响因素进行Meta分析，旨在为TIPS术后HE的临床诊治提供流行病学及病因证据，以便临床医生更好地管理HE患者。

1 资料与方法

1.1 纳入与排除标准

纳入标准：①研究对象：接受TIPS患者，年龄≥18岁；②研究内容：结局指标包括TIPS术后HE的发生人数或相关影响因素，数据包括比值比（odds ratio，OR）及95%置信区间（95% confidence interval，95%CI）；③诊断工具：采用至少1项HE症状诊断标准或评估工具；④研究类型：病例对照研究或队列研究；⑤文献语种：中英文。

排除标准：①重复发表文献、综述及会议文献；②全文不可获取或数据报告缺失；③数据无法转换或使用；④仅报道单因素分析结 果。

1.2 文献检索策略

采用主题词与自由词结合策略对Cochrane Library、Embase、PubMed、Web of Science、CINAHL、中国知网、维普、万方、中国生物医学文献数据库进行计算机检索。检索时限为建库至2024年10月20日，并追溯纳入文献的参考文献。中文关键词包括：TIPS、经颈静脉门体分流术、HE、肝性脑病。英文关键词包括：TIPS、transjugular intrahepatic portosystemic shunt、HE、hepatic encephalopathy。以PubMed为例，具体检索策略见框1。

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  框图1 PubMed检索策略

  Box1.Search strategy in PubMed

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1.3 文献筛选与资料提取

由2位研究人员单独进行文献筛选、数据提取。将检索到的文献数据剔重后依次阅读题目和摘要，依照纳排标准初步排除研究内容明显不符的研究，再阅读文献全文筛选。采用自制的研究特征提取表提取数据，提取内容包括：①标题、第一作者、发表年份、研究设计类型、样本量、HE评估工具；②效应量：HE发生人数、HE发生率、影响因素（报告同一影响因素的原始文献数量≥2篇）、OR值及95%CI。

1.4 纳入研究的偏倚风险评价

由2位研究者依照纽卡斯尔-渥太华量表（NOS）对病例对照和队列研究进行评价[13]。评价内容包括3个维度、8项条目，分别从“研究对象选择”（4个条目共4分）、“组间可比性”（1个条目共2分）和“结果或暴露因素测量”（3个条目共3分）进行评价。 ≤4分提示文献研究质量较低，5~6分为中等质量文献，≥7分表示文献质量较高。若研究者持不同意见，则由两位研究者讨论协商解决。

1.5 统计学分析

使用Stata 14.0软件对HE发生率进行效应量合并；采用Revman 5.3软件对影响因素的OR值及95%CI进行效应量合并。异质性检验通过Q检验及I²检验判断，若P＞0.1、I²＜50%，表明各研究间不存在统计学异质性；若P＜0.1、I²≥50%，表明各研究间存在统计学异质性。Borenstein及Dettori等[14-15]认为不应基于异质性的统计检验结果选择效应模型类型，考虑到各临床研究间异质性较大，相关测量指标均存在客观差异，因此本研究均采用随机效应模型进行效应量合并。使用逐步法剔除文献进行敏感性分析，采用亚组分析探查异质性来源。对结局指标纳入研究采用Begg检验及Egger检验评估潜在发表偏倚。除异质性检验中以P＜0.1为差异具有统计学意义外，其余分析均以P＜0.05为差异具有统计学意义。

2 结果

2.1 文献筛选流程及结果

共检索获得文献2 826篇，依次经阅读题目、摘要和全文筛选后最终纳入40篇文献 [12,  16- 54]，文献筛选流程见图1。

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  图1 文献筛选流程图

  Figure1.Flow chart of literature screening

  注：*检索的数据库及检出文献数具体为中国知网（n=620）、万方（n=223）、维普（n=334）、中国生物医学文献数据库（n=108）、PubMed（n=725）、Embase（n=278）、The Cochrane Library（n=87）、Web of Science（n=376）、CINAHL（n=75）。

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2.2 纳入文献基本特征及偏倚风险评价

纳入的40篇文献中，中文文献12篇，英文文献28篇，其中病例对照研究36篇（NOS评分为6~8分，均为中、高质量研究），队列研究4 篇（NOS评分≥7分，均为高质量研究），共涉及8 509例患者。40项研究均报道了HE的发生率，31项研究涉及TIPS术后患者发生HE的影响因素。纳入文献基本特征及偏倚风险评价结果见表1。

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  表格1 纳入研究基本特征与偏倚风险评价结果

  Table1.Basic characteristics and risk of bias assessment results of included studies注：①.闪光融合临界频率，Critical Fusion Frequency（CFF）；②.West-Haven分级标准；③.2014年 EASL/AASLD HE实践指南；④.《肝硬化肝性脑病诊疗指南》（2018年）；⑤.第十一届世界胃肠病大会报道标准；⑥.意大利肝脏研究协会(AISF)临床实践指南（2018年）；⑦.美国及欧洲肝病学会HE实践指南；A. 年龄；B. MELD评分；C. 术前HE史；D. 低蛋白血症；E. Child-Pugh评分；F. 术前胆红素；G. 术前血肌酐；H. 术前血氨；I.  Child-Pugh分级；J. 术前血钠；K. 合并腹水。

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2.3 Meta分析结果

2.3.1 HE发生率

40项研究[12, 16-54]报道了HE发生率，研究间存在统计学异质性（I²=90.9%，P＜0.001），采用随机效应模型进行Meta分析，结果显示TIPS术后患者HE发生率为31%[95%CI（28%，34%）]。

2.3.2 HE的影响因素

本研究纳入的40篇原始文献中，有31项研究报道了TIPS术后患者发生HE的影响因素，包括年龄、MELD评分、术前HE史、低蛋白血症、Child-Pugh评分、术前胆红素、术前血肌酐、术前血氨、Child-Pugh分级、术前血钠、合并腹水。对≥2篇原始文献报告的影响因素进行Meta合并，结果显示，年龄[OR=1.22，95%CI（1.15，1.29）]、MELD评分[OR=1.46，95%CI（1.29，1.65）]、术前血肌酐[OR=1.27，95%CI（1.14，1.41）]、Child-Pugh分级[OR=2.83，95%CI（1.56，5.13）]、术前血氨[OR=1.25，95%CI（1.18，1.33）]、Child-Pugh评分[OR=1.21，95%CI（1.08，1.35）]、术前胆红素[OR=1.35，95%CI（1.11，1.65）]、术前血钠[OR=1.30，95%CI（1.16，1.45）]及 术前HE史[OR=2.00，95%CI（1.06，3.76）]是 TIPS术后患者发生HE的影响因素（P＜0.05），见表2。

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  表格2 TIPS术后患者发生HE影响因素的Meta分析及发表偏倚检验结果

  Table2.Results of Meta-analysis and publication bias of influence factors for HE in post-TIPS patients

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2.4 亚组分析

将TIPS术后HE发生率按患者BMI、Child-Pugh分级、放入支架直径及是否合并腹水进行亚组分析。亚组分析结果显示，BMI＜18.5  kg/ m²的患者术后HE发生率最高，为33.8%[95%CI（16.1%，51.4%）]；Child-Pugh分级为A级、B级、C级患者的HE发生率分别为22.1%[95%CI（14.9%，29.2%）]、30.9%[95%CI（25.3%，36.5%）]和48.2%[95%CI（36.9%，59.4%）]；支架直径≤8 mm及＞8 mm的HE发生率分别为30.8%[95%CI（22.9%，38.8%）]、34.0%[95%CI （21.8%，46.3%）]；合并腹水患者HE发生率为34.5%[95%CI（26.8%，42.2%）]，见表3。

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  表格3 TIPS术后患者HE发生率的亚组分析

  Table3.Subgroup analysis of the prevalence for HE in post-TIPS patients

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2.5 敏感性分析

对TIPS术后HE发生率的合并效应量通过逐步法逐一剔除文献进行敏感性分析，结果显示合并效应量未发生明显变化，提示研究结果较为稳定。采用转换效应模型方法对HE影响因素Meta分析结果进行敏感性分析，结果显示固定效应模型和随机效应模型的OR值及95%CI变化不大，见表4。

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  表格4 TIPS术后患者发生HE影响因素的敏感性分析

  Table4.Sensitivity analysis of influence factors for HE in post-TIPS patients

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2.6 发表偏倚检验

对TIPS术后HE发生率进行发表偏倚检验，Egger检验及Begg检验结果提示，本研究存在发表偏倚的可能性较小（Egger检验：P=0.94；Begg检验：P=0.30）。对各影响因素进行发表偏倚检验，Egger结果显示，除年龄外，其余影响因素均不存在明显的发表偏倚，见表2。采用剪补法对年龄进行校正，校正前结果为[OR=1.22，95%CI（1.15，1.29）]，校正后结果为[OR=1.11，95%CI（1.04，1.17）]，校正前后结果无显著改变，结果较为稳定。

3 讨论

本研究通过Meta分析对36篇病例对照及4篇队列研究进行汇总合并，结果显示，TIPS术后患者HE发生率为31%，处于较高水平，这与此前指南报道的TIPS术后HE发生率30%~40%相 符[55]。

亚组分析发现，相较于BMI为18.5~ 23.9  kg/m²及BMI＞24 kg/m²的患者，BMI＜ 18.5 kg/m²的患者TIPS术后HE的发生率最高。相关研究显示，低BMI常与老年肌肉减少症有关，而肌肉减少症已成为肝硬化患者TIPS术后发生HE的危险因素且与患者多种不良预后相关 [56- 57]。一项系统评价纳入1 794例患者结果显示，肌肉减少症与HE的发生呈正相关[58]。Child-Pugh分级为C级的患者术后HE发生率最高。Child-Pugh分级可反映肝脏储备能力，其可直接决定肝脏的解毒能力及降低肝脏内血氨水平，Child-Pugh分级越高，则肝功能状态越差，血氨水平升高可干扰正常脑细胞代谢从而导致HE的发生 [59]。相较于≤8 mm的支架直径，＞8 mm的支架直径术后HE的发生率更高，这与既往研究结果一致 [60-61]。相关研究证实，术中使用8  mm支架HE的发生率显著低于放置10 mm支架，且支架直径 ＞8 mm是TIPS术后发生HE的独立危险因素 [62-63]，这可能与支架直径越大，门体分流的血液越多，导致体循环中血氨水平增加从而引起HE有关。与未合并腹水患者相比，合并腹水患者术后HE发生率更高，可能是由于患者并发腹水时机体处于水钠潴留状态，抗利尿激素水平异常，此外针对难治性腹水应用利尿剂或穿刺放腹水治疗均易加重电解质紊乱，从而导致HE的发 生[64]。

Meta分析结果显示，年龄、术前HE病史、Child-Pugh分级、Child-Pugh评分、MELD评分均为TIPS术后发生HE的影响因素。多项研究已证实，高龄是TIPS术后患者发生HE的独立危险因素 [65- 66] 。随着年龄的增长，老年患者机体功能逐渐退化，易出现肠道排空时间延长、便秘等问题，使得肠道产氨及吸收增多，增加HE发生风险。国内外多项研究表明，术前HE病史也是HE发生的独立危险因素[67-68]，这与本研究结果一致，提示临床医务人员应在行TIPS术前详细询问患者病史，以做到更为精确化管理及控制HE的发生。目前临床上常使用Child-Pugh分级、Child-Pugh评分来反映肝病患者病情轻重，利用MELD评分来预测肝病患者的预后生存率，其均可作为TIPS术后发生HE的预测因素 [69]。相关研究指出，MELD评分每增加1分，HE发生率可增加70%[70]，此外Child-Pugh分级为C级患者术后发生HE的风险较A、B级高12.696倍[71]。因此临床上应对TIPS患者肝功能进行多次反复评估，以最大程度的规避风险，降低术后HE的发生。

Meta分析结果显示，术前血肌酐、术前血氨、术前胆红素及术前血钠等生化指标均为TIPS术后发生HE的影响因素。终末期肝病患者常合并肾功能受损，这也提示着肝功能进一步失代偿，有研究指出，当血肌酐值＞1.2 mg/dL时，可导致术后HE的发生风险增加3倍[72]。TIPS术后含氨丰富的血液可直接进入体循环，导致增多的氨离子经血脑屏障进入大脑，破坏脑内星形胶质细胞，干扰谷氨酰胺代谢循环，抑制正常神经递质功能，从而诱发HE[73-74]。此外，国内相关指南提出高血氨水平可与机体炎症相互作用形成恶性循环，使得氨离子及其他炎性细胞因子通过被炎症破坏的血脑屏障进入脑组织，致大脑水肿造成HE的发生[75]。高胆红素水平是公认的可作为肝衰竭的良好预测指标，这与本研究结果一致。四川大学华西医院研究团队指出，直接胆红素与总胆红素比值与HE严重程度及MELD均呈负相关且该比值可有效预测肝衰竭患者90 d内死亡风险[76]。目前低钠血症与HE的发生机制尚未有确切定论，但国外一项队列研究纳入1 116例患者以探究血清钠及血清钠变化与HE发生率之间的关系，在控制混杂因素后结果显示，血清钠离子浓度每降低1 mmol/L，HE的发生风险增高8%[77]。其原因可能与当机体处于低钠血症状态时，易致细胞及脑组织水肿，损害血脑屏障导致神经性有害递质及神经毒性代谢产物通过增多从而导致HE的发生。

本研究存在一定的局限性。第一，各纳入研究间异质性较大，研究质量水平不一，可能对结果产生一定影响；第二，各研究间的样本量大小、HE评估工具存在一定差异，可能存在混杂因素的影响；第三，部分影响因素涉及的研究数量较少，合并后的结果需审慎对待。建议未来可开展更多高质量、多中心、大样本的前瞻性队列研究，以进一步评估TIPS患者HE发生的影响因素。

综上所述，TIPS术后HE的发生率处于较高水平，应引起临床医务人员充分重视。年龄、MELD评分、术前血肌酐、Child-Pugh分级、术前血氨、Child-Pugh评分、术前胆红素、术前血钠及术前HE史是TIPS术后患者发生HE的影响因素。综合评估以上影响因素有助于临床医师简单可行地判断TIPS术后HE发生的可能性，及早给予预防及干预，以降低HE发生风险。

伦理声明：不适用

作者贡献：研究构思、文献检索、数据提取、统计分析与论文撰写：唐煜寒；数据提取、论文修订：罗焮榆

数据获取：本研究中使用和（或）分析的所有数据均包含在本文中

利益冲突声明：无

致谢：不适用

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