Research progress on roles of bile acids and its receptors in pathogenesis of non-alcoholic fatty liver disease and pharmacological treatment
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摘要:
非酒精性脂肪性肝病(NAFLD)是以肝细胞内脂质蓄积为主要特征的肝脏代谢紊乱疾病，已成为全球范围内慢性肝病的主要病因。20%~30%的NAFLD会进展为非酒精性脂肪性肝炎(NASH), NASH的发展与多种代谢紊乱密切相关。胆汁酸及其受体功能在NASH的发病机制中起着重要作用，胆汁酸受体是治疗NASH重要的靶点。本文对胆汁酸及其受体在NAFLD和NASH发展中的作用，特别是关于法尼醇X受体(FXR)在不同组织(包括肝脏和肠道)中的功能的研究予以综述，介绍基于胆汁酸及其受体的NASH治疗药物的研究进展。
Abstract:Non-alcoholic fatty liver disease (NAFLD) is a liver metabolic disorder characterized by lipid accumulation in liver cells, and it has become the main cause of chronic liver disease worldwide. 20% to 30% of patients with NAFLD were able to progress to non-alcoholic steatohepatitis (NASH), and the development of NASH is closely related to various metabolic disorders. Bile acids and its receptor function play important roles in the pathogenesis of NASH, and bile acid receptors are the important targets for the treatment of NASH. This article reviewed the roles of bile acids and their receptors in the development of NAFLD and NASH, especially the functional research of farnesol X receptors (FXR) in different tissues (including liver and intestine), and introduced the research progress of NASH therapeutic drugs based on bile acids and their receptors.
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食管胃底静脉曲张破裂出血(EGVB)是肝硬化合并门脉高压的严重并发症，发病率和致死率极高[1]。经颈静脉肝内门体分流术(TIPS)作为EGVB的重要治疗手段，是通过建立肝内门静脉系统分流，将门静脉右支或主支与肝静脉连接起来，不仅可降低门静脉压力梯度，还可保持充足的肝脏灌注[2]。然而, TIPS患者术后可能出现肝衰竭、肝性脑病、心脏失代偿等并发症[3], 其中显性肝性脑病(OHE)的1年累积发病率为10%~50%[4], 不仅影响患者的生活质量及心理健康，还会严重影响预后，因此早期识别OHE并及时干预尤为重要。相关研究[5-6]显示，年龄可能是肝硬化伴EGVB患者TIPS治疗后发生OHE的独立影响因素。白蛋白-胆红素(ALBI)评分最初被用于评价肝细胞癌患者的肝功能[7], 此后多项研究[8-10]发现其与多种病因导致的肝硬化患者预后密切相关。本研究探讨年龄联合ALBI评分对TIPS患者术后OHE发生风险的预测价值，现报告如下。
1. 对象与方法
1.1 研究对象
选取2017年8月—2022年8月于苏州大学附属第一医院接受TIPS治疗的87例肝硬化伴EGVB患者作为研究对象。87例患者中，女32例，男55例; 肝硬化类型为乙肝肝硬化42例，丙肝肝硬化8例，血吸虫性肝硬化8例，酒精性肝硬化9例，自身免疫性肝硬化15例，不明原因肝硬化5例; Child-Pugh分级为A级21例, B级56例, C级10例。纳入标准: ①符合2023年《肝硬化门静脉高压食管胃静脉曲张出血的防治指南》[11]中的肝硬化EGVB诊断标准者; ②符合TIPS治疗适应证者[12]; ③年龄18~80岁者。排除标准: ①病例资料缺失者; ②既往有TIPS史患者; ③此次入院前发生OHE者; ④合并肝癌或其他恶性肿瘤病史患者; ⑤严重感染者; ⑥合并严重心肺功能衰竭、肝肾功能衰竭者; ⑦消化道出血由非肝硬化门脉高压引起者; ⑧ TIPS治疗后行肝移植手术者。本研究方案经苏州大学附属第一医院伦理委员会审核批准，批号为(2023)伦研批第303号。
1.2 方法
术前准备: 完善腹部增强CT检查，评估肝脏、门静脉及肝静脉血管解剖关系和门体侧支循环情况; 完善血常规、肝肾功能、电解质、血凝、术前血氨检查，检测生命体征主要指标，评估患者全身情况，签署手术知情同意书。
手术方式: 选择右侧颈内静脉为穿刺点，消毒铺巾，局部麻醉后，穿刺并置入导丝，经导丝将经颈静脉肝内穿刺系统(美国库克医疗，型号RUPS-100)送入至下腔静脉肝段，监测压力值，再将穿刺鞘内芯置入门静脉，引入导丝，沿导丝送入5F Pigtail导管。若Pigtail造影显示目标静脉增粗扭曲，撤至门静脉主干测压，交换Cobra导管置入目标静脉，行弹簧圈栓塞或组织胶栓塞治疗，造影显示目标静脉闭塞后，使用8 mm×60 mm球囊导管扩张分流道直至“切迹”消失，再沿导丝引入TIPS覆膜支架系统，透视下精确放置VIATORR支架(美国戈尔公司，规格8 mm), 造影后显示目标静脉未再显影，同时支架内血流通畅。手术治疗目标为术后门静脉压力梯度＜12 mmHg或较基线值下降50%[12]。
术后治疗: 术后实施心电监护，给予门冬氨酸鸟氨酸降血氨，依据术中情况制订抗感染方案; 出院后患者均未接受预防肝性脑病的药物治疗。
1.3 观察指标
1.3.1 临床资料
通过电子病例系统检索并收集患者的临床资料。①一般资料，包括姓名、性别、年龄、肝硬化类型; ②术前实验室指标，包括生化指标[丙氨酸转氨酶(ALT)、天门冬氨酸氨基转移酶(AST)、白蛋白、总胆红素、肌酐、血钠、血钾]、血常规指标[血小板、中性粒细胞与淋巴细胞比值(NLR)、血小板与淋巴细胞比值(PLR)]、血凝指标[凝血酶原时间(PT)、国际标准化比值(INR)]; ③术前影像学资料，包括B超、CT检查结果; ④术后随访资料，并根据实验室检测指标及一般资料计算患者入院时Child-Pugh评分、终末期肝病模型(MELD)评分。
1.3.2 ALBI评分
ALBI评分=0.66×log10总胆红素(μmol/L)+(-0.085)×白蛋白(g/L)。ALBI评分≤-2.60分为1级, ALB评分>-2.60~-1.39分为2级, ALBI评分>-1.39分为3级[7]。
1.3.3 OHE发生情况及分组
术后随访6个月，依据《肝硬化肝性脑病诊疗指南(2018年，北京)》[13]中的OHE诊断标准，将87例患者分为OHE组27例和非OHE组60例。
1.4 统计学分析
应用SPSS 25.0软件对数据进行统计学处理，连续变量的2组间比较采用t检验或Mann-Whitney U检验，分类变量的2组间或多组间比较采用χ2检验或Fisher确切概率法。将单因素分析筛选出的差异有统计学意义的变量纳入二元Logistic回归分析，明确OHE发生的独立危险因素; 绘制受试者工作特征(ROC)曲线，评估年龄联合ALBI评分对OHE的预测效能，并应用MedCalc软件比较不同曲线下面积(AUC)间的差异。P＜0.05为差异有统计学意义。
2. 结果
2.1 肝硬化伴EGVB患者TIPS治疗后发生OHE的单因素分析
单因素分析结果显示，OHE组性别、肝硬化类型、合并症、ALT、AST、总胆红素、肌酐、血钾、NLR、PLR、血小板、PT、INR、MELD评分、Child-Pugh评分与非OHE组比较，差异均无统计学意义(P>0.05); OHE组年龄、白蛋白、血钠、ALBI评分与非OHE组比较，差异均有统计学意义(P＜0.05), 见表 1。
表 1 肝硬化伴EGVB患者TIPS治疗后发生OHE的单因素分析结果(x±s)[n(%)][M(P25, P75)]变量 分类 非OHE组(n=60) OHE组(n=27) t/χ2/Z P 年龄/岁 53.50±11.61 59.81±9.56 2.47 0.02 性别 男 37(61.67) 18(66.67) 0.20 0.66 女 23(38.33) 9(33.33) 肝硬化类型 乙肝肝硬化 28(46.67) 14(51.85) — 0.46 丙肝肝硬化 7(11.67) 1(3.70) 血吸虫性肝硬化 4(6.67) 4(14.81) 酒精性肝硬化 6(10.00) 3(11.11) 自身免疫性肝硬化 10(16.67) 5(18.52) 不明原因肝硬化 5(8.33) 0 合并症 高血压 7(11.67) 3(11.11) ＜0.01 ＞0.99 糖尿病 9(15.00) 7(25.93) 0.84 0.36 实验室指标 ALT/(U/L) 25.90(17.75, 40.95) 23.00(16.60, 43.30) 0.79 0.43 AST/(U/L) 32.90(25.78, 45.48) 30.00(24.00, 44.00) 0.72 0.47 总胆红素/(μmol/L) 19.70(13.28, 27.63) 23.40(16.80, 43.00) 1.17 0.24 白蛋白/(g/L) 33.42±4.16 29.60±4.93 -3.74 ＜0.01 肌酐/(μmol/L) 63.86±17.16 65.41±19.35 0.37 0.71 血钠/(mmol/L) 139.15(137.65, 140.68) 141.00(138.10, 143.20) 2.01 0.04 血钾/(mmol/L) 3.89(3.61, 4.18) 3.91(3.68, 4.16) 0.57 0.57 PT/s 15.55(14.30, 17.08) 15.20(14.00, 16.00) 1.01 0.32 INR 1.31(1.20, 1.48) 1.25(1.16, 1.40) 0.74 0.46 血小板/(×109/L) 70.00(50.00, 112.50) 70.00(48.00, 92.00) 0.05 0.96 NLR 3.76(2.45, 8.19) 5.43(1.62, 11.29) 0.37 0.71 PLR 98.81(67.35, 144.88) 88.89(71.67, 130.00) 0.87 0.39 Child-Pugh评分/分 7.00(6.00, 8.00) 8.00(7.00, 9.00) 1.42 0.16 MELD评分/分 9.75(7.67, 11.79) 9.70(7.83, 12.14) 0.24 0.81 ALBI评分/分 -1.98±0.37 -1.61±0.47 3.99 ＜0.01 ALT: 丙氨酸转氨酶; AST: 天门冬氨酸氨基转移酶; PT: 凝血酶原时间; INR: 国际标准化比值; NLR: 中性粒细胞与淋巴细胞比值; PLR: 血小板与淋巴细胞比值; MELD: 终末期肝病模型; ALBI: 白蛋白-胆红素。 2.2 肝硬化EGVB患者TIPS治疗后发生OHE的二元Logistic回归分析
将单因素分析中差异有统计学意义的指标作为协变量(为避免变量间共线性，未纳入白蛋白)，将是否发生OHE作为因变量，进行二元Logistic回归分析。分析结果显示，年龄(OR=1.08, 95%CI: 1.02~1.14, P=0.01)、ALBI评分(OR=13.68, 95%CI: 3.00~62.44, P＜0.01)均为肝硬化伴EGVB患者TIPS治疗后发生OHE的独立影响因素，见表 2。
表 2 肝硬化伴EGVB患者TIPS治疗后发生OHE的二元Logistic回归分析结果变量 β SE Wald χ2 P OR 95%CI 血钠 0.08 0.08 1.02 0.31 1.08 0.93~1.26 年龄 0.07 0.03 6.30 0.01 1.08 1.02~1.14 ALBI评分 2.62 0.78 11.41 ＜0.01 13.68 3.00~62.44 2.3 ROC曲线分析
ROC曲线分析结果显示，年龄、ALBI评分预测肝硬化伴EGVB患者TIPS治疗后发生OHE的AUC分别为0.67(95%CI: 0.55~0.79, P=0.01)、0.72(95%CI: 0.60~0.85，P＜0.01), 年龄联合ALBI评分预测OHE的AUC为0.80(95%CI: 0.70~0.91, P＜0.01), 敏感度为77.8%, 特异度为75.0%, 见图 1、表 3。应用MedCalc软件比较不同AUC后发现，年龄、ALBI评分单独预测的AUC比较，差异无统计学意义(P>0.05); 年龄联合ALBI评分预测的AUC大于年龄、ALBI评分单独预测的AUC, 差异有统计学意义(P＜0.05), 见表 4。
表 3 年龄、ALBI评分单独及联合预测肝硬化伴EGVB患者TIPS治疗后OHE的效能指标 临界值 AUC(95%CI) 敏感度/% 特异度/% P 年龄/岁 53.50 0.67(0.55~0.79) 74.1 56.7 0.01 ALBI评分/分 -1.49 0.72(0.60~0.85) 48.1 95.0 ＜0.01 年龄+ALBI评分 — 0.80(0.70~0.91) 77.8 75.0 ＜0.01 表 4 基于MedCalc软件的AUC比较结果成组变量 Z SE 95%CI P 年龄AUC、ALBI评分AUC 0.59 0.09 -0.13~0.24 0.56 年龄AUC、年龄+ALBI评分AUC 2.11 0.06 0.01~0.26 0.04 ALBI评分AUC、年龄+ALBI评分AUC 2.08 0.04 0.01~0.16 0.04 3. 讨论
OHE是肝硬化患者TIPS术后常见并发症之一，一旦发生，即使及时治疗，复发率仍然很高[14]。相关研究[15]表明，肝性脑病发作与住院率升高、医疗负担加重、预后差和死亡风险增加均相关，因此早期识别TIPS术后肝性脑病对提高肝硬化患者生活质量和减轻疾病负担格外重要。既往研究[6, 16-17]报道，年龄、术前肝功能状态、术前肝性脑病史、糖尿病史、门静脉系统压力梯度、肌肉减少症、质子泵抑制剂使用情况、自发性门静脉分流总面积、支架类型及直径在预测TIPS术后肝性脑病发生方面均具有重要作用。肝功能状态是必要的术前评估指标，临床常采用综合性评分指标(如Child-Pugh评分、MELD评分)评估患者的肝功能及预后。既往研究[5-6, 18]显示，较高的Child-Pugh评分、MELD评分是TIPS治疗后发生OHE的危险因素。但这2种评分系统均存在一定缺陷[19-20], 其中Child-Pugh评分包含腹水、肝性脑病这2个主观变量，容易受到利尿剂等药物的影响，准确性较差，而MELD评分计算相对繁琐，且INR实验室检测结果差异较大，具有局限性。
ALBI评分基于白蛋白、总胆红素计算，可评价患者的肝脏储备功能，相较于Child-Pugh评分、MELD评分，其具有客观、不受药物影响、计算简便等优点[19-20]。ZOU D L等[21]研究显示，与Child-Pugh评分、MELD评分相比, ALBI评分对肝硬化患者急性上消化道出血住院病死率具有较好的预测性能。RONALD J等[22]研究显示, TIPS治疗后生存的预测因子有ALBI评分、MELD评分，其中ALBI评分的预测效能低于MELD评分。LIN X R等[23]研究显示, ALBI评分是肝硬化伴EGVB患者TIPS治疗后发生OHE的独立影响因素，其预测术后1年发生OHE的AUC为0.74。李朝先[24]发现, ALBI评分预测肝硬化伴EGVB患者TIPS术后1年发生OHE的AUC为0.689。本研究结果显示, ALBI评分是肝硬化伴EGVB患者TIPS治疗后6个月内发生OHE的独立危险因素，与既往研究[23-24]结论一致。本研究还发现, ALBI评分预测肝硬化EGVB患者TIPS治疗后6个月内发生OHE的AUC为0.72, 提示其预测能力相对较低，需与其他危险因素联合应用。
研究[4-6, 25]表明，年龄是肝硬化患者TIPS治疗后发生OHE的独立影响因素。分析可能原因[24]: ①随着年龄的增长，患者肝脏解毒功能减退，血脑屏障通透性改变，血氨更易进入大脑干扰能量代谢; ②老年患者胃肠道功能较弱，易发生便秘，导致血氨的来源增加。CORONADO W M等[5]回顾性分析376例接受TIPS治疗的肝硬化患者的资料，发现年龄每增加1岁，肝硬化患者术后OHE发生风险增加1.04倍。FONIO P等[25]研究结果显示，年龄预测肝硬化患者TIPS术后1年发生OHE的AUC为0.70。本研究二元Logistic回归分析结果显示，年龄增长是肝硬化伴EGVB患者TIPS治疗后6个月内发生OHE的独立危险因素，预测OHE的AUC为0.67, 预测能力较低; 但年龄联合ALBI评分预测OHE的AUC为0.80(预测能力中等)，敏感度和特异度均较高，提示两者联用具有较高的临床应用价值。
综上所述，年龄、ALBI评分均为肝硬化伴EGVB患者TIPS治疗后发生OHE的独立影响因素，两者联用对TIPS治疗后短期(6个月)OHE发生情况具有较高的预测价值。但本研究存在一定局限性: ①本研究为小样本量回顾性研究，还需进一步开展大样本量的多中心前瞻性实验进一步验证; ②本研究纳入患者中, Child-Pugh分级为A级、B级者占比很高(88.5%), 临床应用范围较窄，未来的研究中还需进一步增加不同肝功能分级的样本加以验证。
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