修回日期: 2018-11-05
接受日期: 2018-11-15
在线出版日期: 2019-01-28
尽管近年来非酒精性脂肪肝(non-alcoholic fatty liver disease, NAFLD)的发病率在不断增加, 但是临床上仍缺乏公认的对NAFLD具有明显疗效的药物干预. 目前治疗NAFLD的主要方法是改变生活方式, 包括减肥和饮食调整. 然而, 这些治疗方法有时效果不佳, 尤其是对于非酒精性脂肪性肝炎(non-alcoholic steatohepatitis, NASH)的患者. 针对NAFLD的发病机制, 多种药物已被用于治疗NASH的临床试验, 部分展示了一定的临床价值. 目前, 欧美一些指南只推荐作为胰岛素增敏剂的吡格列酮和作为抗氧化剂的维生素E用于治疗NASH. 包括他汀类药物和贝特类药物的降脂药、己酮可可碱、血管紧张素受体阻断剂、熊去氧胆酸、益生菌和合生素是目前潜在治疗NASH的有益药物, 但来源于小样本量的随机双盲对照临床试验所获得的证据强度尚不足以至得到监管部门的批准. 一些新兴的药物正在开发用于治疗NASH, 例如奥贝胆酸、利拉鲁肽、elafibranor、cenicriviroc、aramchol、成纤维细胞生长因子(FGF)-21或FGF-19类似物、IMM-124e、奥利司他、solithromycin, simtuzumab和GR-MD-02、remogliflozin etabonate、lipaglyn、SHP626、PXS4728A等已在临床试验中测试或正在完成试验. 因此, 本文主要针对NAFLD的肝脏脂肪蓄积和由此产生的代谢应激、氧化应激、肠道微生物紊乱、纤维化进程等药物治疗学前沿进展进行综述.
核心提要: 目前已经被应用于治疗非酒精性脂肪肝(non-alcoholic fatty liver disease, NAFLD)的药物在临床疗效方面仍存在较多的争议, 需要更多规范、大样本的临床实验以及真实世界研究探索其治疗NAFLD的可靠性, 从而改变新的适应症获得批准. 新兴的药物大多从机制靶点入手, 虽有很多令人兴奋的动物实验结果, 但部分在临床上难以重现, 或虽已获一些临床实验数据支持, 但仍需要更进一步的有效性和安全性研究以支撑其最终上市应用于NAFLD的治疗.
引文著录: 张姗姗, 王来友. 非酒精性脂肪性肝病药物治疗学前沿与展望. 世界华人消化杂志 2019; 27(2): 73-79
Revised: November 5, 2018
Accepted: November 15, 2018
Published online: January 28, 2019
Although the prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing in recent years, acknowledged pharmacological intervention with obvious effectiveness specifically for NAFLD is still absent clinically. Currently, the mainstay treatment for patients suffering from NAFLD is life style modification including weight reduction and dietary regimen. However, sometimes these modalities do not work well, especially for patients with non-alcoholic steatohepatitis (NASH). Several medications, mainly targeting disease pathogenesis of NAFLD, have been investigated in clinical trials for treatment of NASH with promising results. At present, only pioglitazone acting as an insulin sensitizing agent and vitamin E as an anti-oxidant have been recommended for treatment of NASH by the American Association for the study of liver disease and European Association for study of the Liver. Lipid lowering agents including statins and fibrates, pentoxifylline, angiotensin receptor blockers, ursodeoxycholic acid, probiotics and synbiotics are current agents with beneficial effects for treatment of NASH but have not been approved yet due to the lack of strong evidence from available RCT trials in small populations. Several emerging medications aiming to treat NASH, such as obeticholic acid, liraglutide, elafibranor, cenicriviroc, aramchol, fibroblast growth factor (FGF)-21 or FGF-19 analogues, IMM-124e, orlistat, solithromycin, simtuzumab, GR-MD-02, remogliflozin etabonate, lipaglyn, SHP626 and PXS4728A, have been tested in clinical trials or are completing trials. Herein, current and upcoming pharmacotherapies targeting four main pathogenesis pathways including hepatic fat accumulation and the resultant metabolic stress, oxidative stress, involved gut microbiome disorders, and fibrotic process are reviewed.
- Citation: Zhang SS, Wang LY. Frontiers and prospects of pharmacotherapy for non-alcoholic fatty liver disease. Shijie Huaren Xiaohua Zazhi 2019; 27(2): 73-79
- URL: https://www.wjgnet.com/1009-3079/full/v27/i2/73.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v27.i2.73
脂肪性肝病(fatty liver disease, FLD), 简称为脂肪肝, 是近年来被人们逐渐认识的一种多因素导致的肝细胞内脂肪蓄积过多的慢性进展性病变, 包括单纯性脂肪肝和由其演变发生的脂肪性肝炎、肝纤维化、肝硬化及肝癌, 临床上根据有无过量饮酒史分为酒精性脂肪肝和(alcoholic fatty liver disease, AFLD)和非酒精性脂肪肝(non-alcoholic fatty liver disease, NAFLD), 而后者占到FLD的70%-90%[1,2]. NAFLD不但是肝硬化等的重要前期病变, 而且是代谢紊乱动脉硬化性心脑血管疾病的独立高危因素[3]. 随着社会发展和生活方式的变化, 环境污染、药物滥用以及酗酒问题的广泛存在, 脂肪肝现已成为世界上最普遍的疾病之一, 我国人群中发生率已达15%-20%, 并且逐年升高[3-5]. 目前, 随着肥胖患病率的不断增加, 以及2型糖尿病、血脂异常及相关代谢综合征的相继增多, NAFLD正成为中国继慢性乙型肝炎病毒感染后的又一个新的重大课题, 也已成为当代医学领域的新挑战.
鉴于NAFLD为代谢综合征的重要组分并且大多数患者肝组织学改变处于NAFL阶段, 治疗NAFLD的首要目标是改善胰岛素抵抗(insulin resistance, IR), 防治代谢综合征及其相关终末期器官病变, 从而改善患者生活质量和延长存活时间; 次要目标为减少肝脏脂肪沉积并避免因"二次打击"而导致NASH和肝功能失代偿, NASH患者则需阻止肝病进展, 减少或防止肝硬化、肝癌及其并发症的发生[6,7].
NAFLD是遗传-环境-代谢应激相关性疾病, 与IR及其相关代谢综合征和遗传易感性密切相关. "二次打击"学说基础上NAFLD发病的"四部模型"似可解释其复杂的发病机制. 初次打击主要为IR, 原发性NAFLD几乎普遍存在IR现象, 后者通过促使外周脂解增加和高胰岛素血症引起肝细胞脂肪蓄积, 并诱致对内、外源性损害因子敏感性增高; 二次打击主要为增多的反应性氧化代谢产物、脂肪细胞因子、肠应激和肠细菌内毒素等各种损害因子诱导活化UCP-2、Fas配体等, 进而引起脂肪变性的肝细胞发生炎症、坏死, 炎症的持续存在启动肝脏损伤的修复效应, 导致肝纤维化的发生和发展. 继发的微循环障碍和慢性间隙性缺氧可进一步加剧肝损伤, 并影响肝小叶结构, 从而最终发生肝硬化. 伴随的肝细胞增生、异型变和凋亡不足则可能与肝癌的发生有关. 肠道菌群改变、小肠细菌过度生长、肠源性内毒素血症、肝毒药物、肝脏CYP2E1表达增强, 以及肝组织铁负荷过重和遗传易感因素, 均可作为二次或三次打击促进NASH的发生和发展.
在"二次打击"学说基础上, Wanless等通过大量活检病理研究, 提出NAFLD发病的"四步模型". 第一步: 由于IR引起脂肪变性; 第二步: 由于细胞内脂质毒性或脂质过氧化导致的炎症坏死; 第三步: 大量脂质从坏死的肝细胞释放到间质组织, 引起对肝静脉直接损伤和炎症损伤; 第四步: 是静脉堵塞并伴随实质的塌陷、纤维分割的形成和硬化[6,8].
在"二次打击"学说基础上的NAFLD发病"四步模型"曾是NASH发病机制的经典阐释, 而如今这种观点被多数学者认为已经过时, 目前有很多分子通路阐释NAFLD的发展. 近年来PPARs (peroxisome proliferator-activated receptor)、FXRs (Farnesoid X receptor)、LXRs (Liver X recpetor)、PXR (Pregnane X receptor)等[9]代谢性核受体的发现与功能研究为阐释NAFLD的发病机制提供了新的可能. 另外, NAFLD的发生发展的多个易感基因也被引起重视. 比如, PNPLA3(Patatin-like phospholipase domain containing-3)和跨膜转运蛋白编码基因TM6SF2(Trans-membrane 6 superfamily member 2), 它们的功能丧失性突变会导致肝细胞损伤或脂肪性肝炎[10,11], 是NAFLD的重要易感基因. 还有研究表明甲状腺激素水平异常和维生素D缺乏也可能是引发NAFLD的病因[12]. 通过肠道菌群操控NAFLD的预防与治疗也正在蓬勃开展, 但尚未形成对NAFLD病理机制的确切阐释.
强化改变生活方式的非药物治疗, 可降低NAFLD儿童的血清转氨酶水平并改善其肝组织学改变, 为此一般推荐作为NAFLD儿童的一线治疗措施. 伴或不伴体育锻炼的低热量饮食减轻体重, 通常可以减少肝脏脂肪沉积. 有证据表明, 体重降低7%-10%, NAFLD的活动分数(NAFLD activity score, NAS)可以得到明显改善[13]. 通过健康宣教纠正不良生活方式和行为, 参照代谢综合征的治疗意见, 推荐中等强度的热量限制, 肥胖成人每日热量摄入需减少2092-4184 KJ(500-1000千卡); 改变饮食组分, 建议低糖低脂的平衡饮食, 减少含蔗糖饮料以及饱和脂肪和反式脂肪的摄入并增加膳食纤维含量; 中等量有氧运动, 每周四次以上, 累计锻炼时间至少150 min. 通常需要有一定程度的体重下降才能有益于包括NAFLD在内的代谢综合征组分的康复.
值得注意的是, NAFLD患者特别是NASH患者应避免体重急剧下降, 禁用极低热卡饮食和空-回场短路手术减肥, 避免小肠细菌过度生长, 避免接触肝毒物质, 慎重使用可能有肝毒性的中西药物和保健品, 严禁过量饮酒.
对于控制饮食和增强体育锻炼难以改善的NASH或者肝硬化等NAFLD患者, 则需要药物治疗, 如二甲双胍、胰岛素增敏剂噻唑烷二酮类药物, 降血脂药, 维生素E 及熊去氧胆酸(UDCA)等.
美国肝病研究协会(American Association for the study of liver disease, AASLD)指南显示NAFLD患者发生心血管类疾病的风险较高. 因此, 他汀被用于治疗NAFLD合并高血脂症, 他汀类药物也可用于非失代偿性肝硬化的NASH患者. 吡格列酮和维生素E可用于经活检确诊的NASH并可改善肝脏组织学. 维生素E不应该用于患有糖尿病的NASH, NASH肝硬化或者基因型肝硬化[14].
二甲双胍通过减少肝糖异生和甘油三酯的产生来治疗2型糖尿[15]. 但一些动物实验、儿科和成人实验结果显示二甲双胍并不能改善NAFLD的组织学指标[16]. 目前AASLD和欧洲肝脏研究协会(European Association for study of the Liver, EASL)指南不建议使用二甲双胍治疗NAFLD [17,18].
UDCA有抗炎和抗凋亡特性, 其阻止NAFLD进展的效应已经被一些研究证实[19]. 一项随机安慰剂对照试验结果显示, 高剂量UDCA能有效改善经肝活检确诊的NASH患者血清转氨酶及肝纤维化标志水平[20]. 一个系统回顾实验显示UDCA能有效的改善NASH患者的症状[21]. 然而, 由于缺乏设计较好的大型随机试验对照试验和缺乏关于组织学的证据, UDCA对NAFLD有效性并未得到国际上的认可.
总的来说, 目前尚未证实任何药物对NAFLD是有益的, 所以也没有任何药物获得FDA或EMEA批准. 抗氧化剂和细胞保护剂虽然曾经试用于治疗NAFLD, 包括维生素E、维生素C、谷胱甘肽、甜菜碱、乙酰半胱氨酸、S-腺苷-L-甲硫胺酸和UDCA等, 但近期循证医学分析表明这些药物在确切的随机研究中没有一个显示出明显的益处[22,23]. 因此, 寻求NAFLD的防治靶点从而发现新药迫在眉睫. 靶点的确认工作除要证实其与疾病的相关性外, 还有一个标准是发现特异作用于该靶点的化学分子或抗体分子[24], NAFLD尤其是NASH的新药研发是近几年兴起的热点, 生物医药的研究同仁和制药工业界近年来在这方面做了大量卓有成效的工作, 涌现了一些新兴的极具前景的治疗药物.
在治疗NAFLD的新兴化学实体中, 奥贝胆酸(obeticholic acid ,OCA)较其他正在研发的药物有更多的临床实验依据支持. FXR在肝脏中表达并且参与胆汁酸的合成. 胆汁酸与FXR的结合可导致胆汁酸合成的下调, 肝脂肪生成、肝糖异生和改善外周血胰岛素敏感性[25]. FXR激活可防止大鼠体重增加, 减少肝脏/肌肉脂肪沉积和肝脏脂肪变性[26]. FXR激动剂OCA是一种合成的亲脂性胆汁酸, 已被证明能够减少小鼠的肝脂肪变性[27]. 并且在RDBPCT FLINT 研究中, 有283个经活检确诊的不带有肝硬化的NAFLD患者, 随机接受长达72 wk的OCA(25 mg/d)或安慰剂治疗[28]. 研究的主要终点是组织学改善, 定义为NAS减少2个点, 纤维变性没有恶化. 在接受OCA治疗的患者中, 有45%的患者组织学得到改善, 相比之下接受安慰剂治疗的人中有21%的患者组织学得到改善. 随机对照实验的结果显示实验组较对照组NAS评分和纤维化水平都有所下降. 但OCA也会带来总胆固醇升高、低密度胆固醇升高、高密度胆固醇降低以及瘙痒的不良反应.
利拉鲁肽(liraglutide)是一种内分泌模拟物, 它作为胰高血糖素样肽-1受体的激动剂主要用于Ⅱ型糖尿病的治疗[29]. 在动物实验中, 利拉鲁肽可改善高脂饲料诱导的小鼠NAFLD模型组织学病变. 在Wistar大鼠模型中, 利拉鲁肽可通过激活蛋白激酶改善胰岛素抵抗和肝脂肪变性[30]. 但在一项临床随机试验中, NASH患者同服利拉鲁肽和胰岛素改善血糖和肝脂肪变性的作用较单独服用胰岛素没有统计学上的差异[31].
Aramchol是由胆酸和花生四烯酸两个组分组成的共轭分子, 主要用于治疗胆固醇结石[32]. Aramchol是硬脂酰辅酶A去饱和酶(Stearoyl CoA desaturase , SCD1)抑制剂, 与脂质代谢和肝胰岛素抵抗密切有关[32,33]. NAFLD患者口服100或300毫克aramchol治疗3 mo后, 肝脂肪含量虽有所降低, 但肝酶却没有明显改善[34].
PPAR有三个亚型, α, β/γ和δ. PPARα表达于脂肪组织、肝脏、骨骼肌、心脏并参与调节脂质和葡萄糖代谢[35]. Elafibranor是一个双重的 PPAR α/δ激动剂, 经过动物研究验证可以调节脂质平衡和减少肝脂肪生成[36]. 在随机交叉临床试验中, 肥胖患者每天服用80毫克Elafibranor, 结果显示可以改善肝脏和外周胰岛素抵抗[37]. 最近的一项随机临床试验表明, 与安慰剂相比, 每天口服120 mg Elafibranor可改善NASH患者的肝脂肪变性和纤维化, 也可改善全身炎症、糖脂代谢紊乱及血清肝转氨酶水平[38]. Elafibranor可能将成为NASH患者治疗极有前途的候选药物, 目前正在进行Ⅲ期临床试验.
靶向凋亡和TNFα通路也是NAFLD药物开发热点. Emricasan是不可逆pan-caspase抑制剂, 这使其成为治疗与细胞凋亡相关肝病的潜在药物[39]. Emricasan已经被证明可以降低慢性丙型肝炎患者的转氨酶水平, 能显著改善高脂饮食小鼠的炎症、肝细胞损伤和纤维化, 但不影响肝脏脂肪蓄积或代谢综合征特征[40-42]. 在一个28 d的Ⅱ期RDBPCT临床试验中, 38个非肝硬化性NAFLD患者随机分成Emricasa实验组(每日两次每次25 mg)和安慰剂对照组, Emricasa组较安慰剂组显著降低了血清转氨酶, 且肝脏组织学病变也得到了改善[43].
NASH患者通常过度表达炎性趋化因子CCL2(MCP-1)和CCL5(RANTES), 而这通常进一步导致其肝脏炎症和纤维性恶化[44]. Cenicriviroc是可口服的CCL2和CCL5的受体拮抗剂. cenicriviroc的抗纤维化作用已经在硫代乙酰胺诱导的小鼠模型中得到验证[45]. 目前正在进行用于NASH成人患者的临床试验疗效评估[46], 在香港等地区已进入Ⅲ期临床试验阶段.
其它尚有靶向激素信号通路的成纤维细胞生长因子(FGF)-21或FGF-19类似物BMS-986036与NGM-282, 从脂多糖免疫过的牛初乳提取出的富含IgG的提取物并作用于肠道微生物的IMM-124e、奥利司他、第四代大环内酯类抗生素solithromycin, 免疫调节剂simtuzumab和半乳糖凝结素抑制剂GR-MD-02、钠-葡萄糖协同转运蛋白-2抑制剂remogliflozin etabonate、用于他汀类药物无法控制的Ⅱ型糖尿病血脂异常或高甘油三脂血症的Glitazar类药物lipaglyn、顶膜钠依赖性胆汁酸运转体(Apical Sodium-dependent Bile Acid Transporter, ASBT)的抑制剂SHP626、选择性的VAP-1(vascular adhesion protein 1)不可逆抑制剂PXS-4728A等正在开展临床Ⅰ-Ⅲ期实验, 部分治疗NASH的药物有望成为重磅药物[47](表1).
| 药物 | 作用机制 | 效应 | 当前状态 |
| 吡格列酮 | PPARγ 激动剂 | 改善脂肪变性、小叶炎症和气球样肿胀 | AASLD/EASL推荐 |
| 维生素E | 抗氧化剂 | 改善肝细胞气球样肿胀 | AASLD/EASL推荐 |
| 二甲双胍 | 缓解胰岛素抵抗 | 无明显组织学获益 | 证据不充分, 尚不推荐 |
| 己酮可可碱 | 抑制TNFα和抗氧化 | 改善炎症和气球样肿胀 | 超适应症证据不充分, 尚不推荐 |
| 熊去氧胆酸 | 预防凋亡和炎症 | 缺乏质量较高的临床研究数据 | 超适应症证据不充分, 尚不推荐 |
| 洛沙坦 | 血管紧张素Ⅱ受体抑制剂 | 改善脂肪变性、小叶炎症和气球样肿胀及纤维化 | 超适应症证据不充分, 尚不推荐 |
| 贝特类 | PPARα激动剂 | 改善肝细胞气球样肿胀 | 超适应症证据不充分, 尚不推荐 |
| 他汀类 | HMG-CoA还原酶抑制剂 | 无明显肝组织学获益 | 超适应症证据不充分, 尚不推荐 |
| 依泽麦布 | 抑制胆固醇吸收 | 改善肝细胞气球样肿胀 | 超适应症证据不充分, 尚不推荐 |
| 奥贝胆酸 | FXR激动剂 | 改善脂肪变性、小叶炎症和气球样肿胀及纤维化 | 超适应症临床实验补充中, 暂未获推荐 |
| Orlistat | 肠脂酶抑制剂 | 改善肝组织学病变 | 超适应症应用Ⅱ期临床试验证据不充分, 尚不推荐 |
| 利拉鲁肽 | GLP-1激动剂 | 改善脂肪变性和肝细胞气球样肿胀 | 超适应症临床试验中 |
| Saroglitazar | PPARα/γ激动剂 | 改善肝脏组织学病变 | 超适应症临床试验中 |
| remogliflozin etabonate | SGLT2抑制剂 | 有效临床数据缺乏 | 超适应症临床试验中 |
| Aramchol | SCD1抑制剂 | 缺乏临床实验数据 | 已获积极临床Ⅱb期数据 |
| Elafibranor | PPARα/δ激动剂 | 脂肪变性和纤维化 | 临床Ⅲ期试验中 |
| Emricasan | Caspase 抑制剂 | 降低血清转氨酶, 改善肝脏组织学病变 | 已获积极临床Ⅱ期数据 |
| Cenicriviroc | CCR2/CCR5拮抗剂 | 改善IR, 降低血清转氨酶, 改善肝脏组织学病变 | 临床Ⅲ期试验中 |
| Selonsertib | ASK1抑制剂 | 改善肝脏组织学病变 | 已获积极临床Ⅱ期数据 |
| NGM282 | FGF-19类似物 | 降低血清转氨酶, 改善肝脏组织学病变 | 已完成临床Ⅱ期试验中 |
| Simtuzumab | LOXL2抗体 | 对肝组织学病变无改善 | 临床Ⅱ期试验已完成 |
| GR-MD-02 | Galectin-3抑制剂 | 对肝脏炎症指标与纤维化无改善 | 临床Ⅱ期试验已完成 |
| Volixibat | ASBT抑制剂 | 临床数据缺乏 | 临床Ⅱ期试验中 |
| PXS-4728A | VAP-1抑制剂 | 临床数据缺乏 | 临床Ⅱ期试验中 |
目前已经被应用于治疗NAFLD的药物在临床疗效方面仍存在较多的争议, 需要更多规范、大样本的临床实验以及真实世界研究探索其治疗NAFLD的可靠性, 从而改变新的适应症获得批准. 新兴的药物大多从机制靶点入手, 虽有很多令人兴奋的动物实验结果, 但部分在临床上难以重现, 或虽已获一些临床实验数据支持, 但仍需要更进一步的有效性和安全性研究以支撑其最终上市应用于NAFLD的治疗.
虽然近几年NAFLD药物治疗学以及以药探索发病机制的研究取得了一定的进展, 但仍有诸多关键科学问题尚未解决. 比如, 确定相关发病诱导因素如何引发炎症, 如何加速单纯脂肪性肝病转化为NASH; 肝脏炎症反应是疾病发展的驱动因素还是结果反应; 尽管肝脏炎症促使肝纤维化得到研究结果验证, 肝病疾病死亡率与肝脏炎症的关系还有待进一步确认. 目前研究成果依然没有可行的方法在临床上逆转疾病进程. 由于NAFLD的复杂性, 每个患者都可能携带不同的诱发因素(饮食、代谢表型、基因等), 如何针对不通人群(伴有超重、肥胖、糖尿病或其他代谢病)进行不同程度的区分是将来的研究关键, 而这种关键需要系统性研究方法(整合代谢组学、蛋白组学、表型组学等)去揭示NAFLD的分子特征谱, 这些方法可以促进生物标记物发现并有助于提供更精准的药物治疗学方法, 并有助于改进目前的药物疗效评价的临床终点检测指标. 另外, 研发初期积极探索有效合理联合用药也应该引起重视.
学科分类: 胃肠病学和肝病学
手稿来源地: 广东省
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编辑:崔丽君 电编:张砚梁
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