乙型肝炎病毒相关慢加急性肝衰竭患者IL-6的表达及其对预后的影响

肝脏 ›› 2021, Vol. 26 ›› Issue (1): 12-15.

乙型肝炎病毒相关慢加急性肝衰竭患者IL-6的表达及其对预后的影响

周超, 张宁, 何婷婷, 王焱, 余思邈, 付双楠, 张晶晶, 王宣, 李昕, 梁肖肖, 李筠, 宫嫚

100039 北京中国人民解放军总医院第五医学中心

收稿日期:2020-08-31 出版日期:2021-01-31 发布日期:2021-02-26
通讯作者: 宫嫚,Email:gongman302@163.com
基金资助:
国家科技重大专项(2012ZX10005-005,2018ZX10725506-002)

Study on the expression of IL-6 in patients with hepatitis B virus related acute on-chronic liver failure and its impact on prognosis

ZHOU Chao, ZHANG Ning, HE Ting-ting, WANG Yan, WANG Yao, ZHANG Jing-jing, WANG Xuan, FU Shuang-nan, LIANG Xiao-xiao, LI Xin, LI Jun, GONG Man

Department of Integrative Medicine, 5th Medical Center of Chinese PLA General Hospital, Beijing 100039, China

Received:2020-08-31 Online:2021-01-31 Published:2021-02-26
Contact: GONG Man, Email: gongman302@163.com

摘要/Abstract

摘要： 目的分析乙型肝炎病毒相关慢加急性肝衰竭人群中白细胞介素6(IL-6)的表达及其对于疾病转归的影响。方法以“十二五”重大专项课题入组的乙型肝炎病毒相关慢加急性肝衰竭754例患者为研究对象,分析IL-6与肝损伤的相关性及其对于4周、48周病死率的影响。结果 IL-6与国际标准化比值、总胆红素、MELD评分呈正相关,相关系数分别为0.108、0.143、0.173;与血小板计数、ALT、AST、白蛋白呈负相关,相关系数依次是-0.160、-0.151、-0.129、-0.126;差异均有统计学意义(P<0.01)。早期患者的IL-6水平为7.25(3.95,16.36) pg/mL,低于中期患者的9.88(5.39,22.95) pg/mL和晚期患者的13.64(5.11,30.40) pg/mL;合并2个及以上器官衰竭人群的IL-6水平高于合并1个器官衰竭(P=0.014); IL-6高水平组(＞9.78 pg/mL)的4周、48周病死率高于IL-6低水平组(≤9.78 pg/mL)(4周:17.2%比8.2%,P=0.002;48周:33.7%比22.0%,P<0.01),经校正年龄、MELD评分后,相对于IL-6低水平组,IL-6高水平组4周死亡风险为1.93(P=0.003),48周死亡风险为1.47(P=0.008)。结论 IL-6可作为一种辅助指标用于临床判断乙型肝炎病毒相关慢加急性肝衰竭的损伤程度和转归。

关键词: 乙型肝炎病毒, 慢加急性肝衰竭, 白细胞介素-6

Abstract: Objective To identify the association between IL-6 and liver impairment, and the impact of IL-6 on the prognosis of patients with hepatitis B virus related acute on-chronic liver failure (HBV -ACLF).Methods A total of 754 HBV - ACLF patients was included and analyzed the association between IL-6 level and indexes for liver impairment, and the impact of IL-6 on prognosis.Results IL-6 level was positively correlated with the international standardized ratio, total bilirubin, and MELD scores, and the correlation coefficients were 0.108, 0.143, and 0.173 (P<0.001), respectively. It was negatively correlated with platelet count, alanine aminotransferase, aspartate aminotransferase, and albumin, and the correlation coefficients were -0.160, -0.151, -0.129 (P<0.001). The patients at the early stage had lower IL-6 level than those at the mediate or late stages (P<0.001). The patients with 2 organ failures at least had higher level of IL-6 than those with no more than 1 organ failure (P=0.014). The 4-week and 48-week mortality rates in patients with high level of IL-6 (> 9.78 pg/ml) were significantly higher than those in patients with low level of IL-6 (≤9.78 pg/mL) (4 weeks: 17.2% vs 8.2%, P=0.002; 48 weeks: 33.7% vs 22.0%, P<0.001); after adjusting for age and MELD score, The HR were 1.93 (P=0.003), 1.47 (P=0.008), respectively.Conclusion IL-6 level is a promising candidate marker to reflect the severity of liver injury and to predict mortality in patients with HBV-ACLF.

Key words: Hepatitis B virus, Acute on-chronic liver failure, IL-6

周超, 张宁, 何婷婷, 王焱, 余思邈, 付双楠, 张晶晶, 王宣, 李昕, 梁肖肖, 李筠, 宫嫚. 乙型肝炎病毒相关慢加急性肝衰竭患者IL-6的表达及其对预后的影响[J]. 肝脏, 2021, 26(1): 12-15.

ZHOU Chao, ZHANG Ning, HE Ting-ting, WANG Yan, WANG Yao, ZHANG Jing-jing, WANG Xuan, FU Shuang-nan, LIANG Xiao-xiao, LI Xin, LI Jun, GONG Man. Study on the expression of IL-6 in patients with hepatitis B virus related acute on-chronic liver failure and its impact on prognosis[J]. Chinese Hepatolgy, 2021, 26(1): 12-15.

参考文献

[1] Jalan R, Williams R. Acute-on-chronic liver failure: pathophysiological basis of therapeutic options. Blood Purif, 2002, 20:252-261.
[2] Katoonizadeh A, Laleman W, Verslype C, et al. Early features of acute-on-chronic alcoholic liver failure: a prospective cohort study. Gut, 2010, 59:1561-1569.
[3] Arroyo V, Moreau R, Jalan R, et al. Acute-on-chronic liver failure: a new syndrome that will re-classify cirrhosis. J Hepatol, 2015, 62:S131-S143.
[4] Solé C, Solà E, Morales-Ruiz M, et al. Characterization of inflammatory response in acute-on-chronic liver failure and relationship with prognosis. Sci Rep, 2016, 6:32341.
[5] Moreau R. The pathogenesis of ACLF: the inflammatory response and immune function. Semin Liver Dis, 2016, 36:133-140.
[6] Bernsmeier C, Pop OT, Singanayagam A, et al. Patients with acute-on-chronic liver failure have increased numbers of regulatory immune cells expressing the receptor tyrosine kinase MERTK. Gastroenterology, 2015, 148:603-615.e614.
[7] Iwasaki A, Medzhitov R. Control of adaptive immunity by the innate immune system. Nat Immunol, 2015, 16:343-353.
[8] Jalan R, Gines P, Olson JC, et al. Acute-on chronic liver failure. J Hepatol, 2012, 57:1336-1348.
[9] Medzhitov R, Schneider DS, Soares MP. Disease tolerance as a defense strategy. Science, 2012, 335:936-941.
[10] Medzhitov R. Inflammation 2010: new adventures of an old flame. Cell, 2010, 140:771-776.
[11] Schmidt-Arras D, Rose-John S. IL-6 pathway in the liver: from physiopathology to therapy. J Hepatol, 2016, 64:1403-1415.
[12] 中华医学会感染病学分会肝衰竭与人工肝学组. 肝衰竭诊治指南(2012年版). 中华肝脏病杂志, 2013, 3:177-183.
[13] Moreau R, Jalan R, Gines P, et al. Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis. Gastroenterology, 2013, 144:1426-U1189.
[14] Kim AR, Park JI, Oh HT, et al. TAZ stimulates liver regeneration through interleukin-6-induced hepatocyte proliferation and inhibition of cell death after liver injury. FASEB J, 2019, 33:5914-5923.
[15] Hassan W, Ding L, Gao R-Y, et al. Interleukin-6 signal transduction and its role in hepatic lipid metabolic disorders. Cytokine, 2014, 66:133-142.
[16] Tanaka T, Kishimoto T. The biology and medical implications of interleukin-6. Cancer Immunol Res, 2014, 2:288-294.
[17] Shakiba E, Ramezani M, Sadeghi M. Evaluation of serum interleukin-6 levels in hepatocellular carcinoma patients: a systematic review and meta-analysis. Clin Exp Hepatol, 2018, 4:182-190.
[18] Karatayli E, Hall RA, Weber SN, et al. Effect of alcohol on the interleukin 6-mediated inflammatory response in a new mouse model of acute-on-chronic liver injury. Biochim Biophys Acta Mol Basis Dis, 2019, 1865:298-307.
[19] Fazel Modares N, Polz R, Haghighi F, et al. IL-6 trans-signaling controls liver regeneration after partial hepatectomy. Hepatology, 2019, 70:2075-2091.
[20] Qi ZX, Wang LY, Fan YC, et al. Increased peripheral ROR alpha and ROR gammat mRNA expression is associated with acute-on-chronic hepatitis B liver failure. J Viral hepat, 2012, 19:811-822.
[21] Ruiz-Margáin A, Pohlmann A, Ryan P, et al. Fibroblast growth factor 21 is an early predictor of acute-on-chronic liver failure in critically ill patients with cirrhosis. Liver Transpl, 2018, 24:595-605.
[22] Wan Z, Xie G, Wu Y, et al. Cytokines elevated in patients with HBV-related acute-on-chronic liver failure promote NK cell mediated cytotoxicity through TRAIL. Dig Liver Dis, 2016, 48:528-535.
[23] Wan YM, Li YH, Xu ZY, et al. Therapeutic plasma exchange versus double plasma molecular absorption system in hepatitis B virus-infected acute-on-chronic liver failure treated by entercavir: a prospective study. J Clin Apher, 2017, 32:453-461.