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Research advances in the serological diagnosis of nonalcoholic fatty liver disease
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摘要:
近年来非酒精性脂肪性肝病（NAFLD）的患病率明显升高,已逐渐成为我国常见的慢性肝病之一。而NAFLD相关终末期或恶化性肝病患者已成为肝移植的主要人群之一。NAFLD发病率的增加和非酒精性脂肪性肝炎（NASH）的严重后果使得有必要使用有效的方法来识别NAFLD。基于此,总结了目前血清学方法诊断NAFLD,包括脂肪变性、NASH和肝纤维化,并探讨了其优缺点。尽管大部分血清标志物真正应用于临床的价值有限,但血清标志物模型在诊断肝脂肪变性及评估纤维化程度和初步筛查方面均有较好的应用前景。由于联合不同血清学模型可以提高诊断的准确度,因此开展多角度、多中心的联合诊断将是未来的研究热点。
Abstract:In recent years,the prevalence rate of nonalcoholic fatty liver disease( NAFLD) has increased significantly and NAFLD has gradually become one of the common chronic liver diseases in China. Patients with NAFLD-related end-stage or deteriorative liver diseases have become one of the main populations for liver transplantation. The increasing prevalence rate of NAFLD and the severe outcomes of nonalcoholic steatohepatitis( NASH) make it necessary to use effective methods to identify NAFLD. Therefore,this article summarizes the current serological methods for the diagnosis of NAFLD,including steatosis,NASH,and liver fibrosis,and discusses their advantages and disadvantages. Although most of the serum markers have limited clinical value,serum marker models have a good application prospect in the diagnosis of hepatic steatosis,the evaluation of fibrosis degree,and preliminary screening. Since a combination of different serological models can improve the accuracy of diagnosis,multi-angle and multicenter joint diagnosis will be a research hotspot in the future.
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Key words:
- nonalcoholic fatty liver disease /
- diagnosis /
- biomarkers
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慢性乙型肝炎(CHB)相关的慢加急性肝衰竭(acute-on-chronic hepatitis B liver failure，ACHBLF)是在慢性HBV感染引起的CHB基础上出现的急性严重肝功能障碍临床综合征，病死率极高。因我国慢性HBV的高感染率，ACHBLF已成为影响患者生存质量的重要因素[1]。在CHB向ACHBLF进展过程中，存在着患者肝功能急剧恶化，但尚未达到肝衰竭的“肝衰竭前期(pre-ACHBLF)”阶段[2]，如能在此阶段进行预警及干预，则有可能预防进一步发展为肝衰竭。
目前普遍认为细胞免疫功能紊乱是ACHBLF发生的病理机制之一，许多免疫细胞如髓系抑制性细胞(myeloid-derived suppressor cells, MDSC)、调节性T淋巴细胞(Treg)、分泌IL-17的CD4 T淋巴细胞(IL-17-producing CD4 T cells，Th17)和细胞毒性T淋巴细胞等在肝衰竭的发病中发挥重要作用[3-5]。尽管既往许多研究已证实肝衰竭发病与免疫密切相关，但pre-ACHBLF阶段的免疫状态及其与疾病进展的关系尚不清楚，因此本研究探讨了MDSC、Th17、Treg和分泌IL-17的CD8 T淋巴细胞(IL-17-producing CD8 T cells, Tc17)在pre-ACHBLF和ACHBLF患者中的表达，以期为ACHBLF的早期治疗提供思路。
1. 资料与方法
1.1 研究对象
选取2018年8月—2019年5月于石家庄市第五医院住院患者45例，其中ACHBLF患者、pre-ACHBLF患者和CHB患者各15例，同时选取于本院健康体检者15例作为健康对照组(HC组)。ACHBLF和pre-ACHBLF的临床诊断均符合《肝衰竭诊治指南(2018年版)》[6]；CHB的临床诊断符合《慢性乙型肝炎防治指南(2015年版)》[7]。排除标准为合并其他病毒性肝炎或由酒精、药物等原因导致的肝脏疾病；肝癌或其他恶性肿瘤伴有肝脏转移；患有自身免疫性疾病、HIV感染、妊娠或有严重的心、肺、肾脏、神经系统等疾病。
1.2 标本采集与储存
采用EDTA-K2抗凝的真空采血管于清晨空腹采集外周静脉血约3 mL，取100 μL用于流式细胞仪检测外周血MDSC频数，剩余全血分离外周血单个核细胞(peripheral blood mononuclear cells, PBMC)。所有标本均为新鲜抗凝血，且在采集后4 h内处理。
1.3 流式细胞仪检测外周血免疫细胞的水平
MDSC细胞检测：取100 μL全血加至流式管中，然后分别加入CD11b-APC、CD33-PE和HLA-DR-PE/Cy7流式抗体各2 μL，避光孵育15 min后，每管加入溶血素500 μL，室温避光静置15 min，离心洗涤，加入流式鞘液300 μL重悬细胞，流式细胞仪检测MDSC细胞比例。
Treg细胞检测：收集PBMC，加入CD4-FITC和CD25-APC抗体各2 μL，4 ℃避光孵育30 min。经固定破膜处理后，离心洗涤2次，重悬细胞，然后加入10 μL Foxp3-PE抗体，4 ℃避光孵育45 min，离心洗涤，加入流式鞘液200 μL重悬细胞，流式细胞仪检测。
Th17、Tc17细胞检测：收集PBMC，用佛波醇酯和离子霉素刺激，同时加入GolgiStop，4 h后收集细胞至流式管，加入CD4-FITC和CD8a-PerCP/Cy5.5抗体各2 μL，4 ℃避光孵育30 min。经固定破膜处理后，离心洗涤2次，然后加入10 μL IL-17-APC抗体，避光孵育30 min，离心洗涤，加入流式鞘液200 μL重悬细胞，流式细胞仪检测。
1.4 临床检验指标的测定
肝功能检测采用美国雅培公司C8000型生化分析仪，HBeAg检测采用瑞士罗氏公司全自动Cobase601型电化学发光免疫分析仪，血常规检测采用日本希森美康公司XN1000血液分析仪，并计算炎症指标，包括中性粒细胞/淋巴细胞比值(neutrophil-to-lymphocyte ratio, NLR)、单核细胞/淋巴细胞比值(monocyte-to-lymphocyte ratio, MLR)、血小板/淋巴细胞比值(platelet-to-lymphocyte ratio, PLR)与全身免疫炎症指数(systemic immune inflammation index，SIRS)，SIRS=中性粒细胞×血小板/淋巴细胞。
1.5 统计学方法
采用SPSS 21.0统计软件进行数据分析。符合正态分布的计量资料以x±s表示，多组间比较采用独立样本方差分析，组间进一步两两比较采用LSD-t检验；不服从正态分布的计量资料以M(P25~P75)表示，多组间比较采用Kruskal-Wallis H检验，进一步两两比较采用Nemenyi检验。变量间的相关性采用Pearson线性相关或Spearman秩相关分析，P＜0.05为差异有统计学意义。
2. 结果
2.1 一般资料
四组间年龄与性别构成具有可比性，差异均无统计学意义(P值均＞0.05)。ACHBLF组、pre-ACHBLF组和CHB组患者ALT与AST水平、HBeAg阳性比均明显高于HC组(P值均＜0.05)。ACHBLF组和pre-ACHBLF组患者TBil水平均明显高于HC组(P值均＜0.05)。ACHBLF组和pre-ACHBLF组患者PTA水平均明显低于CHB组(P值均＜0.05)(表 1)。
表 1 四组研究对象一般特征比较Table 1. Comparison of general characteristics of four groups组别 例数 年龄(岁) 性别(男/女，例) ALT(U/L) AST(U/L) HBeAg (+/-) TBil(μmol/L) PTA(%) ACHBLF组 15 45.00±10.86 11/4 67.00(33.00~132.00)1) 88.00(57.70~117.00)1) 10/51) 279.00(241.00~337.00)1) 38.00(25.00~65.50)2) pre-ACHBLF组 15 48.50±7.47 11/4 57.40(31.20~114.00)1) 54.90(34.00~112.00)1) 10/51) 76.40(54.70~129.00)1) 43.90(37.50~51.00)2) CHB组 15 43.10±11.72 12/3 57.00(44.00~261.00)1) 46.00(29.00~135.00)1) 12/31) 20.00(12.00~33.00)1) 84.00(70.50~91.20) HC组 15 42.10±6.37 12/3 21.10(11.00~32.30) 21.70(17.20~27.90) 0/15 11.60(9.90~14.40) - 统计值 F=1.326 χ2=0.373 F=18.594 F=27.525 χ2=23.571 F=48.781 F=26.217 P值 0.275 0.946 ＜0.001 ＜0.001 ＜0.001 ＜0.001 ＜0.001 注：与HC组比较，1)P＜0.05；与CHB组比较，2)P＜0.05。 2.2 MDSC、Th17、Treg和Tc17细胞的表达
MDSC、Th17、Treg和Tc17细胞水平在四组间差异均有统计学意义(P值均＜0.01)。与CHB组比较，ACHBLF和pre- ACHBLF组的Th17、Treg和Tc17细胞水平均明显升高(P值均＜0.05)，同时pre-ACHBLF患者的MDSC细胞水平明显升高，差异有统计学意义(P＜0.05)(图 1)。
图 1 四组研究对象MDSC、Th17、Treg和Tc17表达水平Figure 1. The expression levels of MDSC, Th17, Treg and TC17 in four groups2.3 pre-ACHBLF患者中免疫细胞与炎症指标的关系
相关性分析显示，在pre-ACHBLF患者中，MDSC与白细胞数、中性粒细胞数及NLR、MLR、SIRS呈正相关(P值均＜0.05)，而Treg细胞仅与白细胞数呈正相关(P=0.043)。相反，Th17/Treg值和Tc17细胞水平与淋巴细胞数呈负相关(P值均＜0.05)(表 2)。
表 2 pre-ACHBLF患者免疫细胞水平与炎症指标的关系Table 2. The relationship between the expression of immune cells and the degree of inflammation in patients with pre-ACHBLF炎症指标 MDSC Th17 Treg Th17/Treg Tc17 r值 P值 r值 P值 r值 P值 r值 P值 r值 P值 白细胞 0.775 0.001 0.167 0.668 0.618 0.043 -0.286 0.493 -0.533 0.139 中性粒细胞 0.727 0.002 0.250 0.516 0.491 0.125 -0.238 0.570 -0.417 0.265 淋巴细胞 0.079 0.781 -0.611 0.081 0.333 0.318 -0.790 0.020 -0.795 0.010 NLR 0.571 0.026 0.483 0.187 0.255 0.450 0.048 0.911 -0.150 0.700 MLR 0.786 0.001 0.233 0.546 0.236 0.484 0.024 0.955 -0.433 0.244 PLR 0.161 0.567 0.600 0.088 0.018 0.958 0.429 0.289 0.106 0.787 SIRS 0.846 ＜0.001 0.233 0.546 0.336 0.312 0.024 0.955 -0.433 0.244 3. 讨论
ACHBLF的发生发展涉及固有免疫和获得性免疫的多个环节，已有许多研究[8]证实免疫细胞如树突状细胞、巨噬细胞、MDSC、T淋巴细胞等与ACHBLF的进展及预后密切相关，但尚未有研究评价这些细胞在pre-ACHBLF中的变化。本研究发现pre-ACHBLF患者中MDSC、Th17、Treg和Tc17均比CHB患者明显升高，提示ACHBLF前期已存在严重的细胞免疫功能紊乱。因此，关注患者的病期变化，对pre-ACHBLF患者及早进行干预，维持细胞免疫平衡，可能对防止疾病进展起到重要作用。
MDSC是机体重要的免疫抑制细胞，具有抑制固有免疫和适应性免疫应答的作用，参与多种炎症和免疫性疾病的发生发展。近年来，一些研究[9]相继分析了MDSC在ACHBLF中的作用，发现ACHBLF患者MDSC频数明显升高，且随患者病期程度加重，本研究也证实了以上结果。为了探讨MDSC在ACHBLF疾病进程中的变化，本研究还观察了pre-ACHBLF患者中MDSC的频数，结果发现pre-ACHBLF患者中MDSC频数明显高于CHB患者，且高于ACHBLF患者。推测随着各种诱因导致CHB患者病情加重，肝细胞坏死及炎症反应产生的多种因子诱导机体MDSC快速升高，以抑制过强的免疫反应；而在ACHBLF发生时，机体以免疫炎症反应占主导，使MDSC频数相应降低。目前国内外关于MDSC在CHB-pre-ACHBLF-ACHBLF进程中如何发挥作用的研究还很少，尚需要进一步深入探讨。
值得注意的是，笔者团队观察到MDSC和Treg细胞的变化过程存在差异，MDSC水平在pre-ACHBLF患者中最高，而Treg细胞在ACHBLF患者中更高，此结果提示MDSC的增殖具有相对前置性，这两类重要的抑制性细胞在ACHBLF进展的不同时期分别发挥作用。此外还发现pre-ACHBLF患者中MDSC水平与炎症指标之间存在正相关性，而Treg水平仅与白细胞数呈正相关。目前炎症和免疫反应是ACHBLF发生发展过程中的重要病理生理机制，随着系统性炎症反应综合征的发生，炎症介质的持续释放导致ACHBLF患者出现血管内皮障碍，毛细血管渗漏和组织灌注不足而引起微循环紊乱, 继而引发器官衰竭。既往研究表明循环炎症介质及肝细胞坏死释放的损伤相关模式分子等可促进MDSC的增殖和分化[10]，而MDSC具有诱导Treg细胞扩增和分化的作用[11-12]。因此，这些研究提示在肝衰竭前期，过强的炎症反应激活MDSC使其表达升高，形成以MDSC为主的免疫抑制状态；随着疾病进展，MDSC诱导Treg细胞表达，转变为以Treg细胞为主的状态。
Th17和Tc17是以分泌IL-17为主要特征的T淋巴细胞亚群，他们有着共同的分化刺激因子及分化调节通路，共同在炎症性疾病、病毒感染、自身免疫性疾病、肿瘤等疾病中发挥作用[13]。但是，这两类细胞在许多方面如分子和代谢调节网络、可塑性、表达变化也存在差异[14]。一项肝癌相关的研究[15]显示，肝癌组织中分泌IL-17的细胞主要是Tc17细胞，而外周血中则主要是Th17细胞。在ACHBLF病理损伤过程中，已有大量研究证实ACHBLF患者的Th17细胞明显升高，且与预后密切相关[16]，但仅有极少数研究报道了Tc17细胞在ACHBLF发生发展中的作用[17-18], 特别是罕有研究观察Tc17细胞在pre-ACHBLF患者的表达。本研究发现pre-ACHBLF和ACHBLF患者外周血Th17与Tc17细胞频数显著高于CHB患者，且Tc17的变化更明显，推测Th17与Tc17细胞可能协同参与ACHBLF的疾病进程。
综上所述，本研究发现pre-ACHBLF患者外周血MDSC、Treg、Th17细胞和Tc17细胞水平均明显升高，特别是MDSC表达与炎症指标呈密切相关性。尽管本研究病例数偏少，但研究结果对理解ACHBLF的疾病进展具有重要意义。将来进一步扩大样本量进行验证，并深入探讨这些免疫细胞的作用机制，将为ACHBLF早期抗免疫治疗提供更多的理论依据。
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[1]YOUNOSSI ZM,KOENIG AB,ABDELATIF D,et al.Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence,incidence,and outcomes[J].Hepatology,2016,64(1):73-84. [2]KIM GA,LEE HC,CHOE J,et al.Association between nonalcoholic fatty liver disease and cancer incidence rate[J].J Hepatol,2017.[Online ahead of print] [3]STARLEY BQ,CALCAGNO CJ,HARRISON SA.Nonalcoholic fatty liver disease and hepatocellular carcinoma:A weighty connection[J].Hepatology,2010,51(5):1820-1832. [4]VERNON G,BARANOVA A,YOUNOSSI ZM.Systematic review:The epidemiology and natural history of non-alcoholic fatty liver disease and non-alcoholic steatohepatitis in adults[J].Aliment Pharmacol Ther,2011,34(3):274-285. [5]BEDOGNI G,BELLENTANI S,MIGLIOLI L,et al.The Fatty LiverIndex:A simple and accurate predictor of hepatic steatosis in the general population[J].BMC Gastroenterol,2006,6:33. [6]KOTRONEN A,PELTONEN M,HAKKARAINEN A,et al.Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors[J].Gastroenterology,2009,137(3):865-872. [7]KOOT BG,van der BAAN-SLOOTWEG OH,BOHTE AE,et al.Accuracy of prediction scores and novel biomarkers for predicting nonalcoholic fatty liver disease in obese children[J].Obesity(Silver Spring),2013,21(3):583-590. [8]WANG J,XU C,XUN Y,et al.ZJU index:A novel model for predicting nonalcoholic fatty liver disease in a Chinese population[J].Sci Rep,2015,5:16494. [9]LI L,YOU W,REN W.The ZJU index is a powerful index for identifying NAFLD in the general Chinese population[J].Acta Diabetol,2017,54(10):905-911. [10]POYNARD T,RATZIU V,NAVEAU S,et al.The diagnostic value of biomarkers(SteatoTest)for the prediction of liver steatosis[J].Comp Hepatol,2005,4:10. [11]HE L,DENG L,ZHANG Q,et al.Diagnostic value of CK-18,FGF-21,and related biomarker panel in nonalcoholic fatty liver disease:A systematic review and Meta-analysis[J].Biomed Res Int,2017,2017:9729107. [12]ANTY R,IANNELLI A,PATOURAUX S,et al.A new composite model including metabolic syndrome,alanine aminotransferase and cytokeratin-18 for the diagnosis of non-alcoholic steatohepatitis in morbidly obese patients[J].Aliment Pharmacol Ther,2010,32(11-12):1315-1322. [13]GRIGORESCU M,CRISAN D,RADU C,et al.A novel pathophysiological-based panel of biomarkers for the diagnosis of nonalcoholic steatohepatitis[J].J Physiol Pharmacol,2012,63(4):347-353. [14]ALKHOURI N,ALISI A,OKWU V,et al.Circulating soluble fasand fas ligand levels are elevated in children with nonalcoholic steatohepatitis[J].Dig Dis Sci,2015,60(8):2353-2359. [15]QI S,XU D,LI Q,et al.Metabonomics screening of serum identifies pyroglutamate as a diagnostic biomarker for nonalcoholic steatohepatitis[J].Clin Chim Acta,2017,473:89-95. [16]UCHIHARA M,IZUMI N.High-sensitivity C-reactive protein(hs-CRP):A promising biomarker for the screening of nonalcoholic steatohepatitis(NASH)[J].Nihon Rinsho,2006,64(6):1133-1138. [17]BOGA S,KOKSAL AR,ALKIM H,et al.Plasma pentraxin 3 differentiates nonalcoholic steatohepatitis(NASH)from non-NASH[J].Metab Syndr Relat Disord,2015,13(9):393-399. [18]ZHANG X,SHEN J,MAN K,et al.CXCL10 plays a key role as an inflammatory mediator and a non-invasive biomarker of non-alcoholic steatohepatitis[J].J Hepatol,2014,61(6):1365-1375. [19]SHEN J,CHAN HL,WONG GL,et al.Non-invasive diagnosis of non-alcoholic steatohepatitis by combined serum biomarkers[J].J Hepatol,2012,56(6):1363-1370. [20]TIETGE UJ,SCHMIDT HH,SCHUTZ T,et al.Reduced plasma adiponectin in NASH:Central obesity as an underestimated causative risk factor[J].Hepatology,2005,41(2):401;author reply 401-402. [21] YONEDA M,NOZAKI Y,ENDO H,et al.Serum ferritin is a clinical biomarker in Japanese patients with nonalcoholic steatohepatitis(NASH)independent of HFE gene mutation[J].Dig Dis Sci,2010,55(3):808-814. [22]KOWDLEY KV,BELT P,WILSON LA,et al.Serum ferritin is an independent predictor of histologic severity and advanced fibrosis in patients with nonalcoholic fatty liver disease[J].Hepatology,2012,55(1):77-85. [23]OKANOUE T,EBISE H,KAI T,et al.A simple scoring system using type IV collagen 7S and aspartate aminotransferase for diagnosing nonalcoholic steatohepatitis and related fibrosis[J].J Gastroenterol,2018,53(1):129-139. [24]LIU CH,AMPUERO J,GIL-GOMEZ A,et al.miRNAs in patients with non-alcoholic fatty liver disease:A systematic review and meta-analysis[J].J Hepatol,2018,69(6):1335-1348. [25]PIROLA CJ,FERNANDEZ GIANOTTI T,CASTANO GO,et al.Circulating microRNA signature in non-alcoholic fatty liver disease:From serum non-coding RNAs to liver histology and disease pathogenesis[J].Gut,2015,64(5):800-812. [26]BECKER PP,RAU M,SCHMITT J,et al.Performance of serum microRNAs-122,-192 and-21 as biomarkers in patients with non-alcoholic steatohepatitis[J].PLoS One,2015,10(11):e0142661. [27]YOUNOSSI ZM,LOOMBA R,ANSTEE QM,et al.Diagnostic modalities for non-alcoholic fatty liver disease(NAFLD),non-alcoholic steatohepatitis(NASH)and associated fibrosis[J].Hepatology,2017,68(1):349-360. [28]POYNARD T,RATZIU V,CHARLOTTE F,et al.Diagnostic value of biochemical markers(NashTest)for the prediction of non alcoholo steato hepatitis in patients with non-alcoholic fatty liver disease[J].BMC Gastroenterol,2006,6:34. [29]ZHOU Y,ORESIC M,LEIVONEN M,et al.Noninvasive detection of nonalcoholic steatohepatitis using clinical markers and circulating levels of lipids and metabolites[J].Clin Gastroenterol Hepatol,2016,14(10):1463-1472.e6. [30]HANSEN JF,JUUL NIELSEN M,NYSTROM K,et al.PROC3:A new and more precise collagen marker for liver fibrosis in patients with chronic hepatitis C[J].Scand J Gastroenterol,2018,53(1):83-87. [31] DANIELS SJ,LEEMING DJ,ESLAM M,et al.ADAPT:An algorithm incorporating PRO-C3 accurately identifies patients with NAFLD and advanced fibrosis[J].Hepatology,2019,69(3):1075-1086. [32]CHERNBUMROONG S,GROVE JI,ASTBURY S,et al.Advanced machine learning techniques to identify a panel of biomarkers that identify nonalcoholic steatohepatitis[J].Hepatol-ogy,2017,66(S1):53A-54A. [33]POLYZOS SA,SLAVAKIS A,KOUMERKERIDIS G,et al.Noninvasive liver fibrosis tests in patients with nonalcoholic fatty liver disease:An external validation cohort[J].Horm Metab Res,2019,51(2):134-140. [34]TANWAR S,TREMBLING PM,GUHA IN,et al.Validation of terminal peptide of procollagen III for the detection and assessment of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease[J].Hepatology,2013,57(1):103-111. [35]SUZUKI A,ANGULO P,LYMP J,et al.Hyaluronic acid,an accurate serum marker for severe hepatic fibrosis in patients with non-alcoholic fatty liver disease[J].Liver Int,2005,25(4):779-786. [36]ABDELAZIZ R,ELBASEL M,ESMAT S,et al.Tissue inhibitors of metalloproteinase-1 and 2 and obesity related non-alcoholic fatty liver disease:Is there a relationship[J].Digestion,2015,92(3):130-137. [37]LICHTINGHAGEN R,PIETSCH D,BANTEL H,et al.The Enhanced Liver Fibrosis(ELF)score:Normal values,influence factors and proposed cut-off values[J].J Hepatol,2013,59(2):236-242. [38]XIAO G,ZHU S,XIAO X,et al.Comparison of laboratory tests,ultrasound,or magnetic resonance elastography to detect fibrosis in patients with nonalcoholic fatty liver disease:A meta-analysis[J].Hepatology,2017,66(5):1486-1501. [39]European Association for Study of Liver,Asociacion Latinoamericana para el Estudio del Higado.EASL-ALEH clinical practice guidelines:Non-invasive tests for evaluation of liver disease severity and prognosis[J].J Hepatol,2015,63(1):237-264. [40]ADAMS LA,GEORGEJ,BUGIANESI E,et al.Complex noninvasive fibrosis models are more accurate than simple models in non-alcoholic fatty liver disease[J].J Gastroenterol Hepatol,2011,26(10):1536-1543. [41]RATZIU V,MASSARD J,CHARLOTTE F,et al.Diagnostic value of biochemical markers(FibroTest-FibroSURE)for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease[J].BMC Gastroenterol,2006,6:6. [42]ZHANG YL,MA YJ,WANG ZL,et al.Evaluation of four scoring systems in diagnosis of hepatic fibrosis in patients with nonalcoholic fatty liver disease[J].Chin J Modern Med,2017,27(22):112-126.(in Chinese)张意兰,马英杰,王志凌,等.4种评分系统在非酒精性脂肪肝病肝纤维化程度的诊断效能评价[J].中国现代医学杂志,2017,27(22):112-126. [43]GUO ZQ,WANG QY,QI XS,et al.Recommendations for the diagnosis and management of nonalcoholic fatty liver disease:Practice guidance from the American Association for the Study of Liver Diseases(2017)[J].J Clin Hepatol,2017,33(12):2275-2277.(in Chinese)郭泽淇,王倩怡,祁兴顺,等.《2017年美国肝病学会非酒精性脂肪性肝病诊疗指导》摘译[J].临床肝胆病杂志,2017,33(12):2275-2277. [44]National Workshop on Fatty Liver and Alcoholic Liver Disease,Chinese Society of Hepatology,Chinese Medical Association;Fatty Liver Expert Committee,Chinese Medical Doctor Association.Guidelines of prevention and treatment for nonalcoholic fatty liver disease:A 2018 update[J].J Clin Hepatol,2018,34(5):947-957.(in Chinese)中华医学会肝病学分会脂肪肝和酒精性肝病学组,中国医师协会脂肪性肝病专家委员会.非酒精性脂肪性肝病防治指南(2018年更新版)[J].临床肝胆病杂志,2018,34(5):947-957. 期刊类型引用(2)
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