魯冰潔， 陳 曦， 孫明瑜

(1 上海中醫(yī)藥大學(xué)附屬曙光醫(yī)院， 上海中醫(yī)藥大學(xué)肝病研究所，肝腎疾病病證教育部重點(diǎn)實(shí)驗(yàn)室，上海 201203； 2 上海中醫(yī)藥大學(xué)， 上海 201203)

調(diào)脂藥物在防治非酒精性脂肪性肝病中的應(yīng)用進(jìn)展

魯冰潔1,2， 陳 曦1,2， 孫明瑜1,2

(1 上海中醫(yī)藥大學(xué)附屬曙光醫(yī)院， 上海中醫(yī)藥大學(xué)肝病研究所，肝腎疾病病證教育部重點(diǎn)實(shí)驗(yàn)室，上海 201203； 2 上海中醫(yī)藥大學(xué)， 上海 201203)

非酒精性脂肪性肝病(NAFLD)是指除外過量飲酒及其他明確肝損傷因素所致的，以彌漫性肝細(xì)胞大泡性脂肪變性為主要特征的臨床病理綜合征。其中，脂質(zhì)代謝紊亂是NAFLD的重要特征，改善血脂異常乃是防治NAFLD的重要手段，而調(diào)脂藥物在降低血脂的同時(shí)，也可能促使脂質(zhì)更集中運(yùn)輸至肝臟進(jìn)行代謝，造成肝脂蓄積而加重肝損傷。目前，國內(nèi)對(duì)于調(diào)脂藥物在NAFLD中的應(yīng)用仍持謹(jǐn)慎態(tài)度甚至存在爭議。如何合理應(yīng)用調(diào)脂藥物，已成為防治NAFLD的重要課題。簡要綜述了調(diào)脂藥物在NAFLD中的應(yīng)用進(jìn)展，以期對(duì)調(diào)脂藥物防治NAFLD提供一定參考。

非酒精性脂肪性肝??； 藥物療法； 綜述

非酒精性脂肪性肝病(NAFLD)是一種導(dǎo)致機(jī)體能量穩(wěn)態(tài)失衡的遺傳、環(huán)境、代謝應(yīng)激相關(guān)性肝病，是代謝綜合征在肝臟的表現(xiàn)。NAFLD的發(fā)病病因與胰島素抵抗(IR)和遺傳易感密切相關(guān)，其特征表現(xiàn)為肝臟內(nèi)以TG形式堆積的脂肪過度蓄積，肝活組織檢查脂肪變累及5%以上肝細(xì)胞或1H-磁共振質(zhì)譜分析肝脂肪含量>5.6%[1]。NAFLD的疾病譜主要包括非酒精性單純性脂肪肝(NAFL)和非酒精性脂肪性肝炎(NASH)以及由其演變的非酒精性脂肪性肝纖維化、非酒精性脂肪性肝硬化及肝細(xì)胞癌(HCC)等一系列嚴(yán)重肝病事件[2]。

近年來，隨著飲食結(jié)構(gòu)和生活方式的改變，NAFLD的全球發(fā)病率逐年增高。其中，歐美國家的NAFLD發(fā)病率為17%～46% ，是導(dǎo)致慢性肝臟疾病的首要病因；亞洲國家的NAFLD發(fā)病率為12%～30%[3]，在我國也已成為繼慢性乙型肝炎之后的第2大慢性肝病病因。NAFLD的發(fā)病機(jī)制復(fù)雜，以經(jīng)典的“二次打擊”學(xué)說為基礎(chǔ)。其中，IR構(gòu)成的第一次打擊貫穿于NAFLD的整個(gè)發(fā)病過程。IR促使血清游離脂肪酸釋放增多，導(dǎo)致脂肪在肝實(shí)質(zhì)細(xì)胞內(nèi)的過度聚集，并引起脂肪變性[4]；建立在IR基礎(chǔ)上的脂肪變性，引發(fā)肝損傷修復(fù)，即啟動(dòng)第二次打擊：由氧化應(yīng)激、脂質(zhì)過氧化、線粒體功能不全、脂肪細(xì)胞因子介導(dǎo)的發(fā)生在肝實(shí)質(zhì)細(xì)胞內(nèi)的炎癥反應(yīng)[5],可引起細(xì)胞凋亡和壞死，導(dǎo)致NAFL向NASH、NASH相關(guān)肝硬化的轉(zhuǎn)變[6]。近年來，部分學(xué)者在“二次打擊”學(xué)說的基礎(chǔ)上將腸肝軸、自噬與凋亡、遺傳變異等因素納入NAFLD的發(fā)生機(jī)制，形成“多重打擊”理論[7]。

研究[8]顯示NAFLD是不明原因肝酶異常的主要原因，可通過直接或間接方式誘導(dǎo)并存的其他肝病的病程進(jìn)展，增加肝功能衰竭和HCC的發(fā)生風(fēng)險(xiǎn)，同時(shí)與動(dòng)脈粥樣硬化和心血管事件的發(fā)病呈較高相關(guān)性。其中，高脂血癥作為NAFLD的獨(dú)立危險(xiǎn)因素，其并存的血脂代謝紊亂可進(jìn)一步增加NAFLD并發(fā)心血管疾病的風(fēng)險(xiǎn)，而心血管意外事件正是導(dǎo)致NAFLD致死的最主要誘因[9]。因此，應(yīng)用調(diào)脂藥物改善血脂異常，有效防治NAFLD，以阻止NASH及NASH相關(guān)肝硬化的進(jìn)展，降低心血管等高危事件的發(fā)生，具有重要臨床意義[10]。然而，多種調(diào)脂藥物的使用，在改善NAFLD患者血脂的同時(shí)，可能加重其肝脂代謝負(fù)擔(dān)而誘發(fā)肝損傷，故臨床應(yīng)用尚存有一定爭議和治療矛盾，現(xiàn)分述如下：

1 調(diào)脂藥物在NAFLD中應(yīng)用的合理性

肥胖、IR、血脂紊亂和2型糖尿病均為NAFLD肯定的危險(xiǎn)因素。其中，高血脂癥是NAFLD發(fā)生的血清學(xué)基礎(chǔ)。在肥胖或有明確糖尿病史的NAFLD患者中，高脂血癥較常見。其中，NAFLD患者的高脂血癥檢出率為27%～92%，NASH患者的高脂血癥檢出率為20%～80%[11]。即使在無肥胖或無明確病因的NAFLD患者中, 亦常有血脂代謝的紊亂，因此對(duì)NAFLD患者進(jìn)行調(diào)脂治療乃是必要之策。

2015年日本胃腸病學(xué)會(huì)NAFLD臨床實(shí)踐指南[12]推薦他汀類藥物用于治療NAFLD伴高脂血癥患者。2017年亞太工作組NAFLD指南[13]表明他汀類藥物可用于NAFLD伴輕度ALT升高患者的調(diào)脂治療，減少這一人群中相關(guān)心血管疾病及HCC的發(fā)病率，但不推薦常規(guī)使用他汀類藥物治療失代償期肝硬化和急性肝功能衰竭患者。2010年中華醫(yī)學(xué)會(huì)肝病學(xué)分會(huì)NAFLD診療指南[14]明確提出：對(duì)于經(jīng)基礎(chǔ)治療和(或)應(yīng)用減肥降糖藥物3～6個(gè)月以上，仍呈混合性或高脂血癥合并2個(gè)以上危險(xiǎn)因素者，應(yīng)考慮加用貝特類、他汀類等調(diào)脂藥物，以延緩動(dòng)脈硬化進(jìn)程及減少心腦血管事件的發(fā)生，但應(yīng)注意肝功能的監(jiān)測。調(diào)脂藥物的治療目的不僅限于對(duì)NAFLD患者生化和肝組織學(xué)的改善，脂質(zhì)代謝紊亂的糾正，更應(yīng)強(qiáng)調(diào)其遠(yuǎn)期預(yù)后，即降低心腦血管事件的發(fā)生，延長生存期，提高生活質(zhì)量。

2 調(diào)脂藥物在NAFLD中應(yīng)用的潛在危害性

一方面，調(diào)脂藥物主要通過促進(jìn)血液中的脂質(zhì)集中運(yùn)輸至肝代謝,從而降低外周血脂水平,但并未能有效清除肝脂質(zhì)沉積，反而可能加重肝的代謝負(fù)荷，導(dǎo)致肝脂沉積加劇，誘發(fā)肝損傷。另一方面，部分調(diào)脂藥物在降低膽固醇TC濃度的同時(shí),也降低了肌膜TC水平，使細(xì)胞膜和血漿脂質(zhì)間的動(dòng)態(tài)平衡遭到破壞，降低了細(xì)胞膜的穩(wěn)定性[15]。以他汀類為代表的調(diào)脂藥物，其不良反應(yīng)可累及全身多個(gè)系統(tǒng)，包括肌肉損害[16]、肝功能異常、皮膚和胃腸反應(yīng)、神經(jīng)毒性，還可增加糖尿病的發(fā)病風(fēng)險(xiǎn)等[17]。

2.1 調(diào)脂藥物可能造成藥物性肝損傷 多數(shù)藥物性肝損傷見于老年人群、免疫薄弱者和肝腎功能失代償患者，表現(xiàn)除肝酶升高以外，還可伴隨不同程度的肝細(xì)胞死亡、肝纖維化和炎性反應(yīng)[18]。Abdoli等[19]在動(dòng)物研究中探討阿托伐他汀、洛伐他汀和辛伐他汀對(duì)新鮮分離大鼠肝細(xì)胞的毒性機(jī)理，發(fā)現(xiàn)他汀類藥物可促進(jìn)活性氧生成，增加肝細(xì)胞內(nèi)的氧化谷胱甘肽含量，并誘導(dǎo)脂質(zhì)過氧化和線粒體去極化，從而產(chǎn)生肝細(xì)胞毒性，并表明這種細(xì)胞毒性呈劑量依賴性。Tolosa等[20]就他汀類藥物引起肝損傷的機(jī)制進(jìn)行初步分析，表明與該類藥物介導(dǎo)的肝細(xì)胞線粒體損傷密切相關(guān)，但這種藥物性肝損傷僅表現(xiàn)為輕中度水平。Szabo等[21]表明他汀類藥物主要通過改變多藥耐藥相關(guān)蛋白2/3的功能，影響大鼠肝膽管對(duì)結(jié)合膽紅素和非結(jié)合膽紅素的轉(zhuǎn)運(yùn)，從而導(dǎo)致血清膽紅素水平升高。但指出多藥耐藥相關(guān)蛋白2/3功能改變與膽紅素水平升高為主要表現(xiàn)的肝損傷之間并無直接聯(lián)系。

2.2 調(diào)脂藥物容易誘發(fā)其他系統(tǒng)的不良反應(yīng) 一項(xiàng)動(dòng)物實(shí)驗(yàn)[22]研究他汀類藥物誘導(dǎo)的神經(jīng)肌肉損傷，表明發(fā)生機(jī)制與nAChR基因片段上rs137852808位點(diǎn)突變相關(guān)。Dormuth等[23]在一項(xiàng)多中心、大樣本的Meta分析中，對(duì)他汀類藥物與新發(fā)糖尿病的風(fēng)險(xiǎn)進(jìn)行評(píng)估，表明使用他汀類藥物2年，新發(fā)糖尿病的風(fēng)險(xiǎn)即有顯著增加，其中低劑量的他汀用藥可使糖尿病的發(fā)病風(fēng)險(xiǎn)增加約3.9%，而加強(qiáng)劑量的他汀用藥則使糖尿病的發(fā)病風(fēng)險(xiǎn)增加至4.1%。前期發(fā)表于Lancet的研究[24]提示他汀類用藥超過4年，糖尿病的發(fā)病風(fēng)險(xiǎn)增加9%。另一項(xiàng)發(fā)表于JAMA的Meta分析[25]也支持這一觀點(diǎn)，并揭示他汀類藥物與糖尿病的發(fā)病風(fēng)險(xiǎn)呈現(xiàn)劑量相關(guān)性。Carter等[26]進(jìn)一步比較不同他汀類藥物與新發(fā)糖尿病的關(guān)系，表示與普伐他汀相比，辛伐他汀、羅蘇伐他汀和阿托伐他汀均增加了新發(fā)糖尿病的風(fēng)險(xiǎn)，其風(fēng)險(xiǎn)比分別為1.10、1.18和1.22。Ridker等[27]隨后進(jìn)行的隨機(jī)雙盲臨床試驗(yàn)，分別對(duì)合并糖尿病危險(xiǎn)因素者和未合并糖尿病危險(xiǎn)因素者進(jìn)行他汀類藥物干預(yù)，發(fā)現(xiàn)糖尿病的發(fā)生率僅在合并糖尿病危險(xiǎn)因素人群中有所增加，而在那些未合并糖尿病危險(xiǎn)因素人群中并未增加，提示他汀類藥物治療導(dǎo)致的新發(fā)糖尿病與糖尿病危險(xiǎn)因素相關(guān)。Goldstein等[28]探討他汀類藥物與出血性腦中風(fēng)發(fā)生率的關(guān)系，發(fā)現(xiàn)經(jīng)他汀藥物治療的患者更易發(fā)生出血性腦卒中，尤其是既往有出血性卒中病史、男性和高齡患者。

3 經(jīng)典調(diào)脂藥物在NAFLD中的應(yīng)用

3.1 他汀類藥物用于NAFLD治療的研究 他汀類藥物是目前國內(nèi)外應(yīng)用較為廣泛的具有代表性的一類經(jīng)典調(diào)脂藥物，主要包括辛伐他汀、普伐他汀、阿托伐他汀和羅蘇伐他汀等[29]，其作用機(jī)制為競爭性抑制羥甲戊二酰輔酶A ( hydroxy methylglutaryl coenzyme A，HMG-CoA)還原酶的活性，阻止HMG-CoA轉(zhuǎn)變成甲基二羥戊酸，減少TC合成，降低LDL水平，減輕肝細(xì)胞脂肪變性及肝纖維化。多項(xiàng)研究[30-31]表明他汀類藥物在改善血脂異常、穩(wěn)定肝酶的同時(shí)，兼具有免疫調(diào)節(jié)作用。Fraulob等[32]建立高脂飲食誘導(dǎo)的NAFLD大鼠模型，發(fā)現(xiàn)羅蘇伐他汀可通過改善IR，減輕肝細(xì)胞脂肪變性及炎癥反應(yīng)。Yokohama等[33]同樣于動(dòng)物實(shí)驗(yàn)發(fā)現(xiàn)羅蘇伐他汀可抑制TNFα、IL-6、TGFβ1、血管內(nèi)皮細(xì)胞生長因子受體、表皮生長因子受體、血小板衍生因子等因子的表達(dá)，有效預(yù)防NAFLD和HCC的發(fā)生。Alkhatatbeh等[34]使用油酸誘導(dǎo)HepG2細(xì)胞脂肪變性，建立NAFLD的體外模型，發(fā)現(xiàn)低濃度(4～10 μM)的辛伐他汀即可使40%的肝細(xì)胞減輕脂質(zhì)沉積。Samy等[35]于臨床試驗(yàn)中發(fā)現(xiàn)，阿托伐他汀可增強(qiáng)NAFLD患者的血清對(duì)氧磷酯酶1活性，降低血清丙二醛水平，從而改善氧化應(yīng)激，減輕肝炎癥反應(yīng)。Foster等[36]表明長期使用阿伐他汀聯(lián)合維生素C/E治療能夠有效降低NASH的發(fā)生率，提示對(duì)NAFLD的臨床預(yù)后有一定改善作用。

2016年歐洲肝病學(xué)會(huì)NAFLD臨床實(shí)踐指南[37]評(píng)估他汀類藥物對(duì)NAFLD的防治作用，表明他汀類藥物可降低LDL水平，預(yù)防心血管事件發(fā)生，但并未能促進(jìn)或改善肝臟疾病。Nelson等[38]發(fā)現(xiàn)單用辛伐他汀尚不能改善患者的生化及組織學(xué)指標(biāo)。Bjornsson等[39]認(rèn)為部分他汀類降脂藥可能改變肝酶指標(biāo)，導(dǎo)致不同程度的血清ALT升高。另有研究[40]報(bào)道138例急性肝衰竭患者中有10例因他汀類藥物導(dǎo)致，這些研究警示他汀類藥物的安全應(yīng)用不容忽視。但也有部分學(xué)者表明，他汀類藥物相關(guān)的無癥狀性肝酶異常，與臨床或肝組織學(xué)檢查所認(rèn)為的急性或慢性肝損傷之間并無關(guān)聯(lián)[41]。因此，他汀類藥物防治NAFLD的確切療效，尚需大樣本、前瞻性、隨機(jī)對(duì)照研究加以證實(shí)。

3.2 貝特類藥物用于NAFLD治療的研究 貝特類藥物即苯氧乙酸類藥物，是過氧化物酶體增殖體激活受體激動(dòng)劑，主要包括非諾貝特、非那貝特、吉非羅齊等。其中非諾貝特不良反應(yīng)較小，臨床應(yīng)用較為常見。其作用機(jī)制通過抑制腺苷酸環(huán)化酶，增強(qiáng)脂蛋白酯酶活性，加速TG分解和HDL合成，降低TG水平及升高HDL水平。動(dòng)物實(shí)驗(yàn)[42]研究表明，非諾貝特能顯著改善NAFLD模型大鼠的血脂障礙、肝脂堆積、IR及氧化應(yīng)激反應(yīng)。Fabbrini等[43]進(jìn)行的臨床研究則顯示，使用非諾貝特治療NAFLD后，盡管血清TG水平有所下降，但肝組織內(nèi)TG水平卻未有明顯變化。另一項(xiàng)國外臨床研究[44]觀察非諾貝特治療NAFLD患者28周，患者僅肝酶指標(biāo)復(fù)常，而肝細(xì)胞脂肪變性、肝小葉炎癥和纖維化等并未得到有效改善。此外，已有研究[45]證實(shí)，貝特類藥物單獨(dú)或與他汀類藥物合用，可增加橫紋肌溶解的發(fā)病風(fēng)險(xiǎn)，并增加膽結(jié)石的發(fā)生率。因此，臨床應(yīng)當(dāng)慎用貝特類調(diào)脂藥物，必要時(shí)應(yīng)嚴(yán)密觀測肝功能等指標(biāo)。

4 調(diào)脂藥物的合理應(yīng)用

4.1 調(diào)脂藥物是否與肝酶異常有關(guān) 部分調(diào)脂藥物可能造成一定程度的肝損傷, 組織學(xué)改變?yōu)楦渭?xì)胞型、淤膽型或混合型, 臨床上多表現(xiàn)為無癥狀性血清轉(zhuǎn)氨酶輕度升高[46]，且這種肝酶異常具有一過性特點(diǎn)，超過70%的患者在停藥后數(shù)周便很快恢復(fù)[47]。

4.2 長期應(yīng)用調(diào)脂藥物是否增加肝損傷 Younoszai等[48]對(duì)長期使用他汀類調(diào)脂藥物的9207例既往合并肝臟疾病的患者隨訪，表明服用他汀類藥物與肝病死亡事件之間并無明顯相關(guān)性。Demyen等[49]在一項(xiàng)納入48 000例受試者的Meta分析中表明，與安慰劑組比較，他汀類藥物組的肝損傷發(fā)生率并無差異，由此認(rèn)為他汀類藥物服用相對(duì)安全。Kim等[50]采用Meta分析對(duì)失代償肝硬化患者應(yīng)用他汀類藥物的安全性進(jìn)行評(píng)估，表示他汀類藥物可使肝病進(jìn)展風(fēng)險(xiǎn)降低約46%。但仍有研究報(bào)道了相關(guān)不良事件，提示可能與這類患者肝功能受損，藥物耐受性下降有關(guān)。

4.3 應(yīng)用調(diào)脂藥物過程中出現(xiàn)肝酶異常的停藥原則 對(duì)于血脂異常的NAFLD患者，在應(yīng)用調(diào)脂藥物治療之前，需要對(duì)其臟功能進(jìn)行較好的評(píng)估，尤其注意鑒別是否合并潛在的肝臟疾病，是否繼發(fā)NASH的肝酶異常[51]。若患者既往無基礎(chǔ)肝病，且無臨床癥狀提示肝損傷，或僅有肝酶輕度升高，可繼續(xù)服用降脂藥物，并避免不當(dāng)停藥。若患者既往合并基礎(chǔ)肝病，需在肝酶異常時(shí)小心停藥，并分析肝酶異常的具體原因。無論患者服藥前肝酶是否異常，若3個(gè)月內(nèi)肝酶升高至基線水平的2倍，都應(yīng)考慮停藥[52]。若服藥期間發(fā)生明顯肝損傷甚至肝功能衰竭，則需立即停藥，并尋求?？漆t(yī)生積極診治[53]。

5 小結(jié)

綜上所述, 國內(nèi)外已廣泛開展調(diào)脂藥物防治NAFLD的相關(guān)研究，評(píng)估他汀類為代表的調(diào)脂藥物治療NAFLD的有效性和相對(duì)安全性，獲得較好結(jié)論[54-55]，初步認(rèn)為調(diào)脂藥物治療NAFLD的整體獲益大于風(fēng)險(xiǎn)，可能擁有良好前景。但目前國內(nèi)對(duì)他汀類藥物的研究多屬于小型臨床研究，尚缺乏大樣本、前瞻性的臨床研究進(jìn)一步證實(shí)，并且僅觀察了NAFLD患者的生化和肝組織學(xué)等近期終點(diǎn)指標(biāo)的變化，缺乏對(duì)應(yīng)用前的風(fēng)險(xiǎn)評(píng)估及遠(yuǎn)期治療終點(diǎn)指標(biāo)的觀察。同時(shí)鑒于少數(shù)NAFLD患者可能出現(xiàn)肝酶異常甚至藥物性肝損傷，因此應(yīng)用調(diào)脂藥物治療NAFLD，應(yīng)建立嚴(yán)格的臨床實(shí)驗(yàn)設(shè)計(jì)以評(píng)估其應(yīng)用價(jià)值及安全性，并注意監(jiān)測肝酶指標(biāo)，合理把握停藥指征。

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Applicationoflipid-regulatingdrugsinpreventionandtreatmentofnonalcoholicfattyliverdisease

LUBingjie,CHENXi,SUNMingyu.

(ShuguangHospital&InstituteofHepatology,ShanghaiUniversityofTraditionalChineseMedicine,KeyLaboratoryofLiverandKidneyDiseasesoftheEducationMinistryofChina,Shanghai201203,China)

Nonalcoholic fatty liver disease (NAFLD) is a clinicopathological syndrome characterized by diffuse macrovesicular steatosis in hepatocytes and is caused by the factors except excessive drinking and other specific factors for liver injury. In particular, lipid metabolism disorder is a significant characteristic of NAFLD, and improvement of dyslipidemia is an important method for the prevention and treatment of NAFLD. Lipid-regulating drugs can not only reduce blood lipids, but also promote the transportation of lipids to the liver for metabolism, which may cause liver lipid accumulation and aggravate liver injury. At present, there are still controversies over the application of lipid-regulating drugs in the treatment of NAFLD in China. Rational use of lipid-regulating drugs has become an important topic in the prevention and treatment of NAFLD. This article summarizes the application of lipid-regulating drugs in NAFLD, in order to provide a reference for lipid-regulating drugs in the prevention and treatment of NAFLD.

nonalcoholic fatty liver disease； drug therapy； review

R575.5

A

1001-5256(2017)12-2444-05

10.3969/j.issn.1001-5256.2017.12.043

2017-07-26；修回日期：2017-08-08。 基金項(xiàng)目：國家自然科學(xué)基金項(xiàng)目(81273729)；上海市科委專項(xiàng)項(xiàng)目(15DZ1900104) 作者簡介：魯冰潔(1991-)，女，在讀博士，主要從事中醫(yī)藥防治肝病的基礎(chǔ)與臨床研究。 通信作者：孫明瑜，電子信箱：mysun248@hotmail.com。

引證本文：LU BJ, CHEN X, SUN MY. Application of lipid-regulating drugs in prevention and treatment of nonalcoholic fatty liver disease[J]. J Clin Hepatol, 2017, 33(12): 2444-2448. (in Chinese)

魯冰潔， 陳曦， 孫明瑜. 調(diào)脂藥物在防治非酒精性脂肪性肝病中的應(yīng)用進(jìn)展[J]. 臨床肝膽病雜志, 2017, 33(12): 2444-2448.

(本文編輯：林 姣)