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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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慢加急性肝衰竭（acute-on-chronic liver failure，ACLF）是在慢性肝病（包括慢性肝炎或肝硬化）基础上因各种诱因引起的急性肝衰竭，病情进展快，病死率达60%～80%。肝移植是挽救ACLF患者的最终手段，然而由于治疗费用高、供体肝脏少、技术难度较大等问题使其极大程度地受到了限制。近年来，人工肝治疗技术发展迅速，临床疗效肯定。大量研究［1-3］证明人工肝是治疗ACLF的有效措施。但血液通过管路和血浆分离器时血细胞的成分有一定的破坏，当血小板过低时，有增加出血的危险，在一定程度上限制了人工肝的治疗。由乙烯和乙烯醇共聚物制备的Evacure-4A膜型血浆分离器由于截孔面积小，膜交换面积大，组织相容性好，可以耐受高达250 mmHg的跨膜压，且随物质分子量的加大而筛选系数越来越低，因此血液通过时对血细胞的影响较小。叶俊茂等［4］研究表明，使用Evacure-4A膜型血浆分离器进行血浆置换治疗慢性重型肝炎伴严重血小板减少患者是安全的。本研究通过对不同分层血小板计数ACLF患者据病情选择不同模式非生物型人工肝治疗，观察其疗效及安全性。
1. 资料与方法
1.1 研究对象
选取2021年1月—2023年5月入住本院的ACLF患者，根据血小板计数将其分为3组：A组（明显低下组），25×109/L～50×109/L；B组（中等程度低下组），51×109/L～80×109/L；C组（轻度低下组），81×109/L～100×109/L。纳入标准：ACLF诊断符合《肝衰竭诊治指南（2018年版）》［5］。排除标准：（1）合并肿瘤、妊娠、原发性心源性休克、原发性肾衰竭且规律透析、肝移植患者；（2）血小板计数<25×109/L的患者；（3）活动性出血的患者；（4）合并血液系统恶性病的患者，如血液肿瘤、骨髓抑制；使用具有明确骨髓抑制药物的患者；（5）入院前至住院1周有明确出血的患者；（6）近期有使用抗血小板药物的患者；（7）既往接受过脾脏切除术的患者；（8）不愿参加本研究者。
1.2 方法
1.2.1 内科综合治疗
包括卧床休息，静脉滴注多烯磷脂酰胆碱、丁二磺酸腺苷蛋氨酸、复方甘草酸苷等保肝及人血白蛋白等支持治疗，乙型肝炎有抗病毒治疗指征者加用恩替卡韦或富马酸替诺福韦二吡呋酯或富马酸丙酚替诺福韦，同时依据病情联合不同模式人工肝治疗。
1.2.2 人工肝支持治疗
在持续空气消毒的人工肝治疗室内，心电监护下行股静脉穿刺置入股静脉双腔管建立体外循环，治疗过程中使用低分子肝素抗凝，根据患者凝血时间、体质量、跨膜压、分浆流速及治疗时间调整其剂量，使用Evacure-4A膜型选择性血浆分离器（旭化成医疗株式会社，日本）。治疗方式包括：血浆灌流联合血浆置换（plasma perfusion combined with plasma exchange，PP+PE）、胆红素吸附联合血浆置换（plasma bilirubin adsorption combined with plasma exchange，PBA+PE）、双重血浆分子吸附联合血浆置换（double plasma molecular adsorption combined with plasma exchange，DPMAS+PE）：使用德国贝朗Dia Pact CRRT机，采用BS330血浆胆红素吸附器（珠海健帆生物科技股份有限公司）和大分子树脂HA-330 Ⅱ型灌流器（广东丽珠医用生物），治疗过程血流量100～130 mL/min，时间2～3 h［6］，每次置换血浆量1 500 mL［7］，在置换血浆前常规应用10%葡萄糖酸钙3 g及地塞米松5 mg静注，预防过敏等不良反应。
1.3 观察指标
人工肝治疗前后患者临床症状、体征、肝功能、国际标准化比值（INR）、血小板计数，相关检验数据系人工肝后立即采集。采用Labospect 008全自动生化分析仪和迈克生物生化试剂检测肝功能各项指标，包括ALT、AST、Alb、TBil；INR由Sysmex CS-2000血凝仪及武汉中太生物技术有限公司血凝试剂进行检测；血小板计数由Sysmex XF-2000检测。记录治疗过程中的不良反应。
1.4 统计学方法
采用SPSS 19.0软件对数据进行统计分析。符合正态分布的计量资料以
2. 结果
2.1 一般资料
共纳入行人工肝治疗的ACLF患者302例，其中男236例（78.15%），女66例（21.85%），年龄24～87岁，中位年龄51.3岁。A组101例，男82例、女19例，平均年龄（51.75±11.38）岁；B组98例，男75例、女23例，平均年龄（51.53±10.96）岁；C组103例，男81例、女22例，平均年龄（50.72±12.49）岁。3组患者一般资料比较，年龄、性别、治疗前各组INR、Alb差异均无统计学意义（P值均>0.05）（表1）。
表 1 血小板计数不同分层ACLF患者的一般资料比较Table 1. Comparison of general data of ACLF patients with different levels of platelet count组别 例数 男/女（例） 年龄（岁） INR Alb（g/L） A组 101 82/19 51.75±11.38 2.11±0.71 27.79±3.76 B组 98 75/23 51.53±10.96 1.98±0.46 28.79±3.61 C组 103 81/22 50.72±12.49 2.11±0.77 28.97±3.59 统计值 F=0.223 F=1.221 F=3.058 P值 0.723 0.804 0.361 0.060 2.2 3组患者治疗前后临床症状、肝功能、INR及血小板变化
302例ACLF患者治疗后有268例临床症状呈不同程度的改善，表现为精神好转，乏力减轻，食欲增加，腹胀缓解，未见明显出血倾向。各组治疗前后比较ALT、AST、TBil呈不同程度下降，肝功能好转（P值均<0.001）。INR呈不同程度降低，各组治疗前后比较，差异亦有统计学意义（P值均<0.05）。血小板计数呈不同程度的下降，但A组治疗前后无统计学差异（P>0.05）（表2）。
表 2 血小板计数不同分层ACLF患者人工肝治疗前后肝功能、凝血、血小板变化Table 2. Changes of liver function， blood coagulation and platelet count in patients with ACLF before and after artificial liver treatment分组 例数 ALT（U/L） AST（U/L） Alb（g/L） TBil（μmol/L） INR 血小板计数（×109/L） A组 101 治疗前 1.97±0.34 2.05±0.33 27.79±3.76 322.30±149.56 2.11±0.71 37.73±6.27 治疗后 1.78±0.28 1.88±0.31 25.71±2.79 197.25±103.20 1.91±0.66 36.59±7.96 t值 14.755 11.491 9.650 19.182 3.497 1.820 P值 <0.001 <0.001 <0.001 <0.001 0.001 0.072 B组 98 治疗前 2.06±0.43 2.09±0.37 28.79±3.61 262.28±113.56 1.98±0.46 66.97±7.64 治疗后 1.87±0.38 1.90±0.32 25.78±3.89 159.23±78.79 1.86±0.56 62.59±7.37 t值 21.614 19.301 7.878 17.486 3.327 12.993 P值 <0.001 <0.001 <0.001 <0.001 0.001 <0.001 C组 103 治疗前 2.37±0.50 2.31±0.44 28.97±3.59 311.16±128.73 2.11±0.77 93.82±5.38 治疗后 2.11±0.44 2.07±0.36 26.26±3.27 183.96±96.01 1.89±0.80 85.99±12.49 t值 15.965 13.919 8.045 21.750 4.358 8.240 P值 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 2.3 3组患者人工肝治疗不同模式构成情况
A、B、C组行PP+PE患者分别为40例（40%）、44例（45%）、41例（40%）；行DPMAS+PE患者分别为32例（32%）、30例（31%）、35例（34%）；行PBA+PE患者分别为29例（28%）、24例（24%）、27例（26%）。3组ACLF患者人工肝治疗模式各组间比较差异无统计学意义（
2.4 3组患者人工肝治疗过程中不良反应比较
ACLF患者人工肝治疗中最常见的不良反应为血浆过敏，发生率15.23%（46/302），较少见的不良反应为凝血，发生率0.66%（2/302），其余不良反应为低血压4.64%（14/302）、畏寒寒战0.99%（3/302）。3组患者发生不良反应分别有19例、21例、25例，发生率比较差异无统计学意义（18.81% vs 21.43% vs 24.27%，
3. 讨论
肝脏具有合成、代谢、解毒和生物转化功能，在维持人体正常凝血功能中具有重要作用。肝脏受损时，会导致凝血因子合成减少或其活性降低，进而伴随凝血机制和纤溶功能异常，表现为多种凝血功能障碍，INR也会相应的延长。当前，ACLF是一种无法完全治愈的综合征。具有发病率高、发病机制复杂、治疗难度大、预后极差等特点［8］。治疗的关键是早期诊断、积极预防、控制疾病诱因。治疗的主要原则是提供衰竭器官的功能支持、促进肝功能恢复。人工肝是目前其他方案无法替代的治疗手段［9-10］，已被纳入肝衰竭治疗的指南中。血清TBil是反映肝功能损害严重程度的可靠指标，INR是肝衰竭早期预警和病情进展的敏感指标，与患者预后显著相关［11-13］。杨景毅等［14］研究表明INR和TBil是影响ACLF患者预后的独立危险因素。本研究结果显示：3组患者治疗前TBil分别由（322.30±149.56）μmol/L、（262.28±113.56）μmol/L、（311.16±128.73）μmol/L下降至治疗后（197.25±103.20）μmol/L、（159.23±78.79）μmol/L、（183.96±96.01）μmol/L，ALT、AST亦呈不同程度下降，肝功能好转，INR分别由治疗前2.11±0.71、1.98±0.46、2.11±0.77降至治疗后1.91±0.66、1.86±0.56、1.89±0.80，且均有统计学差异（P值均<0.05）。说明人工肝治疗能改善ACLF患者的肝功能及INR。3组治疗后约88.74%患者乏力、腹胀等临床症状呈不同程度的改善。在前期的临床研究［7，15-16］中，使用不同模式人工肝治疗重型肝炎亦取得了较好的临床效果，包括肝功能好转、凝血功能改善、临床症状减轻。
ACLF的发病机制尚不明确，近年来大量研究证据表明全身炎症反应是驱动肝病进展的重要因素。Moreau等［17］研究显示，ACLF患者体内白细胞和急性反应时相蛋白水平更高；Clària等［18］研究表明，ACLF患者比非ACLF患者有着更高的炎症相关细胞因子和全身氧化应激标志物。人工肝支持系统的主要作用是为患者提供暂时的代谢支持，清除血液中过多的胆红素、内毒素、致炎因子等，维持内环境的稳定，为肝细胞再生创造条件。其原理是将患者的血液引出，通过膜型血浆分离器将血液的有形成分（血细胞）和血浆分离，分离出的血浆按20％～30％的比例丢弃，再补充等量正常人的新鲜血浆并和患者的血细胞混合后由静脉输入，形成循环回路。由于血浆分离的效果受膜的性质、血浆成分、血流量、跨膜压及滤过分数的影响，故选用制膜材料和制膜工艺不同的膜型血浆分离器，所带来的临床效果也不尽相同。如使用聚乙烯磺基制备的Plasman 06膜型血浆分离器进行血浆置换治疗，治疗后血小板平均下降22.17×109/L［4］。因此，当血小板过低时，血浆置换后有增加出血的危险。人工肝治疗一般要求患者血小板计数在50×109/L以上，而有些肝衰竭患者因有长期肝病史，或伴脾功能亢进，或在肝硬化基础上发生，常伴有明显的血小板减少，血小板计数常在50×109/L以下，当病情需要人工肝治疗时则会受到一定的限制。罗玲等［19］研究表明人工肝血浆置换治疗中Evacure-4A膜型血浆分离器对血小板无明显影响。王璐等［20］研究证实人工肝治疗对血小板计数的影响是暂时性的，基线血小板计数>80.5×109/L是降低人工肝治疗后出血风险的最佳界值。本研究根据血小板计数将其分为3组，据患者病情分别选择PP+PE、DPMAS+PE、PBA+PE不同模式人工肝，均使用Evacure-4A膜型选择性血浆分离器，结果显示，B、C组血小板计数治疗前后比较均有统计学差异（P值均<0.001）。3组患者治疗过程中均未发生出血，不良反应发生率无统计学差异（P>0.05）。说明Evacure-4A膜型选择性血浆分离器对血小板影响较小，对血小板明显低下ACLF患者行人工肝治疗是安全的。
多因素分析发现血小板是慢性肝病患者的独立预后因素之一［21］。肝病患者引起血小板减少的因素是多种多样的。有研究［22］表明，肝硬化和肝衰竭患者血小板减少的原因主要是肝脏凝血机制异常引起肝内弥散性血管内凝血形成，导致血小板的凝血消耗所致。许姗姗等［23］研究表明，ACLF患者基线血小板显著低于正常血小板的范围，血小板变化可能参与了ACLF的发生发展，其原因可能是参与肝脏微循环消耗所致。本研究中302例ACLF患者血小板计数呈不同程度的下降，其机制有待进一步探讨。人工肝治疗对肝衰竭患者的血细胞有一定影响，尤其是对PLT的破坏。选用对血小板影响较小的Evacure-4A膜型选择性血浆分离器，减少了人工肝治疗过程中对血小板的破坏，尤其对血小板计数在25×109/L～50×109/L分层组治疗前后无明显差异，亦未发生出血，在一定程度上拓宽了治疗的条件，对降低不良反应发生率及提高患者的抢救成功率有重要意义，值得临床进一步推广应用。
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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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