劉 燕，張 霞

重慶醫(yī)科大學(xué)附屬第二醫(yī)院消化內(nèi)科，重慶 400010

身體成分與非酒精性脂肪性肝病相關(guān)性研究進(jìn)展

劉 燕，張 霞

重慶醫(yī)科大學(xué)附屬第二醫(yī)院消化內(nèi)科，重慶 400010

非酒精性脂肪性肝病(non-alcoholic fatty liver disease，NAFLD)發(fā)病率逐年上升，其易并發(fā)多種代謝性疾病。身體成分包括脂肪成分和非脂成分，與NAFLD關(guān)系密切，其相關(guān)指標(biāo)有助于預(yù)測(cè)NAFLD發(fā)病及進(jìn)展。本文對(duì)身體成分與NAFLD相關(guān)性作一概述，以期通過(guò)改善身體成分作為預(yù)防和治療NAFLD的方式之一。

身體成分；非酒精性脂肪性肝病

非酒精性脂肪性肝病(non-alcoholic fatty liver disease，NAFLD)是一種與胰島素抵抗(insulin resistance，IR)及炎癥反應(yīng)相關(guān)的代謝性疾病。身體成分與NAFLD的發(fā)生、發(fā)展及并發(fā)癥的發(fā)生關(guān)系密切相關(guān)?，F(xiàn)就身體成分與NAFLD間的關(guān)聯(lián)及其臨床應(yīng)用的研究進(jìn)展作一概述。

1 身體成分

身體成分指身體各組織的總成分，包括脂肪成分和非脂成分及其分布。前者總稱體脂，后者稱瘦體質(zhì)量，瘦體質(zhì)量包括肌肉、骨骼、皮膚、血液、內(nèi)臟器官等。體脂含量占體質(zhì)量百分比稱體脂率。

身體成分有諸多測(cè)量方法。其中人體測(cè)量法可用于預(yù)測(cè)脂肪量及分布，包括體質(zhì)量、體質(zhì)量指數(shù)(body mass index，BMI)、皮褶厚度、腰圍、臀圍、大腿圍、腰臀比、腰身比等[1]。雙能X線法、水下稱重法、生物電阻抗法可用于評(píng)估體脂含量、瘦體質(zhì)量及體脂率[2]。超聲、CT及磁共振成像(MRI)可用于評(píng)估區(qū)域脂肪分布[3]，如皮下及內(nèi)臟脂肪。

2 身體成分與NAFLD

NAFLD發(fā)病機(jī)制復(fù)雜，“二次打擊”學(xué)說(shuō)占主要地位。初次打擊主要指IR和脂質(zhì)代謝紊亂所致的肝細(xì)胞脂質(zhì)沉積，再次打擊是氧化應(yīng)激及脂質(zhì)過(guò)氧化反應(yīng)。同時(shí)，細(xì)胞因子與炎癥反應(yīng)既參與初次打擊脂肪肝形成，也參與再次打擊中肝纖維化的啟動(dòng)與進(jìn)展。而身體成分被證實(shí)與IR及炎癥反應(yīng)關(guān)系密切。

2.1 瘦體質(zhì)量 Barsalani等[4]發(fā)現(xiàn)瘦體質(zhì)量減少可增強(qiáng)絕經(jīng)期婦女炎癥反應(yīng)，獨(dú)立地引起高敏C反應(yīng)蛋白升高。另Fornari等[5]研究顯示瘦體質(zhì)量較高者表現(xiàn)為較低的穩(wěn)態(tài)模型胰島素抵抗指數(shù)(homeostasis model assessment of insulin resistance，HOMA-IR)，即瘦體質(zhì)量與IR呈負(fù)相關(guān)，即瘦體質(zhì)量低者易發(fā)NAFLD，甚至增加死亡率。但Linder等[6]研究顯示在青少年男性中瘦體質(zhì)量較高者IR亦較強(qiáng)，女性則不然。這與男性隨年齡變化的睪酮相關(guān)，其既能增加身高和肌肉量，也能增加血清胰島素及HOMA-IR。然而，成人瘦體質(zhì)量則主要與鍛煉引起的骨骼肌增加相關(guān)。故瘦體質(zhì)量與IR甚至NAFLD的相關(guān)性受年齡及性別影響。

2.2 體脂重 脂肪分布包括外周脂肪與腹部脂肪，腹部脂肪又含皮下脂肪與內(nèi)臟脂肪。Ayonrinde等[7]發(fā)現(xiàn)脂肪分布男女有異，男性有較高內(nèi)臟脂肪而女性則有較高皮下脂肪。體脂及脂肪分布在NAFLD發(fā)生、發(fā)展中起重要作用，同時(shí)或存在性別差異。

2.2.1 總脂：高BMI、高脂肪量及高體脂率與NAFLD明顯相關(guān)[3]。然而Saida等[8]納入1 851名男性和1 259名女性研究發(fā)現(xiàn)，BMI和體脂率的交互作用對(duì)NAFLD的影響只存在于男性，而非女性。同時(shí)他們發(fā)現(xiàn)無(wú)論性別，年齡>20歲者體質(zhì)量增加超過(guò)10 kg與脂肪肝明顯相關(guān)。IR、炎癥反應(yīng)、高脂血癥、高胰島素血癥與BMI密切相關(guān)[1]，意味著高脂肪量者易發(fā)生代謝綜合征(metabolic syndrome，MS)、2型糖尿病(type 2 diabetes mellitus，T2DM)及心血管疾病(cardiovascular disease，CVD)。因此有學(xué)者[9]認(rèn)為BMI可作為體脂量及體脂率的代表，預(yù)測(cè)脂肪肝的進(jìn)展及其并發(fā)癥的發(fā)生。但這個(gè)理論是否存在性別差異有待進(jìn)一步研究。

2.2.2 外周脂肪：Jun等[10]指出在女性中大腿脂肪減少為NAFLD獨(dú)立危險(xiǎn)因素，而在男性中則未表現(xiàn)。同時(shí)無(wú)論男女，大腿脂肪均與許多代謝危險(xiǎn)因素呈負(fù)相關(guān)，包括HOMA-IR、甘油三酯、谷丙轉(zhuǎn)氨酶(alanine transaminase，ALT)和載脂蛋白B。類似地，有研究[11]報(bào)道外周脂肪對(duì)脂肪肝起保護(hù)作用。但缺乏更多關(guān)于性別差異的證據(jù)。Cheung等[12]在2007年報(bào)道了在成人中頸背部脂肪與炎癥反應(yīng)及肝纖維化相關(guān)，加重NAFLD進(jìn)展。但此結(jié)論缺乏近期的研究。

2.2.3 皮下脂肪：目前關(guān)于皮下脂肪對(duì)NAFLD的發(fā)生、發(fā)展起抑制或促進(jìn)作用尚存爭(zhēng)議。Gealekman等[13]認(rèn)為健康皮下脂肪組織對(duì)脂肪肝起保護(hù)作用，因?yàn)橹拘纬尚枰?，皮下脂肪組織比內(nèi)臟脂肪有更好的儲(chǔ)脂作用及促進(jìn)血管生成的能力，可減少內(nèi)臟脂肪。另Borel等[14]發(fā)現(xiàn)皮下脂肪可以分泌脂聯(lián)素及促進(jìn)β細(xì)胞釋放胰島素，減輕IR。但隨著皮下脂肪聚集增多超負(fù)荷，其功能異常導(dǎo)致血管生成能力及儲(chǔ)脂能力下降，更多的脂肪轉(zhuǎn)移至內(nèi)臟，這個(gè)過(guò)程涉及到基因表達(dá)、IR、炎癥反應(yīng)及脂肪壓力[13-15]。因此，健康的皮下脂肪對(duì)NAFLD發(fā)生、發(fā)展及T2DM等并發(fā)癥出現(xiàn)具有保護(hù)作用，而受損的皮下脂肪則起相反作用。尚需進(jìn)一步研究探索皮下脂肪健康與受損之間的界限。

2.2.4 內(nèi)臟脂肪：研究[11]表明，包括肝臟、腸系膜、網(wǎng)膜在內(nèi)的內(nèi)臟脂肪與NAFLD的發(fā)生及惡化相關(guān)，如非酒精性脂肪性肝炎(NASH)及肝纖維化。同時(shí)它是NAFLD患者發(fā)生T2DM及CVD的重要危險(xiǎn)因素[14]。另外，內(nèi)臟脂肪被證實(shí)與ALT相關(guān)[11]，其為NAFLD中的一種早期生物學(xué)指標(biāo)[16]。在健康人中內(nèi)臟脂肪為NAFLD臨床發(fā)作前的表現(xiàn)，能預(yù)測(cè)其發(fā)生。某研究[17]在獲取患者肝病理的基礎(chǔ)上發(fā)現(xiàn)，在無(wú)MS及T2DM的非肥胖者中，內(nèi)臟脂肪亦與各種程度NAFLD相關(guān)，其預(yù)測(cè)價(jià)值優(yōu)于BMI及皮下脂肪。Ayonrinde等[7]發(fā)現(xiàn)相同腰圍下男性比女性有更多內(nèi)臟脂肪，正符合了男性脂肪肝患者進(jìn)展更迅速的現(xiàn)象。然而，F(xiàn)racanzani等[18]研究顯示內(nèi)臟脂肪影響MS及NAFLD的發(fā)生率及臨床表現(xiàn)，但并不影響肝損傷的嚴(yán)重程度及NASH肝纖維化的發(fā)生。

此外，研究[19]發(fā)現(xiàn)增加的心外膜脂肪與BMI、腰圍呈正相關(guān)，同時(shí)在校正腹部脂肪等傳統(tǒng)指標(biāo)后發(fā)現(xiàn)其與NAFLD獨(dú)立相關(guān)。這表明心外膜脂肪影響腹部脂肪代謝，其中涉及到系統(tǒng)性IR、血管及免疫細(xì)胞的炎癥反應(yīng)。

內(nèi)臟脂肪與代謝性疾病相關(guān)性涉及到諸多機(jī)制。首先，內(nèi)臟脂肪相關(guān)的促炎基因轉(zhuǎn)錄作為先決條件使CD11c+CD206+和CCR2+的巨噬細(xì)胞膨脹，分泌促炎因子[20]。增加的趨化因子及脂肪因子包括白介素6、白介素8、腫瘤壞死因子、抵抗素，而抗炎因子(脂聯(lián)素、瘦素、白介素10)則降低[21]。而這些因子將影響炎癥反應(yīng)、氧化代謝、能量消耗、內(nèi)皮功能及脂肪分布[22]，從而影響NAFLD及其他代謝疾病。其次，研究[23]發(fā)現(xiàn)腹部脂肪與系統(tǒng)性IR相關(guān)，獨(dú)立于年齡、性別，因細(xì)胞脂質(zhì)沉積破壞胰島素信號(hào)轉(zhuǎn)導(dǎo)途徑。NAFLD及MS則為系統(tǒng)性IR的產(chǎn)物。另外，內(nèi)臟脂肪相鄰解剖結(jié)構(gòu)引起相關(guān)血管及代謝疾病，如肝內(nèi)脂肪代謝物可通過(guò)肝內(nèi)血管肝內(nèi)傳播，腸系膜、大網(wǎng)膜等處代謝產(chǎn)物可通過(guò)門靜脈系統(tǒng)入肝而造成肝損傷[24]。

3 身體成分在NAFLD中的應(yīng)用

3.1 疾病預(yù)測(cè) 既然身體成分與代謝性疾病發(fā)生、發(fā)展、轉(zhuǎn)歸密切相關(guān)，這對(duì)臨床預(yù)測(cè)、預(yù)防、治療疾病有指導(dǎo)意義。研究[1]發(fā)現(xiàn)，BMI、腰圍、腰身比與體脂量及體脂率相關(guān)，而體脂量和體脂率與NAFLD相關(guān)。相較內(nèi)臟脂肪，腰圍、腰身比與皮下脂肪關(guān)聯(lián)更密切，而軀干四肢脂肪比、腰臀比則與內(nèi)臟脂肪關(guān)聯(lián)最密切[25]。因此，BMI、腰圍、腰身比、腰臀比可作為普篩項(xiàng)目來(lái)預(yù)測(cè)NAFLD。Monteiro等[3]認(rèn)為腰圍作為一個(gè)特異性高于敏感性的指標(biāo)，在兒童和成人中對(duì)NAFLD均有高預(yù)測(cè)價(jià)值。Kim等[26]發(fā)現(xiàn)在韓國(guó)男性中脂肪指數(shù)聯(lián)合腰身比相較其他指標(biāo)對(duì)代謝因素有最佳預(yù)測(cè)效果。而體脂率及體脂分布尤其內(nèi)臟脂肪更與NAFLD和MS相關(guān)，預(yù)測(cè)價(jià)值高。因此，人們可及時(shí)監(jiān)測(cè)身體成分相關(guān)指標(biāo)，其異常結(jié)果有助于醫(yī)者在看似正常人群中預(yù)測(cè)和預(yù)防NAFLD發(fā)生，同時(shí)在疾病期有針對(duì)地減肥治療，避免嚴(yán)重并發(fā)癥的發(fā)生。

3.2 綜合治療 長(zhǎng)期飲食調(diào)節(jié)(包括減少反式脂肪酸、果糖和增加多不飽和脂肪酸)可降低BMI，減少脂肪量、皮下及內(nèi)臟脂肪，進(jìn)而改善NAFLD患者肝功能[27]。此外，有氧運(yùn)動(dòng)尤其抗阻訓(xùn)練可減少總脂肪量、軀干脂肪和增加瘦體質(zhì)量，從而改善炎癥反應(yīng)、IR及肝纖維化[28]。近期Meta分析[29]展現(xiàn)了減肥手術(shù)治療病態(tài)肥胖合并NAFLD的優(yōu)越性，其可使BMI平均下降15.13，腹部脂肪亦有不同程度下降。其可改善IR及慢性炎癥，表現(xiàn)為不加重各階段肝纖維化，同時(shí)降低肝脂肪變性、肝氣球樣變、小葉炎癥及HOMA-IR。但關(guān)于手術(shù)遠(yuǎn)期副反應(yīng)報(bào)道少，且在肝硬化患者中有效性及安全性尚不明確，需大樣本研究及長(zhǎng)期隨訪。Marchesini等[30]對(duì)手術(shù)者(十二指腸轉(zhuǎn)位術(shù)、膽胰分流術(shù)、胃旁路術(shù)、胃束帶術(shù)、袖狀胃減容術(shù))隨訪12個(gè)月，用BAROS評(píng)估生活質(zhì)量、體質(zhì)量減輕量、臨床條件、并發(fā)癥、再手術(shù)率等，發(fā)現(xiàn)十二指腸轉(zhuǎn)位術(shù)評(píng)分最高。關(guān)于減肥藥物，研究[31]認(rèn)為脂肪因子類的胰淀素受體激動(dòng)劑(普蘭林肽)和瘦素類似物(曲美普汀)均能減少體脂及內(nèi)臟脂肪，但副作用較大。而納洛酮和丁胺苯丙酮融合的緩釋劑(納曲酮)、選擇性5羥色胺受體激動(dòng)劑(氯卡色林)、GLP-1受體(利拉魯肽)及脂肪酶抑制劑(奧利司他)均能降低脂肪，但缺乏遠(yuǎn)期不良反應(yīng)觀察。總之，生活方式干預(yù)聯(lián)合減重手術(shù)可改善患者身體成分，最終改善NAFLD等代謝病。

總脂及脂肪分布與NAFLD發(fā)生發(fā)展轉(zhuǎn)歸及其并發(fā)癥的出現(xiàn)明顯相關(guān)，人體測(cè)量學(xué)指標(biāo)有助于預(yù)測(cè)NAFLD發(fā)病及進(jìn)展風(fēng)險(xiǎn)，并通過(guò)改善身體成分的綜合治療可達(dá)到預(yù)防和治療疾病的目的。但仍待進(jìn)一步研究明確何種指標(biāo)對(duì)NAFLD預(yù)測(cè)效果最佳，是否存在年齡及性別差異，及針對(duì)改善生活方式無(wú)效者如何通過(guò)更安全有效的藥物減少腹部脂肪以改善NAFLD。

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(責(zé)任編輯：王全楚)

Progress of the correlation between body composition and non-alcoholic fatty liver disease

LIU Yan,ZHANG Xia

Department of Gastroenterology,the Second Affiliated Hospital of Chongqing Medical University,Chongqing 400010,China

The incidence of non-alcoholic fatty liver disease (NAFLD) is increasing year by year,which can develop into multiple metabolic diseases. Body composition,containing fat mass and lean mass,is closely related with NAFLD. Some correlative indicators can be used to predict risk and progress of NAFLD. This article will summarize the correlation between body composition and NAFLD,aiming to prevent and treat NAFLD through improving body composition.

Body composition; Non-alcoholic fatty liver disease

劉燕，在讀碩士研究生，研究方向：肝病。E-mail：jianjian200909@163.com

張霞，博士，教授，主任醫(yī)師，研究方向：肝病與代謝綜合征。E-mail：sunnyzhangx@gmail.com

10.3969/j.issn.1006-5709.2016.04.004

R575.5

A

1006-5709(2016)04-0375-03

2015-07-11