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非酒精性脂肪性肝病多组学研究现状
DOI: 10.12449/JCH240626
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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。Abstract: The prevalence rate of nonalcoholic fatty liver disease （NAFLD） reaches up to 30% around the world， and the disease has a serious impact on human health and constitutes a public health burden. Due to difficulties in the diagnosis and monitoring of NAFLD， it is important to identify potential drug targets and biomarkers， and multi-omics techniques hold great promise in the search for early diagnostic markers， therapeutic targets， and outcome and prognostic assessment of NAFLD. This article reviews the research advances in multi-omics techniques in the field of NAFLD in recent years， in order to provide a richer theoretical basis and new strategies for the prevention and treatment of NAFLD.
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Key words:
- Non-alcoholic Fatty Liver Disease /
- Genomics /
- Proteomics /
- Metabolomics /
- Gastrointestinal Microbiome
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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。
1. 临床表现
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。
2. ATD肝损伤的机制
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］。
3. 诊断与鉴别诊断
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DILI［13-14］，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 diagnosissATD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。
4. 治疗原则
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。
4.1 及时停药
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。
4.2 药物治疗
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。
4.3 血浆置换和人工肝治疗
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］。
4.4 131I治疗
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。
5. 总结与展望
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。
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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］ 
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