慢性HBV感染重叠非酒精性脂肪性肝病临床与基础研究的现状及展望

蒋丽娜; 李玮; 赵景民

doi:10.3969/j.issn.1001-5256.2021.07.001

慢性HBV感染重叠非酒精性脂肪性肝病临床与基础研究的现状及展望

DOI: 10.3969/j.issn.1001-5256.2021.07.001

解放军总医院第五医学中心，北京 100039

利益冲突声明：所有作者均声明不存在利益冲突。

作者贡献声明：蒋丽娜、李玮负责文献检索、数据分析及初稿撰写工作；赵景民负责述评总体设计、主要述评观点撰写、修改及定稿。

详细信息

通信作者:
赵景民，jmzhao302@163.com

中图分类号: R512.62;R575.5
计量
- 文章访问数: 782
- HTML全文浏览量: 143
- PDF下载量: 165
- 被引次数: 0
出版历程
- 收稿日期: 2021-06-24
- 录用日期: 2021-06-24
- 出版日期: 2021-07-20

Current status and perspectives of the clinical and basic research on concomitant chronic hepatitis B virus infection and nonalcoholic fatty liver disease

The Fifth Medical Center of Chinese PLA General Hospital, Beijing 100039, China

摘要

摘要: 慢性乙型肝炎病毒感染(CBI)与非酒精性脂肪性肝病(NAFLD)是世界范围内慢性肝病常见的两大病因，CBI重叠或合并NAFLD(Co-CBI&NAFLD)的情况较普遍。Co-CBI&NAFLD两者的相互影响作用，尤其是NAFLD对慢性乙型肝炎(CHB)疾病进展、抗病毒疗效及结局的影响作用尚存在争议。现有的Co-CBI&NAFLD临床与基础研究结果显示，NAFLD能够一定程度上抑制HBV DNA复制，表现为血清HBV DNA载量相对较低，并可能增加慢性CHB患者血清HBsAg转阴率；基于临床前瞻性或回顾性队列研究显示，Co-CBI&NAFLD较单纯CHB肝纤维化进展呈加快趋势，乃至肝硬化及HCC发生率亦呈增加态势；Co-CBI/NAFLD组织学上两者病变并存，各自特征性病变鉴别困难。目前Co-CBI&NAFLD的自然史、发病机制尚不清楚，其病理学特征尚待确认，NAFLD对CHB疾病进程的影响作用，尤其是对抗病毒疗效的影响及疾病结局尚缺乏高等级的循证医学证据，国内外尚无Co-CBI&NAFLD诊疗或管理指南。对上述问题的解决，无疑将有助于加深对Co-CBI&NAFLD的理解与认识，规范并提高临床诊疗或管理效果，降低相关终末期肝病的发生率和病死率。
- 乙型肝炎病毒 /
- 乙型肝炎，慢性 /
- 非酒精性脂肪性肝病
Abstract: Chronic hepatitis B virus infection (CBI) and nonalcoholic fatty liver disease (NAFLD) are the two main etiologies of chronic liver diseases worldwide, and therefore, concomitant CBI and NAFLD (Co-CBI&NAFLD) is relatively common. There are still controversies over the influence of the interaction between CBI and NAFLD, especially NAFLD, on the progression, antiviral response, and outcome of chronic hepatitis B (CHB). Current clinical and basic research on Co-CBI&NAFLD have shown that NAFLD could inhibit HBV DNA replication to a certain degree, manifesting as a relatively low HBV DNA load, and it might increase HBsAg clearance rate in patients with CHB. Prospective or retrospective cohort studies have shown that patients with Co-CBI&NAFLD tend to have more rapid progression of liver fibrosis than those with CHB alone, as well as increased incidence rates of liver cirrhosis and hepatocellular carcinoma. Histologically, Co-CBI&NAFLD has the pathological changes of both CHB and NAFLD, and therefore, it is difficult to identify their own characteristic lesions. At present, the natural history and pathogenesis of Co-CBI&NAFLD remain unclear, and its pathological characteristics have not been fully identified. There is still a lack of high-level evidence-based supporting information on the influence of NAFLD on the course of CHB, especially its impact on antiviral response and disease outcome, and there are also no guidelines for the diagnosis/treatment or management of Co-CBI&NAFLD in China and globally. Solutions to the above issues will definitely deepen the understanding of Co-CBI&NAFLD, standardize and improve clinical diagnosis/treatment or management, and thus reduce the incidence and mortality rates of related end-stage liver diseases.
- Hepatitis B virus /
- Hepatitis B, Chronic /
- Non-alcoholic Fatty Liver Disease

HTML全文

参考文献(60)

[1]	Chinese Society of Infectious Diseases, Chinese Medical Association, Chinese Society of Infectious Diseases, Chinese Medical Association. Guidelines for the prevention and treatment of chronic hepatitis B(version 2019)[J]. J Clin Hepatol, 2019, 35(12): 2648-2669. DOI: 10.3969/j.issn.1001-5256.2019.12.007. 中华医学会肝病学分会, 中华医学会感染病学分会. 慢性乙型肝炎防治指南(2019年版)[J]. 临床肝胆病杂志, 2019, 35(12): 2648-2669. DOI: 10.3969/j.issn.1001-5256.2019.12.007.
[2]	TERRAULT NA, LOK A, MCMAHON BJ, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance[J]. Hepatology, 2018, 67(4): 1560-1599. DOI: 10.1002/hep.29800.
[3]	HANIF H, KHAN MM, ALI MJ, et al. A new endemic of concomitant nonalcoholic fatty liver disease and chronic hepatitis B[J]. Microorganisms, 2020, 8(10): 1526. DOI: 10.3390/microorganisms8101526.
[4]	Fatty Liver Expert Committee, Chinese Medical Doctor Association, ational Workshop on Fatty Liver and Alcoholic Liver Disease, Chinese Society of Hepatology, Chinese Medical 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. 中国医师协会脂肪性肝病专家委员会, 中华医学会肝病学分会脂肪肝和酒精性肝病学组. 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.
[5]	CHALASANI N, YOUNOSSI Z, LAVINE JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases[J]. Hepatology, 2018, 67(1): 328-357. DOI: 10.1002/hep.29367.
[6]	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]. J Hepatol, 2016, 64(6): 1388-1402. DOI: 10.1016/j.jhep.2015.11.004.
[7]	CHAN AW, WONG GL, CHAN HY, et al. Concurrent fatty liver increases risk of hepatocellular carcinoma among patients with chronic hepatitis B[J]. J Gastroenterol Hepatol, 2017, 32(3): 667-676. DOI: 10.1111/jgh.13536.
[8]	ESLAM M, SANYAL AJ, GEORGE J. 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]	MACHADO MV, OLIVEIRA AG, CORTEZ-PINTO H. Hepatic steatosis in hepatitis B virus infected patients: Meta-analysis of risk factors and comparison with hepatitis C infected patients[J]. J Gastroenterol Hepatol, 2011, 26(9): 1361-1367. DOI: 10.1111/j.1440-1746.2011.06801.x.
[10]	SPRADLING PR, BULKOW L, TESHALE EH, et al. Prevalence and causes of elevated serum aminotransferase levels in a population-based cohort of persons with chronic hepatitis B virus infection[J]. J Hepatol, 2014, 61(4): 785-791. DOI: 10.1016/j.jhep.2014.05.045.
[11]	JOO EJ, CHANG Y, YEOM JS, et al. Hepatitis B virus infection and decreased risk of nonalcoholic fatty liver disease: A cohort study[J]. Hepatology, 2017, 65(3): 828-835. DOI: 10.1002/hep.28917.
[12]	FAN JG, KIM SU, WONG VW. New trends on obesity and NAFLD in Asia[J]. J Hepatol, 2017, 67(4): 862-873. DOI: 10.1016/j.jhep.2017.06.003.
[13]	LIN CW, HUANG XL, LIU HL, et al. Interactions of hepatitis B virus infection with nonalcoholic fatty liver disease: Possible mechanisms and clinical impact[J]. Dig Dis Sci, 2015, 60(12): 3513-3524. DOI: 10.1007/s10620-015-3772-z.
[14]	CHENG YL, WANG YJ, KAO WY, et al. Inverse association between hepatitis B virus infection and fatty liver disease: A large-scale study in populations seeking for check-up[J]. PLoS One, 2013, 8(8): e72049. DOI: 10.1371/journal.pone.0072049.
[15]	SHI JP, FAN JG, WU R, et al. Prevalence and risk factors of hepatic steatosis and its impact on liver injury in Chinese patients with chronic hepatitis B infection[J]. J Gastroenterol Hepatol, 2008, 23(9): 1419-25. DOI: 10.1111/j.1440-1746.2008.05531.x.
[16]	LIU A, LE A, ZHANG J, et al. Increasing co-morbidities in chronic hepatitis B patients: Experience in primary care and referral practices during 2000-2015[J]. Clin Transl Gastroenterol, 2018, 9(3): 141. DOI: 10.1038/s41424-018-0007-6.
[17]	PAIS R, RUSU E, ZILISTEANU D, et al. Prevalence of steatosis and insulin resistance in patients with chronic hepatitis B compared with chronic hepatitis C and non-alcoholic fatty liver disease[J]. Eur J Intern Med, 2015, 26(1): 30-36. DOI: 10.1016/j.ejim.2014.12.001.
[18]	WANG MF, LIN S, WU YL, et al. The correlation between fatty liver disease and serum and histological viral parameters in patients with chronic hepatitis B[J]. Chin J Infect Dis, 2016, 34(3): 141-145. DOI: 10.3760/cma.j.issn.1000-6680.2016.03.002. 王明芳, 林苏, 吴银莲, 等. 慢性乙型肝炎患者肝脂肪变性与血清、肝组织病毒因素的关系[J]. 中华传染病杂志, 2016, 34(3): 141-145. DOI: 10.3760/cma.j.issn.1000-6680.2016.03.002.
[19]	MI YQ, LIU YG, XU L, et al. Analysis of clinical and pathological features of chronic hepatitis B with hepatic steatosis[J]. Chin J Hepatol, 2009, 17(11): 817-820. DOI: 10.3760/cma.j.issn.1007-3418.2009.11.006. 宓余强, 刘勇钢, 徐亮, 等. 慢性乙型肝炎合并肝脂肪变的临床与病理学特征分析[J]. 中华肝脏病杂志, 2009, 17(11): 817-820. DOI: 10.3760/cma.j.issn.1007-3418.2009.11.006.
[20]	MI YQ, SHI QY, XU L, et al. Controlled attenuation parameter for noninvasive assessment of hepatic steatosis using Fibroscan^®: Validation in chronic hepatitis B[J]. Dig Dis Sci, 2015, 60(1): 243-251. DOI: 10.1007/s10620-014-3341-x.
[21]	XU L, LU W, LI P, et al. A comparison of hepatic steatosis index, controlled attenuation parameter and ultrasound as noninvasive diagnostic tools for steatosis in chronic hepatitis B[J]. Dig Liver Dis, 2017, 49(8): 910-917. DOI: 10.1016/j.dld.2017.03.013.
[22]	MAK LY, YUEN MF, SETO WK. Letter regarding "A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement"[J]. J Hepatol, 2020, 73(6): 1573-1574. DOI: 10.1016/j.jhep.2020.07.008.
[23]	WONG VW, WONG GL, CHU WC, et al. Hepatitis B virus infection and fatty liver in the general population[J]. J Hepatol, 2012, 56(3): 533-540. DOI: 10.1016/j.jhep.2011.09.013.
[24]	CHAN AW, WONG GL, CHAN HY, et al. Concurrent fatty liver increases risk of hepatocellular carcinoma among patients with chronic hepatitis B[J]. J Gastroenterol Hepatol, 2017, 32(3): 667-676. DOI: 10.1111/jgh.13536.
[25]	CHAN TT, CHAN WK, WONG GL, et al. Positive hepatitis B core antibody is associated with cirrhosis and hepatocellular carcinoma in nonalcoholic fatty liver disease[J]. Am J Gastroenterol, 2020, 115(6): 867-875. DOI: 10.14309/ajg.0000000000000588.
[26]	KIM K, KIM KH, KIM HH, et al. Hepatitis B virus X protein induces lipogenic transcription factor SREBP1 and fatty acid synthase through the activation of nuclear receptor LXRalpha[J]. Biochem J, 2008, 416(2): 219-230. DOI: 10.1042/BJ20081336.
[27]	WU YL, PENG XE, ZHU YB, et al. Hepatitis B virus X protein induces hepatic steatosis by enhancing the expression of liver fatty acid binding protein[J]. J Virol, 2016, 90(4): 1729-1740. DOI: 10.1128/JVI.02604-15.
[28]	ZHANG J, LIN S, JIANG D, et al. Chronic hepatitis B and non-alcoholic fatty liver disease: Conspirators or competitors?[J]. Liver Int, 2020, 40(3): 496-508. DOI: 10.1111/liv.14369.
[29]	ZHANG RN, PAN Q, ZHANG Z, et al. Saturated fatty acid inhibits viral replication in chronic hepatitis B virus infection with nonalcoholic fatty liver disease by toll-like receptor 4-mediated innate immune response[J]. Hepat Mon, 2015, 15(5): e27909. DOI: 10.5812/hepatmon.15(5)2015.27909.
[30]	XIAO W, REN M, ZHANG C, et al. Amelioration of nonalcoholic fatty liver disease by hepatic stimulator substance via preservation of carnitine palmitoyl transferase-1 activity[J]. Am J Physiol Cell Physiol, 2015, 309(4): c215-c227. DOI: 10.1152/ajpcell.00133.2014.
[31]	SCHUSTER S, CABRERA D, ARRESE M, et al. Triggering and resolution of inflammation in NASH[J]. Nat Rev Gastroenterol Hepatol, 2018, 15(6): 349-364. DOI: 10.1038/s41575-018-0009-6.
[32]	ISHAK K, BAPTISTA A, BIANCHI L, et al. Histological grading and staging of chronic hepatitis[J]. J Hepatol, 1995, 22(6): 696-699. DOI: 10.1016/0168-8278(95)80226-6.
[33]	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.
[34]	SUN Y, ZHOU J, WANG L, et al. New classification of liver biopsy assessment for fibrosis in chronic hepatitis B patients before and after treatment[J]. Hepatology, 2017, 65(5): 1438-1450. DOI: 10.1002/hep.29009.
[35]	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.
[36]	BEDOSSA P. 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.
[37]	LIU F, GOH GB, TINIAKOS D, et al. qFIBS: An automated technique for quantitative evaluation of fibrosis, inflammation, ballooning, and steatosis in patients with nonalcoholic steatohepatitis[J]. Hepatology, 2020, 71(6): 1953-1966. DOI: 10.1002/hep.30986.
[38]	ZHUANG Z, QU H, YANG W, et al. Comparing hepatic steatosis distribution patterns between non-alcoholic fatty liver disease and fatty liver disease with chronic hepatitis B by second-harmonic generation/two-photon excited fluorescence method[J]. Ann Hepatol, 2020, 19(3): 313-319. DOI: 10.1016/j.aohep.2019.11.003.
[39]	European Association for Study of Liver; Association 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. DOI: 10.1016/j.jhep.2015.04.006.
[40]	XU L, LU W, LI P, et al. A comparison of hepatic steatosis index, controlled attenuation parameter and ultrasound as noninvasive diagnostic tools for steatosis in chronic hepatitis B[J]. Dig Liver Dis, 2017, 49(8): 910-917. DOI: 10.1016/j.dld.2017.03.013.
[41]	QU Y, SONG YY, CHEN CW, et al. Diagnostic performance of fibrotouch ultrasound attenuation parameter and liver stiffness measurement in assessing hepatic steatosis and fibrosis in patients with nonalcoholic fatty liver disease[J]. Clin Transl Gastroenterol, 2021, 12(4): e00323. DOI: 10.14309/ctg.0000000000000323.
[42]	LIANG J, LIU F, WANG F, et al. A noninvasive score model for prediction of nash in patients with chronic hepatitis B and nonalcoholic fatty liver disease[J]. Biomed Res Int, 2017, 2017: 8793278. DOI: 10.1155/2017/8793278.
[43]	ZHANG H, LI QY, GUO ZZ, et al. Serum levels of microRNAs can specifically predict liver injury of chronic hepatitis B[J]. World J Gastroenterol, 2012, 18(37): 5188-5196. DOI: 10.3748/wjg.v18.i37.5188.
[44]	YANG M, JIANG L, WANG Y, et al. Step layered combination of noninvasive fibrosis models improves diagnostic accuracy of advanced fibrosis in nonalcoholic fatty liver disease[J]. J Gastrointestin Liver Dis, 2019, 28(3): 289-296. DOI: 10.15403/jgld-420.
[45]	YANG M, XU D, LIU Y, et al. Combined serum biomarkers in non-invasive diagnosis of non-alcoholic steatohepatitis[J]. PLoS One, 2015, 10(6): e0131664. DOI: 10.1371/journal.pone.0131664.
[46]	LI Q, LU C, LI W, et al. The gamma-glutamyl transpeptidase to platelet ratio for non-invasive assessment of liver fibrosis in patients with chronic hepatitis B and non-alcoholic fatty liver disease[J]. Oncotarget, 2017, 8(17): 28641-28649. DOI: 10.18632/oncotarget.16162.
[47]	ZHANG GL, XU SC, ZENG J, et al. Optimizing the use of the gamma-glutamyl transpeptidase-to-platelet ratio and transient elastography to identify liver cirrhosis in patients with chronic hepatitis B concurrent with nonalcoholic fatty liver disease[J]. Dis Markers, 2019, 2019: 2585409. DOI: 10.1155/2019/2585409.
[48]	SHEN F, MI YQ, XU L, et al. Moderate to severe hepatic steatosis leads to overestimation of liver stiffness measurement in chronic hepatitis B patients without significant fibrosis[J]. Aliment Pharmacol Ther, 2019, 50(1): 93-102. DOI: 10.1111/apt.15298.
[49]	XU N, XIE Q, LI J, et al. Improvement in liver stiffness measurement for diagnosis of liver fibrosis in patients with concurrent chronic hepatitis B and nonalcoholic fatty liver disease[J]. J Int Med Res, 2020, 48(2): 300060520903667. DOI: 10.1177/0300060520903667.
[50]	CHU CM, LIN DY, LIAW YF. Does increased body mass index with hepatic steatosis contribute to seroclearance of hepatitis B virus (HBV) surface antigen in chronic HBV infection?[J]. Int J Obes (Lond), 2007, 31(5): 871-875. DOI: 10.1038/sj.ijo.0803479.
[51]	HUI R, SETO WK, CHEUNG KS, et al. Inverse relationship between hepatic steatosis and hepatitis B viremia: Results of a large case-control study[J]. J Viral Hepat, 2018, 25(1): 97-104. DOI: 10.1111/jvh.12766.
[52]	WANG L, WANG Y, LIU S, et al. Nonalcoholic fatty liver disease is associated with lower hepatitis B viral load and antiviral response in pediatric population[J]. J Gastroenterol, 2019, 54(12): 1096-1105. DOI: 10.1007/s00535-019-01594-6.
[53]	JIN X, CHEN YP, YANG YD, et al. Association between hepatic steatosis and entecavir treatment failure in Chinese patients with chronic hepatitis B[J]. PLoS One, 2012, 7(3): e34198. DOI: 10.1371/journal.pone.0034198.
[54]	LI J, LE AK, CHAUNG KT, et al. Fatty liver is not independently associated with the rates of complete response to oral antiviral therapy in chronic hepatitis B patients[J]. Liver Int, 2020, 40(5): 1052-1061. DOI: 10.1111/liv.14415.
[55]	HUI R, SETO WK, CHEUNG KS, et al. Inverse relationship between hepatic steatosis and hepatitis B viremia: Results of a large case-control study[J]. J Viral Hepat, 2018, 25(1): 97-104. DOI: 10.1111/jvh.12766.
[56]	LI J, LE AK, CHAUNG KT, et al. Fatty liver is not independently associated with the rates of complete response to oral antiviral therapy in chronic hepatitis B patients[J]. Liver Int, 2020, 40(5): 1052-1061. DOI: 10.1111/liv.14415.
[57]	KIM NH, CHO YK, KIM BI, et al. Effect of metabolic syndrome on the clinical outcomes of chronic hepatitis B patients with nucleos(t)ide analogues treatment[J]. Dig Dis Sci, 2018, 63(10): 2792-2799. DOI: 10.1007/s10620-018-5165-6.
[58]	ZHU LY, WANG YG, WEI LQ, et al. The effects of the insulin resistance index on the virologic response to entecavir in patients with HBeAg-positive chronic hepatitis B and nonalcoholic fatty liver disease[J]. Drug Des Devel Ther, 2016, 10: 2739-2744. DOI: 10.2147/DDDT.S114761.
[59]	CINDORUK M, KARAKAN T, UNAL S. Hepatic steatosis has no impact on the outcome of treatment in patients with chronic hepatitis B infection[J]. J Clin Gastroenterol, 2007, 41(5): 513-517. DOI: 10.1097/01.mcg.0000225586.78330.60.
[60]	CHOI H, BROUWER WP, ZANJIR W, et al. Nonalcoholic steatohepatitis is associated with liver-related outcomes and all-cause mortality in chronic hepatitis B[J]. Hepatology, 2020, 71(2): 539-548. DOI: 10.1002/hep.30857.