非酒精性脂肪性肝病的治疗进展

王全楚，步子恒

解放军第153中心医院感染科，河南 郑州 450042

非酒精性脂肪性肝病的治疗进展

王全楚，步子恒

解放军第153中心医院感染科，河南 郑州 450042

非酒精性脂肪性肝病(non-alcoholic fatty liver disease，NAFLD)的治疗主要分为基础治疗、药物治疗和外科手术治疗。其中，基础治疗主要是通过行为、饮食和运动治疗来缓解NAFLD的发生和发展，药物治疗多是针对疾病不同病理环节而选取相应的药物，主要包括改善胰岛素抵抗(insulin resistance,IR)、对抗脂质过氧化损伤、保护肝细胞及纠正血脂紊乱等,外科手术治疗包括减肥手术和肝移植手术。本文对NAFLD治疗的相关进展作一概述。

非酒精性脂肪性肝病；治疗；进展

非酒精性脂肪性肝病(non-alcoholic fatty liver disease，NAFLD)已成为21世纪全球重要的公共健康问题和常见疾病。其中非酒精性脂肪性肝炎(non-alcoholic steatohepatitis,NASH)容易发展为肝硬化[1]。事实上，NASH是肝移植的第三大适应证，并且预计在十年后将会成为肝移植最主要的原因[2],现在迫切需要寻找有效的治疗方法。本文结合国内外资料，对NAFLD的治疗进展作一概述。

1 基础治疗

NAFLD的发生、发展与不良的生活习惯、嗜好和饮食有关。行为治疗主要是通过改善患者不良生活习惯，纠正不合理的饮食行为[3]。有研究[4]显示，不同饮食结构的同年龄组人群，脂肪肝和高脂血症发病率明显不同，长期进食深海鱼类，脂肪肝、高脂血症的发病明显低于普通饮食。事实证明，通过优化饮食结构，调整饮食范围，能够改善胰岛素抵抗(insulin resistance,IR)和高脂血症，进而减轻肝脏负担，缓解NAFLD的发生和发展[5]。运动治疗主要通过提高胰岛素敏感性、降低游离脂肪酸(FFA)的浓度及抑制脂肪细胞和肌细胞TNF-α的超表达，从而改善IR。步行是NAFLD患者容易接受的治疗方式[6]。

2 药物治疗

2.1胰岛素增敏剂盐酸二甲双胍和噻唑烷二酮类(TZDs)可以作为改善NAFLD患者脂肪组织胰岛素敏感性的药物。最近的一项数据分析显示，尽管使用二甲双胍后体质量和转氨酶下降，但是在组织学方面并无明显改善[7]。而TZDs可激活特异性过氧化物酶体增殖物激活受体(PPARs)，从而改善胰岛素敏感性和脂质代谢。虽然有研究显示，TZDs对改善组织学有益，但要注意长期使用有致心力衰竭、膀胱癌和骨质丢失的安全性问题[8]。尽管如此，胰岛素信号传导的调节仍然是有吸引力的治疗方向，但是可能需要靶向PPARs甚至TZDs的其他药物，独立于PPARs激活作用，例如Blx-1002。在动物模型中，Blx-1002联合盐酸二甲双胍可减少肝脂肪变性，改善血脂异常和降低血糖[9]。

2.2抗氧化剂维生素E是治疗NAFLD中常用的抗氧化剂，在一组多中心对照试验中，患者服用维生素E的剂量为800 IU/d，持续96周后发现，其中约一半患者获得组织学上的改善，但氧化应激改善不明显[10]。水飞蓟素作为NAFLD患者潜在治疗的植物提取物，能够改善肝星状细胞活化及减少TNF-α的释放[11]。然而，迄今为止仅有转氨酶改善的数据，而缺乏肝活检组织学改善的可靠数据[12]。在一项非安慰剂对照的儿科研究[13]中，对服用半胱胺治疗的患者随访24周后发现转氨酶有改善。核红细胞2相关因子(Nrf2)是另一种抗氧化剂，与单脂肪变性的对照动物相比，高脂饮食的Nrf2基因敲除小鼠发展为NASH可能性增加[14]。Nrf2激活剂—奥替普拉可减少动物模型中的NASH的组织学进展[15]，在临床研究中却未显示治疗24周后组织学改善的迹象[16]。

2.3抗纤维化药奥贝胆酸(OCA)是胆固醇X受体(FXR)的天然激动剂的半合成衍生物，参与调节葡萄糖和脂质代谢和免疫应答的核激素受体，FXR的活化促进动物模型中肝纤维化的改善[17-18]。在包括NAFLD轻度至中度肝纤维化的2型糖尿病患者2期试验中，25 mg OCA组平均肝纤维化评分(NAFLDFS)显著降低[19]。已酮可可碱通过减少TNF-α的转录来减少促炎性细胞因子的生成[20]。由于酒精性肝炎和NASH均出现TNF-α水平的升高，一项随机对照试验[21]表明，受试者服用已酮可可碱1 200 mg/d持续1年后，与对照组相比,脂肪变性和转氨酶水平有改善的趋势。

2.4降脂药研究发现，他汀类药物在NAFLD患者中使用是安全的[22]，而且他汀类药物的使用与肝活检中脂肪变性的减少有关[23]。然而也有研究[24]发现，他汀类药物对转氨酶或组织学改善作用不明显。依泽替米贝可以抑制胃肠道中胆固醇的吸收，用于他汀类控制不佳血脂异常者的辅助治疗[25]。一项RCT研究[26]显示,使用6个月的依泽替米贝(10 mg/d)纤维化分期评分均有所改善。二酰基甘油酰基转移酶(DGAT)是催化甘油三酯合成中最后步骤的酶。在高脂饮食的动物中，DGAT2基因敲除后动物肝内脂质量下降，脂肪酸氧化增强和肝胰岛素敏感性改善[27]。但也有可能会增加氧化应激、炎症和纤维化，提示甘油三酯积累可能是一种肝脏的自我保护机制[28]。

2.5咖啡最新研究[29]发现，咖啡在NAFLD治疗中除了能够降低脂肪变性的程度，还可以使实验室检测指标降低并使促炎因子减轻。同时有研究[30]发现，咖啡的摄入不仅可以减轻NASH患者纤维化，还可以减轻重症肥胖患者肝纤维化程度。尽管效果还需进一步证明，但是从动物模型实验和临床数据来看，咖啡确实对NAFLD患者有益。

3 手术治疗

3.1减肥手术75%～100%的肥胖患者都患有NAFLD。一项前瞻性研究[31]显示，减肥手术对肝功能和肝脂肪变性有着积极的影响。但对肝炎和肝纤维化的远期影响尚不明确。目前最常用的减肥手术是袖状胃切除术和胃旁路手术，这两种术式效果最佳，并且经过适当选择能够降低患者术后风险。

3.2肝移植手术肝移植能够给终末期NAFLD患者提供更多益处，但目前的关注点主要集中在术后NAFLD的复发和心血管疾病、高血压和糖尿病的发生[32]。免疫抑制剂疗法虽不会促进NAFLD的发展，但持久和多变的潜在代谢综合征使得他们更易发生心血管疾病、高血压和糖尿病及肾功能衰竭等并发症。所以，代谢综合征尤其是糖尿病和肝病复发是NAFLD患者术后应当格外关注的[33]。对列入移植患者合并代谢综合征的可接受程度目前仍不确定。术前对高脂高糖食品和饮料的严格限制，糖尿病和血压的严密控制等管理措施是获得移植后良好生存率和改善生活质量的关键因素[34]。

随着对NAFLD发病机制研究的深入，相应的治疗方法和手段也在逐步完善，但基础治疗仍是治疗NAFLD的基石，药物治疗更多地倾向个体化用药，针对不同的人群采取不同的药物治疗，外科手术治疗是无禁忌证病态肥胖NAFLD患者和终末期NAFLD患者最好、也是最有效的治疗手段。总之，对NAFLD的研究进展为我们防治该病提供了新的选择和希望，但问题最终的解决仍依赖于发病机制的进一步研究和阐明。

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Thetherapeuticprogressofnon-alcoholicfattyliverdisease

WANG Quanchu, BU Ziheng

Department of Infectious Diseases, the 153 Hospital of PLA, Zhengzhou 450042, China

The treatments of non-alcoholic fatty liver disease (NAFLD) mainly include basic treatment, drug therapy and surgical treatment. The basic treatment is mainly through behavior, diet and exercise therapy to alleviate the occurrence and development of NAFLD. Drug therapy is mainly aimed at selecting the appropriate drugs to different pathological aspects of the disease, and the drugs mainly include: improving insulin resistance (IR) drugs, antagonizing lipid peroxidation damage drugs, protecting liver cells drugs and rectifying blood lipid disorders drugs. Surgical treatments mainly involve bariatric surgery and liver transplantation. This article summarized the progress of NAFLD therapy to offer new options for the prevention and treatment of the disease.

Non-alcoholic fatty liver disease; Therapy; Progress

R575.5

A

1006-5709(2017)10-1091-03

2017-08-15

王全楚，主任医师，硕士生导师，研究方向：慢性肝病的临床诊治。E-mail： a414073680@163.com

10.3969/j.issn.1006-5709.2017.10.004