慢性乙型肝炎合并非酒精性脂肪性肝病的研究進(jìn)展

劉璐璐， 任 藝， 何毅懷， 林世德

(遵義醫(yī)學(xué)院附屬醫(yī)院 感染科， 貴州 遵義 563000)

綜述

慢性乙型肝炎合并非酒精性脂肪性肝病的研究進(jìn)展

劉璐璐， 任 藝， 何毅懷， 林世德

(遵義醫(yī)學(xué)院附屬醫(yī)院 感染科， 貴州 遵義 563000)

近年來，隨著人們生活質(zhì)量的提高，非酒精性脂肪性肝病(NAFLD)的發(fā)病率逐年上升，成為發(fā)病率僅次于病毒性肝炎的常見肝病。因此，慢性乙型肝炎合并NAFLD的患者越來越多。綜述了HBV感染對(duì)NAFLD發(fā)生發(fā)展的影響，以及NAFLD對(duì)慢性乙型肝炎患者病程和抗病毒療效的影響。

肝炎， 乙型， 慢性； 脂肪肝； 綜述

慢性乙型肝炎(CHB)在我國(guó)較為常見[1-2]。同時(shí)，隨著人們生活水平的提高，非酒精性脂肪性肝病(NAFLD)的發(fā)病率日益上升，引起廣泛關(guān)注[3]。NAFLD主要是脂類代謝紊亂所導(dǎo)致的肝損傷，與遺傳易感性及胰島素抵抗(IR)密切相關(guān)，肝脂肪酸攝取增加和轉(zhuǎn)運(yùn)障礙導(dǎo)致脂肪酸水平升高，抑制線粒體β-氧化[4]。CHB合并NAFLD較為常見，二者以不同的機(jī)制作用于共同的靶器官——肝臟，協(xié)同促進(jìn)肝臟疾病的進(jìn)展[5]。

1 CHB合并NAFLD的流行病學(xué)研究

有研究[6]顯示，歐洲及中東地區(qū)CHB合并NAFLD的比例為18%～62%，亞太地區(qū)為14%～17%。對(duì)中國(guó)農(nóng)村的一項(xiàng)隨訪研究[7]顯示，CHB合并NAFLD的發(fā)病率呈逐年上升的趨勢(shì)，從第1年的6.40%上升至第4年的21.54%。有研究[8]對(duì)CHB患者進(jìn)行肝穿刺活組織檢查發(fā)現(xiàn)，39%的CHB患者合并NAFLD，且不同的CHB患者合并NAFLD的程度差異較大，其中70%表現(xiàn)為輕度脂肪肝，30%NAFLD程度較重，且男性合并肝脂肪變性的比例明顯高于女性(47% vs 22%)。另一項(xiàng)研究[9]顯示，HBeAg陰性的CHB患者合并NAFLD的比例為34.6%，而HBeAg陽(yáng)性患者為16.2%，并且前者肝纖維化評(píng)分明顯高于后者。

2 HBV感染對(duì)NAFLD發(fā)生發(fā)展的影響

HBV感染引起的肝損傷和IR主要與機(jī)體免疫反應(yīng)及炎癥因子水平有關(guān)[10]。細(xì)胞內(nèi)信號(hào)傳導(dǎo)通過炎癥因子的介導(dǎo)，可導(dǎo)致肝細(xì)胞、脂肪細(xì)胞、肌肉細(xì)胞等胰島素敏感細(xì)胞內(nèi)的胰島素受體底物1的絲氨酸磷酸化，使酪氨酸磷酸化受抑制，導(dǎo)致胰島素信號(hào)傳導(dǎo)受阻，從而誘發(fā)IR[11-12]。炎性因子在脂肪組織中可引起脂質(zhì)代謝紊亂，使游離脂肪酸增加而誘發(fā)IR。IR與細(xì)胞因子關(guān)系的相關(guān)文獻(xiàn)[13]報(bào)道顯示，TNFα、IL-6、CRP和細(xì)胞因子信號(hào)3抑制物等均與IR密切相關(guān)。HBV感染的患者體內(nèi)炎癥因子明顯升高，尤其是TNFα水平，可以導(dǎo)致IR。有研究[14]發(fā)現(xiàn)，TNFα?xí)种萍?xì)胞膜的胰島素受體1和受體3，使胰島素在細(xì)胞內(nèi)的信號(hào)轉(zhuǎn)導(dǎo)和(或)轉(zhuǎn)化過程受阻，誘導(dǎo)IR，從而導(dǎo)致人體代謝紊亂，血糖水平升高，肝細(xì)胞易發(fā)生脂質(zhì)代謝異常。

HBV感染還可影響肝細(xì)胞脂質(zhì)代謝通路，HBx蛋白可通過固醇調(diào)節(jié)元件結(jié)合蛋白(sterol regulatory element binding protein，SREBP)1、過氧化物酶增生物激活受體(PPAR)γ、肝臟X受體及TNF-8、IL-13細(xì)胞因子等多種途徑促進(jìn)肝細(xì)胞內(nèi)脂肪積累[15]。HBx蛋白的過度表達(dá)能夠使CHB合并NAFLD轉(zhuǎn)基因小鼠肝細(xì)胞內(nèi)及HepG2細(xì)胞株的脂質(zhì)沉積，可能與肝細(xì)胞PPARγ mRNA 和SREBP1及其蛋白表達(dá)增強(qiáng)有關(guān)[16]。HBx蛋白可經(jīng)影響TNF受體1誘導(dǎo)脂肪肝的發(fā)生，TNF受體1可調(diào)節(jié)PPARγ及SREBP1的表達(dá)，前者可通過調(diào)控線粒體和激活氧化酶來影響脂質(zhì)代謝，而后者可促進(jìn)肝細(xì)胞內(nèi)游離脂肪酸的合成，同時(shí)TNF受體1可調(diào)控核因子-κB使脂肪肝進(jìn)行性加重[17]。有研究[18]利用酵母雙雜交篩檢系統(tǒng)發(fā)現(xiàn)，HBsAg主蛋白與烯酰輔酶A水合酶相互結(jié)合可損傷肝細(xì)胞，并通過干擾脂肪酸代謝中某些基因的表達(dá)而影響細(xì)胞的脂肪代謝。此外，HBV還可通過磷酯酰肌醇-3-激酶/蛋白激酶B信號(hào)通路引起SREBP-1c介導(dǎo)的脂質(zhì)生成[19-20]。

3 NAFLD對(duì)CHB的影響及機(jī)制

3.1 對(duì)肝功能指標(biāo)的影響 肝功能是對(duì)肝損傷嚴(yán)重程度進(jìn)行評(píng)估的最常用指標(biāo)，在CHB、NAFLD等多種肝臟疾病中都有不同程度的升高。合并NAFLD的CHB患者肝酶水平、總膽汁酸、Alb較單純CHB組患者明顯增高，并有研究[21]發(fā)現(xiàn)肝功能指標(biāo)恢復(fù)效果隨著肝脂肪變性的加重而變差。通過進(jìn)一步研究[22]發(fā)現(xiàn)，在CHB合并NAFLD的患者中，脂肪變性程度輕者比程度重者血清TNFα、IL-6、IL-8等細(xì)胞因子水平低，表明肝臟脂肪變性程度可能與血清細(xì)胞因子水平存在相關(guān)性。另有研究[23]顯示，CHB合并NAFLD患者的外周血CD4+CD25+T淋巴細(xì)胞百分比明顯低于單純CHB患者，且肝組織中Foxp3 mRNA的表達(dá)減弱，肝組織Foxp3陽(yáng)性細(xì)胞數(shù)量也相對(duì)減少，提示肝細(xì)胞脂肪變性可通過降低調(diào)節(jié)性T淋巴細(xì)胞的水平，改變CHB患者的免疫狀態(tài)，導(dǎo)致對(duì)炎癥的抑制作用減弱，促進(jìn)CHB病情的發(fā)展。

3.2 對(duì)HBV感染的影響 最新臨床研究[24]發(fā)現(xiàn)，CHB患者出現(xiàn)肝脂肪變性與HBV DNA、HBeAg等病毒因素關(guān)系不大，甚至NAFLD患者中HBV感染率更低，采用傾向性評(píng)分方法，通過匹配研究對(duì)象的性別、年齡及多種代謝因素，發(fā)現(xiàn)CHB患者的病毒學(xué)因素與是否合并肝脂肪變性以及與合并脂肪肝嚴(yán)重程度無關(guān)，肝細(xì)胞脂肪變性不影響肝組織內(nèi)HBsAg、HBcAg的表達(dá)。張志僑等[25]在對(duì)性別和年齡進(jìn)行配對(duì)減少混雜效應(yīng)后發(fā)現(xiàn)，超重/肥胖、膽固醇、TC、LDL、尿酸指標(biāo)升高和飲酒為CHB患者易發(fā)生肝細(xì)胞脂肪變性的因素，肝細(xì)胞脂肪變性與HBV DNA、HBeAg之間無明顯關(guān)系。也有研究[21]表明，CHB合并NAFLD的患者比單純CHB患者的HBsAg、HBeAg表達(dá)水平以及HBV復(fù)制水平均降低。一項(xiàng)關(guān)于臺(tái)北某醫(yī)院的多變量分析研究[26]發(fā)現(xiàn)，BMI、年齡、腰圍、收縮壓、空腹血糖、膽固醇、ALT、PLT與NAFLD的發(fā)生率呈正相關(guān)，HBsAg狀態(tài)與脂肪肝的發(fā)生呈負(fù)相關(guān)，特別是在BMI>22.4 kg/m2、年齡>50歲的患者中表現(xiàn)更明顯。在建立CHB合并NAFLD轉(zhuǎn)基因小鼠模型中發(fā)現(xiàn)，小鼠血清中HBV DNA 載量隨建模時(shí)間的延長(zhǎng)而下降，提示肝脂肪變性可能會(huì)抑制HBV復(fù)制[27]。此外，HBV復(fù)制也受糖代謝和脂質(zhì)代謝的影響，在HBV轉(zhuǎn)染細(xì)胞發(fā)生脂肪變性時(shí)和合并脂肪肝HBV轉(zhuǎn)基因小鼠中均發(fā)現(xiàn)HBV復(fù)制水平降低，且CHB患者合并NALFD時(shí)HBV復(fù)制減少[28]。同時(shí)，肝細(xì)胞內(nèi)參與脂肪、糖代謝的轉(zhuǎn)錄因子也可影響HBV復(fù)制，如控制脂肪酸氧化的轉(zhuǎn)錄因子PPARγ，參與胰島素調(diào)節(jié)糖代謝的翼狀-螺旋轉(zhuǎn)錄因子家族成員中的轉(zhuǎn)錄因子以及調(diào)控膽固醇、脂代謝的膽汁酸受體等均可激活HBV增強(qiáng)子[29]。

3.3 對(duì)CHB患者疾病進(jìn)展的影響 HBV對(duì)肝細(xì)胞長(zhǎng)期損傷可引起肝纖維化、肝硬化和肝癌，NAFLD對(duì)CHB肝纖維化的影響及肝癌的進(jìn)展是否具有協(xié)同作用，目前觀點(diǎn)并不一致。但大多研究結(jié)果都提示肝細(xì)胞脂肪變性與肝損傷有一定關(guān)聯(lián)。國(guó)外學(xué)者[30]對(duì)64例CHB合并NAFLD的患者進(jìn)行肝活組織檢查發(fā)現(xiàn)，86%的患者有不同程度的纖維化，其中39%患者存在進(jìn)展性的肝纖維化，并且肝纖維化程度與腰圍、HBV DNA載量和肝酶水平密切相關(guān)。一項(xiàng)關(guān)于CHB合并NAFLD的纖維化進(jìn)展速率的研究[31]顯示，1/3患者在平均第4.3年時(shí)有肝纖維化進(jìn)展，進(jìn)展速率約為0.059單位/年，大約相當(dāng)于慢性丙型肝炎患者肝纖維化進(jìn)展速率的一半，并且與BMI增高明顯相關(guān)。上述研究表明，肝細(xì)胞脂肪變性在一定程度上影響了CHB的纖維化進(jìn)展。其機(jī)制可能是由單核細(xì)胞趨化蛋白1通過趨化和活化單核/巨噬細(xì)胞，分泌IFNγ、TNFα等促炎性細(xì)胞因子從而引起炎癥反應(yīng)，同時(shí)作為促纖維化介質(zhì)，單核細(xì)胞趨化蛋白1的升高可直接加速肝纖維化[32]。HBV對(duì)肝細(xì)胞長(zhǎng)期損傷可導(dǎo)致CHB患者脂代謝系統(tǒng)失調(diào)，對(duì)脂肪酸攝取及降解作用減弱，而肝功能水平與脂肪因子代謝關(guān)系密切，脂肪因子水平失調(diào)作為啟動(dòng)因子，可引起下游炎性反應(yīng)，通過募集巨噬細(xì)胞、釋放炎性因子，導(dǎo)致肝細(xì)胞受損，酶類釋放增加，從而加速肝硬化的進(jìn)展[33]。近年來，NAFLD相關(guān)性肝癌發(fā)病明顯增多，而HBV感染引起的肝癌則相對(duì)減少[34]，其相關(guān)機(jī)制的研究也在增多，游離脂肪酸在肝細(xì)胞脂肪變性時(shí)蓄積于肝內(nèi)，其本身可能誘導(dǎo)釋放炎性因子使胰島素信號(hào)傳導(dǎo)受阻而加重IR，與肝纖維化進(jìn)展、肝癌的發(fā)生密切相關(guān)[35]。但目前這些研究均為橫斷面分析，具有一定的局限性，NAFLD對(duì)CHB患者病程進(jìn)展的影響需要更深入的研究。

3.4 對(duì)CHB患者抗病毒治療的影響 抗-HBV最有效的藥物是核苷和核苷酸類藥物及干擾素[36]。國(guó)外有研究[37]用長(zhǎng)效IFN治療CHB合并NAFLD患者與單純CHB患者，觀察24周時(shí)抗病毒應(yīng)答情況無明顯差異，即NAFLD對(duì)CHB的抗病毒應(yīng)答無影響。國(guó)外最新一項(xiàng)研究[38]發(fā)現(xiàn)，合并NAFLD組與單純CHB患者抗病毒治療48周HBV DNA抑制率和肝酶水平下降率無統(tǒng)計(jì)學(xué)意義，即對(duì)抗病毒治療無影響。國(guó)內(nèi)也有學(xué)者[39]通過觀察抗病毒治療48、96周時(shí)的療效發(fā)現(xiàn)，單純CHB患者與CHB合并NAFLD患者的病毒學(xué)應(yīng)答情況無統(tǒng)計(jì)學(xué)意義，可能影響其生化學(xué)反應(yīng)。相反，有研究[40]認(rèn)為，肝脂肪變性可能會(huì)降低CHB患者的抗病毒療效，NAFLD使正常肝組織結(jié)構(gòu)發(fā)生改變，藥物與肝細(xì)胞有效接觸面積減少，導(dǎo)致病毒清除障礙。有學(xué)者[41]用恩替卡韋分別治療267例CHB合并NAFLD患者和單純CHB患者，觀察第24、48和96周時(shí)的抗病毒療效、生化學(xué)反應(yīng)，發(fā)現(xiàn)前者的抗病毒療效較單純CHB患者低，說明肝細(xì)胞脂肪變性可降低恩替卡韋的抗病毒療效。董紅筠等[42]對(duì)比發(fā)現(xiàn)CHB合并NAFLD患者使用替比夫定治療1年后的酶學(xué)水平復(fù)常率及病毒載量下降率均高于單純CHB患者。目前，NAFLD對(duì)CHB患者抗病毒治療的影響及影響程度尚不十分明確，需要進(jìn)一步研究證實(shí)。

4 展望

目前研究表明肝細(xì)胞脂肪變性、肝臟炎性反應(yīng)和纖維化之間可能存在一定的相關(guān)性，但無法證實(shí)是否存在因果關(guān)系，雖有研究顯示兩種疾病相互作用可降低HBV DNA載量，但并不能阻止病情的進(jìn)展，無法避免肝纖維化的發(fā)生。因此，開展大樣本、多中心的前瞻性研究，并深入探討分子機(jī)制層面，尋找其內(nèi)在關(guān)系，阻止肝損傷的發(fā)展進(jìn)程，對(duì)提高患者遠(yuǎn)期生存率具有重要意義。

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引證本文：LIU LL, REN Y, HE YH, et al. Research advances in chronic hepatitis B complicated by nonalcoholic fatty liver disease[J]. J Clin Hepatol, 2017, 33(3): 538-542. (in Chinese)

劉璐璐， 任藝， 何毅懷， 等. 慢性乙型肝炎合并非酒精性脂肪性肝病的研究進(jìn)展[J]. 臨床肝膽病雜志, 2017, 33(3): 538-542.

(本文編輯：邢翔宇)

Research advances in chronic hepatitis B complicated by nonalcoholic fatty liver disease

LIULulu,RENYi,HEYihuai,etal.

(DepartmentofInfectiousDiseases,TheAffiliatedHospitalofZunyiMedicalCollege,Zunyi,Guizhou563000,China)

In recent years, with the improvement in quality of life, the incidence of nonalcoholic fatty liver disease (NAFLD) has been gradually increasing, and NAFLD has become a common liver disease with an incidence rate second only to viral hepatitis. Therefore, the number of patients with chronic hepatitis B (CHB) complicated by NAFLD has also been increasing. This article reviews the research advances in the role of hepatitis B virus in promoting NAFLD and the influence of NAFLD on the course of disease and the antiviral effect in CHB patients.

hepatitis B, chronic; fatty liver; review

10.3969/j.issn.1001-5256.2017.03.032

2016-10-17；

2016-11-30。

國(guó)家自然科學(xué)基金資助項(xiàng)目(814600124/H0316)

劉璐璐(1989-)，女，主要從事病毒性肝炎基礎(chǔ)與臨床研究。

林世德，電子信箱：linshide6@hotmail.com。

R512.62； R575.5

A

1001-5256(2017)03-0538-05