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非酒精性脂肪性肝病多组学研究现状

段明秀 陈新利 常伟宇 杨媛 杨仕琦 吴晖

杨睿涛, 杨锐, 邓勋, 等 . 抗甲状腺药物所致肝损伤的诊断与治疗原则[J]. 临床肝胆病杂志, 2024, 40(3): 621-625. DOI: 10.12449/JCH240331.
引用本文: 杨睿涛, 杨锐, 邓勋, 等 . 抗甲状腺药物所致肝损伤的诊断与治疗原则[J]. 临床肝胆病杂志, 2024, 40(3): 621-625. DOI: 10.12449/JCH240331.
YANG RT, YANG R, DENG X, et al. Diagnosis and treatment principles of liver injury induced by antithyroid drugs[J]. J Clin Hepatol, 2024, 40(3): 621-625. DOI: 10.12449/JCH240331.
Citation: YANG RT, YANG R, DENG X, et al. Diagnosis and treatment principles of liver injury induced by antithyroid drugs[J]. J Clin Hepatol, 2024, 40(3): 621-625. DOI: 10.12449/JCH240331.

非酒精性脂肪性肝病多组学研究现状

DOI: 10.12449/JCH240626
基金项目: 

云南省应用基础研究专项项目 (202301AT070152)

利益冲突声明:本文不存在任何利益冲突。
作者贡献声明:段明秀负责课题设计,资料分析,撰写论文;吴晖、陈新利、常伟宇参与收集数据,修改论文;杨媛、杨仕琦负责拟定写作思路,指导撰写文章并最后定稿。
详细信息
    通信作者:

    吴晖, kyz_ggyx@163.com (ORCID: 0009-0003-5966-3570)

Advances in the multi-omics research on nonalcoholic fatty liver disease

Research funding: 

Yunnan Province Applied Basic Research Special Project (202301AT070152)

More Information
    Corresponding author: WU Hui, kyz_ggyx@163.com (ORCID: 0009-0003-5966-3570)
  • 摘要: 非酒精性脂肪性肝病(NAFLD)在全球范围内患病率高达30%,严重影响人类健康并构成公共卫生负担。由于该病难以诊断和监控,因此,识别潜在的药物靶点和生物标志物具有重要价值,多组学技术在探索NAFLD早期诊断标志物、治疗靶点、疗效和预后评估方面具有广阔的前景。本文对近年来多组学技术在NAFLD中领域的研究进展进行综述,以期为NAFLD的防治提供更为丰富的理论依据和新的策略。

     

  • 甲状腺功能亢进症是一种常见的内分泌疾病,其治疗方法主要有药物、手术和同位素治疗,其中药物治疗是目前最常用、最主要的治疗方法。抗甲状腺药物(anti-thyroid drug,ATD)主要包括甲巯咪唑(MMI)和丙硫氧嘧啶(PTU)。MMI和PTU疗效确切,口服用药方便,总体安全性较高,但少数患者使用后可出现粒细胞减少、皮疹、肝功能损害以及关节疼痛等不良反应,尤其以药物性肝损伤(DILI)较为严重,起病急,病情重,预后差,可致死亡1。本文就ATD所致肝损伤(下文简称ATD肝损伤)的诊断和治疗原则进行阐述,指导临床医师规范用药。

    ATD致肝损伤无特异性表现,急性起病,与其他各种急、慢性肝病类似。轻者可无任何症状,重者可出现黄疸,伴或不伴不同程度的乏力、食欲减退、肝区胀痛及上腹部不适等。胆汁淤积明显者可出现黄疸、大便颜色变浅和瘙痒等表现2

    过去我国将急性DILI的严重程度分为1~5级(轻度、中度、重度、急性肝衰竭、致命)3,但分级不统一,不便于制订规范的治疗方案。随着循证证据的累积和进展,目前我国将急性DILI按严重程度不同分为4级,分别为1级轻度、2级中度、3级重度和4级致命4

    PTU较MMI更容易引发肝损伤。PTU治疗后14.3%的患者出现ALT无症状性升高,提示亚临床肝损伤,其中严重肝损伤发生率约为0.1%5。PTU诱导的肝损伤大多为肝细胞型,病理可见实质性坏死伴出血、小叶结构塌陷和门静脉前混合炎症浸润6,起病急且进展迅速,呈非剂量依赖性,肝功能和肝酶检测对于评估肝功能损伤情况无明确的预测作用7。MMI引起的肝损伤主要是胆汁淤积型8,通常在药物使用的最初几周发生,发生率为0.1%~0.2%,表现为肝细胞和/或胆小管内胆汁淤积,肝活检显示门静脉水肿和炎症,并伴有小管内胆汁淤积和中度微血管脂肪变性,其不良反应呈剂量依赖性,停药后多数患者能恢复正常,但所需时间较长。

    目前ATD肝损伤的发生机制尚不十分明确,可能与药物代谢动力学及免疫学机制、年龄、性别、药物相互作用以及潜在疾病(如Graves病)等因素有关9。在药物代谢方面,MMI在人体内主要由CYP450酶和FMO酶代谢,MMI的主要代谢产物N-甲基硫脲可能是导致肝损伤的主要因素,N-甲基硫脲使氧自由基和过氧化脂质体形成增多,损伤肝细胞,同时,减少了还原型谷胱甘肽的储存量,造成肝细胞进一步损伤10。PTU在人体内主要在肝脏被葡萄糖醛酸化代谢,在髓过氧化物酶(MPO)介导下生成的代谢活性代谢产物与白蛋白共价结合,抑制谷胱甘肽转移酶和谷胱甘肽过氧化物酶,导致肝细胞抗氧化作用明显减弱。此外,PTU活性代谢产物可损伤细胞线粒体,出现线粒体形状异常,可见巨大线粒体。同时,线粒体功能异常,可出现线粒体内外膜破碎和基质溶解,从而诱导细胞损伤11。在免疫方面,部分接受ATD治疗的患者体内存在细胞因子和自身抗体,激活免疫反应造成肝细胞损伤。此外,ATD改变了肠道微生物群的结构,通过脂多糖相关信号通路,引起肝损伤12

    目前虽有多个DILI的特异性生物学标志物(如miR-122、GLDH、HMGB1等)被报道用于协助诊断DILI13-14,但尚未进行严格的临床验证,无法推广使用。当前诊断DILI仍是基于病史采集、临床症状、血清生化、影像学及组织学等排他性诊断4,诊断标准主要有:(1)用药、停药与肝脏生化改变有明确合理的时效关系;(2)肝损伤的临床或病理表现与使用药物已知的肝毒性一致;(3)停药或减量后肝损伤明显改善或恢复正常;(4)再次用药后肝损伤再次出现:(5)排除肝损伤其他病因且无法用其他原发疾病或治疗手段解释。

    在ATD肝损伤的诊断与鉴别诊断流程中,推荐采用先分型,再排除,后病因的诊断原则。关于ATD肝损伤的诊断与鉴别诊断流程可见图1

    注: 在《中国药物性肝损伤诊治指南(2023年版)》[ 4]中“DILI的诊断和鉴别诊断流程图”基础上补充修订。
    图  1  ATD肝损伤诊断和鉴别诊断流程
    Figure  1.  The procedure of ATD liver damage diagnosis and differential diagnosiss

    ATD肝损伤诊断有困难时可行肝穿刺活检,适应证为:(1)其他竞争性病因无法排除,尤其是自身免疫性肝炎仍无法排除;(2)停用MMI或PTU后,肝酶仍持续升高者;或肝细胞损伤型(主要为使用PTU)患者的ALT峰值在发病后的30~60天,胆汁淤积型(主要为使用MMI)患者的ALP峰值在180天内,未下降>50%者;(3)持续肝酶升高超过180天,怀疑存在慢性肝病者。药物再暴露,因其具有潜在的严重后果,可能会导致快速、更严重的再次肝损伤甚至急性肝衰竭,且除ATD外还可使用131I等方法治疗,因此不建议对ATD肝损伤患者进行再暴露,且避免患者再次暴露于相似的可疑药物。因此,在诊断ATD肝损伤时,应遵循宁可活检不再暴露的原则。

    目前,ATD肝损伤的治疗方法和流程并不统一15。常规的ATD肝损伤防治措施应包括:及时停药,促进肝损伤尽早恢复,防止肝损伤重症化及慢性化,降低死亡风险。

    只要怀疑ATD肝损伤,首先应做到及时停药,尽量避免再次使用同类药物,停药是对因治疗中最重要的措施,也是最基本的治疗原则。及时停药后约95%患者可自行改善甚至痊愈,少数发展为慢性,极少数进展为急性/亚急性肝衰竭。有报道16肝细胞损伤型恢复时间约(3.3±3.1)周,胆汁淤积型约(6.6±4.2)周。对于轻度亚临床肝损伤时,可减少ATD剂量,密切监测肝功能,如肝损伤显著,则立即停药。若出现下列情况之一应考虑停药:(1)血清ALT或AST>8倍正常值上限;(2)ALT或AST>5倍正常值上限,持续2周;(3)ALT或AST>3倍正常值上限,且TBil>2倍正常值上限或INR>1.5;(4)ALT或AST>3倍正常值上限,伴逐渐加重的疲劳、恶心、呕吐、右上腹疼痛或压痛、发热、皮疹和/或嗜酸性粒细胞增多(>5%)17。及时停药,不再暴露是治疗ATD肝损伤的基本原则。

    在大多数ATD引起的肝损伤病例中,除了及时停药与监测肝功能外,应结合循证医学证据,合理选择护肝治疗药物。ATD肝损伤治疗中常用药物包括:

    4.2.1   糖皮质激素

    糖皮质激素常用于甲亢危象的治疗18,可抑制免疫或变态反应,减少外周T4向T3的转换,抑制甲状腺素的合成,也有利于改善患者黄疸。糖皮质激素可减轻MMI引起的肝炎19,泼尼松龙可改善ATD肝损伤黄疸患者病情20。糖皮质激素联合甘草素治疗DILI可同时改善肝生化和组织学,且安全性良好。糖皮质激素使用的适应证,主要有重症DILI患者,合并甲亢危象和有过敏性皮疹的DILI患者;慢性DILI患者伴转氨酶升高超过10倍,或者超过5倍伴有TBil超过2倍,或者病理提示肝炎活动明显,可以考虑糖皮质激素治疗21。一些研究也指出,糖皮质激素可能增加不良事件的发生。糖皮质激素的使用并非ATD肝损伤的常规治疗方案,需严格掌握适应证,充分权衡获益与风险。

    4.2.2   N-乙酰半胱氨酸(NAC)/谷胱甘肽(GSH)

    NAC是由L-半胱氨酸和乙酰基形成,是细胞内还原型谷胱甘肽的前体,可促进GSH的生成;同时含有活性巯基,可对抗不同原因所致组织氧化损伤。NAC可用于预防MMI诱导的肝损伤22;静脉注射NAC可显著提高Ⅰ~Ⅱ级早期昏迷患者的无移植生存率23。GSH属于解毒类药物,提供活性的巯基,参与肝细胞代谢过程,减轻组织损伤,促进修复,促进有毒物的转化和排泄。GSH对MMI所致肝损伤具有较好的疗效24。目前,NAC静脉注射被普遍用于药物急性肝衰竭的成人患者,且应尽早使用,每天50~150 mg/kg。同时,使用还原型谷胱甘肽,1.8 g,静脉滴注,每天1次。

    4.2.3   异甘草酸镁/甘草酸二胺/双环醇

    异甘草酸镁/甘草酸二胺可抑制炎症因子、调节肝细胞免疫功能、抑制氧化应激、保护干细胞膜等,可有效降低急性DILI患者的ALT和AST水平,促进ALT和AST及肝损伤恢复25。异甘草酸镁可显著改善MMI致DILI患者的肝功能,并促进机体自身免疫调节功能26。双环醇具有抗细胞凋亡、清除氧自由基、抗脂质过氧化等功能,可降低ALT和AST,尤其是降低ALT。双环醇治疗DILI,可以显著提高ALT正常化比率27。双环醇治疗急性肝损伤,50 mg,每天3次,效果优于25 mg,每天3次28。异甘草酸镁0.2 g,静脉滴注,每天1次。使用异甘草酸镁/甘草酸二胺时,注意复查电解质,关注血钾水平。

    4.2.4   S-腺苷蛋氨酸/熊去氧胆酸

    S-腺苷蛋氨酸退黄作用较好,适用于胆汁代谢障碍、ALP升高为主的胆汁淤积型DILI。熊去氧胆酸可以促进内源性胆汁酸的代谢,抑制其重吸收,增加胆汁排泄。腺苷蛋氨酸1 g,口服,每天3次。熊去氧胆酸胶囊,0.2 g,口服,每天2次。

    4.2.5   多烯磷脂酰胆碱

    进入肝细胞后,以完整的分子与肝细胞膜及细胞器膜结合,增加膜的完整性、稳定性和流动性,促进肝细胞再生。多烯磷脂酰胆碱注射液,465~930 mg,每天1次,静脉注射。

    在ATD肝损伤的护肝治疗中,不宜同时使用多种同一类型的护肝药,应根据导致肝损伤的药物和损伤程度选择恰当的护肝药物,做到有的放矢,精准治疗。

    治疗性血浆置换可以有效清除胆红素、胆汁酸和高水平的甲状腺激素等,减少甲状腺素对肝脏的直接损伤,并可以暂时部分替代肝脏的解毒功能,稳定机体内环境,为肝细胞再生及进一步治疗赢得宝贵时间。血浆置换可以明显降低血中T3和T4水平29。推荐ATD所致3级或4级肝损伤、普通护肝治疗措施效果不佳等情况下,及时行血浆置换。推荐使用新鲜冷冻血浆作为置换液,以提高甲状腺结合球蛋白水平,置换容积应为总血浆体积的1~1.5倍,根据病情每天或每2~3天进行1次血浆置换,持续置换到临床症状和肝功能指标显著改善。血浆置换是手术或131I治疗之前有效和安全的治疗选择。分子吸附再循环人工肝是一种将白蛋白透析和常规透析结合的技术,可以减少置换的次数,减少甲状腺激素的反弹,缩短肝功能恢复时间,在普通血浆置换效果欠佳时可选择使用30

    在DILI得到一定程度控制后,及时、足量的131I治疗,可以降低ATD相关肝损伤的死亡31。因此ATD肝损伤后,应及时停用ATD,综合护肝治疗,β-受体阻滞剂改善高代谢症状,适时予131I治疗。

    ATD的使用已有近70年历史,这类药物在治疗甲亢方面迄今仍占据着极其重要的地位。由于其所引起的肝损伤等不良反应并非罕见,有些甚至为致命性损伤32。因此,在使用ATD时应遵循充分评估,识别风险,监测肝功能,权衡利弊,及时停药,综合治疗的基本原则,最大限度降低ATD肝损伤的发生或进展。

    除此之外,医药专业人员和公众可利用LiverTox和HepaTox网络平台,了解各类肝毒性药物的信息并增加对DILI的认知。临床药师也应加入治疗决策团队,通过审核药物配伍、提醒潜在的药物相互作用,以及必要时的血药浓度监测等,降低DILI风险。同时,加强针对公众的健康和合理用药教育,指导患者按药品说明书用药,纠正错误的服药习惯。

  • 图  1  NAFLD多组学研究

    Figure  1.  Multi-omics study of NAFLD

    表  1  NAFLD的代谢组学研究

    Table  1.   Metabolomics studies in NAFLD

    样本类型 组别 重要代谢物 涉及代谢通路 参考文献
    血清 NAFLD组(n=157),NASH组(n=138),健康对照组(n=66) 脂肪酸;甘油酯;甘油磷脂,溶血磷脂酸、溶血磷脂酰胆碱、溶血磷脂酰乙醇胺、磷脂酰胆碱、磷脂酰乙醇胺和磷脂酰肌醇;鞘脂 脂质代谢 53
    血清 NAFLD组(n=144),健康对照组(n=368) s-腺苷蛋氨酸、s-腺苷同型半胱氨酸和同型半胱氨酸 氨基酸代谢、脂质代谢 56
    血浆 NAFLD组(n=132),健康对照组(n=42) 磷脂酰胆碱、溶血磷脂酰乙醇胺、磷脂酰胆碱、天冬氨酸转氨酶、丙氨酸转氨酶、γ-谷氨酰转肽酶、白蛋白、总胆红素、甘油三酯、总胆固醇、低密度脂蛋白、胆碱酯酶、透明质酸、C反应蛋白、铁蛋白 磷脂酰胆碱、胆汁酸途径、烟酸和烟酰胺途径、磷脂酰肌醇和三羧酸循环 57
    血浆 NAFLD组(n=427) 5-羟廿碳四烯酸,7,17-二氢吡啶二羧酸,肾上腺酸,花生四烯酸,二十碳五烯酸,16-羟基二十二碳六烯酸,9-羟基十八碳二烯酸 58
    血清 NAFLD组(n=627) 2-羟基丁酸、3-羟基丁酸、柠檬酸、异亮氨酸、赖氨酸、油酸、3-OH-苯甲酸、5-OH-1H-吲哚-3-乙酸、吲哚-3-乳酸 59
    尿液 NASH组(男68例,女65例) 高丙二酸乙酯、β-羟基丁酸、乙基丙二酸酯、硫酸盐水平、高甲氨基谷氨酸、对羟苯乳酸、琥珀酸盐、甲酰亚胺谷氨酸酯、香草扁桃酸酯、吡啶甲酸酯 酪氨酸分解代谢 60
    尿液 NAFLD组(n=33),NASH组(n=45),健康对照组(n=30) 氨基酸代谢物、瓜氨酸、精氨酸、缬氨酸、吲哚乙酸以及葡萄糖和葡萄糖酸、次黄嘌呤、黄嘌呤和肉碱 脂质过氧化和氧化应激、氨基酸代谢和戊糖磷酸途径 61
    下载: 导出CSV

    表  2  NAFLD的代谢靶点

    Table  2.   Metabolic targets of NAFLD

    靶点 机制 参考文献
    抑制CD36棕榈酰化 激活AMPK改善脂质积累,抑制JNK缓解炎症反应 64
    胆汁酸受体法尼酯X受体、CYP450酶、PPAR、ChREBP、JNK 负调节胆汁酸合成,减少肝脏和肝外组织的糖异生、脂肪生成和脂肪变性、氧化应激、胰岛素抵抗和脂肪酸的调节 65
    线粒体丙酮酸载体、FFA、ACC 线粒体电子传递链、线粒体β-氧化减少、活性氧过度产生和脂质过氧化 66
    法尼酯X受体激动剂 反馈调节胆汁酸合成、调节糖脂代谢、调节肝脏炎症和纤维化 67
    下载: 导出CSV
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