非酒精性脂肪性肝病无创诊断和评估的临床研究进展

顾天翊 陆伦根

上海交通大学附属第一人民医院消化科(200080)

非酒精性脂肪性肝病无创诊断和评估的临床研究进展

顾天翊 陆伦根*

上海交通大学附属第一人民医院消化科(200080)

非酒精性脂肪性肝病(NAFLD)是指除外长期大量饮酒和其他损伤肝脏因素所引起的以肝脏脂肪沉积为主要表现的临床综合征，其发病机制与环境、遗传、免疫等多种因素相关。早期诊断有助于鉴别单纯性非酒精性脂肪肝(NAFL)和非酒精性脂肪性肝炎(NASH)，同时可对NAFLD病变程度进行分级并延缓其进一步发展。本文就NAFLD无创诊断和评估的临床研究进展作一综述。

非酒精性脂肪性肝病； 非酒精性脂肪性肝炎； 肝硬化； 生物学标记； 无创诊断

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)是指除外长期大量饮酒和其他损伤肝脏因素所引起的以肝脏脂肪沉积为主要表现的一组临床综合征。患者肝脏脂肪代谢功能出现明显障碍，使大量脂肪类物质蓄积于肝细胞内，导致肝细胞发生脂肪变性，从单纯性非酒精性脂肪肝(NAFL)发展到非酒精性脂肪性肝炎(non-alcoholic steatohepatitis, NASH)，最终发展为肝纤维化、肝硬化和终末期肝病，甚至肝癌。NAFL是一种相对良性的临床过程，但10%～15%的NASH可能发展为肝硬化甚至肝癌。因此对NAFLD进行预防、诊断、评估和治疗显得尤为重要，尤其是NAFLD无创诊断的建立对患者的随访和监测具有更重要的临床意义。本文就NAFLD无创诊断和评估的临床研究进展作一综述。

一、流行病学

虽然NAFLD在全世界范围内的流行病学和人口学特征各不相同，但其总体发病率呈上升趋势，病死率明显高于年龄和性别相同的普通人群，因而NAFLD已成为全球不可忽视的公共健康问题。全球超过6亿人口患有NAFLD，其中欧美约4亿，中国约2亿。中国NAFLD患者例数约占全国总人口数的15%，占肝病患者总例数的49.3%[1]。44%～64%的NAFL患者在发病后3～7年可进展为NASH，其中10%～25%的NASH患者在NAFL确诊后8～14年可进展为晚期肝纤维化或肝硬化(平均每7年进展至下一个肝纤维化阶段)；2%～13%的晚期肝纤维化或肝硬化患者在确诊后3～7年可进展为肝癌；22%～24%的NAFL患者在发病后3～7年可进展为晚期肝纤维化或肝硬化[2]。一般认为，NAFL是进展缓慢的良性、可逆性疾病，而NASH更容易发展为肝纤维化、肝硬化甚至肝癌，NAFL进展为NASH是病情恶化的转折点，NASH或显著肝纤维化患者的终末期肝病并发症发生风险最大。

二、NAFLD的诊断和评估

NAFLD可导致血脂异常、胰岛素抵抗增强、血糖升高以及严重的心血管疾病[3]，因此早期诊断尤为重要。NAFLD的诊断和评估取决于肝脏脂肪变程度、肝脏炎症程度以及肝纤维化程度。NAFLD的诊断方法分为无创和有创两种。无创诊断包括临床评估、血清生物标记物、影像学检查和综合诊断等；有创诊断主要指组织病理学检查。目前肝穿刺活检仍是诊断NASH以及评估肝纤维化程度的金标准[4]。根据WGO指南，肝活检对于疾病诊断、分期、鉴别诊断以及治疗方案选择具有重要意义[5]。然而，肝穿刺活检的有创性及其并发症的发生风险限制了其在临床的广泛应用。因此，建立新的或进一步评价现有的无创诊断方法，从而及时发现并诊断NASH和进展期肝纤维化，对于患者的治疗和预后具有重要意义。

NAFLD的组织学评估方法一般利用NAFLD活动度(NAS)评分系统来评估疾病严重程度，主要包括肝脂肪变(0～3分)、小叶炎症(0～2分)和肝细胞气球样变(0～2分)，总分≥5分诊断为NASH，<3分排除NASH，4分疑似NASH。尽管NAS评分与稳态模型评估胰岛素抵抗指数(HOMA-IR)的相关性良好，但其预后价值较低。近年提出的NAFLD脂肪变性、活动度和纤维化(SAF)评分系统评估指标与NAS评分相同，但其评判标准不同。已证实SAF评分系统重复性更好，且描述更为准确全面[6]，已得到越来越广泛的应用。

三、NAFLD的无创诊断方法

1. 临床评估：NAFLD的高危人群包括年龄>40岁、体质指数(BMI)>24 kg/m2、糖耐量异常、2型糖尿病、高血压、高脂血症和代谢综合征患者。Li等[7]通过对21项队列研究进行meta分析发现，肥胖人群的NAFLD患病风险是正常人群的3.5倍，且与BMI呈正相关；多项研究[8-10]结果证实，NAFLD的发病与特定基因(如PNPLA3和TM6SF2)突变也有一定相关性，且基因突变型NAFLD一般不易发生心血管疾病。

2. 血清生物标记物：生化指标对NAFLD肝脂肪变、炎症和纤维化有一定诊断价值。现有指标包括铁蛋白、IgA、IgG、IgM、细胞角蛋白18(CK-18)、视黄醇结合蛋白、Ⅲ型前胶原、脂联素、瘦素、微RNA(miRNA)、β抑制蛋白、热休克蛋白70和炎症标记物(如IL-6、超敏C反应蛋白和TNF-α)等[11-13]，但这些指标的诊断价值和临床应用仍有待进一步验证[14]。多项研究[15-16]发现，SteatoTest用于预测肝脏脂肪变性时，具有无创、操作简单和定量评估的特点，在一定程度上可减少肝穿刺的需求，尤其是对伴有重度肥胖伴代谢危险因素的患者。Fedchuk等[17]的研究表明脂肪肝指数(FLI)、NAFLD-肝脏脂肪分数(NAFLD-LFS)、三酰甘油-葡萄糖指数、内脏脂肪指数(VAI)和肝脂肪变性指数(HSI)这五项指标可用于诊断肝脂肪变性，且与胰岛素抵抗有相关性，但因受肝纤维化和炎症影响，无法精确定量评估脂肪变性程度，使其临床应用受到限制。丙氨酸氨基转移酶(ALT)水平升高的NAFLD患者的NASH患病风险更高，但ALT水平正常的患者亦无法完全排除NASH的可能，因此ALT水平并不能确诊NASH[18]。此外，较有应用前景的NAFLD诊断标记物还包括CK-18、脂联素、IL-6和CCL2[19]。为提高实验室指标预测NAFLD相关肝纤维化的评估价值，许多研究者将其与临床指标联合用于肝纤维化的预测评分，包括BARD评分[20]、FIB-4评分[21]、NAFLD纤维化评分[22]和FibroMeter评分[23]等。

3. 影像学检查：NAFLD的影像学检查方法包括腹部超声、CT、磁共振成像(MRI)和瞬时弹性成像(TE)等[24]，目前这些方法均无法鉴别诊断单纯性脂肪肝和NASH。Imajo等[25]认为MRI与MRE相比，在诊断肝脏脂肪变性和肝纤维化方面更具优势。

腹部超声是最常用和经济的检查方法，是无症状的肝脏酶升高患者和NAFLD患者的首选方法。腹部超声的敏感性为60%～94%，与肝脏脂肪变性程度呈正相关；当肝脏脂肪变性程度>33%时，腹部超声的敏感性为100%，特异性为84%～95%；当肝脏脂肪变性程度<30%时，超声检查难以检出，可能会漏诊25%～33%的患者。对于肥胖症患者，腹部超声的敏感性还将降低40%[26]。弥漫性肝脏脂肪变性和肝纤维化有类似的超声表现，因此超声检测有时很难区分两者。

CT诊断脂肪肝的特异性高于超声检查，但其敏感性较差。对肝脏脂肪变性程度的诊断价值，增强CT并不优于CT平扫。CT平扫可观察肝脏的密度改变，并可利用密度梯度管对肝脏脂肪进行半定量分析。存在脂肪变性的肝脏CT成像较脾脏深且两者衰减参数不同[27]，通过计算肝脾比值可对脂肪肝严重程度进行分级：轻度0.7～1.0，中度0.5～0.7，重度<0.5。

质子磁共振频谱分析(1H-MRS)是近年发展起来的新型影像学检查手段，可检测极低含量脂肪，诊断价值优于超声、CT和传统MRI，可鉴别诊断无纤维化NASH，是目前无创定量诊断脂肪肝最准确的方法，在一定程度上可取代病理检查[28-29]。定量MRI所测的质子密度脂肪分数和单能量CT(SECT)所测的脂肪衰减参数(FAP)与MRS测量结果的相关性良好，可作为精确量化脂肪变性程度的非侵入性指标[30]。FAP是利用超声衰减原理重新定义的新参数，是一种准确、可靠的非侵入性检查指标，可结合其他生物标记物，全面检测和量化肝脏脂肪变性程度[31]。

TE技术是采用低频剪切波对肝脏组织实施主动激励以形成应变，同时利用专业探头捕捉低频剪切波在肝脏中的传播过程以及超声信号在传播过程中的能量衰减，从而快速定量肝脏组织弹性值和脂肪变性程度，评估肝纤维化程度和脂肪肝病变程度。目前常用于临床的肝脏硬度测定仪是法国的FibroScan和我国的FibroTouch。FibroTouch是一类影像(超声)引导的肝纤维化和脂肪肝程度的集成检测系统，可同时完成肝脏硬度值和FAP值的测定，提供对肝脏组织形态、纤维化程度和脂肪变性程度的一体化检测和全方位评估方案。Wong等[32]证实，肝脏硬度值不受肝脂肪变性的影响。研究[33]表明，FibroTouch能较好反映慢性乙型肝炎(CHB)患者的肝脏脂肪变性程度，可用于CHB合并NAFLD患者的临床诊治。

受控衰减参数(CAP)是衡量肝脏脂肪变性程度的重要指标[34]，其与肝脏脂肪含量独立相关，可有效区分不同程度的肝脏脂肪变性[24,35]。然而有研究显示TE技术用于诊断NAFLD的可靠性不高。Gaia等[36]通过对219例(35%为慢性丙型肝炎，32%为CHB，33%为NAFLD)6个月内接受过肝脏活检的慢性肝病患者进行TE检测发现，TE技术可作为评估慢性丙型肝炎患者肝纤维化的有力手段，但其用于CHB和NAFLD患者时，易受患者本身以及疾病相关因素的影响，无法作出准确诊断。

四、结语

综上所述，肝活检仍是评估NAFLD严重程度的金标准。NAFLD的无创诊断研究较多，但尚未广泛应用于临床，其准确性和有效性仍需进一步综合评估加以证实，评估内容包括代谢相关因素、肝脏脂肪变性程度、肝脏炎症和肝纤维化程度等。随着医学技术的不断发展，NAFLD的无创诊断将具有越来越广阔的前景。

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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