慢性乙型肝炎及肝硬化患者血清血管生成素1、2及其比值变化与HBV DNA和ALT的相关性分析

林明华; 常远; 刘芳; 黄雁翔; 徐航飞

doi:10.12449/JCH240609

慢性乙型肝炎及肝硬化患者血清血管生成素1、2及其比值变化与HBV DNA和ALT的相关性分析

DOI: 10.12449/JCH240609

林明华^1, , ,,
常远²,
刘芳¹,
黄雁翔¹,
徐航飞¹

1.
首都医科大学附属北京佑安医院北京肝病研究所，北京 100069
2.
聊城市人民医院检验科，山东聊城 252000

基金项目:

北京市属医学科研院所公益发展改革试点项目 (JING YI YAN 2021-10);

北京市工程技术研究中心 (BG0320)

伦理学声明： 本研究方案于2023年6月21日经由首都医科大学附属北京佑安医院伦理委员会审批，批号：京佑科伦字〔2023〕59号。

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：林明华负责课题设计，资料分析，撰写论文；常远、刘芳、黄雁翔负责收集标本，实验工作；徐航飞负责数据处理，统计分析。

详细信息

通信作者:
林明华， minghualin@ccmu.edu.cn （ORCID： 0000-0003-1220-461X）

计量
- 文章访问数: 324
- HTML全文浏览量: 137
- PDF下载量: 49
- 被引次数: 2
出版历程
- 收稿日期: 2023-08-22
- 录用日期: 2023-11-16
- 出版日期: 2024-06-25

Correlation of serum angiopoietin-1， angiopoietin-2， and angiopoietin-1/angiopoietin-2 ratio with HBV DNA and alanine aminotransferase in patients with chronic hepatitis B or liver cirrhosis

1.
Beijing YouAn Hospital，Beijing Institute of Liver Diseases，Capital Medical University，Beijing 100069，China
2.
Department of Clinical Laboratory，Liaocheng People’s Hospital，Liaocheng，Shandong 252000，China

Research funding:

Beijing Municipal Institute of Public Medical Research Development and Reform Pilot Project (JING YI YAN 2021-10);

Beijing Engineering Research Center for Precision Medicine and Transformation of Hepatitis and Liver Cancer (BG0320)

More Information

Corresponding author: LIN Minghua， minghualin@ccmu.edu.cn （ORCID： 0000-0003-1220-461X）

摘要

摘要: 目的分析血清血管生成素（Ang）1、2及其比值变化与慢性乙型肝炎（CHB）、肝硬化患者HBV DNA和ALT的相关性。方法选取2018年3月—2019年10月首都医科大学附属北京佑安医院收治的CHB患者99例，肝硬化患者59例，收集临床资料和血清标本；另选同期46例健康体检者作为对照组。所有患者均采用PCR法检测血清HBV DNA；采用酶联免疫吸附法检测血清Ang-1和Ang-2水平，比较各组血清Ang-1和Ang-2及Ang-1/Ang-2的差异。非正态分布的计量资料多组间比较采用Kruskal-Wallis H检验，进一步两两比较采用Bonferroni法；采用Spearman方法分析Ang-1、Ang-2、Ang-1/Ang-2与HBV DNA、ALT的相关性。结果与对照组（671.0 pg/mL）相比，CHB组（479.0 pg/mL）和肝硬化组（208.4 pg/mL）Ang-1水平显著降低（P值均<0.05）；与CHB组相比，肝硬化组Ang-1水平显著降低（P<0.001）。与对照组（198.0 pg/mL）相比，CHB组（286.1 pg/mL）和肝硬化组（438.4 pg/mL）Ang-2水平显著升高（P值均<0.001）；与CHB组相比，肝硬化组Ang-2水平显著升高（P<0.001）。与对照组（3.4）相比，CHB组（1.6）和肝硬化组（0.5）Ang-1/Ang-2比值显著降低（P值均<0.001）；与CHB组相比，肝硬化组Ang-1/Ang-2比值显著降低（P<0.001）。Spearman分析显示，CHB组Ang-1与HBV DNA及ALT均呈负相关（r值分别为-0.400、-0.394，P值均˂0.001）；Ang-2与HBV DNA及ALT均呈正相关（r值分别为0.365、0.351，P值均˂0.001）；Ang-1/Ang-2与HBV DNA及ALT均呈负相关（r值分别为-0.463、-0.473，P值均˂0.001）；而肝硬化组Ang-1、Ang-2及Ang-1/Ang-2均与HBV DNA和ALT无相关性（P值均˃0.05）。结论 CHB、肝硬化患者血清Ang-1、Ang-2及Ang-1/Ang-2有显著改变，其中肝炎组Ang-1、Ang-2及Ang-1/Ang-2在一定程度上反映CHB患者肝损伤的程度。
- 血管生成素1 /
- 血管生成素2 /
- 乙型肝炎，慢性 /
- 肝硬化 /
- 乙型肝炎病毒 /
- 丙氨酸转氨酶
Abstract: Objective To investigate the correlation of serum angiopoietin-1 （Ang-1）， angiopoietin-2 （Ang-2）， and Ang-1/Ang-2 ratio with HBA DNA and alanine aminotransferase （ALT） in patients with chronic hepatitis B （CHB） or liver cirrhosis. Methods Clinical data and serum specimens were collected from 99 patients with CHB and 59 patients with liver cirrhosis who were admitted to Beijing YouAn Hospital， Capital Medical University， from March 2018 to October 2019， and 46 individuals who underwent physical examination were enrolled as control group. PCR was used to measure serum HBV DNA level， and ELISA was used to measure the serum levels of Ang-1 and Ang-2. The serum levels of Ang-1 and Ang-2 and Ang-1/Ang-2 ratio were compared between groups. The Kruskal-Wallis H test was used for comparison of non-normally distributed continuous data between multiple groups， and the Bonferroni method was used for further comparison between two groups； the Spearman correlation analysis was used to investigate the correlation of Ang-1， Ang-2， and Ang-1/Ang-2 ratio with HBV DNA and ALT. Results Compared with the control group， the CHB group and the liver cirrhosis group had a significant reduction in the level of Ang-1 （479.0 pg/mL and 208.4 pg/mL vs 671.0 pg/mL， both P<0.05）， and compared with the CHB group， the liver cirrhosis group had a significant reduction in the level of Ang-1 （P<0.001）. Compared with the control group， the CHB group and the liver cirrhosis group had a significant increase in the level of Ang-2 （286.1 pg/mL and 438.4 pg/mL vs 198.0 pg/mL， both P<0.001）， and compared with the CHB group， the liver cirrhosis group had a significant increase in the level of Ang-2 （P<0.001）. Compared with the control group， the CHB group and the liver cirrhosis group had a significant reduction in Ang-1/Ang-2 ratio （1.6 and 0.5 vs 3.4， both P<0.001）， and compared with the CHB group， the liver cirrhosis group had a significant reduction in Ang-1/Ang-2 ratio （P<0.001）. The Spearman correlation analysis showed that in the CHB group， Ang-1 was negatively correlated with HBV DNA and ALT （r=-0.400 and -0.394， both P˂0.001）， Ang-2 was positively correlated with HBV DNA and ALT （r=0.365 and 0.351， both P<0.001）， and Ang-1/Ang-2 ratio was negatively correlated with HBV DNA and ALT （r=-0.463 and -0.473， both P<0.001）； in the liver cirrhosis group， Ang-1， Ang-2， and Ang-1/Ang-2 ratio had no correlation with HBV DNA or ALT （all P>0.05）. Conclusion There are significant changes in the serum levels of Ang-1 and Ang-2 and Ang-1/Ang-2 ratio in patients with CHB or liver cirrhosis， and Ang-1， Ang-2， and Ang-1/Ang-2 ratio reflects the degree of liver injury in patients with CHB to a certain extent.
- Angiopoietin-1 /
- Angiopoietin-2 /
- Hepatitis B， Chronic /
- Liver Cirrhosis /
- Hepatitis B virus /
- Alanine Transaminase

HTML全文

抗病毒治疗是慢性乙型肝炎(CHB)的关键措施，其中恩替卡韦(ETV) 是治疗HBV的一线核苷(酸)类似物(NAs) 之一。尽管其他研究曾报道了长期ETV治疗CHB的疗效和安全性，但其在中国慢性CHB(主要为基因型B和C)患者中的临床数据仍然有限。

马来酸ETV是正大天晴药业股份有限公司开发的ETV衍生物，多中心、随机、双盲双模拟、阳性药物对照临床研究显示其治疗48周时与原研ETV在治疗CHB时等效，基于上述结果，国家食品药品管理局已经批准其上市。作为此项研究的主要研究者，北京大学第一医院于岩岩教授对其长期疗效和安全性进行了进一步研究：此前已经报告144周的马来酸ETV治疗中国慢性CHB(主要为基因型B和C)患者有效而且安全。更长疗程的药物治疗效果和安全性如何，尚无知晓。

2022年7月6日于岩岩教授团队在线发表研究论文，旨在更新马来酸ETV治疗中国患者240周疗程的病毒学、血清学和生化结果。CHB受试者被随机分配接受0.5 mg/d ETV(A组)或0.5 mg/d马来酸ETV(B组)治疗48周，此后所有受试者从第49周开始接受0.5 mg/d马来酸ETV治疗。定期对患者进行随访，监测血清HBV标志物、肝生化等指标，记录不良事件(AE)。主要终点是治疗结束时每组HBV DNA的下降。次要终点包括治疗结束时HBV DNA不可测(＜20 IU/mL) 的比率、HBeAg消失率、HBeAg血清转化率和血清ALT复常率。137例(A组71例) HBeAg阳性CHB患者和46例(A组21例)HBeAg阴性CHB患者完成了240周的治疗和随访。两组的基线特征可比。在HBeAg阳性CHB组，240周时两组的HBV DNA较基线下降平均值可比(A：6.67 log₁₀ IU/mL vs B：6.74 log₁₀ IU/mL；P＞0.05)，血清HBV DNA不可测率(A：91.55% vs B：87.88%；P＞0.05)、HBeAg血清学转换率(A：26.98% vs B：20.97%；P＞0.05)和ALT复常率(A：87.32% vs B：83.61%；P＞0.05)均在组间可比。在HBeAg阴性CHB组，240周时两组的HBV DNA较基线下降平均值可比(A：6.05 log₁₀ IU/mL vs B：6.10 log₁₀ IU/mL；P＞0.05)，血清HBV DNA不可测比例(A：100% vs B：100%)和ALT复常率(A：90.91% vs B：95.45%)(P＞0.05)也可比。在耐药方面，HBeAg阴性CHB组耐药率为0；HBeAg阳性CHB组144周时耐药率1.16%，此后直至240周新增1例ETV耐药。安全性方面，没有因为AE导致停药，无肝癌或死亡病例。

总之，作为国产抗HBV药物代表之一的马来酸ETV，长期治疗中国CHB(主要是基因型B或C)是安全有效的。

摘译自XU JH, FAN YN, YU YY, et al. 240-week entecavir maleate treatment in Chinese chronic hepatitis B predominantly genotype B or C[J]. J Viral Hepat, 2022, 29(10): 862-867. DOI: 10.1111/jvh.13724.

(北京大学第一医院感染疾病科徐京杭报道)

图 1 各组血清Ang-1、Ang-2表达水平及Ang-1/Ang-2比值

Figure 1. The levels of Ang-1、Ang-2 and radio of Ang-1/Ang-2 in groups

下载: 全尺寸图片幻灯片

表 1 各组血清Ang-1、Ang-2表达水平及Ang-1/Ang-2比值

Table 1. The levels of Ang-1、Ang-2 and radio of Ang-1/Ang-2 in groups

组别	例数	Ang-1（pg/mL）	Ang-2（pg/mL）	Ang-1/Ang-2
对照组	46	671.0（410.8～1 072.5）	198.0（149.3～263.1）	3.4（1.9～4.8）
CHB组	99	479.0（320.9～740.0）^1）	286.1（224.3～373.2）^2）	1.6（0.8～2.6）^2）
肝硬化组	59	208.4（140.1～370.0）^1）3）	438.4（338.0～590.5）^2）3）	0.5（0.2～0.9）^2）3）
χ²值		56.66	70.20	86.33
P值		<0.001	<0.001	<0.001
注：与对照组比较，1）P<0.05，2）P<0.001；与CHB组比较，3）P<0.001。

下载: 导出CSV

表 2 CHB组Ang-1、Ang-2及Ang-1/Ang-2比值与HBV DNA、ALT的相关性分析

Table 2. Correlation analysis of Ang-1， Ang-2， and Ang-1/Ang-2 ratios with HBV DNA and ALT in hepatitis group

指标	HBV DNA（IU/mL）		ALT（U/L）
指标	r值	P值	r值	P值
Ang-1	-0.400	<0.001	-0.394	<0.001
Ang-2	0.365	<0.001	0.351	<0.001
Ang-1/Ang-2	-0.463	<0.001	-0.473	<0.001

下载: 导出CSV

表 3 肝硬化组Ang-1、Ang-2及Ang-1/Ang-2比值与HBV DNA、ALT的相关性分析

Table 3. Correlation analysis of Ang-1， Ang-2， and Ang-1/Ang-2 ratios with HBV DNA and ALT in cirrhosis group

指标	HBV DNA（IU/mL）		ALT（U/L）
指标	r值	P值	r值	P值
Ang-1	0.204	0.121	-0.001	0.992
Ang-2	0.032	0.812	-0.089	0.501
Ang-1/Ang-2	0.141	0.287	0.007	0.960

下载: 导出CSV

参考文献(22)

[1]	SAHARINEN P, LEPPÄNEN VM, ALITALO K. SnapShot: Angiopoietins and their functions[J]. Cell, 2017, 171( 3): 724- 724. DOI: 10.1016/j.cell.2017.10.009.
[2]	JEANSSON M, GAWLIK A, ANDERSON G, et al. Angiopoietin-1 is essential in mouse vasculature during development and in response to injury[J]. J Clin Invest, 2011, 121( 6): 2278- 2289. DOI: 10.1172/JCI46322.
[3]	LEE SJ, LEE CK, KANG S, et al. Angiopoietin-2 exacerbates cardiac hypoxia and inflammation after myocardial infarction[J]. J Clin Invest, 2018, 128( 11): 5018- 5033. DOI: 10.1172/JCI99659.
[4]	MELENDEZ E, WHITNEY JE, NORTON JS, et al. Systemic angiopoietin-1/2 dysregulation in pediatric sepsis and septic shock[J]. Int J Med Sci, 2019, 16( 2): 318- 323. DOI: 10.7150/ijms.27731.
[5]	KUMAR NP, VELAYUTHAM B, NAIR D, et al. Angiopoietins as biomarkers of disease severity and bacterial burden in pulmonary tuberculosis[J]. Int J Tuberc Lung Dis, 2017, 21( 1): 93- 99. DOI: 10.5588/ijtld.16.0565.
[6]	van MEURS M, KÜMPERS P, LIGTENBERG JJ, et al. Bench-to-bedside review: Angiopoietin signalling in critical illness-a future target?[J]. Crit Care, 2009, 13( 2): 207. DOI: 10.1186/cc7153.
[7]	Chinese Society of Infectious Diseases, Chinese Medical Association; Chinese Society of Hepatology, 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. 中华医学会感染病学分会, 中华医学会肝病学分会. 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.
[8]	PARIKH SM. Dysregulation of the angiopoietin-Tie-2 axis in sepsis and ARDS[J]. Virulence, 2013, 4( 6): 517- 524. DOI: 10.4161/viru.24906.
[9]	FAILLACI F, MARZI L, CRITELLI R, et al. Liver angiopoietin-2 is a key predictor of de novo or recurrent hepatocellular cancer after hepatitis C virus direct-acting antivirals[J]. Hepatology, 2018, 68( 3): 1010- 1024. DOI: 10.1002/hep.29911.
[10]	UEHARA M, ENOMOTO N, MIKAMO M, et al. Impact of angiopoietin-1 and-2 on clinical course of idiopathic pulmonary fibrosis[J]. Respir Med, 2016, 114: 18- 26. DOI: 10.1016/j.rmed.2016.03.001.
[11]	LIN MH, SHI Y, XIE F, et al. Research progress of angiogenesis in liver fibrosis[J]. Beijing Med J, 2014, 36( 6): 468- 470. DOI: 10.15932/j.0253-9713.2014.06.031. 林明华, 石英, 谢放, 等. 血管生成在肝纤维化中的研究进展[J]. 北京医学, 2014, 36( 6): 468- 470. DOI: 10.15932/j.0253-9713.2014.06.031.
[12]	SAHARINEN P, EKLUND L, ALITALO K. Therapeutic targeting of the angiopoietin-TIE pathway[J]. Nat Rev Drug Discov, 2017, 16( 9): 635- 661. DOI: 10.1038/nrd.2016.278.
[13]	PAUTA M, RIBERA J, MELGAR-LESMES P, et al. Overexpression of angiopoietin-2 in rats and patients with liver fibrosis. Therapeutic consequences of its inhibition[J]. Liver Int, 2015, 35( 4): 1383- 1392. DOI: 10.1111/liv.12505.
[14]	LEFERE S, van de VELDE F, HOORENS A, et al. Angiopoietin-2 promotes pathological angiogenesis and is a therapeutic target in murine nonalcoholic fatty liver disease[J]. Hepatology, 2019, 69( 3): 1087- 1104. DOI: 10.1002/hep.30294.
[15]	WHITEHEAD M, OSBORNE A, WIDDOWSON PS, et al. Angiopoietins in diabetic retinopathy: Current understanding and therapeutic potential[J]. J Diabetes Res, 2019, 2019: 5140521. DOI: 10.1155/2019/5140521.
[16]	YU XL, YE FC. Role of angiopoietins in development of cancer and neoplasia associated with viral infection[J]. Cells, 2020, 9( 2): 457. DOI: 10.3390/cells9020457.
[17]	KHANANI AM, RUSSELL MW, AZIZ AA, et al. Angiopoietins as potential targets in management of retinal disease[J]. Clin Ophthalmol, 2021, 15: 3747- 3755. DOI: 10.2147/OPTH.S231801.
[18]	COLLAZOS-ALEMÁN JD, GNECCO-GONZÁLEZ S, JARAMILLO-ZARAMA B, et al. The role of angiopoietins in neovascular diabetes-related retinal diseases[J]. Diabetes Ther, 2022, 13( 11-12): 1811- 1821. DOI: 10.1007/s13300-022-01326-9.
[19]	ZHANG HM, ZHAO ZB, XIONG YX, et al. Research progress of angiopoietins in hepatocellular carcinoma[J]. J Clin Hepatol, 2011, 27( 4): 433- 436. DOI: 10.3969/j.issn.1001-5256.2011.04.030. 张华敏, 赵正斌, 熊亚星, 等. 血管生成素在肝细胞癌中的研究进展[J]. 临床肝胆病杂志, 2011, 27( 4): 433- 436. DOI: 10.3969/j.issn.1001-5256.2011.04.030.
[20]	FIEDLER U, REISS Y, SCHARPFENECKER M, et al. Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation[J]. Nat Med, 2006, 12( 2): 235- 239. DOI: 10.1038/nm1351.
[21]	LE CRAS TD, MOBBERLEY-SCHUMAN PS, BROERING M, et al. Angiopoietins as serum biomarkers for lymphatic anomalies[J]. Angiogenesis, 2017, 20( 1): 163- 173. DOI: 10.1007/s10456-016-9537-2.
[22]	HERNÁNDEZ-BARTOLOMÉ Á, LÓPEZ-RODRÍGUEZ R, BORQUE MJ, et al. Angiopoietin-2/angiopoietin-1 as non-invasive biomarker of cirrhosis in chronic hepatitis C[J]. World J Gastroenterol, 2016, 22( 44): 9744- 9751. DOI: 10.3748/wjg.v22.i44.9744.