非酒精性脂肪性肝病無(wú)創(chuàng)診斷和評(píng)估的臨床研究進(jìn)展

顧天翊 陸倫根

上海交通大學(xué)附屬第一人民醫(yī)院消化科(200080)

非酒精性脂肪性肝病無(wú)創(chuàng)診斷和評(píng)估的臨床研究進(jìn)展

顧天翊 陸倫根*

上海交通大學(xué)附屬第一人民醫(yī)院消化科(200080)

非酒精性脂肪性肝病(NAFLD)是指除外長(zhǎng)期大量飲酒和其他損傷肝臟因素所引起的以肝臟脂肪沉積為主要表現(xiàn)的臨床綜合征，其發(fā)病機(jī)制與環(huán)境、遺傳、免疫等多種因素相關(guān)。早期診斷有助于鑒別單純性非酒精性脂肪肝(NAFL)和非酒精性脂肪性肝炎(NASH)，同時(shí)可對(duì)NAFLD病變程度進(jìn)行分級(jí)并延緩其進(jìn)一步發(fā)展。本文就NAFLD無(wú)創(chuàng)診斷和評(píng)估的臨床研究進(jìn)展作一綜述。

非酒精性脂肪性肝?。?非酒精性脂肪性肝炎； 肝硬化； 生物學(xué)標(biāo)記； 無(wú)創(chuàng)診斷

Correspondenceto: LU Lungen, Email: lungenlu1965@163.com

AbstractNon-alcoholic fatty liver disease (NAFLD) is a clinical syndrome characterized by hepatic fat deposition, and not caused by chronic heavy drinking and other liver damage factors. The pathogenesis of NAFLD is associated with environmental, genetic, immune and other various factors. Early diagnosis is helpful not only for distinguishing between simple non-alcoholic fatty liver (NAFL) and non-alcoholic steatohepatitis (NASH), but also for grading the extent of NAFLD lesion and delaying its further development. This article reviewed the clinical research progress of non-invasive diagnosis and evaluation of NAFLD.

KeywordsNon-Alcoholic Fatty Liver Disease; Non-Alcoholic Steatohepatitis; Liver Cirrhosis; Biological Markers; Non-Invasive Diagnosis

非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)是指除外長(zhǎng)期大量飲酒和其他損傷肝臟因素所引起的以肝臟脂肪沉積為主要表現(xiàn)的一組臨床綜合征。患者肝臟脂肪代謝功能出現(xiàn)明顯障礙，使大量脂肪類(lèi)物質(zhì)蓄積于肝細(xì)胞內(nèi)，導(dǎo)致肝細(xì)胞發(fā)生脂肪變性，從單純性非酒精性脂肪肝(NAFL)發(fā)展到非酒精性脂肪性肝炎(non-alcoholic steatohepatitis, NASH)，最終發(fā)展為肝纖維化、肝硬化和終末期肝病，甚至肝癌。NAFL是一種相對(duì)良性的臨床過(guò)程，但10%～15%的NASH可能發(fā)展為肝硬化甚至肝癌。因此對(duì)NAFLD進(jìn)行預(yù)防、診斷、評(píng)估和治療顯得尤為重要，尤其是NAFLD無(wú)創(chuàng)診斷的建立對(duì)患者的隨訪和監(jiān)測(cè)具有更重要的臨床意義。本文就NAFLD無(wú)創(chuàng)診斷和評(píng)估的臨床研究進(jìn)展作一綜述。

一、流行病學(xué)

雖然NAFLD在全世界范圍內(nèi)的流行病學(xué)和人口學(xué)特征各不相同，但其總體發(fā)病率呈上升趨勢(shì)，病死率明顯高于年齡和性別相同的普通人群，因而NAFLD已成為全球不可忽視的公共健康問(wèn)題。全球超過(guò)6億人口患有NAFLD，其中歐美約4億，中國(guó)約2億。中國(guó)NAFLD患者例數(shù)約占全國(guó)總?cè)丝跀?shù)的15%，占肝病患者總例數(shù)的49.3%[1]。44%～64%的NAFL患者在發(fā)病后3～7年可進(jìn)展為NASH，其中10%～25%的NASH患者在NAFL確診后8～14年可進(jìn)展為晚期肝纖維化或肝硬化(平均每7年進(jìn)展至下一個(gè)肝纖維化階段)；2%～13%的晚期肝纖維化或肝硬化患者在確診后3～7年可進(jìn)展為肝癌；22%～24%的NAFL患者在發(fā)病后3～7年可進(jìn)展為晚期肝纖維化或肝硬化[2]。一般認(rèn)為，NAFL是進(jìn)展緩慢的良性、可逆性疾病，而NASH更容易發(fā)展為肝纖維化、肝硬化甚至肝癌，NAFL進(jìn)展為NASH是病情惡化的轉(zhuǎn)折點(diǎn)，NASH或顯著肝纖維化患者的終末期肝病并發(fā)癥發(fā)生風(fēng)險(xiǎn)最大。

二、NAFLD的診斷和評(píng)估

NAFLD可導(dǎo)致血脂異常、胰島素抵抗增強(qiáng)、血糖升高以及嚴(yán)重的心血管疾病[3]，因此早期診斷尤為重要。NAFLD的診斷和評(píng)估取決于肝臟脂肪變程度、肝臟炎癥程度以及肝纖維化程度。NAFLD的診斷方法分為無(wú)創(chuàng)和有創(chuàng)兩種。無(wú)創(chuàng)診斷包括臨床評(píng)估、血清生物標(biāo)記物、影像學(xué)檢查和綜合診斷等；有創(chuàng)診斷主要指組織病理學(xué)檢查。目前肝穿刺活檢仍是診斷NASH以及評(píng)估肝纖維化程度的金標(biāo)準(zhǔn)[4]。根據(jù)WGO指南，肝活檢對(duì)于疾病診斷、分期、鑒別診斷以及治療方案選擇具有重要意義[5]。然而，肝穿刺活檢的有創(chuàng)性及其并發(fā)癥的發(fā)生風(fēng)險(xiǎn)限制了其在臨床的廣泛應(yīng)用。因此，建立新的或進(jìn)一步評(píng)價(jià)現(xiàn)有的無(wú)創(chuàng)診斷方法，從而及時(shí)發(fā)現(xiàn)并診斷NASH和進(jìn)展期肝纖維化，對(duì)于患者的治療和預(yù)后具有重要意義。

NAFLD的組織學(xué)評(píng)估方法一般利用NAFLD活動(dòng)度(NAS)評(píng)分系統(tǒng)來(lái)評(píng)估疾病嚴(yán)重程度，主要包括肝脂肪變(0～3分)、小葉炎癥(0～2分)和肝細(xì)胞氣球樣變(0～2分)，總分≥5分診斷為NASH，<3分排除NASH，4分疑似NASH。盡管NAS評(píng)分與穩(wěn)態(tài)模型評(píng)估胰島素抵抗指數(shù)(HOMA-IR)的相關(guān)性良好，但其預(yù)后價(jià)值較低。近年提出的NAFLD脂肪變性、活動(dòng)度和纖維化(SAF)評(píng)分系統(tǒng)評(píng)估指標(biāo)與NAS評(píng)分相同，但其評(píng)判標(biāo)準(zhǔn)不同。已證實(shí)SAF評(píng)分系統(tǒng)重復(fù)性更好，且描述更為準(zhǔn)確全面[6]，已得到越來(lái)越廣泛的應(yīng)用。

三、NAFLD的無(wú)創(chuàng)診斷方法

1. 臨床評(píng)估：NAFLD的高危人群包括年齡>40歲、體質(zhì)指數(shù)(BMI)>24 kg/m2、糖耐量異常、2型糖尿病、高血壓、高脂血癥和代謝綜合征患者。Li等[7]通過(guò)對(duì)21項(xiàng)隊(duì)列研究進(jìn)行meta分析發(fā)現(xiàn)，肥胖人群的NAFLD患病風(fēng)險(xiǎn)是正常人群的3.5倍，且與BMI呈正相關(guān)；多項(xiàng)研究[8-10]結(jié)果證實(shí)，NAFLD的發(fā)病與特定基因(如PNPLA3和TM6SF2)突變也有一定相關(guān)性，且基因突變型NAFLD一般不易發(fā)生心血管疾病。

2. 血清生物標(biāo)記物：生化指標(biāo)對(duì)NAFLD肝脂肪變、炎癥和纖維化有一定診斷價(jià)值?，F(xiàn)有指標(biāo)包括鐵蛋白、IgA、IgG、IgM、細(xì)胞角蛋白18(CK-18)、視黃醇結(jié)合蛋白、Ⅲ型前膠原、脂聯(lián)素、瘦素、微RNA(miRNA)、β抑制蛋白、熱休克蛋白70和炎癥標(biāo)記物(如IL-6、超敏C反應(yīng)蛋白和TNF-α)等[11-13]，但這些指標(biāo)的診斷價(jià)值和臨床應(yīng)用仍有待進(jìn)一步驗(yàn)證[14]。多項(xiàng)研究[15-16]發(fā)現(xiàn)，SteatoTest用于預(yù)測(cè)肝臟脂肪變性時(shí)，具有無(wú)創(chuàng)、操作簡(jiǎn)單和定量評(píng)估的特點(diǎn)，在一定程度上可減少肝穿刺的需求，尤其是對(duì)伴有重度肥胖伴代謝危險(xiǎn)因素的患者。Fedchuk等[17]的研究表明脂肪肝指數(shù)(FLI)、NAFLD-肝臟脂肪分?jǐn)?shù)(NAFLD-LFS)、三酰甘油-葡萄糖指數(shù)、內(nèi)臟脂肪指數(shù)(VAI)和肝脂肪變性指數(shù)(HSI)這五項(xiàng)指標(biāo)可用于診斷肝脂肪變性，且與胰島素抵抗有相關(guān)性，但因受肝纖維化和炎癥影響，無(wú)法精確定量評(píng)估脂肪變性程度，使其臨床應(yīng)用受到限制。丙氨酸氨基轉(zhuǎn)移酶(ALT)水平升高的NAFLD患者的NASH患病風(fēng)險(xiǎn)更高，但ALT水平正常的患者亦無(wú)法完全排除NASH的可能，因此ALT水平并不能確診NASH[18]。此外，較有應(yīng)用前景的NAFLD診斷標(biāo)記物還包括CK-18、脂聯(lián)素、IL-6和CCL2[19]。為提高實(shí)驗(yàn)室指標(biāo)預(yù)測(cè)NAFLD相關(guān)肝纖維化的評(píng)估價(jià)值，許多研究者將其與臨床指標(biāo)聯(lián)合用于肝纖維化的預(yù)測(cè)評(píng)分，包括BARD評(píng)分[20]、FIB-4評(píng)分[21]、NAFLD纖維化評(píng)分[22]和FibroMeter評(píng)分[23]等。

3. 影像學(xué)檢查：NAFLD的影像學(xué)檢查方法包括腹部超聲、CT、磁共振成像(MRI)和瞬時(shí)彈性成像(TE)等[24]，目前這些方法均無(wú)法鑒別診斷單純性脂肪肝和NASH。Imajo等[25]認(rèn)為MRI與MRE相比，在診斷肝臟脂肪變性和肝纖維化方面更具優(yōu)勢(shì)。

腹部超聲是最常用和經(jīng)濟(jì)的檢查方法，是無(wú)癥狀的肝臟酶升高患者和NAFLD患者的首選方法。腹部超聲的敏感性為60%～94%，與肝臟脂肪變性程度呈正相關(guān)；當(dāng)肝臟脂肪變性程度>33%時(shí)，腹部超聲的敏感性為100%，特異性為84%～95%；當(dāng)肝臟脂肪變性程度<30%時(shí)，超聲檢查難以檢出，可能會(huì)漏診25%～33%的患者。對(duì)于肥胖癥患者，腹部超聲的敏感性還將降低40%[26]。彌漫性肝臟脂肪變性和肝纖維化有類(lèi)似的超聲表現(xiàn)，因此超聲檢測(cè)有時(shí)很難區(qū)分兩者。

CT診斷脂肪肝的特異性高于超聲檢查，但其敏感性較差。對(duì)肝臟脂肪變性程度的診斷價(jià)值，增強(qiáng)CT并不優(yōu)于CT平掃。CT平掃可觀察肝臟的密度改變，并可利用密度梯度管對(duì)肝臟脂肪進(jìn)行半定量分析。存在脂肪變性的肝臟CT成像較脾臟深且兩者衰減參數(shù)不同[27]，通過(guò)計(jì)算肝脾比值可對(duì)脂肪肝嚴(yán)重程度進(jìn)行分級(jí)：輕度0.7～1.0，中度0.5～0.7，重度<0.5。

質(zhì)子磁共振頻譜分析(1H-MRS)是近年發(fā)展起來(lái)的新型影像學(xué)檢查手段，可檢測(cè)極低含量脂肪，診斷價(jià)值優(yōu)于超聲、CT和傳統(tǒng)MRI，可鑒別診斷無(wú)纖維化NASH，是目前無(wú)創(chuàng)定量診斷脂肪肝最準(zhǔn)確的方法，在一定程度上可取代病理檢查[28-29]。定量MRI所測(cè)的質(zhì)子密度脂肪分?jǐn)?shù)和單能量CT(SECT)所測(cè)的脂肪衰減參數(shù)(FAP)與MRS測(cè)量結(jié)果的相關(guān)性良好，可作為精確量化脂肪變性程度的非侵入性指標(biāo)[30]。FAP是利用超聲衰減原理重新定義的新參數(shù)，是一種準(zhǔn)確、可靠的非侵入性檢查指標(biāo)，可結(jié)合其他生物標(biāo)記物，全面檢測(cè)和量化肝臟脂肪變性程度[31]。

TE技術(shù)是采用低頻剪切波對(duì)肝臟組織實(shí)施主動(dòng)激勵(lì)以形成應(yīng)變，同時(shí)利用專業(yè)探頭捕捉低頻剪切波在肝臟中的傳播過(guò)程以及超聲信號(hào)在傳播過(guò)程中的能量衰減，從而快速定量肝臟組織彈性值和脂肪變性程度，評(píng)估肝纖維化程度和脂肪肝病變程度。目前常用于臨床的肝臟硬度測(cè)定儀是法國(guó)的FibroScan和我國(guó)的FibroTouch。FibroTouch是一類(lèi)影像(超聲)引導(dǎo)的肝纖維化和脂肪肝程度的集成檢測(cè)系統(tǒng)，可同時(shí)完成肝臟硬度值和FAP值的測(cè)定，提供對(duì)肝臟組織形態(tài)、纖維化程度和脂肪變性程度的一體化檢測(cè)和全方位評(píng)估方案。Wong等[32]證實(shí)，肝臟硬度值不受肝脂肪變性的影響。研究[33]表明，F(xiàn)ibroTouch能較好反映慢性乙型肝炎(CHB)患者的肝臟脂肪變性程度，可用于CHB合并NAFLD患者的臨床診治。

受控衰減參數(shù)(CAP)是衡量肝臟脂肪變性程度的重要指標(biāo)[34]，其與肝臟脂肪含量獨(dú)立相關(guān)，可有效區(qū)分不同程度的肝臟脂肪變性[24,35]。然而有研究顯示TE技術(shù)用于診斷NAFLD的可靠性不高。Gaia等[36]通過(guò)對(duì)219例(35%為慢性丙型肝炎，32%為CHB，33%為NAFLD)6個(gè)月內(nèi)接受過(guò)肝臟活檢的慢性肝病患者進(jìn)行TE檢測(cè)發(fā)現(xiàn)，TE技術(shù)可作為評(píng)估慢性丙型肝炎患者肝纖維化的有力手段，但其用于CHB和NAFLD患者時(shí)，易受患者本身以及疾病相關(guān)因素的影響，無(wú)法作出準(zhǔn)確診斷。

四、結(jié)語(yǔ)

綜上所述，肝活檢仍是評(píng)估NAFLD嚴(yán)重程度的金標(biāo)準(zhǔn)。NAFLD的無(wú)創(chuàng)診斷研究較多，但尚未廣泛應(yīng)用于臨床，其準(zhǔn)確性和有效性仍需進(jìn)一步綜合評(píng)估加以證實(shí)，評(píng)估內(nèi)容包括代謝相關(guān)因素、肝臟脂肪變性程度、肝臟炎癥和肝纖維化程度等。隨著醫(yī)學(xué)技術(shù)的不斷發(fā)展，NAFLD的無(wú)創(chuàng)診斷將具有越來(lái)越廣闊的前景。

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(2017-03-24收稿；2017-04-04修回)

ProgressinNon-invasiveDiagnosisandAssessmentofNon-alcoholicFattyLiverDisease

GUTianyi,LULungen.

DepartmentofGastroenterology,ShanghaiGeneralHospital,ShanghaiJiaoTongUniversitySchoolofMedicine,Shanghai(200080)

10.3969/j.issn.1008-7125.2017.09.011

*本文通信作者，Email: lungenlu1965@163.com