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ISSN 1001-5256 (Print)
ISSN 2097-3497 (Online)
CN 22-1108/R

Value of platelet-albumin-bilirubin index combined with AIMS65 score in predicting the short-term prognosis of patients with liver cirrhosis and acute upper gastrointestinal bleeding

DOI: 10.12449/JCH240213
Research funding:

Liaoning Science and Technology Plan Project (2021JH2/10300042)

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  • Corresponding author: LI Jing, jz7203@139.com (ORCID: 0000-0001-8283-5789)
  • Received Date: 2023-04-22
  • Accepted Date: 2023-07-10
  • Published Date: 2024-02-19
  •   Objective  To investigate the value of platelet-albumin-bilirubin index (PALBI) combined with AIMS65 score in predicting rebleeding and death within 6 weeks after admission in patients with liver cirrhosis and acute upper gastrointestinal bleeding (AUGIB).  Methods  A retrospective study was conducted for 238 patients with liver cirrhosis and AUGIB who were hospitalized in The First Affiliated Hospital of Jinzhou Medical University from February 2021 to October 2022, and all patients were followed up for 6 weeks. According to the prognosis, they were divided into death group with 65 patients and survival group with 173 patients, and according to the presence or absence of rebleeding, they were divided into non-rebleeding group with 149 patients and rebleeding group with 89 patients. General data and laboratory markers (including blood routine, liver/renal function, and coagulation), and PALBI, AIMS65 score, Child-Turcotte-Pugh (CTP) score, and Model for End-stage Liver Disease (MELD) score were calculated on admission. The independent-samples t test or the Mann-Whitney U test was used for comparison of continuous data between two groups, and the chi-square test was used for comparison of categorical data between two groups. A multivariate logistic regression model analysis was used to investigate the risk factors for death or rebleeding within 6 weeks after admission in patients with liver cirrhosis and AUGIB. The receiver operating characteristic (ROC) curve and the area under the ROC curve (AUC) were used to investigate the predictive efficacy of each scoring system, and the DeLong test was used for comparison of AUC.  Results  There were significant differences between the death group and the survival group in hematemesis, past history of varices, albumin (Alb), total bilirubin (TBil), international normalized ratio (INR), creatinine (Cr), prothrombin time (PT), systolic blood pressure, PALBI, AIMS65 score, CTP score, and MELD score (all P<0.05). The multivariate logistic regression analysis showed that hematemesis (odds ratio [OR]=4.34, 95% confidence interval [CI]: 1.88‍ ‍—‍ ‍10.05, P<0.001), past history of varices (OR=3.51, 95%CI: 1.37‍ ‍—‍ ‍8.98, P=0.009), PALBI (OR=4.49, 95%CI: 1.48‍ ‍—‍ ‍13.64, P=0.008), and AIMS65 score (OR=3.85, 95%CI: 2.35‍ ‍—‍ ‍6.30, P<0.001) were independent risk factors for death. The ROC curve analysis of each scoring system in predicting survival showed that CTP score, MELD score, PALBI, AIMS65 score, and PALBI combined with AIMS65 score had an AUC of 0.758, 0.798, 0.789, 0.870, and 0.888, respectively, suggesting that PALBI combined with AIMS65 score had a significantly larger AUC than the four scoring systems used alone (all P<0.05). There were significant differences between the rebleeding group and the non-rebleeding group in hematemesis, history of diabetes, Alb, TBil, INR, Cr, PT, PALBI, AIMS65 score, CTP score, and MELD score (all P<0.05). The multivariate logistic regression analysis showed that PALBI (OR=2.41, 95%CI: 1.17‍ ‍—‍ ‍4.95, P=0.017) and AIMS65 score (OR=1.58, 95%CI: 1.17‍ ‍—‍ ‍2.15, P=0.003) were independent risk factors for rebleeding. The ROC curve analysis of each scoring system in predicting rebleeding showed that CTP score, MELD score, PALBI, AIMS65 score, and PALBI combined with AIMS65 score had an AUC of 0.680, 0.719, 0.709, 0.711, and 0.741, respectively, suggesting that PALBI combined with AIMS65 score had the largest AUC (all P<0.05), but with a relatively low specificity.  Conclusion  PALBI combined with AIMS65 score has a certain value in predicting death within 6 weeks after admission in patients with liver cirrhosis and AUGIB, with a better value than CTP score and MELD score alone. PALBI combined with AIMS65 score has a relatively low value in predicting rebleeding within 6 weeks, with an acceptable accuracy.

     

  • 肝性脑病(HE)是肝硬化失代偿期最严重的并发症之一,严重HE一旦发生,则预后不良,病死率高1。轻微型肝性脑病(minimal hepatic encephalopathy,MHE)是HE的早期阶段,因此,尽早控制MHE是防止严重HE发生的关键。目前MHE的西医治疗2与HE的治疗方法相似,中医则主要是以“醒脑通腑开窍”3作为理论基础治疗MHE,既往临床研究证实了灌肠方对于MHE患者降低血氨、改善神志方面显示了良好的疗效4;也证明了口服益气养阴解毒化瘀方可以明显改善MHE患者的神经智能测试评分并降低血氨5,但是关于中药治疗MHE的作用机制研究很少。根据“肠-肝轴”理论6,肝硬化HE与肠道菌群关系密切,肠道菌群的结构和功能改变、肠屏障受损以及小肠细菌过度生长均可以导致血氨及肠道毒素增加,系统性炎症加重,这些毒素通过肠肝循环再次造成肝损伤,肝脏解毒功能下降,更多的血氨及肠道毒素通过血脑屏障入脑,加重了神经炎症和脑水肿。因此,探讨益气养阴扶正解毒化瘀方对于肠道代谢的影响,有助于探索中医药治疗MHE的作用机制。本研究拟通过探索益气养阴解毒化瘀方对于MHE肠道代谢的影响,探讨中药治疗MHE的可能作用机制。

    本研究选取2024年3月—2024年5月于本院住院且经肝性脑病心理测量评分(psychometric hepatic encephalopathy score,PHES)诊断为MHE的11例肝硬化患者(MHE组)作为研究对象,同时招募11例健康患者家属(无基础肝病及各种高血压、糖尿病、冠心病、肠道疾病等且BMI正常)作为对照组。

    参考《肝硬化肝性脑病诊疗指南》2及2014年美国肝病学会和欧洲肝病学会指南7,使用PHES测试作为诊断MHE的金标准:PHES测试中的数字连接试验(NCT-A)、数字符号试验(DST)同时阳性可诊断MHE8

    (1)结合生化学、影像学及临床症状,除酒精性肝硬化及肝豆状核变性以外的肝硬化患者;(2)经PHES测试诊断为MHE患者;(3)中医辨证为气阴两虚血瘀证者;(4)BMI在正常范围内;(5)之前未经过MHE的营养治疗和药物治疗。

    (1)5年内有过胃肠道大手术及肠道切除手术者;(2)炎症性肠病,肠易激综合征者;(3)持久性、传染性胃肠炎,结肠炎,慢性腹泻原因不明者;(4)慢性便秘者;(5)胃肠道出血及存在历史性胃肠道疾病者;(6)近期使用含碱式水杨酸铋或其他类似药物成分的药物者;(7)取样前1个月内使用过抗生素者;(8)生理期女性。

    1.5.1   试剂

    益气养阴解毒化瘀方(超纯水浓缩至42%;沙参15 g,麦冬15 g,大黄15 g,厚朴15 g,枳实15 g,赤芍15 g,石菖蒲15 g)(北京康仁堂药业有限公司);高纯度盐酸甲氧胺、脂肪酸甲酯、无水吡啶、无水硫酸钠(美国圣路易斯公司);MSTFA(1% TMCS)、甲醇、氯仿、二氯甲烷、己烷、丙酮、乙腈(美国费尔劳恩公司)。

    1.5.2   粪便采集方法

    分别采集对照组患者、MHE组患者及其经益气养阴解毒化瘀方治疗12周后的粪便。尽量在同一时间采样(考虑人肠道微生物的节律性变化),按照以下程序进行粪便样本的采集:(1)排尽尿液;(2)排便;(3)取样;(4)转运和冷藏。

    1.5.3   代谢组学检测的样本制备

    采集的粪便样本标记后冻存于-80 ℃的低温冰箱中,将样品在冰浴上解冻,取50 mg粪便样品到1.5 mL离心管中,加入10 μL内标,轻微混匀,加入175 μL预冷的甲醇/氯仿(3∶1混合液)进行提取。将混合物在14 000×g和4 ℃下离心20 min,并在-20 ℃的冰箱中静置20 min,将上清液小心地转移至自动进样玻璃瓶中。放到真空离心浓缩仪中浓缩5 min以除去氯仿,然后转移入低温冷冻干燥机完全冻干。加入50 μL的甲氧胺吡啶溶液,在30 ℃孵育2 h之后,加入50 μL的MSTFA于37.5 ℃孵育1 h。

    1.5.4   代谢组学检测

    本项目在委托上海麦特绘普公司基于气相色谱飞行时间质谱(GC-TOF/MS)的非靶向代谢学的技术平台XploreMET上检测,采用了Agilent 7890B气相色谱仪,飞行时间质谱系统(美国力可公司)。

    1.5.6   GC-TOF/MS 代谢组学数据分析

    应用XploreMET软件(V3.0,Metabo-Profile,China)对GC-MS的原始数据进行处理,然后用JiaLab代谢物库进行定性。(1)单变量统计分析,包括t检验、Wilcoxon检验等。(2)多元统计分析,如主成分分析(principal component analysis, PCA)、偏最小二乘判别分析(partial least squares discriminant analysis, PLS-DA)、正交偏最小二乘判别分析(orthogonal partial least squares discriminant analysis, OPLS-DA)法等。

    使用SPSS 23.0软件进行统计分析。计数资料两组间比较采用Fisher精确检验;符合正态分布的计量资料以x¯±s表示,两组间比较采用成组t检验,同组内治疗前后比较采用配对t检验;非正态分布的计量资料以MP25P75)表示,两组间及同组内治疗前后比较采用Wilcoxon秩和检验。P<0.05为差异有统计学意义。

    表1所示,对照组均为患者家属(生活及饮食习惯基本相同),与MHE组相比,年龄、性别和BMI差异均无统计学意义(P值均>0.05);与对照组相比,MHE组的NCT-A用时明显延长(P<0.05),DST得分明显减少(P<0.05)。MHE组患者病因为HBV感染6例,HCV感染2例,自身免疫相关肝病3例;Child-Pugh分级为B级3例和C级8例;MELD评分(18.90±5.36)分。

    表  1  MHE组和对照组的基线资料
    Table  1.  Baseline characteristics of patients with MHE and control groups
    项目 MHE组(n=11) 对照组(n=11) 统计值 P
    男/女(例) 8/3 7/4 0.833
    年龄(岁) 61.00±11.17 60.00±8.44 t=0.237 0.815
    BMI(kg/m2 20.73±5.26 21.90±5.53 t=-0.513 0.613
    NCT-A(s) 68.90±23.00 36.82±15.80 t=3.506 0.002
    DST(分) 17.80±4.50 49.18±16.35 t=-6.101 <0.05
    下载: 导出CSV 
    | 显示表格
    2.2.1   MHE患者肠道微生物代谢分类

    MHE组和对照组肠道代谢物共检测出235种。MHE组主要组成有氨基酸类41.79%,脂肪酸类15.70%,碳水化合物类16.24%,有机胺类8.96%,有机酸类8.58%,脂类4.00%,其他9.69%。对照组主要组成有氨基酸类36.64%,脂肪酸类22.72%,碳水化合物类16.88%,有机胺类8.29%,有机酸类3.02%,脂类5.8%,其他1.57%。Wilcoxon秩和检验结果显示,MHE组肠道代谢物中的有机酸类明显上升,类苯基丙烷酸类、酚类、维生素类、咪唑类、胆汁酸类明显下降(P值均<0.05)(图1)。

    注:*P<0.05,**P<0.01,***P<0.001。
    图  1  MHE组与对照组的主要代谢物分类组成
    Figure  1.  Classification and composition of major metabolites in MHE and control groups
    2.2.2   MHE患者肠道差异性代谢物分析
    2.2.2.1   肠道差异性代谢物单维统计分析

    通过Wilcoxon秩和检验来比较两组的差异代谢物,基于单维统计分析筛选出的41种差异代谢物通过火山图显示[阈值设定:log2FC>0(FC,组间变化倍数)],与对照组相比,MHE组上调代谢物19种,下调代谢物22种(P值均<0.05)(图2)。

    图  2  肠道差异性代谢物的单维统计分析
    Figure  2.  Unidimensional statistical analysis of intestinal differential metabolites
    2.2.2.2   肠道差异性代谢多维统计分析

    基于OPLS-DA模型对MHE组和对照组的差异代谢物进行多维统计分析,采用火山图[阈值设定:代谢物对样本分类的贡献(variable importance in projection,VIP>1)]来展示筛选的差异性代谢物,总共筛到差异代谢物87种(图3)。

    注: Corr.Coeffs,代谢物与第一主成分相关性的相关系数。
    图  3  肠道差异性代谢物的多维统计分析
    Figure  3.  Multidimensional statistical analysis of intestinal differential metabolites
    2.2.2.3   潜在差异性代谢物的筛选

    通过对肠道差异性代谢单维统计分析和多维统计分析结果取交集,对MHE组患者潜在代谢产物进行筛选,筛选标准如下:(1)单维分析P<0.05,log2FC>0;(2)多维分析VIP>1,共筛选了29种潜在的代谢标志物。如表2所示,MHE组明显上调的代谢物有核糖核酸、乳果糖、乳酸、尿素、柠苹酸、木糖内酯、鸟氨酸、酪胺、甲基丙二酸、异麦芽糖和苯基乙胺、2,3-丁二醇12种;如表3所示,下调的代谢物有咪唑丙烯酸、甘油酸、酮亮氨酸、2-油酸单甘油酯、肌氨酸、二氯乙酸、核糖、神经酸、烟酸、己二酸、亚精胺、3-(3-羟基苯基)- 3-羟基丙酸、亚油酸、油酸、α-生育酚、δ-生育醇和γ-生育酚17种,主要为氨基酸类、有机酸类、有机胺类、碳水化合物类、脂肪酸类、维生素类。

    表  2  12种上调的代谢物
    Table  2.  12 up-regulated metabolites
    代谢物分类 代谢物
    脂肪酸类 柠苹酸
    有机胺类 尿素、酪胺
    有机酸类 乳酸、甲基丙二酸
    氨基酸类 鸟氨酸
    碳水化合物类 乳果糖、核糖核酸、木糖内酯、异麦芽糖
    苯类 苯基乙胺
    醇类 2,3-丁二醇
    下载: 导出CSV 
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    表  3  17种下调的代谢物
    Table  3.  17 down-regulated metabolites
    代谢物分类 代谢物
    脂肪酸类 油酸、亚油酸、己二酸、神经酸
    有机酸类 酮亮氨酸
    有机胺类 亚精胺
    氨基酸类 肌氨酸
    碳水化合物类 甘油酸、核糖
    苯丙酸类 3-(3-羟基苯基)-3-羟基丙酸
    维生素类 δ-生育醇、α-生育酚、γ-生育酚
    胆汁酸类 二氯乙酸
    内脂类 2-油酸单甘油酯
    吡啶类 烟酸
    咪唑类 咪唑丙烯酸
    下载: 导出CSV 
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    2.2.2.4   差异性代谢物通路富集分析

    对29种差异代谢物进行通路分析,最主要的代谢通路包括:亚精胺和精胺生物合成、尿素循环、甘氨酸和丝氨酸代谢、D-精氨酸和D-鸟氨酸代谢、蛋氨酸代谢、维生素K代谢、a亚麻酸和亚油酸、精氨酸和脯氨酸代谢、缬氨酸、亮氨酸和异亮氨酸降解、甘油酯代谢、磷酸戊糖通路、氨循环通路、糖原异生、烟酸和烟酰胺代谢、丙酸代谢、组氨酸代谢、丙酮酸代谢、瓦格纳效应、胆汁酸生物合成、酪氨酸代谢。进一步分析发现这些通路主要富集在鸟氨酸循环、支链氨基酸和芳香氨基酸代谢通路中,提示上述通路是MHE患者最重要的代谢通路(图4)。

    图  4  MHE患者的差异代谢通路
    Figure  4.  Differential metabolic pathways in MHE patients
    2.3.1   益气养阴解毒化瘀方治疗前后肝功能比较

    11例MHE患者经益气养阴解毒化瘀方治疗后肝功能指标(ALT、AST、TBil)、血氨指标(NH3)、Child-Pugh评分和MELD评分均较治疗前有明显好转(P值均<0.05)。益气养阴解毒化瘀方治疗前MHE患者的NCT-A用时较治疗后明显缩短(P<0.05),MHE患者的DST得分较治疗前明显增加(P<0.05)(表4)。

    表  4  益气养阴解毒化瘀方治疗前后肝功能的变化
    Table  4.  Changes in liver function before and after treatment with Yiqi Yangyin Jiedu Huayu prescription
    指标 治疗前(n=11) 治疗后(n=11) 统计值 P
    ALT(U/L) 69.65±56.66 17.50±10.87 t=-3.532 0.005
    AST(U/L) 53.80(31.90~87.50) 15.70(9.70~21.50) t=-3.513 <0.001
    TBil(μmol/L) 72.70(39.90~78.95) 25.50(19.28~30.43) Z=-2.856 0.004
    NH3(μmol/L) 43.70±10.96 21.74±6.97 t=5.608 <0.001
    Child-Pugh评分(分) 11.36±2.25 6.73±1.62 t=5.551 <0.001
    MELD评分(分) 12.50(10.63~17.38) 5.00(2.83~9.67) Z=-3.034 0.002
    NCT-A(s) 68.90±23.00 46.18±16.48 t=2.093 0.049
    DST(分) 17.80±4.50 23.45±5.43 t=-2.572 0.018
    下载: 导出CSV 
    | 显示表格
    2.3.2   益气养阴解毒化瘀方治疗前后肠道代谢物组成的比较

    MHE患者治疗前后共检测出164种肠道代谢物,从PCA分析(图5)及PLS-DA分析(图6)可见两组代谢物分离良好,提示两组治疗前后代谢物存在明显差异。治疗前代谢物的主要组成为氨基酸类52.89%,有机酸类20.8%,碳水化合物类0.88%、有机胺类14.46%,无机氧化类6.58%,脂肪酸2.81%,其他1.9%;治疗后代谢物的主要组成为氨基酸类20.48%,有机酸类 28.09%,碳水化合物类34.17%、有机胺类3.22%,无机氧化类6.11%,醇类5.22%,其他2.71%。Wilcoxon秩和检验结果显示,与治疗前相比,治疗后MHE患者的醇类、碳水化合物类、内酯类、核苷酸类、有机酸类、酚类、苯丙酸类、吡啶类明显上升,而有机胺类、氨基酸类、苯类、脂肪酸类、吲哚类、多肽类、吡咯烷类明显下降(图7)。

    图  5  益气养阴解毒化瘀方治疗前后代谢物的PCA分析
    Figure  5.  PCA analysis of metabolites before and after Yiqi Yangyin Jidu Huayu prescription
    图  6  益气养阴解毒化瘀方治疗前后代谢物的PLS-DA分析
    Figure  6.  PLS-DA analysis of metabolites before and after Yiqi Yangyin Jidu Huayu prescription
    图  7  益气养阴解毒化瘀方治疗前后的主要代谢物分类组成
    Figure  7.  Classification and composition of main metabolites before and after treatment with Yiqi Yangyin Jiedu Huayu prescription
    2.3.3   益气养阴解毒化瘀方治疗前后肠道差异性代谢物分析

    通过Wilcoxon秩和检验来比较两组的差异代谢物,基于单维统计分析总共筛选出的126种差异代谢物,通过火山图可见,与治疗前相比,治疗后MHE上调代谢物85种,下调代谢物41种(阈值设定:log2FC>0)(图8)。基于OPLS-DA模型对MHE患者治疗前后的差异代谢物进行多维统计分析,共筛选到差异代谢物81种(图9)。

    图  8  益气养阴解毒化瘀方治疗前后肠道差异性代谢物的单维统计分析
    Figure  8.  Unidimensional statistical analysis of intestinal differential metabolices before and after treatment with Yiqi Yangyin Jiedu Huayu prescription
    图  9  益气养阴解毒化瘀方治疗前后肠道差异性代谢物的多维统计分析
    Figure  9.  Multidimensional statistical analysis of intestinal differential metabolites before and after treatment with Yiqi Yangyin Jiedu Huayu prescription
    2.3.4   益气养阴解毒化瘀方治疗的潜在代谢标志物筛选

    通过对益气养阴解毒化瘀方治疗前后肠道差异性代谢物的单维统计和多维统计分析结果取交集,对MHE潜在代谢产物进行筛选(筛选标准同2.3.4)。共筛选了80种潜在的代谢标志物,经过益气养阴解毒化瘀方治疗后56种代谢物上调,而24种代谢物下调。应用热图(图10)对两组差异性代谢物进行对比分析显示碳水化合物类、有机酸类明显上升,氨基酸类明显下降。而散点图具体展示了经益气养阴解毒化瘀方治疗后上调的56种差异性代谢物和24种下调的差异性代谢物(图11)。

    图  10  益气养阴解毒化瘀方治疗前后的差异性代谢物种类热图
    Figure  10.  Heat map of different metabolites before and after treatment of Yiqi Yangyin Jiedu Huayu prescription
    图  11  益气养阴解毒化瘀方治疗前后的差异性代谢物散点图
    Figure  11.  Scatter diagram of differential metabolites before and after treatment of Yiqi Yangyin Jiedu Huayu prescription
    2.3.5   益气养阴解毒化瘀方治疗前后的差异性代谢物通路分析

    对80种益气养阴解毒化瘀方治疗前后的差异代谢通路进行分析,益气养阴解毒化瘀方代谢通路主要富集在半乳糖代谢、谷胱甘肽代谢、同型半胱氨酸降解、乳糖降解、甘氨酸和丝氨酸代谢、丙氨酸循环、甲基组氨酸代谢、尿素循环、蛋氨酸代谢、丙氨酸代谢、淀粉和蔗糖代谢、谷氨酸代谢、甜菜碱代谢、甘油酯代谢、苹果酸-天门冬酸穿梭、半胱氨酸代谢、丙酸代谢、海藻糖降解、缬氨酸、亮氨酸和异亮氨酸降解、苯丙氨酸、酪氨酸代谢等通路(图12),这些通路主要富集在鸟氨酸代谢、支链和芳香氨基酸代谢通路中,与MHE患者特异性代谢通路相似,故益气养阴解毒化瘀方很有可能通过改善鸟氨酸代谢及支链氨基酸和芳香氨基酸代谢等途径达到治疗MHE的作用。

    图  12  益气养阴解毒化瘀方治疗前后的差异性代谢通路分析
    Figure  12.  Analysis of different metabolic pathways before and after treatment with Yiqi Yangyin Jiedu Huayu prescription

    HE是发生在严重肝病基础上,以代谢紊乱为主要病理基础的神经精神异常综合征,是肝疾病常见的并发症及死亡原因之一9,严重影响了肝病患者及监护人的生活质量10,认知功能损害造成的医疗相关资源消耗远远超过了其他肝硬化并发症11。近些年来,中医药治疗MHE取得了良好的疗效12-14,然而机制目前尚不明确,本试验开展了中医药对于MHE肠道代谢作用的研究,旨在探索中医药治疗MHE的可能作用机制,为更好地发挥中医药治疗MHE的作用奠定理论基础。

    肠道微生态系统是由肠道菌群和肠道微环境构成的庞大复杂的微生态系统15。肠道菌群的结构和功能常常会受到肠道微环境等因素的影响,因此本试验在临床中选取了MHE患者服用中药前后的粪便样本进行对比研究。研究发现,MHE患者的肠道代谢物与正常人相比具有明显异常。经过单维和多维统计分析,MHE组和对照组共筛选出29种潜在的代谢标志物,这些差异性代谢物的主要代谢通路富集在鸟氨酸循环、支链氨基酸和芳香氨基酸中。肝脏是鸟氨酸循环重要的代谢器官,在肝损伤严重引起肝功能明显下降时,肝脏无法正常通过鸟氨酸循环进行解毒,故导致血氨增高,使星状胶质细胞合成谷氨酰胺增加,导致细胞变性、肿胀及退行性变,同时可直接影响假性神经递质,引发神经认知功能障碍16。肝功能严重受损时,肝脏代谢芳香氨基酸的能力下降,芳香氨基酸主要包括酪氨酸、苯丙氨酸和色氨酸,增多的苯丙氨酸和酪氨酸生成苯乙醇胺和羟苯乙醇胺即假性递质,也是导致HE发生的机制之一。支链氨基酸包括亮氨酸、缬氨酸和异亮氨酸,是人体必需的氨基酸,这几种氨基酸可以通过血流进入大脑,降低大脑5-羟色胺的产生,支链氨基酸支持大脑合成谷氨酰胺,促进氨的解毒代谢,而且还可以减少过多的芳香族氨基酸进入大脑17-18。通过对益气养阴解毒化瘀方治疗前后的肠道代谢物通路分析,发现MHE患者治疗前后差异性代谢物通路与MHE患者特异性代谢通路在鸟氨酸、支链氨基酸、芳香氨基酸代谢方面有交集,说明益气养阴解毒化瘀方有可能是通过鸟氨酸、支链氨基酸和芳香氨基酸代谢通路发挥了改善MHE的作用。

    MHE由于起病隐匿,临床中往往不易发现,然而一旦进展为显性HE,则预后不良,因此早期诊断、早期治疗MHE至关重要。中医药在MHE的治疗中发挥了良好的作用,肠道微生态与MHE有着密不可分的联系,通过探索肠道代谢物的变化有助于探讨中医药治疗MHE的作用机制,更好地发挥中医药治疗MHE的作用。本研究首次通过人群队列验证了益气养阴解毒化瘀方可能通过调节MHE患者的相关代谢发挥了治疗作用,但是研究仍然具有一定的局限性,代谢组学研究在统计学上无固定的样本量计算公式,本研究属于小规模的探索性研究,实验样本量仍然较少,目前基于样本量限制,无法进一步针对病因进行分层分析,肠道菌群仍可能受到食物、药物及环境等多种因素的影响,MHE的肠道机制仍需要开展大规模的临床试验和动物实验探索诊断及治疗MHE的肠道生物标记,为早期诊断及治疗MHE提供思路。

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