Advances in Clinical Medicine
Vol.
12
No.
03
(
2022
), Article ID:
49654
,
9
pages
10.12677/ACM.2022.123316
肝硬化门静脉高压及其并发症治疗新进展
程文瑾
山东大学附属公共卫生临床中心,山东 济南
收稿日期:2022年2月23日;录用日期:2022年3月15日;发布日期:2022年3月24日
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摘要
门静脉高压是肝硬化失代偿期常见的并发症之一。肝细胞凋亡后肝脏微循环功能发生障碍,内质网(ER)应激、肝窦内皮细胞(LSECs)毛细血管化,肝星状细胞(HSC)及肝巨噬细胞活化等一系列变化导致细胞外基质沉积和血管物质失调,最终发展为门脉高压。若不加以控制,门静脉压力会随着肝硬化的进展逐渐升高,进而发生上消化道出血、腹水及肝性脑病等并发症,危及患者生命。本文综述了门静脉高压的发生机制,归纳了降低门静脉压力以及延缓肝硬化进展药物的探索,并总结了目前在并发症治疗上的新进展,从而为临床工作提供新的思路。
关键词
门静脉高压,肝硬化,治疗
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New Advances in the Treatment of Portal Hypertension and Its Complications in Cirrhosis
Wenjin Cheng
Public Health Clinical Center Affiliated to Shandong University, Jinan Shandong
Received: Feb. 23rd, 2022; accepted: Mar. 15th, 2022; published: Mar. 24th, 2022
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ABSTRACT
Portal hypertension is one of the common complications of decompensated cirrhosis. Hepatic microcirculation impaired after hepatocyte apoptosis, endoplasmic reticulum (ER) stress, liver sinusoidal endothelial cells (LSECs) capillarization, hepatic stellate cells (HSC) and activation of hepatic macrophages lead to extracellular matrix deposition and vascular disorders, which eventually develop into portal hypertension. If not controlled, portal vein pressure will gradually increase with the progression of cirrhosis, and then complications such as upper gastrointestinal bleeding, ascites and hepatic encephalopathy will occur, endangering patients’ lives. This article reviews the mechanism of portal hypertension, summarizes the exploration of drugs to reduce portal hypertension and delay the progression of cirrhosis, and summarizes the new progress in the treatment of complications, so as to provide new ideas for clinical work.
Keywords:Portal Hypertension, Cirrhosis, Treatment
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Copyright © 2022 by author(s) and Hans Publishers Inc.
This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).
http://creativecommons.org/licenses/by/4.0/
1. 引言
门静脉是连接胃肠、脾脏等内脏器官与肝脏的血管。门静脉高压症(Portal Hypertension PH)是指各种原因引起的门静脉压力升高的临床综合征,是肝窦循环受损导致肝内血管阻力增加的结果,最常见的原因是肝硬化 [1]。其中5%~15%患者出现胃底静脉曲张出血症状,病情凶险,甚至威胁患者生命,且给患者个人、家庭和社会带来了巨大的负担。因此,有效控制门脉高压 对肝硬化患者十分重要。临床治疗多采取早期、持续、终身的治疗原则,目前多采用药物、内镜、介入等手段等进行干预和控制。本文总结归纳了肝硬化门脉高压患者治疗上的新进展。
2. 肝硬化门脉高压的产生机制
肝硬化门脉高压的病理生理学机制为:肝细胞坏死后,肝小叶原有的网状支架塌陷、聚集、胶原化以及肝星状细胞转变为肌成纤维细胞样细胞产生胶原纤维,并且门管区的成纤维细胞增生并分泌胶原纤维。同时肝细胞在生长因子和其他一些多肽类生长因子的刺激下分裂增殖,由于原有的网状结构崩塌,再生的肝小叶形成不规则的肝结节。胶原纤维包绕形成假小叶,从而导致肝内血流循环障碍,进而产生门静脉高压。目前,越来越多的研究认为肝脏微循环功能障碍是促进肝硬化进展及门静脉高压发展的关键机制之一。肝脏微循环环境主要由肝窦内皮细胞(LSECs)、肝星状细胞(HSC)和肝巨噬细胞组成,主要作用是管理肝细胞功能、调节血管张力和控制炎症。门脉高压发展的主要因素是肝内血管阻力(IHVR)明显增加,肝窦内皮细胞(LSECs)毛细血管化,肝星状细胞(HSC)被激活并且肝巨噬细胞极化,从而导致肝微循环功能障碍。并且通过血管收缩活性物质(如内皮素、血管紧张素-II、去甲肾上腺素和血栓素A2)增加和血管扩张物质活性(如一氧化氮NO)降低进一步增加IHVR [2],内皮素等血管活性物质还会导致大量细胞外基质合成的成纤维化因子和抗纤维化因子之间的不平衡,从而使得细胞外基质沉积在肝窦外周从而进一步增加肝脏硬度 [3]。除此之外研究者发现内质网应激也是肝脏纤维化的关键因素之一 [4]:在各种病理因素(如病毒、酒精、高脂饮食等)刺激性下,内质网(ER)应激后导致未折叠或者异常折叠的蛋白累积,进而发生未折叠蛋白反应(UPR),URP又通过激活下游信号通路而影响细胞凋亡及肝脏纤维化 [5]。虽然目前研究已经证实了内质网应激影响肝硬化的进展,但具体机制仍然不明确,还需进一步研究探索 [4]。
3. 如何延缓肝硬化进展及降低门静脉高压
肝脏纤维化是一个不可逆的过程,随着肝脏硬度的增加,门静脉压力逐渐上升,因此除了降低门静脉压力以外,越来越多的研究开始致力于发现如何延缓肝纤维化。
非选择性β受体阻滞剂(NSBB):NSBB是唯一被认可用于长期治疗门静脉高压的药物 [6]。通过阻断肾上腺素受体减少约35%的门静脉 [7]。除了降低门静脉压力以外,许多研究表明NSBB还可以用于治疗肝硬化门脉高压的并发症。目前一项meta分析发现,卡维地洛在预防食管静脉曲张肝硬化患者首次静脉曲张出血方面与内镜静脉曲张结扎术(EVL)疗效相似,甚至优于EVL [8] [9]。除此之外,卡维地洛还具有降低死亡率的作用 [9]。Tsai等人通过对接受两周普萘洛尔治疗的肝硬化小鼠进行体内实验,发现普萘洛尔可以降低交感神经兴奋性,抑制免疫系统T细胞的功能及活化以及下调脾内β受体水平的过表达而达到预防细菌移位及感染发生的目的 [10]。另外一项对2165名肝硬化患者进行的回顾性研究发现未接受NSBB的患者感染机率(OR = 2.5),自发性细菌性腹膜炎(SBP) (OR = 4.0)和菌血症发生率(OR = 6.0)比NSBB组高 [11]。因此,预防性地服用NSBB可以起到降低感染事件发生的作用。但NSBB的安全性和有效性的要求仍然存在争议,并且由于现有的研究多是对肝癌晚期病人展开的观察性研究,存在偏倚的风险,还需要进一步开展可靠性高的随机对照实验证明。
他汀类药物:支持使用他汀类药物治疗门静脉高压的第一个证据来自一项开创性研究,该研究表明,辛伐他汀治疗可减轻肝硬化患者餐后门静脉压升高。随后的几项研究表明,他汀类药物(主要是辛伐他汀)可以起到保护肝细胞的作用 [3]。另外,有研究发现,在大鼠肝硬化模型中,阿托伐他汀通过抑制肝脏丝氨酸/苏氨酸激酶(RhoA/Rho激酶)信号传导并激活一氧化氮/蛋白激酶G (NO/PKG)途径而降低肝内阻力,使得门静脉压力降低 [12]。虽然他汀类药物可以降低门静脉压力,但诸多研究认为他汀类药物存在一定安全性问题,目前他汀类药物相关肌肉损伤的危险因素已得到充分证实,并且高浓度及药物之间的相互作用可使他汀作用于肝功能受损的患者时发生横纹肌溶解,严重可危及生命 [13]。并且,他汀类药物有加重肝损伤的风险。除此之外,研究者还倾向于探讨他汀类药物在改善肝硬化门脉高压病人预后及生存率中的作用,某些观察性研究发现他汀类药物可提高生存率以及预防并发症的发生 [14]。
甘草甜素(GA):甘草甜素是一种甘草的提取物 [4],目前已被证实具有抗炎、抗感染、抗癌等多种作用 [15]。有研究发现甘草甜素可以通过抑制内皮生长因子(VEGF)信号通路下调从而在肝纤维化阶段的治疗减轻门脉高压和门体侧支循环分流 [16]。除此之外,许多研究发现GA还有延缓肝脏纤维化的作用。研究者通过对毒性物质诱导的肝硬化大鼠使用天狼星红染色及各类蛋白印迹分析等测量方法发现,口服甘草甜素可以使纤维化相关因子表达下降 [17],并调节肝硬化大鼠免疫细胞反应 [18],从而抑制了肝细胞凋亡和HSC活化诱导的肝纤维化。甘草甜素及其常见并且容易获得,目前药物安全性也已被证实,下一步可开展相关的临床研究证实其对肝硬化患者门脉高压的作用。
一氧化氮(NO):目前越来越多的研究热衷于探讨NO对门静脉高压的作用。NO由L-精氨酸通过肝窦内皮细胞内的内皮NO合成酶(eNOS)产生。NO扩散到肝星状细胞激活一氧化氮-环磷鸟苷(NO-cGMP)信号途径通路,鸟苷三磷酸(GTP)转化为环鸟苷单磷酸(cGMP)。cGMP作为第二信使触发级联反应最终起到舒张血管的作用 [19]。因此通过增加NO的产生或者上调NO-cGMP通路可以起到降低门静脉压力的作用。例如对大鼠补充l-精氨酸可以改善NO的产生,促进肝内血管舒张 [20]。另外使用磷酸二酯酶(PDE)抑制剂可以减少PDE对cGMP的灭活,从而使肝硬化大鼠体内cGMP上升来扩张血管 [19]。PietrosiI G等人发现原发性人羊膜来源间充质基质(hAMSC)和上皮干细胞(hAECs)通过恢复LSECs和HSC表型和降低炎症及氧化应激以及上调NO-cGMP途径使肝静脉压梯度(HVPG)降低。并且可以通过恢复细胞表型而使衰老和细胞凋亡标志物的减少,而达到延缓肝硬化进展的作用 [21]。
类二十烷酸合成抑制剂:类二十烷酸是一类脂质介质,包括白三烯,前列腺素和环氧二十碳三烯酸(EET),分别通过脂氧合酶(LOX),环加氧酶(COX)和细胞色素P450酶的活性产生 [22]。塞来昔布是一种COX-2抑制剂,抑制花生四烯酸转化为前列腺素,研究发现,塞来昔布可以降低门静脉压力 [23] [24] 并延缓硫代乙酰胺(TAA)诱导的肝硬化大鼠肝脏纤维化进展 [4] [24] [25],但此前一些研究得出了相反的结论 [26] [27] [28],这可能与诱导肝硬化模型的方法及塞来昔布的浓度和作用时间相关。环氧二十碳三烯酸(EETs)由可溶性环氧化物水解酶(sEH)催化成活性较低的二氢二十三烯酸(DHETS)。研究发现sEH抑制剂可改善肝硬化大鼠体内eNOS磷酸化及NO的生成而降低门脉血压 [29],同时sEH抑制剂可以通过抑制胶原蛋白mRNA表达、缓解内质网应激而延缓肝脏纤维化 [30]。同样,研究者发现孟鲁斯特作为一种白三烯受体拮抗剂,可以通过抑制半胱氨酸基-LT1受体降低了肝硬化大鼠肝脏的门静脉压力 [31]。
糖尿病类药物:目前研究者们发现用于治疗糖尿病的药物可以通过其抗炎及抗氧化作用来减少HCS的活化并降低门静脉高压。比如利拉鲁肽可以改善HCS的表型从而使其活化减少 [32]。KO等人通过发现,二甲双胍组纤维化较轻,因此KO等人认为二甲双胍也可以用于治疗肝硬化门脉高压 [33]。
4. 门脉高压并发症及其治疗
肝硬化引起的门静脉高压多属于肝内型,一般来说,门脉高压症在没有出现并发症时没有症状,随着门静脉压力的升高进而生成肝外侧枝循环,脾功能亢进及腹水,进而产生各种并发症的临床表现。门静脉高压的并发症包括:静脉曲张出血,门静脉高压性胃病、腹水、自发性细菌性腹膜炎、肝肾综合征、肝肺综合征、门静脉性肺动脉高压及肝性脑病。因此目前对门静脉高压治疗的探讨主要集中在并发症的防治方面。目前肝硬化并发症的治疗指南已经比较完善,下面针对一些新的研究发现展开论述。
1) 上消化道出血:上消化道出血是肝硬化门静脉高压最常见的临床表现,出血原因主要是因为曲张的食管胃底静脉出血(EGVB)。据报道,肝硬化患者的静脉曲张出血导致死亡率高达50% [34]。因此,对于肝硬化门脉高压病人并发上消化道出血的治疗旨在有效控制出血及降低再出血风险。
药物治疗:一般来说,对于EGVB患者应立即使用血管活性药物来减少出血。目前被广泛应用的治疗急性上消化道出血的血管活性药物有:生长抑素、奥曲肽、特利加压素及血管加压素。其中特利加压素已被证实具有降低死亡率的作用 [35]。临床上常联合使用质子泵抑制剂(PPI)如奥美拉唑、泮托拉唑等治疗,而有研究认为,生长抑素及其类似物抑制胃酸分泌的作用比质子泵抑制剂效果更好 [36],因此一般不再推荐生长抑素与PPI联合应用 [37],并且PPI会促进细菌过度生长和易位,从而造成SBP的发生与感染的出现 [38],一项以总生存率为主要终点的272例患者的前瞻性研究表明,PPI治疗与较高的MELD评分、腹水和死亡率相关 [39]。除此之外,去甲肾上腺素、云南白药、冻干凝血酶粉、蛇毒血凝酶、维生素K等止血药物使用率也很高,但目前有一项纳入982例患者的研究发现这些止血药物并不能改善急性上消化道出血病人的结局 [40]。
内镜治疗:随着内镜技术的发展,胃镜下治疗逐渐占据主流地位。目前指南推荐在上消化道出血的24小时内行胃镜检查,由于肝硬化病人凝血功能受损等原因有些指南建议将肝硬化出血病人的内镜时间窗缩短为12小时以内,但仍需进一步研究证明。目前被广泛接受的内镜下治疗包括内镜静脉曲张结扎术(EVL)与内镜注射硬化疗法(EIS)。而在临床应用中,静脉曲张出血常用的注射液为组织丙烯酸组织粘合剂(2-N-丁基-氰基丙烯酸酯)注射液,止血成功率在95%至100%之间 [41],但近年来临床上新兴的注射剂及方法越来越多,比如内镜下“三明治”夹心疗法,是指经内镜分层向曲张静脉依次推注聚桂醇、组织胶、聚桂醇。该方法不仅可以降低栓塞等副作用,也可减少再出血的发生 [42]。有研究者对肝病合并食管胃底静脉曲张出血患者胃镜下注射凝血酶发现该方法安全且有效 [43],但仍需要大量多中心实验明确。EVL是一种较为简单的机械性治疗当时,缺点包括吞咽困难,绑带后粘膜溃疡和食管狭窄 [44] 但EVL较EIS再出血率低、静脉曲张根除率高并且并发症发生率低 [45],目前仍是治疗食管静脉曲张出血和二级预防的首选方法 [46]。目前研究者发现一种新型的无机粉末,附着在出血部位通过吸收水分使组织脱水,并形成血凝块附着在出血部位止血,并对机体无副作用,通过胃镜将其喷洒在出血部位,可起到止血作用 [44],但仍然需要进一步研究探索。
自扩式食管支架(SEMS):在治疗AVB的病人时,上消化道内镜检查可以确认出血来源并提供内镜治疗,止血率几乎可达80%。然而,仍有20%的难治性出血 患者需要经颈静脉肝内门体分流术(TIPS)治疗,术前经常使用球囊填塞作为过渡。传统的球囊压塞被证实存在各种各样的并发症 [47]。自扩式食管支架(SEMS)应运而生,并较球囊有着更高的治疗成功率 [48]。SEMS多作为肝衰竭比病人TIPS或肝移植的过渡治疗。
TIPS:目前TIPS在治疗门静脉高压症的应用越来越广泛。起初TIPS使用的未覆盖的金属支架易发生分流功能障碍、肝性脑病和肝功能紊乱。但随着聚四氟乙烯(e-PTFE)覆膜支架的出现,分流功能障碍的发生率已显着降低 [49],而肝性脑病和早期肝衰竭仍然是TIPS目前所面临的问题。目前认为早期(入院后72小时内)行TIPS对于高危AVB病人的治疗更有效,可以降低短期和长期死亡率、再出血风险以及新发或恶化的腹水 [50]。另外,有研究者通过开展回顾性研究发现TIPS合并冠状静脉和胃脾静脉栓塞可减少再出血率 [51]。虽然TIPS的疗效已被认可,但如何降低术后并发症及减少再出血率等问题有待解决,需要开展进一步的研究。
2) 肝性脑病:众所周知,肝性脑病(HE)是一种发生在肝病患者中的神经精神综合征,其特点包括意识障碍、人格和智力障碍、神经肌肉活动改变和脑电图(EEG)异常。目前利福昔明及乳果糖均被认为可以改善HE,并且利福昔明效果较好 [52] 外Kang等人对1042名HE的病人开展了一项回顾性研究发现,利福昔明还可以降低非肝细胞癌患者的死亡风险(调整后的风险比[aHR],0.697;P = 0.024)复发性HE的风险(aHR, 0.452; P < 0.001) SBP (aHR, 0.210; P < 0.001)和静脉曲张出血风险(aHR, 0.425; P = 0.011) [52]。近五年来对l-鸟氨酸l-天冬氨酸(LOLA)治疗HE的研究也越来越多,LOLA治疗HE的效果与现有氨降低剂(包括支链氨基酸、乳果糖、新霉素、益生菌和利福昔明)相当甚至更好 [53] [54]。除此之外,有队列研究发现二甲双胍可通过抑制肝硬化病人的谷氨酰胺酶活性而达到预防肝性脑病的作用 [55],未来也可以展开相应的研究。
3) 自发性细菌性腹膜炎(SBP)是腹水肝硬化患者最常见的并发症之一。慢性肝病和腹水住院患者的SBP发病率在10%~30%之间 [56]。细菌性腹膜炎(SBP)的发生机制尚未完全明确,可能与肝硬化病人肠道动力下降、肠道细菌过度生长及免疫功能障碍而造成肠道细菌的移位相关。目前被研究所证明的SBP的危险因素包括腹水总蛋白小于1 g/dL、血清总胆红素大于2.5 mg/dL、静脉曲张出血和既往SBP发作 [56]。Rogers等人收集了肝硬化病人的腹水进行细菌DNA测序,发现变形杆菌占主导地位。这种分布水平可能与肝硬化病人较肠道菌群改变有关。除此之外,该研究还发现了一些非肠道细菌,同时说明SBP的发生不全因为肠道细菌移位 [57]。目前主张对怀疑SBP的患者立即开始使用抗生素以减少并发症并提高生存率,第三代广谱头孢菌素是首选药物 [56] [58]。肝硬化合并SBP的死亡率达20% [56],且预后较差,因此对SBP的预防显得尤为重要,研究者发现利福昔明在预防SBP方面比一般的抗生素(诺氟沙星、环丙沙星等)更有效 [59],并且可以起到降低死亡率的作用 [59] [60]。这可能与利福昔明不被肠道吸收的有关 [52]。
5. 总结
综上所述,近年来对于肝硬化门脉高压发生机制的研究,为治疗门脉高压提供了新思路、新方向,但目前大多新型药物仅仅在动物实验中体现出优越性,到应用于临床实践中还有很长一段距离。而且已被临床应用的药物(NBSS、他汀类药物等)若想用于改善门脉高压,仍需大量临床实验证实。目前临床上对于肝硬化门静脉高压的治疗主要是对并发症的对症处理,但并发症的出现则意味着肝硬化门脉高压已经发展到晚期,生存率及并发症发生率都显著升高,严重影响了患者的预后,因此关于并发症的治疗研究重点应该放在并发症的二级预防上。总之,对于如何控制门静脉高压,改善患者生活治疗仍然是一个难题。
文章引用
程文瑾. 肝硬化门静脉高压及其并发症治疗新进展
New Advances in the Treatment of Portal Hypertension and Its Complications in Cirrhosis[J]. 临床医学进展, 2022, 12(03): 2192-2200. https://doi.org/10.12677/ACM.2022.123316
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