干扰素λ3在慢性乙型肝炎患者血清中的表达及临床意义
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摘要
目的了解慢性乙型肝炎患者血清IFNλ3水平,探究其临床意义及其与核苷和核苷酸类药物治疗的关系。方法选取2017年1月-2018年5月在安徽医科大学第二附属医院就诊的慢性乙型肝炎患者119例,收集同期HBsAg阴性的22例健康体检者作为健康对照。采用ELISA法检测血清中IFNλ3的表达水平,比较慢性乙型肝炎患者与健康人血清IFNλ3水平差异,分析慢性乙型肝炎患者血清IFNλ3水平与HBeAg的关系,观察不同核苷和核苷酸类药物治疗慢性乙型肝炎患者的血清IFNλ3水平,以及核苷和核苷酸类药物对外周血单个核细胞培养上清中IFNλ3水平的影响。满足正态性和方差齐性的计量资料多组间比较采用方差分析;对非正态或方差不齐的计量资料,两组比较采用Wilcoxon秩和检验,多组比较采用Kruskal-Wallis H检验,进一步两两比较采用Nemenyi法检验。相关性分析用Spearman相关性分析法。结果慢性乙型肝炎患者血清IFNλ3水平明显低于健康对照组[14. 7(5. 9～28. 5) pg/ml vs 76. 1(39. 4～112. 0) pg/ml,Z=-10. 114,P <0. 001]。未抗病毒治疗的慢性乙型肝炎患者血清IFNλ3水平与log HBV DNA呈负相关(r=-0. 621,P <0. 001)。HBeAg阴性慢性乙型肝炎患者血清IFNλ3水平高于HBeAg阳性患者,2组间差异有统计学意义[16. 4(9. 0～31. 3) pg/ml vs 8. 7(2. 9～23. 2) pg/ml,Z=-2. 205,P=0. 02]。服用阿德福韦酯抗病毒治疗的患者血清IFNλ3水平显著高于服用恩替卡韦、替诺福韦、替比夫定、拉米夫定治疗的患者,差异均有统计学意义(P值均<0. 05);体外实验核苷和核苷酸类药物处理的外周血单个核细胞培养上清中未见IFNλ3水平明显升高。结论慢性乙型肝炎患者血清IFNλ3显著低于健康人群,阿德福韦酯抗病毒治疗患者具有较高的血清IFNλ3水平。
Objective To investigate the serum level of interferon-λ3( IFN-λ3) and its clinical significance in patients with chronic hepatitis B( CHB),as well as its association with nucleos( t) ide analogue( NA) treatment. Methods A total of 119 CHB patients who were treated in The Second Affiliated Hospital of Anhui Medical University from January 2017 to May 2018 were enrolled,and 22 HBsAg-negative individuals who underwent physical examination were enrolled as healthy control group. ELISA was used to measure the serum level of IFN-λ3,which was compared between CHB patients and healthy individuals. The association between serum IFN-λ3 level and HBeAg in CHB patients was analyzed; serum IFN-λ3 level was compared between the patients treated with different NAs; the influence of NAs on the level of IFN-λ3 in the supernatant of peripheral blood mononuclear cells( PBMCs) was analyzed. An analysis of variance was used for comparison of normally distributed continuous data with homogeneity of variance between multiple groups; the Wilcoxon rank-sum test was used for comparison of non-normally distributed continuous data or continuous data with heterogeneity of variance between two groups,the Kruskal-Wallis H test was used for comparison between multiple groups,and the Nemenyi test was used for further comparison between two groups. A Spearman correlation analysis was also performed. Results The CHB group had a significantly lower serum IFN-λ3 level than the healthy control group [14. 7( 5. 9-28. 5) pg/ml vs 76. 1( 39. 4-112. 0) pg/ml,Z =-10. 114,P < 0. 001]. In the CHB patients who did not receive antiviral therapy,serum IFN-λ3 level was negatively correlated with log HBV DNA( r =-0. 621,P < 0. 001). The HBeAg-negative CHB patients had a significantly higher serum IFN-λ3 level than the HBeAg-positive CHB patients [16. 4( 9. 0-31. 3) pg/ml vs 8. 7( 2. 9-23. 2) pg/ml,Z =-2. 205,P = 0. 02]. The patients who received antiviral therapy with adefovir dipivoxil had a significantly higher serum IFN-λ3 level than those who were treated with entecavir,tenofovir,telbivudine,or lamivudine( P < 0. 05). In vitro experiment showed that there was no significant increase in serum IFN-λ3 level in the supernatant of PBMCs treated with NAs. Conclusion CHB patients have a significantly lower serum IFN-λ3 level than healthy individuals,and the CHB patients receiving antiviral therapy with adefovir dipivoxil have a relatively high serum IFN-λ3 level.
Objective To investigate the serum level of interferon-λ3( IFN-λ3) and its clinical significance in patients with chronic hepatitis B( CHB),as well as its association with nucleos( t) ide analogue( NA) treatment. Methods A total of 119 CHB patients who were treated in The Second Affiliated Hospital of Anhui Medical University from January 2017 to May 2018 were enrolled,and 22 HBsAg-negative individuals who underwent physical examination were enrolled as healthy control group. ELISA was used to measure the serum level of IFN-λ3,which was compared between CHB patients and healthy individuals. The association between serum IFN-λ3 level and HBeAg in CHB patients was analyzed; serum IFN-λ3 level was compared between the patients treated with different NAs; the influence of NAs on the level of IFN-λ3 in the supernatant of peripheral blood mononuclear cells( PBMCs) was analyzed. An analysis of variance was used for comparison of normally distributed continuous data with homogeneity of variance between multiple groups; the Wilcoxon rank-sum test was used for comparison of non-normally distributed continuous data or continuous data with heterogeneity of variance between two groups,the Kruskal-Wallis H test was used for comparison between multiple groups,and the Nemenyi test was used for further comparison between two groups. A Spearman correlation analysis was also performed. Results The CHB group had a significantly lower serum IFN-λ3 level than the healthy control group [14. 7( 5. 9-28. 5) pg/ml vs 76. 1( 39. 4-112. 0) pg/ml,Z =-10. 114,P < 0. 001]. In the CHB patients who did not receive antiviral therapy,serum IFN-λ3 level was negatively correlated with log HBV DNA( r =-0. 621,P < 0. 001). The HBeAg-negative CHB patients had a significantly higher serum IFN-λ3 level than the HBeAg-positive CHB patients [16. 4( 9. 0-31. 3) pg/ml vs 8. 7( 2. 9-23. 2) pg/ml,Z =-2. 205,P = 0. 02]. The patients who received antiviral therapy with adefovir dipivoxil had a significantly higher serum IFN-λ3 level than those who were treated with entecavir,tenofovir,telbivudine,or lamivudine( P < 0. 05). In vitro experiment showed that there was no significant increase in serum IFN-λ3 level in the supernatant of PBMCs treated with NAs. Conclusion CHB patients have a significantly lower serum IFN-λ3 level than healthy individuals,and the CHB patients receiving antiviral therapy with adefovir dipivoxil have a relatively high serum IFN-λ3 level.
引文
[1]WANG WJ,XIE Q.Challenges and strategies of antiviral therapy for chronic hepatitis B-how to achieve the maximization of clinical cure?[J].J Clin Hepatol,2017,33(8):1415-1418.(in Chinese)王伟静,谢青.慢性乙型肝炎抗病毒治疗的挑战与策略---如何实现临床治愈最大化[J].临床肝胆病杂志,2017,33(8):1415-1418.
[2]PAPATHEODORIDIS GV,LAMPERTICO P,MANOLAKOPOU-LOS S,et al.Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy:A systematic review[J].J Hepatol,2010,53(2):348-356.
[3]WONG LH,CHAN LY,MAK WH,et al.Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients With liver cirrhosis[J].Hepatology,2013,58(5):1537-1547.
[4]TRPO C,CHAN HL,LOK A.Hepatitis B virus infection[J].Lancet,2014,384(9959):2053-2063.
[5]MARCELLIN P,LAU GK,BONINO F,et al.Peginterferon alfa-2a alone,lamivudine alone,and the two in combination in patients with HBe Ag-negative chronic hepatitis B[J].N Engl JMed,2004,351(12):1206-1217.
[6]QI X.Peginterferon alfa-2a,lamivudine,and the combination for HBe Ag-positive chronic hepatitis B[J].N Engl J Med,2005,352(26):2682-2695.
[7]Chinese Society of Hepatology and Chinese Society of Infectious Diseases,Chinese Medical Association.The guideline of prevention and treatment for hepatitis C:A 2015 update[J].JClin Hepatol,2015,31(12):1961-1979.(in Chinese)中华医学会肝病学分会,中华医学会感染病学分会.丙型肝炎防治指南(2015年更新版)[J].临床肝胆病杂志,2015,31(12):1961-1979.
[8]HRUSKA M,WANG X,CHAN P,et al.Derivation of phase 3dosing for peginterferon lambda-1a in chronic hepatitis C,Part 2:Exposure-response analyses for efficacy and safety variables[J].J Clin Pharmacol,2015,55(1):73-80.
[9]BOLEN CR,DING S,ROBEK MD,et al.Dynamic expression profiling of type I and type III interferon-stimulated hepatocytes reveals a stable hierarchy of gene expression[J].Hepatology,2014,59(4):1262-1272.
[10]LIAO Y,LI Y,CAI B,et al.Lack of association between IL-28Bpolymorphisms and spontaneous virus clearance in HBV patients[J].Clin Infect Dis,2013,75(9):409-417.
[11]SHI X,CHI X,PAN Y,et al.IL-28B is associated with outcomes of chronic HBV infection[J].Yonsei Med J,2015,56(3):625-633.
[12]Chinese Society of Hepatology and Chinese Society of Infectious Diseases,Chinese Medical Association.The guideline of prevention and treatment for hepatitis B:A 2015 update[J].J Clin Hepatol,2015,31(12):1941-1960.(in Chinese)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(2015年更新版)[J].临床肝胆病杂志,2015,31(12):1941-1960.
[13]MURATA K,ASANO M,MATSUMOTO A,et al.Induction of IFN-λ3 as an additional effect of nucleotide,not nucleoside,analogues:A new potential target for HBV infection[J].Gut,2018,67(2):362-371.
[14]ZOU HX,WANG JH,CUI HL,et al.The relativity study between abnormal serum markers of hepatitis B and HBV-DNA[J].Int J Virol,2017,27(4):239-242.(in Chinese)邹红霞,王金环,崔海玲,等.乙型肝炎异常血清学诊断模式与HBV-DNA载量的相关性研究[J].国际病毒学杂志,2017,27(4):239-242.
[15]GONG Q.Clinical significance of combined determination of HBV-DNA、five indicators for hepatitis B and liver function parameters in patients with chronic hepatitis B[J].World Clin Med,2017,11(7):230.(in Chinese)龚蔷.HBV-DNA、乙肝两对半和肝功能的联合检测对慢性乙肝患者的临床意义[J].世界临床医学,2017,11(7):230.
[16]ABUSHAHBA W,BALAN M,CASTANEDA I,et al.Antitumor activity of type I and type III interferons in BNL hepatoma model[J].Cancer Immunol Immunother,2010,59(7):1059-1071.
[17]ISOGAWA M,TANAKA Y.The Immunobiology of hepatitis Bvirus infection[J].Hepatol Res,2015,45(2):179-189.
[18]KOTENKO SV.IFN-λs[J].Curr Opin Immunol,2011,23(5):583-590.
[19]SOMMEREYNS C,PAUL S,STAEHELI P,et al.IFN-lambda(IFN-λ)is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo[J].PLo S Pathog,2008,4(3):e1000017.
[20]van der MOLEN RG,SPRENGERS D,BIESTA PJ,et al.Favorable effect of adefovir on the number and functionality of myeloid dendritic cells of patients with chronic HBV[J].Hepatology,2010,44(4):907-914.
[21]YOU J,CHEN J,YE QX,et al.Efficacy of add-on adefovir dipivoxil at week 12/24 in HBe Ag-positive chronic hepatitis Bpatients during PEG-IFN-αtherapy[J].J Clin Hepatol,2016,32(4):687-690.(in Chinese)游佳,陈靖,叶巧霞,等.聚乙二醇干扰素α加用阿德福韦酯治疗HBe Ag阳性慢性乙型肝炎的效果观察[J].临床肝胆病杂志,2016,32(4):687-690.
[22]XIE Q,ZHOU H,BAI X,et al.A randomized,open-label clinical study of combined pegylated interferon alfa-2a(40KD)and entecavir treatment for hepatitis B"e"antigenpositive chronic hepatitis B[J].Clin Infect Dis,2014,59(12):1714-1723.
[2]PAPATHEODORIDIS GV,LAMPERTICO P,MANOLAKOPOU-LOS S,et al.Incidence of hepatocellular carcinoma in chronic hepatitis B patients receiving nucleos(t)ide therapy:A systematic review[J].J Hepatol,2010,53(2):348-356.
[3]WONG LH,CHAN LY,MAK WH,et al.Entecavir treatment reduces hepatic events and deaths in chronic hepatitis B patients With liver cirrhosis[J].Hepatology,2013,58(5):1537-1547.
[4]TRPO C,CHAN HL,LOK A.Hepatitis B virus infection[J].Lancet,2014,384(9959):2053-2063.
[5]MARCELLIN P,LAU GK,BONINO F,et al.Peginterferon alfa-2a alone,lamivudine alone,and the two in combination in patients with HBe Ag-negative chronic hepatitis B[J].N Engl JMed,2004,351(12):1206-1217.
[6]QI X.Peginterferon alfa-2a,lamivudine,and the combination for HBe Ag-positive chronic hepatitis B[J].N Engl J Med,2005,352(26):2682-2695.
[7]Chinese Society of Hepatology and Chinese Society of Infectious Diseases,Chinese Medical Association.The guideline of prevention and treatment for hepatitis C:A 2015 update[J].JClin Hepatol,2015,31(12):1961-1979.(in Chinese)中华医学会肝病学分会,中华医学会感染病学分会.丙型肝炎防治指南(2015年更新版)[J].临床肝胆病杂志,2015,31(12):1961-1979.
[8]HRUSKA M,WANG X,CHAN P,et al.Derivation of phase 3dosing for peginterferon lambda-1a in chronic hepatitis C,Part 2:Exposure-response analyses for efficacy and safety variables[J].J Clin Pharmacol,2015,55(1):73-80.
[9]BOLEN CR,DING S,ROBEK MD,et al.Dynamic expression profiling of type I and type III interferon-stimulated hepatocytes reveals a stable hierarchy of gene expression[J].Hepatology,2014,59(4):1262-1272.
[10]LIAO Y,LI Y,CAI B,et al.Lack of association between IL-28Bpolymorphisms and spontaneous virus clearance in HBV patients[J].Clin Infect Dis,2013,75(9):409-417.
[11]SHI X,CHI X,PAN Y,et al.IL-28B is associated with outcomes of chronic HBV infection[J].Yonsei Med J,2015,56(3):625-633.
[12]Chinese Society of Hepatology and Chinese Society of Infectious Diseases,Chinese Medical Association.The guideline of prevention and treatment for hepatitis B:A 2015 update[J].J Clin Hepatol,2015,31(12):1941-1960.(in Chinese)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(2015年更新版)[J].临床肝胆病杂志,2015,31(12):1941-1960.
[13]MURATA K,ASANO M,MATSUMOTO A,et al.Induction of IFN-λ3 as an additional effect of nucleotide,not nucleoside,analogues:A new potential target for HBV infection[J].Gut,2018,67(2):362-371.
[14]ZOU HX,WANG JH,CUI HL,et al.The relativity study between abnormal serum markers of hepatitis B and HBV-DNA[J].Int J Virol,2017,27(4):239-242.(in Chinese)邹红霞,王金环,崔海玲,等.乙型肝炎异常血清学诊断模式与HBV-DNA载量的相关性研究[J].国际病毒学杂志,2017,27(4):239-242.
[15]GONG Q.Clinical significance of combined determination of HBV-DNA、five indicators for hepatitis B and liver function parameters in patients with chronic hepatitis B[J].World Clin Med,2017,11(7):230.(in Chinese)龚蔷.HBV-DNA、乙肝两对半和肝功能的联合检测对慢性乙肝患者的临床意义[J].世界临床医学,2017,11(7):230.
[16]ABUSHAHBA W,BALAN M,CASTANEDA I,et al.Antitumor activity of type I and type III interferons in BNL hepatoma model[J].Cancer Immunol Immunother,2010,59(7):1059-1071.
[17]ISOGAWA M,TANAKA Y.The Immunobiology of hepatitis Bvirus infection[J].Hepatol Res,2015,45(2):179-189.
[18]KOTENKO SV.IFN-λs[J].Curr Opin Immunol,2011,23(5):583-590.
[19]SOMMEREYNS C,PAUL S,STAEHELI P,et al.IFN-lambda(IFN-λ)is expressed in a tissue-dependent fashion and primarily acts on epithelial cells in vivo[J].PLo S Pathog,2008,4(3):e1000017.
[20]van der MOLEN RG,SPRENGERS D,BIESTA PJ,et al.Favorable effect of adefovir on the number and functionality of myeloid dendritic cells of patients with chronic HBV[J].Hepatology,2010,44(4):907-914.
[21]YOU J,CHEN J,YE QX,et al.Efficacy of add-on adefovir dipivoxil at week 12/24 in HBe Ag-positive chronic hepatitis Bpatients during PEG-IFN-αtherapy[J].J Clin Hepatol,2016,32(4):687-690.(in Chinese)游佳,陈靖,叶巧霞,等.聚乙二醇干扰素α加用阿德福韦酯治疗HBe Ag阳性慢性乙型肝炎的效果观察[J].临床肝胆病杂志,2016,32(4):687-690.
[22]XIE Q,ZHOU H,BAI X,et al.A randomized,open-label clinical study of combined pegylated interferon alfa-2a(40KD)and entecavir treatment for hepatitis B"e"antigenpositive chronic hepatitis B[J].Clin Infect Dis,2014,59(12):1714-1723.