HBV相关慢加急性肝衰竭患者血清HMGB1、sCD163、PGE2的表达水平及其对预后的预测价值

韩晨璐; 梁海军; 杨道坤; 常海燕; 魏帅; 王新伟; 高海丽

doi:10.12449/JCH240610

HBV相关慢加急性肝衰竭患者血清HMGB1、sCD163、PGE2的表达水平及其对预后的预测价值

DOI: 10.12449/JCH240610

新乡医学院第一附属医院感染内科，河南新乡 453000

基金项目:

河南省医学科技攻关计划项目 (LHGJ20210532)

伦理学声明： 本研究方案于2022年6月2日经由新乡医学院第一附属医院伦理委员会审批，批号：EC-022-194，所有患者均签署知情同意书。

利益冲突声明：本文不存在任何利益冲突。

作者贡献声明：韩晨璐、梁海军负责设计研究思路、收集标本与数据、实验操作、撰写论文；常海燕、魏帅负责统计学分析、绘制图表；王新伟、高海丽参与收集标本、修改论文；杨道坤负责拟定写作思路、指导撰写文章并最后定稿。韩晨璐与梁海军对本文贡献等同，同为第一作者。

详细信息

通信作者:
杨道坤， dk13949620669@163.com （ORCID： 0000-0003-4606-7457）

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出版历程
- 收稿日期: 2023-10-12
- 录用日期: 2023-12-25
- 出版日期: 2024-06-25

Expression levels of serum high-mobility group box 1， soluble CD163， and prostaglandin E2 in patients with hepatitis B virus-related chronic-on-acute liver failure and their value in predicting prognosis

Department of Infectious Diseases，The First Affiliated Hospital of Xinxiang Medical University，Xinxiang，Henan 453000，China

Research funding:

Medical Science and Technology Research Project of Henan Province (LHGJ20210532)

More Information

Corresponding author: YANG Daokun， dk13949620669@163.com （ORCID： 0000-0003-4606-7457）

摘要

摘要: 目的观察HBV相关慢加急性肝衰竭（HBV-ACLF）患者血清高迁移率族蛋白B1（HMGB1）、可溶性CD163（sCD163）、前列腺素E2（PGE2）的表达水平，并评估三者单独及联合检测对预后的预测价值。方法收集2022年7月1日—2023年9月30日在新乡医学院第一附属医院感染内科住院的HBV-ACLF患者76例，根据28天预后情况，将其分为生存组（n=48）和死亡组（n=28）。收集患者一般资料，计算MELD评分，并采用ELISA法检测血清HMGB1、sCD163和PGE2水平。正态分布的计量资料两组间比较采用成组t检验，非正态分布的计量资料两组间比较采用Mann-Whitney U检验；计数资料两组间比较采用χ²检验。采用Spearman秩相关性分析HMGB1、sCD163和PGE2与MELD评分的相关性；采用受试者工作特征曲线（ROC曲线）分析HMGB1、sCD163和PGE2单独及联合检测对HBV-ACLF患者预后的预测价值。结果生存组和死亡组间TBil、WBC、中性粒细胞百分数、降钙素原、血清淀粉样蛋白A、IL-6、血清钠（Na⁺）、血清肌酐（SCr）差异均有统计学意义（P值均<0.05）。死亡组血清HMGB1（Z=-2.997，P=0.003）、sCD163（Z=-2.972，P=0.003）和MELD评分（t=-6.997，P<0.001）显著高于生存组，差异均有统计学意义；死亡组血清PGE2水平显著低于生存组，差异有统计学意义（Z=-4.909，P<0.001）。Spearman秩相关性分析发现，HMGB1、sCD163与MELD评分呈正相关（r值分别为0.431、0.319，P值均<0.05），PGE2与MELD评分呈负相关（r=-0.412，P<0.001）。ROC曲线分析发现，HMGB1、sCD163和PGE2单独预测的曲线下面积（AUC）分别为0.717、0.716、0.856，三者联合预测价值最高，AUC为0.930，敏感度为0.778，特异度为0.920。结论血清HMGB1、sCD163、PGE2单独及联合检测在预测HBV-ACLF患者预后方面均具有良好参考价值，三者联合预测价值最高，值得进一步观察和研究。
- 慢加急性肝功能衰竭 /
- 预后 /
- HMGB1蛋白质 /
- 可溶性CD163 /
- 前列腺素E2
Abstract: Objective To investigate the expression levels of serum high-mobility group box 1 （HMGB1）， soluble CD163 （sCD163）， and prostaglandin E2 （PGE2） in patients with hepatitis B virus-related chronic-on-acute liver failure （HBV-ACLF）， and to evaluate the value of the three indicators used alone or in combination in predicting prognosis. Methods A total of 76 patients with HBV-ACLF who were hospitalized in Department of Infectious Diseases， The First Affiliated Hospital of Xinxiang Medical University， from July 1， 2022 to September 30， 2023 were enrolled， and according to the 28-day prognosis， they were divided into survival group with 48 patients and death group with 28 patients. General data were collected， Model for End-Stage Liver Disease （MELD） score was calculated， and ELISA was used to measure the serum levels of HMGB1， sCD163， and PGE2. The independent-samples t test was used for comparison of normally distributed continuous data between two groups， and the Mann-Whitney U test was used for comparison of non-normally distributed continuous data between two groups； the chi-square test was used for comparison of categorical data between two groups. The Spearman rank correlation test was used to analyze the correlation of HMGB1， sCD163， and PGE2 with MELD score； the receiver operating characteristic （ROC） curve was used to analyze the value of HMGB1， sCD163， and PGE2 used alone or in combination in predicting the prognosis of HBV-ACLF patients. Results There were significant differences between the two groups in total bilirubin， white blood cell count， the percentage of neutrophils， procalcitonin， serum amyloid A， interleukin-6， serum sodium， and serum creatinine （all P<0.05）. Compared with the survival group， the death group had significantly higher serum levels of HMGB1 （Z=-2.997， P=0.003） and sCD163 （Z=-2.972， P=0.003）， a significantly higher MELD score （t=-6.997， P<0.001）， and a significantly lower serum level of PGE2 （Z=-4.909， P<0.001）. The Spearman rank correlation test showed that HMGB1 and sCD163 were positively correlated with MELD score （r=0.431 and 0.319， both P<0.05）， while PGE2 was negatively correlated with MELD score （r=-0.412， P<0.05）. The ROC curve analysis showed that HMGB1， sCD163， and PGE2 used alone had an area under the ROC curve （AUC） of 0.717， 0.716， and 0.856， respectively， while the combination of the three indicators had the highest predictive value， with an AUC of 0.930， a sensitivity of 0.778， and a specificity of 0.920. Conclusion Serum HMGB1， sCD163， and PGE2 used alone or in combination have a good reference value in predicting the prognosis of HBV-ACLF patients， and the combination of the three indicators has the highest predictive value， which holds promise for further observation and research.
- Acute-On-Chronic Liver Failure /
- Prognosis /
- HMGB1 Protein /
- Soluble CD163 /
- Prostaglandin E2

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图 1 HMGB1与MELD评分的相关性

Figure 1. Correlation between HMGB1 and MELD score

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图 2 sCD163与MELD评分的相关性

Figure 2. Correlation between sCD163 and MELD score

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图 3 PGE2与MELD评分的相关性

Figure 3. Correlation between PGE2 and MELD score

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图 4 HMGB1、sCD163、PGE2单独及联合检测预测HBV-ACLF患者预后的ROC曲线

Figure 4. ROC curves of HMGB1， sCD163 and PGE2 alone and in combination to predict prognosis of HBV-ACLF patients

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表 1 两组患者一般资料比较

Table 1. Comparison of general data between the two groups

指标	生存组（n=48）	死亡组（n=28）	统计值	P值
男/女（例）	34/14	21/7	χ²=0.154	0.695
年龄（岁）	51.213±13.074	52.643±14.794	t=-0.087	0.931
Alb（g/L）	31.000（28.575～33.775）	30.750（28.725～33.150）	Z=-0.525	0.600
TBil（µmol/L）	355.203±183.567	475.193±229.273	t=-2.370	0.022
ALT（U/L）	105.000（38.500～269.750）	91.000（38.750～271.750）	Z=-0.044	0.965
AST（U/L）	134.500（68.000～191.750）	220.000（82.250～401.500）	Z=-1.083	0.279
LDH（U/L）	245.000（218.000～349.250）	368.000（213.750～591.250）	Z=-1.421	0.155
PT（s）	19.400（15.425～22.400）	23.400（16.650～43.158）	Z=-1.662	0.096
PTA（%）	47.360（38.758～61.998）	36.750（21.503～56.285）	Z=-1.815	0.075
INR	1.660（1.337～1.952）	2.145（1.355～3.845）	Z=-1.783	0.075
WBC（×10⁹/L）	6.690（4.965～9.250）	11.370（8.340～15.557）	Z=-2.821	0.005
PLT（×10⁹/L）	110.500（58.250～202.000）	137.500（65.000～196.500）	Z=-0.087	0.930
中性粒细胞百分数（%）	71.250（61.175～81.050）	84.050（79.150～91.225）	Z=-3.707	<0.001
SCr（µmol/L）	43.750（36.425～57.975）	61.900（56.975～97.925）	Z=-3.161	0.002
Na⁺（mmol/L）	133.625±3.833	128.857±4.928	t=3.599	0.001
CRP（mg/L）	10.945（5.047～36.680）	32.085（19.615～43.933）	Z=-1.689	0.091
PCT（ng/ml）	0.416（0.183～1.100）	1.250（0.388～1.950）	Z=-2.305	0.021
IL-6（pg/ml）	15.315（6.522～29.265）	34.250（21.047～84.992）	Z=-2.960	0.003
SAA（mg/L）	3.100（1.575～5.175）	9.350（4.575～31.125）	Z=-2.877	0.004

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表 2 两组患者血清HMGB1、sCD163、PGE2水平和MELD评分比较

Table 2. Comparison of serum HMGB1， sCD163， PGE2 levels and MELD scores between the two groups

指标	生存组（n=48）	死亡组（n=28）	统计值	P值
HMGB1（pg/mL）	756.492（566.918～1 070.678）	1 011.152（795.188～1 465.057）	Z=-2.997	0.003
sCD163（pg/mL）	508.675（361.567～825.933）	728.298（607.953～1 010.074）	Z=-2.972	0.003
PGE2（pg/mL）	441.120（345.941～632.430）	262.286（158.389～334.938）	Z=-4.909	<0.001
MELD评分（分）	13.705±6.243	26.454±8.928	t=-6.997	<0.001

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表 3 HMGB1、sCD163、PGE2单独及联合检测对HBV-ACLF患者预后的预测价值

Table 3. Prognostic value of HMGB1， sCD163 and PGE2 alone and in combination in HBV-ACLF patients

指标	最佳截断值	约登指数	敏感度	特异度	AUC	95%CI	P值
HMGB1（pg/mL）	788.344	0.400	0.600	0.800	0.717	0.593～0.841	0.003
sCD163（pg/mL）	544.297	0.440	0.600	0.840	0.716	0.596～0.835	0.003
PGE2（pg/mL）	342.819	0.618	0.778	0.840	0.856	0.764～0.948	<0.001
三者联合		0.698	0.778	0.920	0.930	0.875～0.985	<0.001

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参考文献(23)

[1]	XU MM, KONG M, YU PF, et al. Clinical course and outcome patterns of acute-on-chronic liver failure: a multicenter retrospective cohort study[J]. J Clin Transl Hepatol, 2021, 9( 5): 626- 634. DOI: 10.14218/JCTH.2020.00179.
[2]	ABUDEIF A, SAYED E, GALAL GM. Characteristics and predictors of short-term mortality in decompensated cirrhotic patients with acute-on-chronic liver failure[J]. Clin Exp Hepatol, 2022, 8( 4): 300- 308. DOI: 10.5114/ceh.2022.122332.
[3]	ABBAS N, RAJORIYA N, ELSHARKAWY AM, et al. Acute-on-chronic liver failure(ACLF) in 2022: have novel treatment paradigms already arrived?[J]. Expert Rev Gastroenterol Hepatol, 2022, 16( 7): 639- 652. DOI: 10.1080/17474124.2022.2097070.
[4]	CHEN MJ, LI X, TANG SH. Research progress on multidimensional evaluation of liver function in the prognosis of liver failure patients[J]. Clin J Med Offic, 2023, 51( 9): 901- 903, 907. DOI: 10.16680/j.1671-3826.2023.09.05. 陈美娟, 李雪, 汤善宏. 多维度评估肝功能在肝衰竭患者预后中研究进展[J]. 临床军医杂志, 2023, 51( 9): 901- 903, 907. DOI: 10.16680/j.1671-3826.2023.09.05.
[5]	LIU Y, YUAN W, FANG M, et al. Determination of HMGB1 in hepatitis B virus-related acute-on-chronic liver failure patients with acute kidney injury: Early prediction and prognostic implications[J]. Front Pharmacol, 2022, 13: 1031790. DOI: 10.3389/fphar.2022.1031790.
[6]	GRØNBAEK H, MØLLER HJ, SALIBA F, et al. Improved prediction of mortality by combinations of inflammatory markers and standard clinical scores in patients with acute-on-chronic liver failure and acute decompensation[J]. J Gastroenterol Hepatol, 2021, 36( 1): 240- 248. DOI: 10.1111/jgh.15125.
[7]	HUANG XP, WANG Y, CHEN L, et al. Elevated serum prostaglandin E2 predicts the risk of infection in hepatitis B virus-related acute-on-chronic liver failure patients[J]. Asian Pac J Trop Med, 2017, 10( 9): 916- 920. DOI: 10.1016/j.apjtm.2017.08.008.
[8]	Chinese Society of Infectious Diseases, Chinese Society of Hepatology. 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.
[9]	Liver Failure and Artificial Liver Group, Chinese Society of Infectious Diseases, Chinese Medical Association; Severe Liver Disease and Artificial Liver Group, Chinese Society of Hepatology, Chinese Medical Association. Guideline for diagnosis and treatment of liver failure(2018)[J]. J Clin Hepatol, 2019, 35( 1): 38- 44. DOI: 10.3969/j.issn.1001-5256.2019.01.007. 中华医学会感染病学分会肝衰竭与人工肝学组, 中华医学会肝病学分会重型肝病与人工肝学组. 肝衰竭诊治指南(2018年版)[J]. 临床肝胆病杂志, 2019, 35( 1): 38- 44. DOI: 10.3969/j.issn.1001-5256.2019.01.007.
[10]	HERNAEZ R, KRAMER JR, LIU Y, et al. Prevalence and short-term mortality of acute-on-chronic liver failure: A national cohort study from the USA[J]. J Hepatol, 2019, 70( 4): 639- 647. DOI: 10.1016/j.jhep.2018.12.018.
[11]	CHEN KD. Serum levels of miR-122 and HMGB1 and their relationship with disease condition and prognosis in patients with HBV-ACLF[J]. Infect Dis Info, 2022, 35( 2): 135- 140. DOI: 10.3969/j.issn.1007-8134.2022.01.007. 陈科第. HBV-ACLF患者血清miR-122和HMGB1水平及其与病情、预后的关系[J]. 传染病信息, 2022, 35( 2): 135- 140. DOI: 10.3969/j.issn.1007-8134.2022.01.007.
[12]	LAI M, WANG X, YAO QW, et al. Predictive value of the initial MELD score and its derivative scores for early survival rate after liver transplantation in patients with liver failure[J]. Ogran Transplant, 2022, 13( 4): 489- 494. DOI: 10.3969/j.issn.1674-7445.2022.04.012. 赖曼, 王鑫, 姚勤伟, 等. 术后首次MELD评分及其衍生评分对肝衰竭患者肝移植术后早期生存率的预测价值[J]. 器官移植, 2022, 13( 4): 489- 494. DOI: 10.3969/j.issn.1674-7445.2022.04.012.
[13]	CHEN R, KANG R, TANG D. The mechanism of HMGB1 secretion and release[J]. Exp Mol Med, 2022, 54( 2): 91- 102. DOI: 10.1038/s12276-022-00736-w.
[14]	FANG P, DOU B, LIANG J, et al. Quercetin reduces oxidative stress and apoptosis by inhibiting HMGB1 and its translocation, thereby alleviating liver injury in ACLF rats[J]. Evid Based Complement Alternat Med, 2021, 2021: 2898995. DOI: 10.1155/2021/2898995.
[15]	HOU W, WEI X, LIANG J, et al. HMGB1-induced hepatocyte pyroptosis expanding inflammatory responses contributes to the pathogenesis of acute-on-chronic liver failure(ACLF)[J]. J Inflamm Res, 2021, 14: 7295- 7313. DOI: 10.2147/JIR.S336626.
[16]	NI YA, CHEN H, NIE H, et al. HMGB1: An overview of its roles in the pathogenesis of liver disease[J]. J Leukoc Biol, 2021, 110( 5): 987- 998. DOI: 10.1002/JLB.3MR0121-277R.
[17]	RASZEJA-WYSZOMIRSKA J, NIEWIŃSKI G, GRACZYŃSKA A, et al. Clinical implication of plasma CD163 in patients with acute-on-chronic liver failure[J]. Transplant Proc, 2022, 54( 4): 1011- 1016. DOI: 10.1016/j.transproceed.2022.02.048.
[18]	NIELSEN MC, HVIDBJERG GANTZEL R, CLÀRIA J, et al. Macrophage activation markers, CD163 and CD206, in acute-on-chronic liver failure[J]. Cells, 2020, 9( 5). DOI: 10.3390/cells9051175.
[19]	TRIANTAFYLLOU E, WOOLLARD KJ, MCPHAIL M, et al. The role of monocytes and macrophages in acute and acute-on-chronic liver failure[J]. Front Immunol, 2018, 9: 2948. DOI: 10.3389/fimmu.2018.02948.
[20]	ZHAO R, WU W, ZHOU Z, et al. Prognostic utility of novel biomarkers in acute-on-chronic liver failure(ACLF) associated with hepatitis B: A multicenter prospective study[J]. Hepatol Res, 2019, 49( 1): 42- 50. DOI: 10.1111/hepr.13251.
[21]	GRONBAK H, RODGAARD-HANSEN S, AAGAARD NK, et al. Macrophage activation markers predict mortality in patients with liver cirrhosis without or with acute-on-chronic liver failure(ACLF)[J]. J Hepatol, 2016, 64( 4): 813- 822. DOI: 10.1016/j.jhep.2015.11.021.
[22]	WANG Y, CHEN C, QI J, et al. Altered PGE2-EP2 is associated with an excessive immune response in HBV-related acute-on-chronic liver failure[J]. J Transl Med, 2019, 17( 1): 93. DOI: 10.1186/s12967-019-1844-0.
[23]	HANGAI S, AO T, KIMURA Y, et al. PGE2 induced in and released by dying cells functions as an inhibitory DAMP[J]. Proc Natl Acad Sci U S A, 2016, 113( 14): 3844- 3849. DOI: 10.1073/pnas.1602023113.