非酒精性脂肪性肝病的治療進(jìn)展

王全楚，步子恒

解放軍第153中心醫(yī)院感染科，河南 鄭州 450042

非酒精性脂肪性肝病的治療進(jìn)展

王全楚，步子恒

解放軍第153中心醫(yī)院感染科，河南 鄭州 450042

非酒精性脂肪性肝病(non-alcoholic fatty liver disease，NAFLD)的治療主要分為基礎(chǔ)治療、藥物治療和外科手術(shù)治療。其中，基礎(chǔ)治療主要是通過行為、飲食和運(yùn)動治療來緩解NAFLD的發(fā)生和發(fā)展，藥物治療多是針對疾病不同病理環(huán)節(jié)而選取相應(yīng)的藥物，主要包括改善胰島素抵抗(insulin resistance,IR)、對抗脂質(zhì)過氧化損傷、保護(hù)肝細(xì)胞及糾正血脂紊亂等,外科手術(shù)治療包括減肥手術(shù)和肝移植手術(shù)。本文對NAFLD治療的相關(guān)進(jìn)展作一概述。

非酒精性脂肪性肝??；治療；進(jìn)展

非酒精性脂肪性肝病(non-alcoholic fatty liver disease，NAFLD)已成為21世紀(jì)全球重要的公共健康問題和常見疾病。其中非酒精性脂肪性肝炎(non-alcoholic steatohepatitis,NASH)容易發(fā)展為肝硬化[1]。事實(shí)上，NASH是肝移植的第三大適應(yīng)證，并且預(yù)計(jì)在十年后將會成為肝移植最主要的原因[2],現(xiàn)在迫切需要尋找有效的治療方法。本文結(jié)合國內(nèi)外資料，對NAFLD的治療進(jìn)展作一概述。

1 基礎(chǔ)治療

NAFLD的發(fā)生、發(fā)展與不良的生活習(xí)慣、嗜好和飲食有關(guān)。行為治療主要是通過改善患者不良生活習(xí)慣，糾正不合理的飲食行為[3]。有研究[4]顯示，不同飲食結(jié)構(gòu)的同年齡組人群，脂肪肝和高脂血癥發(fā)病率明顯不同，長期進(jìn)食深海魚類，脂肪肝、高脂血癥的發(fā)病明顯低于普通飲食。事實(shí)證明，通過優(yōu)化飲食結(jié)構(gòu)，調(diào)整飲食范圍，能夠改善胰島素抵抗(insulin resistance,IR)和高脂血癥，進(jìn)而減輕肝臟負(fù)擔(dān)，緩解NAFLD的發(fā)生和發(fā)展[5]。運(yùn)動治療主要通過提高胰島素敏感性、降低游離脂肪酸(FFA)的濃度及抑制脂肪細(xì)胞和肌細(xì)胞TNF-α的超表達(dá)，從而改善IR。步行是NAFLD患者容易接受的治療方式[6]。

2 藥物治療

2.1胰島素增敏劑鹽酸二甲雙胍和噻唑烷二酮類(TZDs)可以作為改善NAFLD患者脂肪組織胰島素敏感性的藥物。最近的一項(xiàng)數(shù)據(jù)分析顯示，盡管使用二甲雙胍后體質(zhì)量和轉(zhuǎn)氨酶下降，但是在組織學(xué)方面并無明顯改善[7]。而TZDs可激活特異性過氧化物酶體增殖物激活受體(PPARs)，從而改善胰島素敏感性和脂質(zhì)代謝。雖然有研究顯示，TZDs對改善組織學(xué)有益，但要注意長期使用有致心力衰竭、膀胱癌和骨質(zhì)丟失的安全性問題[8]。盡管如此，胰島素信號傳導(dǎo)的調(diào)節(jié)仍然是有吸引力的治療方向，但是可能需要靶向PPARs甚至TZDs的其他藥物，獨(dú)立于PPARs激活作用，例如Blx-1002。在動物模型中，Blx-1002聯(lián)合鹽酸二甲雙胍可減少肝脂肪變性，改善血脂異常和降低血糖[9]。

2.2抗氧化劑維生素E是治療NAFLD中常用的抗氧化劑，在一組多中心對照試驗(yàn)中，患者服用維生素E的劑量為800 IU/d，持續(xù)96周后發(fā)現(xiàn)，其中約一半患者獲得組織學(xué)上的改善，但氧化應(yīng)激改善不明顯[10]。水飛薊素作為NAFLD患者潛在治療的植物提取物，能夠改善肝星狀細(xì)胞活化及減少TNF-α的釋放[11]。然而，迄今為止僅有轉(zhuǎn)氨酶改善的數(shù)據(jù)，而缺乏肝活檢組織學(xué)改善的可靠數(shù)據(jù)[12]。在一項(xiàng)非安慰劑對照的兒科研究[13]中，對服用半胱胺治療的患者隨訪24周后發(fā)現(xiàn)轉(zhuǎn)氨酶有改善。核紅細(xì)胞2相關(guān)因子(Nrf2)是另一種抗氧化劑，與單脂肪變性的對照動物相比，高脂飲食的Nrf2基因敲除小鼠發(fā)展為NASH可能性增加[14]。Nrf2激活劑—奧替普拉可減少動物模型中的NASH的組織學(xué)進(jìn)展[15]，在臨床研究中卻未顯示治療24周后組織學(xué)改善的跡象[16]。

2.3抗纖維化藥奧貝膽酸(OCA)是膽固醇X受體(FXR)的天然激動劑的半合成衍生物，參與調(diào)節(jié)葡萄糖和脂質(zhì)代謝和免疫應(yīng)答的核激素受體，F(xiàn)XR的活化促進(jìn)動物模型中肝纖維化的改善[17-18]。在包括NAFLD輕度至中度肝纖維化的2型糖尿病患者2期試驗(yàn)中，25 mg OCA組平均肝纖維化評分(NAFLDFS)顯著降低[19]。已酮可可堿通過減少TNF-α的轉(zhuǎn)錄來減少促炎性細(xì)胞因子的生成[20]。由于酒精性肝炎和NASH均出現(xiàn)TNF-α水平的升高，一項(xiàng)隨機(jī)對照試驗(yàn)[21]表明，受試者服用已酮可可堿1 200 mg/d持續(xù)1年后，與對照組相比,脂肪變性和轉(zhuǎn)氨酶水平有改善的趨勢。

2.4降脂藥研究發(fā)現(xiàn)，他汀類藥物在NAFLD患者中使用是安全的[22]，而且他汀類藥物的使用與肝活檢中脂肪變性的減少有關(guān)[23]。然而也有研究[24]發(fā)現(xiàn)，他汀類藥物對轉(zhuǎn)氨酶或組織學(xué)改善作用不明顯。依澤替米貝可以抑制胃腸道中膽固醇的吸收，用于他汀類控制不佳血脂異常者的輔助治療[25]。一項(xiàng)RCT研究[26]顯示,使用6個(gè)月的依澤替米貝(10 mg/d)纖維化分期評分均有所改善。二酰基甘油?；D(zhuǎn)移酶(DGAT)是催化甘油三酯合成中最后步驟的酶。在高脂飲食的動物中，DGAT2基因敲除后動物肝內(nèi)脂質(zhì)量下降，脂肪酸氧化增強(qiáng)和肝胰島素敏感性改善[27]。但也有可能會增加氧化應(yīng)激、炎癥和纖維化，提示甘油三酯積累可能是一種肝臟的自我保護(hù)機(jī)制[28]。

2.5咖啡最新研究[29]發(fā)現(xiàn)，咖啡在NAFLD治療中除了能夠降低脂肪變性的程度，還可以使實(shí)驗(yàn)室檢測指標(biāo)降低并使促炎因子減輕。同時(shí)有研究[30]發(fā)現(xiàn)，咖啡的攝入不僅可以減輕NASH患者纖維化，還可以減輕重癥肥胖患者肝纖維化程度。盡管效果還需進(jìn)一步證明，但是從動物模型實(shí)驗(yàn)和臨床數(shù)據(jù)來看，咖啡確實(shí)對NAFLD患者有益。

3 手術(shù)治療

3.1減肥手術(shù)75%～100%的肥胖患者都患有NAFLD。一項(xiàng)前瞻性研究[31]顯示，減肥手術(shù)對肝功能和肝脂肪變性有著積極的影響。但對肝炎和肝纖維化的遠(yuǎn)期影響尚不明確。目前最常用的減肥手術(shù)是袖狀胃切除術(shù)和胃旁路手術(shù)，這兩種術(shù)式效果最佳，并且經(jīng)過適當(dāng)選擇能夠降低患者術(shù)后風(fēng)險(xiǎn)。

3.2肝移植手術(shù)肝移植能夠給終末期NAFLD患者提供更多益處，但目前的關(guān)注點(diǎn)主要集中在術(shù)后NAFLD的復(fù)發(fā)和心血管疾病、高血壓和糖尿病的發(fā)生[32]。免疫抑制劑療法雖不會促進(jìn)NAFLD的發(fā)展，但持久和多變的潛在代謝綜合征使得他們更易發(fā)生心血管疾病、高血壓和糖尿病及腎功能衰竭等并發(fā)癥。所以，代謝綜合征尤其是糖尿病和肝病復(fù)發(fā)是NAFLD患者術(shù)后應(yīng)當(dāng)格外關(guān)注的[33]。對列入移植患者合并代謝綜合征的可接受程度目前仍不確定。術(shù)前對高脂高糖食品和飲料的嚴(yán)格限制，糖尿病和血壓的嚴(yán)密控制等管理措施是獲得移植后良好生存率和改善生活質(zhì)量的關(guān)鍵因素[34]。

隨著對NAFLD發(fā)病機(jī)制研究的深入，相應(yīng)的治療方法和手段也在逐步完善，但基礎(chǔ)治療仍是治療NAFLD的基石，藥物治療更多地傾向個(gè)體化用藥，針對不同的人群采取不同的藥物治療，外科手術(shù)治療是無禁忌證病態(tài)肥胖NAFLD患者和終末期NAFLD患者最好、也是最有效的治療手段。總之，對NAFLD的研究進(jìn)展為我們防治該病提供了新的選擇和希望，但問題最終的解決仍依賴于發(fā)病機(jī)制的進(jìn)一步研究和闡明。

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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，主任醫(yī)師，碩士生導(dǎo)師，研究方向：慢性肝病的臨床診治。E-mail： a414073680@163.com

10.3969/j.issn.1006-5709.2017.10.004