慢性HBV感染合并非酒精性脂肪性肝病：抗病毒治疗面临的问题

唐艳华; 陆星宇; 孙剑

doi:10.3969/j.issn.1001-5256.2021.07.004

慢性HBV感染合并非酒精性脂肪性肝病：抗病毒治疗面临的问题

DOI: 10.3969/j.issn.1001-5256.2021.07.004

器官衰竭防治国家重点实验室南方医科大学南方医院肝病中心，广州 510515

基金项目:

国家科技重大专项 (2017ZX10202202);

国家自然科学基金 (82070614);

国家自然科学基金 (81871668);

广东省”珠江人才计划”本土创新科研团队项目 (2017BT01S131)

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：唐艳华、陆星宇负责撰写论文及文献收集；孙剑负责拟定写作思路，指导撰写文章并最后定稿。

详细信息

通信作者:
孙剑，doctorsunjian@qq.com

中图分类号: R512.62;R575.5
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出版历程
- 收稿日期: 2021-06-08
- 录用日期: 2021-06-08
- 出版日期: 2021-07-20

Chronic hepatitis B virus infection with nonalcoholic fatty liver disease: Problems faced by antiviral therapy

State Key Laboratory of Organ Failure Research, Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China

Research funding:

National Science and Technology Major Project of China (2017ZX10202202);

National Natural Science Foundation of China (82070614);

National Natural Science Foundation of China (81871668);

Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program (2017BT01S131)

摘要

摘要: 随着非酒精性脂肪性肝病(NAFLD)发病率的增加，慢性HBV感染合并NAFLD在临床实践中变得越来越普遍。在ALT升高的情况下，确定潜在原因并及时实施有效干预可降低疾病进展为肝硬化和肝细胞癌的风险。然而，国内外指南尚缺乏对慢性HBV感染合并NAFLD患者的临床管理建议。回顾了慢性乙型肝炎和NAFLD的新近指南，探讨合并NAFLD对慢性HBV感染者抗病毒治疗适应证、临床疗效和长期预后的影响，为这类患者的临床管理提供借鉴。
- 乙型肝炎病毒 /
- 乙型肝炎，慢性 /
- 非酒精性脂肪性肝病 /
- 治疗学
Abstract: With an increase in the incidence rate of nonalcoholic fatty liver diseases (NAFLD), chronic hepatitis B virus (HBV) infection with NAFLD has become more and more common in clinical practice. In case of elevated alanine aminotransferase, identification of the underlying cause and timely implementation of effective management can prevent disease progression to liver cirrhosis and reduce the risk of hepatocellular carcinoma. Up to now, there is still a lack of recommendation on the clinical management of patients with chronic HBV infection and NAFLD in Chinese and international guidelines. This article reviews the latest guidelines for chronic HBV infection with NAFLD and discusses the influence of NAFLD on the indication for antiviral therapy, clinical outcome, and long-term prognosis in patients with chronic HBV infection and NAFLD, so as to provide a reference for the clinical management of such patients.
- Hepatitis B Virus /
- Hepatitis B, Chronic /
- Non-alcoholic Fatty Liver Disease /
- Therapeutics

HTML全文

表 1 各指南建议的单纯慢性HBV感染抗病毒治疗适应证

实践指南	肝硬化分类	抗病毒治疗适应证
实践指南	肝硬化分类	HBV DNA(IU/ml)	ALT¹⁾
APASL^[10]
2015年
	非肝硬化	＞20 000 (HBeAg+)或＞2000 (HBeAg-)	ALT＞2×ULN；ALT 1~ 2×ULN，活检显示中重度炎症或明显纤维化²⁾
		≤20 000 (HBeAg+)或≤2000 (HBeAg-)	ALT任意水平，活检显示中重度炎症或明显纤维化²⁾
	代偿期肝硬化	＞2000	ALT任意水平
		可检测到	ALT＞1×ULN
	失代偿期肝硬化	可检测到	ALT任意水平
EASL^[9]
2017年
	非肝硬化	＞2000	ALT＞1×ULN，中/重度肝脏坏死性炎症或纤维化
		＞20 000	ALT＞2×ULN，不考虑炎症及纤维化程度
		＞10⁷(HBeAg+)	ALT正常，有下列情况之一：(1)年龄＞30岁，不考虑肝组织学损伤的严重程度；(2)有HBV相关肝外表现³⁾或有HCC/肝硬化家族史
		≤2000	ALT正常，有HCC/肝硬化家族史或HBV相关肝外表现³⁾
	肝硬化	可检测到	ALT任意水平
AASLD^[2]
2018年
	非肝硬化	＞20 000 (HBeAg+)或＞2000 (HBeAg-)	ALT＞2×ULN和/或明显的组织学证据；ALT 1~2×ULN和明显的纤维化
		≤20 000 (HBeAg+)或≤2000 (HBeAg-)	ALT＜2×ULN，符合以下条件之一：(1)年龄＞40岁；(2)肝硬化/HCC家族史；(3)既往曾接受抗病毒治疗；(4)HBV相关肝外表现³⁾
		＞10⁶ (HBeAg+)	ALT正常，年龄＞40岁，肝组织活检显示明显的坏死性炎症或纤维化
	肝硬化	可检测到	ALT任意水平
中华医学会
肝病学分会^[8] 2019年	非肝硬化	可检测到	排除其他原因⁴⁾所致ALT持续升高(＞1×ULN)；ALT正常，有下列情况之一： (1)肝组织学检查提示明显炎症和/或纤维化(G ≥2和/或S ≥2)；(2)有乙型肝炎肝硬化/HCC家族史且年龄＞30岁；(3)年龄＞30岁，建议肝纤维化无创诊断技术检查或肝组织学检查，存在明显肝脏炎症或纤维化；(4)HBV相关肝外表现³⁾
	代偿期肝硬化	可检测到	ALT任意水平
	失代偿期肝硬化	任意水平	ALT任意水平
注：ULN, 正常值上限。1)APASL(2015), ULN: 男30 U/L，女19 U/L; EASL(2017), ULN：40 U/L; AASLD(2018), ULN：男35 U/L，女25 U/L; 中华医学会肝病学分会(2019), ULN：40 U/L。2)肝活检中至重度炎症是指Ishak评分肝脏活动性指数＞3/18或METAVIR活动性评分A2或A3。显著纤维化评估：Ishak纤维化分期≥3或METAVIR纤维化评分F ≥2。LSM ≥8 kPa或APRI ≥1.5表示显著纤维化；LSM ≥11 kPa或APRI ≥2.0表示肝硬化。3)HBV相关肝外表现：肾小球肾炎、血管炎、结节性多动脉炎、周围神经病变等。4)ALT升高的其他原因：其他病原体感染、药物或毒物服用史、饮酒史、脂肪代谢紊乱、自身免疫紊乱、肝脏淤血或血管性疾病、遗传代谢性肝损伤、全身性系统性疾病。

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参考文献(45)

[1]	LIU J, LIANG W, JING W, et al. Countdown to 2030: eliminating hepatitis B disease, China[J]. Bull World Health Organ, 2019, 97(3): 230-238. DOI: 10.2471/BLT.18.219469.
[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]	PAPATHEODORIDIS GV, IDILMAN R, DALEKOS GN, et al. The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B[J]. Hepatology, 2017, 66(5): 1444-1453. DOI: 10.1002/hep.29320.
[4]	ESTES C, ANSTEE QM, ARIAS-LOSTE MT, et al. Modeling NAFLD disease burden in China, France, Germany, Italy, Japan, Spain, United Kingdom, and United States for the period 2016-2030[J]. J Hepatol, 2018, 69(4): 896-904. DOI: 10.1016/j.jhep.2018.05.036.
[5]	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.
[6]	FANNING GC, ZOULIM F, HOU J, et al. Therapeutic strategies for hepatitis B virus infection: Towards a cure[J]. Nat Rev Drug Discov, 2019, 18(11): 827-844. DOI: 10.1038/s41573-019-0037-0.
[7]	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.
[8]	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.
[9]	European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection[J]. J Hepatol, 2017, 67(2): 370-398. DOI: 10.1016/j.jhep.2017.03.021.
[10]	SARIN SK, KUMAR M, LAU GK, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: A 2015 update[J]. Hepatol Int, 2016, 10(1): 1-98. DOI: 10.1007/s12072-015-9675-4.
[11]	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.
[12]	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. DOI: 10.1016/j.jhep.2015.04.006.
[13]	Chinese Foundation for Hepatitis Prevention and Control; Chinese Society of Infectious Disease and Chinese Society of Hepatology, Chinese Medical Association; Liver Disease Committee of Chinese Research Hospital Association. Consensus on clinical application of transient elastography detecting liver fibrosis: A 2018 update[J]. Chin J Hepatol, 2019, 27(3): 182-191. DOI: 10.3760/cma.j.issn.1007-3418.2019.03.004. 中国肝炎防治基金会, 中华医学会感染病学分会, 中华医学会肝病学分会和中国研究型医院学会肝病专业委员会. 瞬时弹性成像技术诊断肝纤维化专家共识(2018年更新版)[J]. 中华肝脏病杂志, 2019, 27(3): 182-191. DOI: 10.3760/cma.j.issn.1007-3418.2019.03.004.
[14]	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.
[15]	MAK LY, HUI RW, FUNG J, et al. Diverse effects of hepatic steatosis on fibrosis progression and functional cure in virologically quiescent chronic hepatitis B[J]. J Hepatol, 2020, 73(4): 800-806. DOI: 10.1016/j.jhep.2020.05.040.
[16]	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.
[17]	NGUYEN LH, CHAO D, LIM JK, et al. Histologic changes in liver tissue from patients with chronic hepatitis B and minimal increases in levels of alanine aminotransferase: A meta-analysis and systematic review[J]. Clin Gastroenterol Hepatol, 2014, 12(8): 1262-1266. DOI: 10.1016/j.cgh.2013.11.038.
[18]	YUEN MF, YUAN HJ, WONG DK, et al. Prognostic determinants for chronic hepatitis B in Asians: Therapeutic implications[J]. Gut, 2005, 54(11): 1610-1614. DOI: 10.1136/gut.2005.065136.
[19]	HSU YC, CHEN CY, CHANG IW, et al. Once-daily tenofovir disoproxil fumarate in treatment-naive Taiwanese patients with chronic hepatitis B and minimally raised alanine aminotransferase (TORCH-B): A multicentre, double-blind, placebo-controlled, parallel-group, randomised trial[J]. Lancet Infect Dis, 2021, 21(6): 823-833. DOI: 10.1016/S1473-3099(20)30692-7.
[20]	CHEN CJ, YANG HI, SU J, et al. Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level[J]. JAMA, 2006, 295(1): 65-73. DOI: 10.1001/jama.295.1.65.
[21]	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.
[22]	LAI CL, SHOUVAL D, LOK AS, et al. Entecavir versus lamivudine for patients with HBeAg-negative chronic hepatitis B[J]. N Engl J Med, 2006, 354(10): 1011-1020. DOI: 10.1056/NEJMoa051287.
[23]	CHANG TT, GISH RG, DE MAN R, et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B[J]. N Engl J Med, 2006, 354(10): 1001-1010. DOI: 10.1056/NEJMoa051285.
[24]	MARCELLIN P, GANE E, BUTI M, et al. Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: A 5-year open-label follow-up study[J]. Lancet, 2013, 381(9865): 468-475. DOI: 10.1016/S0140-6736(12)61425-1.
[25]	Committee of Hepatology, Chinese Research Hospital Association; Fatty Liver Expert Committee, Chinese Medical Doctor Associatio; National Workshop on Fatty Liver and Alcoholic Liver Disease, Chinese Society of Hepatology, et al. Expert recommendations on standardized diagnosis and treatment for fatty liver disease (2019 revised edition)[J]. J Clin Hepatol, 2019, 35(11): 2426-2430. DOI: 10.3969/j.issn.1001-5256.2019.11.007 中国研究型医院学会肝病专业委员会, 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与酒精性肝病学组, 等. 脂肪性肝病诊疗规范化的专家建议(2019年修订版)[J]. 临床肝胆病杂志, 2019, 35(11): 2426-2430. DOI: 10.3969/j.issn.1001-5256.2019.11.007
[26]	WONG VW, WONG GL, CHAN RS, et al. Beneficial effects of lifestyle intervention in non-obese patients with non-alcoholic fatty liver disease[J]. J Hepatol, 2018, 69(6): 1349-1356. DOI: 10.1016/j.jhep.2018.08.011.
[27]	MAZZOTTI A, CALETTI MT, BRODOSI L, et al. An internet-based approach for lifestyle changes in patients with NAFLD: Two-year effects on weight loss and surrogate markers[J]. J Hepatol, 2018, 69(5): 1155-1163. DOI: 10.1016/j.jhep.2018.07.013.
[28]	ARMSTRONG MJ, GAUNT P, AITHAL GP, et al. Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): A multicentre, double-blind, randomised, placebo-controlled phase 2 study[J]. Lancet, 2016, 387(10019): 679-690. DOI: 10.1016/S0140-6736(15)00803-X.
[29]	VILAR-GOMEZ E, MARTINEZ-PEREZ Y, CALZADILLA-BERTOT L, et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis[J]. Gastroenterology, 2015, 149(2): 367-378. e5; quiz e14-15. DOI: 10.1053/j.gastro.2015.04.005.
[30]	ZHANG HJ, PAN LL, MA ZM, et al. Long-term effect of exercise on improving fatty liver and cardiovascular risk factors in obese adults: A 1-year follow-up study[J]. Diabetes Obes Metab, 2017, 19(2): 284-289. DOI: 10.1111/dom.12809.
[31]	TALIANI G, DUCA F, LECCE R, et al. Hepatic lidocaine metabolism in chronic hepatitis C virus hepatitis with or without steatosis[J]. Hepatology, 1995, 21(6): 1760-1761.
[32]	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.
[33]	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.
[34]	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.
[35]	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.
[36]	EL-SERAG HB. epidemiology of viral hepatitis and hepatocellular carcinoma[J]. gastroenterology, 2012, 142(6): 1264-1273. e1. DOI: 10.1053/j.gastro.2011.12.061.
[37]	WONG GL, WONG VW, CHOI PC, et al. Metabolic syndrome increases the risk of liver cirrhosis in chronic hepatitis B[J]. Gut, 2009, 58(1): 111-117. DOI: 10.1136/gut.2008.157735.
[38]	WONG GL, CHAN HL, YU Z, et al. Coincidental metabolic syndrome increases the risk of liver fibrosis progression in patients with chronic hepatitis B—a prospective cohort study with paired transient elastography examinations[J]. Aliment Pharmacol Ther, 2014, 39(8): 883-893. DOI: 10.1111/apt.12658.
[39]	TAI DI, LIN SM, SHEEN IS, et al. Long-term outcome of hepatitis B e antigen-negative hepatitis B surface antigen carriers in relation to changes of alanine aminotransferase levels over time[J]. Hepatology, 2009, 49(6): 1859-1867. DOI: 10.1002/hep.22878.
[40]	LIU J, YANG HI, LEE MH, et al. Incidence and determinants of spontaneous hepatitis B surface antigen seroclearance: A community-based follow-up study[J]. Gastroenterology, 2010, 139(2): 474-482. DOI: 10.1053/j.gastro.2010.04.048.
[41]	LIU J, LEE MH, BATRLA-UTERMANN R, et al. A predictive scoring system for the seroclearance of HBsAg in HBeAg-seronegative chronic hepatitis B patients with genotype B or C infection[J]. J Hepatol, 2013, 58(5): 853-860. DOI: 10.1016/j.jhep.2012.12.006.
[42]	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.
[43]	ALTLPARMAK E, KOKLU S, YALINKILIC M, et al. Viral and host causes of fatty liver in chronic hepatitis B[J]. World J Gastroenterol, 2005, 11(20): 3056-3059. DOI: 10.3748/wjg.v11.i20.3056.
[44]	MINAKARI M, MOLAEI M, SHALMANI HM, et al. Liver steatosis in patients with chronic hepatitis B infection: Host and viral risk factors[J]. Eur J Gastroenterol Hepatol, 2009, 21(5): 512-516. DOI: 10.1097/MEG.0b013e328326792e.
[45]	PENG D, HAN Y, DING H, et al. Hepatic steatosis in chronic hepatitis B patients is associated with metabolic factors more than viral factors[J]. J Gastroenterol Hepatol, 2008, 23(7 Pt 1): 1082-1088. DOI: 10.1111/j.1440-1746.2008.05478.x.