非酒精性脂肪性肝病的诊断与评估

张馨元; 刘宇; 王文玲; 李荣宽

doi:10.3969/j.issn.1001-5256.2023.08.003

非酒精性脂肪性肝病的诊断与评估

DOI: 10.3969/j.issn.1001-5256.2023.08.003

大连医科大学附属第二医院感染科，辽宁大连 116023

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：张馨元负责查找文献，撰写文稿；刘宇、王文玲负责审阅文稿；李荣宽负责审阅文稿及最后定稿。

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李荣宽，dalianlrk@126.com (ORCID: 0000-0002-2927-7017)

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出版历程
- 收稿日期: 2023-05-04
- 录用日期: 2023-06-20
- 出版日期: 2023-08-20

Diagnosis and evaluation of nonalcoholic fatty liver disease

Department of Infectious Diseases, The Second Affiliated Hospital of Dalian Medical University, Dalian, Liaoning 116023, China

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Corresponding author: LI Rongkuan, dalianlrk@126.com (ORCID: 0000-0002-2927-7017)

摘要

摘要: 非酒精性脂肪性肝病(NAFLD)是临床最常见肝病之一，其发病率在全球范围内持续增加。NAFLD包括非酒精性肝脂肪变，并可以进一步进展为非酒精性脂肪性肝炎、肝硬化和肝细胞癌。迄今为止，肝活检被认为是评估肝脂肪变性和纤维化的“金标准”。但鉴于活检在大范围筛查中存在着局限性，用于评估NAFLD各个阶段的非侵入性测试对患者诊断及预后管理的作用显得愈发重要。本文总结了NAFLD诊断与评估的最新进展。
- 非酒精性脂肪性肝病 /
- 诊断 /
- 治疗学
Abstract: Nonalcoholic fatty liver disease (NAFLD) is one of the most common causes of liver disease, and its incidence rate continues to increase globally. NAFLD includes nonalcoholic steatosis and can further progress to nonalcoholic steatohepatitis, liver cirrhosis, and hepatocellular carcinoma. So far, liver biopsy has been regarded as the "gold standard" for evaluating hepatic steatosis and fibrosis; however, due to the limitations of biopsy in large-scale screening, noninvasive tests used to evaluate various stages of NAFLD have become increasingly important in the diagnosis and prognosis management of patients. This article summarizes the latest advances in diagnosis and evaluation of NAFLD.
- Non-alcoholic Fatty Liver Disease /
- Diagnosis /
- Therapeutics

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表 1 常见肝脂肪变生物标志物模型

Table 1. Common biomarker models for liver steatosis

模型	公式或组成部分	AUROC	验证工具	临界值
FLI^[12]	[e0.953×ln(TG)+0.139×BMI+0.718×ln(GGT)+0.053×WC-15.745]/[1+e0.953×ln(TG)+0.139×BMI+0.718×ln(GGT)+0.053×WC-15.745]×100	0.79~0.85	超声	< 30 ≥60
HSI^[13]	8×ALT/AST+BMI (T2DM+2；女性+2)	0.72~0.82	超声	< 30.0 ≥36.0
NAFLD-LFS^[14]	-2.89+1.18×MetS(是=1/否=0)+0.45×T2DM(是=2/否=0)+0.15×胰岛素水平(mU/L)+0.04×AST-0.94×AST/ALT	0.78~0.87	H-MRS	>-0.640
SteatoTest^[15]	由ALT、α2-巨球蛋白、载脂蛋白A1、结合珠蛋白、TB、GGT、TC、TG、FPG、年龄、性别和BMI计算得出	0.72~0.86	肝活检	无脂肪变性：0.31 1级脂肪变性：0.39 2级脂肪变性：0.58 3~4级脂肪变性：0.74
LAP^[16]	[WC(cm)-6 (男)or-58(女)]×TG (mmol/L)	0.72~0.83	超声	男性>4.0 女性>4.4
K-NAFLD评分^[17]	0.913×性别(2，女性；1，男性)+0.089×WC+0.032×(收缩压+FSG)+TG×0.007+ALT×0.105-20.929	0.93	H-MRS	< -3.285 >0.884
NSS^[18]	由年龄、FPG、AST/ALT、TG、BMI和UA计算得出	男性：0.80~0.84 女性：0.82~0.90	超声	男性>33 女性>29
ION^[19]	由性别、腰臀比、TG、ALT、HOMA计算得出	0.77	超声	< 11 >22
注：TG，甘油三酯；WC，腰围；FSG、FPG，空腹血糖；UA，血尿酸；TC，总胆固醇；HOMA，胰岛素抵抗的稳态模型评估。

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表 2 常见肝纤维化的生物标志物模型

Table 2. Common biomarker models for liver fibrosis

模型	公式或组成部分	AUROC	敏感度	特异度	终点	临界值
NFS^[41]	-1.675+0.037×年龄+0.094×BMI+1.13×空腹血糖受损/糖尿病(是=1, 否=0)+0.99×AST/ALT-0.013×PLT(×10⁹/L)-0.66×白蛋白(g/dL)	0.85	0.90	0.60	F≥3	< -1.455 ≥0.676
FIB-4^[42]	(年龄×AST)/[PLT(×10⁹/L)×ALT^1/2]	0.80	0.74	0.71	F≥3	≤-1.30 ≥2.67
APRI^[43]	[AST/(AST正常值上限)]/[PLT(×10⁹/L) ×100]	0.85	0.75	0.86	F≥3	≥0.98
ELF^[44]	2.2781+0.851×ln (HA)(μg/L)+10.751×ln (P3NP)(μg/L)+10.934×ln (TIMP 1)(μg/L)	0.82 0.90	0.70 0.80	0.80 0.90	F≥2 F≥3	>-0.106 8 >0.357 6
FiberTest (FiberSure)^[45]	由年龄、性别、GGT、胆红素、触珠蛋白、α2-巨球蛋白、载脂蛋白A1计算得出	0.81 0.88	0.77 0.15	0.77 0.98	F≥2 F≥3	>-0.106 8 >0.357 6
FiberMeter^[46]	由PLT、凝血酶原指数、AST、α2-巨球蛋白、HA、尿素、年龄计算得出	0.94	0.79	0.96	F≥2	≤0.611 ≥0.715
注：HA，透明质酸；P3NP，前胶原Ⅲ的N-末端肽；TIMP1，金属蛋白酶组织抑制剂1。

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参考文献(59)

[1]	YOUNOSSI Z, ANSTEE QM, MARIETTI M, et al. Global burden of NAFLD and NASH: trends, predictions, risk factors and prevention[J]. Nat Rev Gastroenterol Hepatol, 2018, 15(1): 11-20. DOI: 10.1038/nrgastro.2017.109.
[2]	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. DOI: 10.3969/j.issn.1001-5256.2018.05.007. 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. DOI: 10.3969/j.issn.1001-5256.2018.05.007.
[3]	SUMIDA Y, NAKAJIMA A, ITOH Y. Limitations of liver biopsy and non-invasive diagnostic tests for the diagnosis of nonalcoholic fatty liver disease/nonalcoholic steatohepatitis[J]. World J Gastroenterol, 2014, 20(2): 475-485. DOI: 10.3748/wjg.v20.i2.475.
[4]	TAYLOR RS, TAYLOR RJ, BAYLISS S, et al. Association between fibrosis stage and outcomes of patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis[J]. Gastroenterology, 2020, 158(6): 1611-1625. e12. DOI: 10.1053/j.gastro.2020.01.043.
[5]	RATZIU V, BELLENTANI S, CORTEZ-PINTO H, et al. A position statement on NAFLD/NASH based on the EASL 2009 special conference[J]. J Hepatol, 2010, 53(2): 372-384. DOI: 10.1016/j.jhep.2010.04.008.
[6]	POWELL EE, WONG VW, RINELLA M. Non-alcoholic fatty liver disease[J]. Lancet, 2021, 397(10290): 2212-2224. DOI: 10.1016/S0140-6736(20)32511-3.
[7]	ROMEO S, KOZLITINA J, XING C, et al. Genetic variation in PNPLA3 confers susceptibility to nonalcoholic fatty liver disease[J]. Nat Genet, 2008, 40(12): 1461-1465. DOI: 10.1038/ng.257.
[8]	ESLAM M, SANYAL AJ, GEORGE J, et al. MAFLD: A consensus-driven proposed nomenclature for metabolic associated fatty liver disease[J]. Gastroenterology, 2020, 158(7): 1999-2014. e1. DOI: 10.1053/j.gastro.2019.11.312.
[9]	KLEINER DE, BRUNT EM, VAN NATTA M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease[J]. Hepatology, 2005, 41(6): 1313-1321. DOI: 10.1002/hep.20701.
[10]	PRATI D, COLLI A, CONTE D, et al. Spectrum of NAFLD and diagnostic implications of the proposed new normal range for serum ALT in obese women[J]. Hepatology, 2005, 42(6): 1460-1461; author reply 1461. DOI: 10.1002/hep.20964.
[11]	TAHAN V, CANBAKAN B, BALCI H, et al. Serum gamma-glutamyltranspeptidase distinguishes non-alcoholic fatty liver disease at high risk[J]. Hepatogastroenterology, 2008, 55(85): 1433-1438.
[12]	BEDOGNI G, BELLENTANI S, MIGLIOLI L, et al. The fatty liver index: a simple and accurate predictor of hepatic steatosis in the general population[J]. BMC Gastroenterol, 2006, 6: 33. DOI: 10.1186/1471-230X-6-33.
[13]	LEE JH, KIM D, KIM HJ, et al. Hepatic steatosis index: a simple screening tool reflecting nonalcoholic fatty liver disease[J]. Dig Liver Dis, 2010, 42(7): 503-508. DOI: 10.1016/j.dld.2009.08.002.
[14]	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. DOI: 10.1053/j.gastro.2009.06.005.
[15]	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. DOI: 10.1186/1476-5926-4-10.
[16]	BEDOGNI G, KAHN HS, BELLENTANI S, et al. A simple index of lipid overaccumulation is a good marker of liver steatosis[J]. BMC Gastroenterol, 2010, 10: 98. DOI: 10.1186/1471-230X-10-98.
[17]	JEONG S, KIM K, CHANG J, et al. Development of a simple nonalcoholic fatty liver disease scoring system indicative of metabolic risks and insulin resistance[J]. Ann Transl Med, 2020, 8(21): 1414. DOI: 10.21037/atm-20-2951.
[18]	ZHOU YJ, ZHOU YF, ZHENG JN, et al. NAFL screening score: A basic score identifying ultrasound-diagnosed non-alcoholic fatty liver[J]. Clin Chim Acta, 2017, 475: 44-50. DOI: 10.1016/j.cca.2017.09.020.
[19]	OTGONSUREN M, ESTEP MJ, HOSSAIN N, et al. Single non-invasive model to diagnose non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH)[J]. J Gastroenterol Hepatol, 2014, 29(12): 2006-2013. DOI: 10.1111/jgh.12665.
[20]	AHN SB. Noninvasive serum biomarkers for liver steatosis in nonalcoholic fatty liver disease: Current and future developments[J]. Clin Mol Hepatol, 2023, 29(Suppl): S150-S156. DOI: 10.3350/cmh.2022.0362.
[21]	European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical practice guidelines for the management of non-alcoholic fatty liver disease[J]. Diabetologia, 2016, 59(6): 1121-1140. DOI: 10.1007/s00125-016-3902-y.
[22]	FERRAIOLI G, MAIOCCHI L, RACITI MV, et al. Detection of liver steatosis with a novel ultrasound-based technique: a pilot study using MRI-Derived proton density fat fraction as the gold standard[J]. Clin Transl Gastroenterol, 2019, 10(10): e00081. DOI: 10.14309/ctg.0000000000000081.
[23]	AHN JM, PAIK YH, MIN SY, et al. Relationship between controlled attenuation parameter and hepatic steatosis as assessed by ultrasound in alcoholic or nonalcoholic fatty liver disease[J]. Gut Liver, 2016, 10(2): 295-302. DOI: 10.5009/gnl15155.
[24]	KARLAS T, PETROFF D, SASSO M, et al. Individual patient data meta-analysis of controlled attenuation parameter (CAP) technology for assessing steatosis[J]. J Hepatol, 2017, 66(5): 1022-1030. DOI: 10.1016/j.jhep.2016.12.022.
[25]	CHAN WK, NIK MUSTAPHA NR, WONG GL, et al. Controlled attenuation parameter using the FibroScan^Ⓡ XL probe for quantification of hepatic steatosis for non-alcoholic fatty liver disease in an Asian population[J]. United European Gastroenterol J, 2017, 5(1): 76-85. DOI: 10.1177/2050640616646528.
[26]	CAUSSY C, ALQUIRAISH MH, NGUYEN P, et al. Optimal threshold of controlled attenuation parameter with MRI-PDFF as the gold standard for the detection of hepatic steatosis[J]. Hepatology, 2018, 67(4): 1348-1359. DOI: 10.1002/hep.29639.
[27]	RUNGE JH, SMITS LP, VERHEIJ J, et al. MR spectroscopy-derived proton density fat fraction is superior to controlled attenuation parameter for detecting and grading hepatic steatosis[J]. Radiology, 2018, 286(2): 547-556. DOI: 10.1148/radiol.2017162931.
[28]	PARK J, LEE JM, LEE G, et al. Quantitative evaluation of hepatic steatosis using advanced imaging techniques: focusing on new quantitative ultrasound techniques[J]. Korean J Radiol, 2022, 23(1): 13-29. DOI: 10.3348/kjr.2021.0112.
[29]	KLEINER DE, BRUNT EM. Nonalcoholic fatty liver disease: pathologic patterns and biopsy evaluation in clinical research[J]. Semin Liver Dis, 2012, 32(1): 3-13. DOI: 10.1055/s-0032-1306421.
[30]	SHEKA AC, ADEYI O, THOMPSON J, et al. Nonalcoholic steatohepatitis: a review[J]. JAMA, 2020, 323(12): 1175-1183. DOI: 10.1001/jama.2020.2298.
[31]	BEDOSSA P, FLIP Pathology Consortium. Utility and appropriateness of the fatty liver inhibition of progression (FLIP) algorithm and steatosis, activity, and fibrosis (SAF) score in the evaluation of biopsies of nonalcoholic fatty liver disease[J]. Hepatology, 2014, 60(2): 565-575. DOI: 10.1002/hep.27173.
[32]	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. DOI: 10.1155/2017/9729107.
[33]	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. DOI: 10.1016/j.jhep.2014.07.006.
[34]	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. DOI: 10.1016/j.cca.2017.08.022.
[35]	WONG VW, ADAMS LA, de LÉDINGHEN V, et al. Noninvasive biomarkers in NAFLD and NASH - current progress and future promise[J]. Nat Rev Gastroenterol Hepatol, 2018, 15(8): 461-478. DOI: 10.1038/s41575-018-0014-9.
[36]	CHEN J, TALWALKAR JA, YIN M, et al. Early detection of nonalcoholic steatohepatitis in patients with nonalcoholic fatty liver disease by using MR elastography[J]. Radiology, 2011, 259(3): 749-756. DOI: 10.1148/radiol.11101942.
[37]	KIM TH, JEONG CW, JUN HY, et al. Noninvasive differential diagnosis of liver iron contents in nonalcoholic steatohepatitis and simple steatosis using multiecho dixon magnetic resonance imaging[J]. Acad Radiol, 2019, 26(6): 766-774. DOI: 10.1016/j.acra.2018.06.022.
[38]	BRAZA-BOÏLS A, MARÍ-ALEXANDRE J, MOLINA P, et al. Deregulated hepatic microRNAs underlie the association between non-alcoholic fatty liver disease and coronary artery disease[J]. Liver Int, 2016, 36(8): 1221-1229. DOI: 10.1111/liv.13097.
[39]	TIAN AP, YANG YF. A comparative analysis of pathological grading and staging systems for chronic hepatitis[J]. J Clin Hepatol, 2018, 34(11): 2271-2277. DOI: 10.3969/j.issn.1001-5256.2018.11.002. 田爱平, 杨永峰. 慢性肝炎病理学分级分期评分系统比较[J]. 临床肝胆病杂志, 2018, 34(11): 2271-2277. DOI: 10.3969/j.issn.1001-5256.2018.11.002.
[40]	BEDOSSA P, POYNARD T. An algorithm for the grading of activity in chronic hepatitis C. The METAVIR Cooperative Study Group[J]. Hepatology, 1996, 24(2): 289-293. DOI: 10.1002/hep.510240201.
[41]	ANGULO P, HUI JM, MARCHESINI G, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD[J]. Hepatology, 2007, 45(4): 846-854. DOI: 10.1002/hep.21496.
[42]	SHAH AG, LYDECKER A, MURRAY K, et al. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease[J]. Clin Gastroenterol Hepatol, 2009, 7(10): 1104-1112. DOI: 10.1016/j.cgh.2009.05.033.
[43]	KRUGER FC, DANIELS CR, KIDD M, et al. APRI: a simple bedside marker for advanced fibrosis that can avoid liver biopsy in patients with NAFLD/NASH[J]. S Afr Med J, 2011, 101(7): 477-480.
[44]	GUHA IN, PARKES J, RODERICK P, et al. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: Validating the European Liver Fibrosis Panel and exploring simple markers[J]. Hepatology, 2008, 47(2): 455-460. DOI: 10.1002/hep.21984.
[45]	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. DOI: 10.1186/1471-230X-6-6.
[46]	CALÈS P, OBERTI F, MICHALAK S, et al. A novel panel of blood markers to assess the degree of liver fibrosis[J]. Hepatology, 2005, 42(6): 1373-1381. DOI: 10.1002/hep.20935.
[47]	OZTURK A, GRAJO JR, DHYANI M, et al. Principles of ultrasound elastography[J]. Abdom Radiol (NY), 2018, 43(4): 773-785. DOI: 10.1007/s00261-018-1475-6.
[48]	PAPATHEODORIDI M, HIRIART JB, LUPSOR-PLATON M, et al. Refining the Baveno VI elastography criteria for the definition of compensated advanced chronic liver disease[J]. J Hepatol, 2021, 74(5): 1109-1116. DOI: 10.1016/j.jhep.2020.11.050.
[49]	PETTA S, WONG VW, CAMMÀ C, et al. Improved noninvasive prediction of liver fibrosis by liver stiffness measurement in patients with nonalcoholic fatty liver disease accounting for controlled attenuation parameter values[J]. Hepatology, 2017, 65(4): 1145-1155. DOI: 10.1002/hep.28843.
[50]	NIERHOFF J, CHÁVEZ ORTIZ AA, HERRMANN E, et al. The efficiency of acoustic radiation force impulse imaging for the staging of liver fibrosis: a meta-analysis[J]. Eur Radiol, 2013, 23(11): 3040-3053. DOI: 10.1007/s00330-013-2927-6.
[51]	CASSINOTTO C, BOURSIER J, PAISANT A, et al. Transient versus two-dimensional shear-wave elastography in a multistep strategy to detect advanced fibrosis in NAFLD[J]. Hepatology, 2021, 73(6): 2196-2205. DOI: 10.1002/hep.31655.
[52]	LOOMBA R, WOLFSON T, ANG B, et al. Magnetic resonance elastography predicts advanced fibrosis in patients with nonalcoholic fatty liver disease: a prospective study[J]. Hepatology, 2014, 60(6): 1920-1928. DOI: 10.1002/hep.27362.
[53]	JOHNSON K, LEARY PJ, GOVAERE O, et al. Increased serum miR-193a-5p during non-alcoholic fatty liver disease progression: Diagnostic and mechanistic relevance[J]. JHEP Rep, 2022, 4(2): 100409. DOI: 10.1016/j.jhepr.2021.100409.
[54]	LANG S, FAROWSKI F, MARTIN A, et al. Prediction of advanced fibrosis in non-alcoholic fatty liver disease using gut microbiota-based approaches compared with simple non-invasive tools[J]. Sci Rep, 2020, 10(1): 9385. DOI: 10.1038/s41598-020-66241-0.
[55]	WANG AY, DHALIWAL J, MOUZAKI M. Lean non-alcoholic fatty liver disease[J]. Clin Nutr, 2019, 38(3): 975-981. DOI: 10.1016/j.clnu.2018.08.008.
[56]	WILLIAMS CD, STENGEL J, ASIKE MI, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study[J]. Gastroenterology, 2011, 140(1): 124-131. DOI: 10.1053/j.gastro.2010.09.038.
[57]	BALLESTRI S, ZONA S, TARGHER G, et al. Nonalcoholic fatty liver disease is associated with an almost twofold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis[J]. J Gastroenterol Hepatol, 2016, 31(5): 936-944. DOI: 10.1111/jgh.13264.
[58]	LIU YL, REEVES HL, BURT AD, et al. TM6SF2 rs58542926 influences hepatic fibrosis progression in patients with non-alcoholic fatty liver disease[J]. Nat Commun, 2014, 5: 4309. DOI: 10.1038/ncomms5309.
[59]	RABOT S, MEMBREZ M, BRUNEAU A, et al. Germ-free C57BL/6J mice are resistant to high-fat-diet-induced insulin resistance and have altered cholesterol metabolism[J]. FASEB J, 2010, 24(12): 4948-4959. DOI: 10.1096/fj.10-164921.