慢性乙型肝炎患者血清MMP-2和TIMP-2水平及超声检查指标评估肝纤维化分期意义探讨
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摘要
目的探讨超声检查门静脉指标及血清基质金属蛋白酶-2(MMP-2)和金属蛋白酶组织抑制因子-2(TIMP-2)变化在慢性乙型肝炎(CHB)患者肝纤维化分期中的诊断价值。方法 2014年5月～2018年5月我院收治的CHB患者43例和同期健康体检者40例,使用超声B超检查测定门静脉宽度、脾静脉宽度和脾脏厚度,采用ELISA法检测血清MMP-2和TIMP-2水平,采用微孔板单光子计数仪检测血清透明质酸(HA)、层粘连蛋白(LN)、Ⅳ型胶原蛋白(IV-C)和III前胶原氨基端肽(P III P)水平。常规行肝穿刺活检。结果肝穿组织病理学检查提示,S0～S1患者13例,S2患者11例,S3患者14例和S4患者5例;自S2期到S4期,随着肝纤维化程度的不断加重,患者门静脉宽度、脾静脉宽度和脾脏厚度不断增大,差异具有统计学意义(P<0.05);S0～1、S2、S3和S4期患者血清MMP-2水平分别为(291.5±35.3) mg/L、(357.7±32.5) mg/L、(446.8±47.1) mg/L和(595.3±85.4) mg/L,血清TIMP-2水平分别为(154.3±28.6) mg/L、(210.7±24.1) mg/L、(255.7±31.9) mg/L和(302.5±74.3) mg/L,均显著高于健康人[分别为(246.5±32.1) mg/L和(126.5±20.1) mg/L,P<0.05];存在显著肝纤维化的CHB患者血清HA、LN、IV-C和P III P水平显著高于健康人(P<0.05),且随着肝纤维化加重而逐渐升高。结论超声检测门静脉指标联合血清指标检测将有助于对CHB患者肝纤维化程度的判断,对诊断和治疗疗效的判断可能具有指导意义。
Objective To investigate the diagnostic value of portal vain by ultrasonography and serum matrix metalloproteinase-2(MMP-2) and tissue inhibitor of metalloproteinase-2(TIMP-2) in patients with chronic hepatitis B(CHB). Methods Forty-three patients with CHB and 40 healthy controls were enrolled in our hospital between May 2014 and May 2018,and all patients underwent liver biopsy for liver fibrosis staging. B-ultrasound was performed in all subjects,and the width of portal vein,the width of the splenic vein,and the thickness of the spleen were measured. Serum MMP-2 and TIMP-2 levels as well as hyaluronic acid(HA),laminin(LN),type IV collagen(IV-C) and III procollagen amino terminal peptide(P III P) were assayed. Results Liver biopsy results showed that there were 13 patients with S0-S1,11 patients with S2,14 patients with S3,and 5 patients with S4;From S2 to S4 with the increasing degree of liver fibrosis,the portal vein width,splenic vein width and spleen thickness increased gradually,and the differences between patients with different liver fibrosis was statistically significant(P<0.05);Serum MMP-2 levels in patients with S0-1,S2,S3 and S4 were(291.5 ±35.3) mg/L,(357.7±32.5) mg/L,(446.8±47.1) mg/L and(595.3±85.4) mg/L,and serum TIMP-2 levels were(154.3±28.6)mg/L,(210.7±24.1) mg/L,(255.7±31.9) mg/L and(302.5±74.3) mg/L,significantly higher than(246.5±32.1) mg/L and(126.5±20.1) mg/L(P<0.05) in healthy persons;serum HA,LN,IV-C and P III P levels in patients with significant liver fibrosis were higher than those in healthy control(P<0.05). Conclusion The examination of portal vain parameters by ultrasonography and serum liver fibrosis determination might help predict the intrahepatic liver fibrosis in patients with CHB.
Objective To investigate the diagnostic value of portal vain by ultrasonography and serum matrix metalloproteinase-2(MMP-2) and tissue inhibitor of metalloproteinase-2(TIMP-2) in patients with chronic hepatitis B(CHB). Methods Forty-three patients with CHB and 40 healthy controls were enrolled in our hospital between May 2014 and May 2018,and all patients underwent liver biopsy for liver fibrosis staging. B-ultrasound was performed in all subjects,and the width of portal vein,the width of the splenic vein,and the thickness of the spleen were measured. Serum MMP-2 and TIMP-2 levels as well as hyaluronic acid(HA),laminin(LN),type IV collagen(IV-C) and III procollagen amino terminal peptide(P III P) were assayed. Results Liver biopsy results showed that there were 13 patients with S0-S1,11 patients with S2,14 patients with S3,and 5 patients with S4;From S2 to S4 with the increasing degree of liver fibrosis,the portal vein width,splenic vein width and spleen thickness increased gradually,and the differences between patients with different liver fibrosis was statistically significant(P<0.05);Serum MMP-2 levels in patients with S0-1,S2,S3 and S4 were(291.5 ±35.3) mg/L,(357.7±32.5) mg/L,(446.8±47.1) mg/L and(595.3±85.4) mg/L,and serum TIMP-2 levels were(154.3±28.6)mg/L,(210.7±24.1) mg/L,(255.7±31.9) mg/L and(302.5±74.3) mg/L,significantly higher than(246.5±32.1) mg/L and(126.5±20.1) mg/L(P<0.05) in healthy persons;serum HA,LN,IV-C and P III P levels in patients with significant liver fibrosis were higher than those in healthy control(P<0.05). Conclusion The examination of portal vain parameters by ultrasonography and serum liver fibrosis determination might help predict the intrahepatic liver fibrosis in patients with CHB.
引文
[1]刘国旺,唐克诚,李谦,等.慢性乙型肝炎抗病毒治疗HBe Ag血清学转换的预测模型建立.中华肝脏病杂志,2018,26(9):641-645.
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[11]陈建泉,张建成,陈林,等.肝细胞生长因子和转化生长因子-β1对人心房成纤维细胞基质金属蛋白酶-2及组织抑制剂-2表达的影响.中华心律失常学杂志,2017,21(6):489-495.
[12]Gu X,Fu M,Ding Y,et al.TIMP-3 expression associates with malignant behaviors and predicts favorable survival in HCC.PLo S One,2014,9(8):e106161.
[13]Tiziana L,Claudia M,Ilaria P,et al.Liver fibrosis in HCVmonoinfected and HIV/HCV coinfected patients:Dysregulation of matrix metalloproteinases(MMPs)and their tissue inhibitors TIMPs and effect of HCV protease inhibitors.Int J Mol Sci,2016,17(4):455-466.
[14]Khokha R,Murthy A,Weiss A.Metalloproteinases and their natural inhibitors in inflammation and immunity.Nat Rev Immunol,2013,13(9):649-665.
[15]Pineda JA.Combined use of aspartate aminotransferase,platelet count and matrix metalloproteinase 2 measurements to predict liver fibrosis in HIV/hepatitis C virus-coinfected patients.HIVMed,2015,12(1):14-21.
[16]Julio C,Eulalia VG,Tomás SZ,et al.Matrix metalloproteases and their tissue inhibitors in non-alcoholic liver fibrosis of human immunodeficiency virus-infected patients.J Med Virol,2017,6(2):18-27.
[17]Kurzepa J,Madro A,Czechowska G,et al.Role of MMP-2 and MMP-9 and their natural inhibitors in liver fibrosis,chronic pancreatitis and non-specific inflammatory bowel diseases.Hepatobiliary Pancreat Dis Int,2014,13(6):570-579.
[18]Okazaki I,Noro T,Tsutsui N,et al.Fibrogenesis and carcinogenesis in nonalcoholic steatohepatitis(NASH):involvement of matrix metalloproteinases(MMPs)and tissue inhibitors of metalloproteinase(TIMPs).Cancers(Basel),2014,6(3):1220-1255.
[19]Munsterman ID,Kendall TJ,Khelil N,et al.Extracellular matrix components indicate remodelling activity in different fibrosis stages of human non-alcoholic fatty liver disease.Histopathology,2018,73(4):612-621.
[20]Toyoda H,Kumada T,Kiriyama S,et al.Higher hepatic gene expression and serum levels of matrix metalloproteinase-2 are associated with steatohepatitis in non-alcoholic fatty liver diseases.Biomarkers,2013,18(1):82-87.
[2]Gerstenmaier JF,Gibson RN.Ultrasound in chronic liver disease.Insights Into Imaging,2014,5(4):441-455.
[3]Bramhall SR,Neoptolemos JP,Stamp GWH,et al.Imbalance of expression of matrix metalloproteinases(MMPs)and tissue inhibitors of the matrix metalloproteinases(TIMPs)in human pancreatic carcinoma.J Pathol,2015,182(3):347-355.
[4]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年版).实用肝脏病杂志,2016,19(3):389-400.
[5]王燕,陈香宇,李娅,等.血清微小核糖核酸-122在慢性乙型肝炎肝纤维化中的表达及意义.中华传染病杂志,2018,36(9):533-536.
[6]Zhou Y,Wan Y,Ye ZW,et al.How hepatitis B virus causes cirrhosis and liver cancer.Med Hypoth,2017,108(10):52-53.
[7]Yan LN.Operative techniques in liver resection.Ultrasound elastography in the assessment of liver fibrosis.PLo S One,2013,8(8):e72306.
[8]Calabro SR,Maczurek AE,Morgan AJ,et al.Hepatocyte produced matrix metalloproteinases are regulated by CD147 in liver fibrogenesis.PLo S One,2014,9(7):e90571.
[9]陶然,黄加权,李小丹,等.热休克蛋白47-短发夹RNA对日本血吸虫肝纤维化小鼠的体内干预研究.中华传染病杂志,2014,32(7):7-12.
[10]Cui N,Hu M,Khalil RA.Biochemical and biological attributes of matrix metalloproteinases.Prog Mol Biol Transl Sci,2017,147:1-73.
[11]陈建泉,张建成,陈林,等.肝细胞生长因子和转化生长因子-β1对人心房成纤维细胞基质金属蛋白酶-2及组织抑制剂-2表达的影响.中华心律失常学杂志,2017,21(6):489-495.
[12]Gu X,Fu M,Ding Y,et al.TIMP-3 expression associates with malignant behaviors and predicts favorable survival in HCC.PLo S One,2014,9(8):e106161.
[13]Tiziana L,Claudia M,Ilaria P,et al.Liver fibrosis in HCVmonoinfected and HIV/HCV coinfected patients:Dysregulation of matrix metalloproteinases(MMPs)and their tissue inhibitors TIMPs and effect of HCV protease inhibitors.Int J Mol Sci,2016,17(4):455-466.
[14]Khokha R,Murthy A,Weiss A.Metalloproteinases and their natural inhibitors in inflammation and immunity.Nat Rev Immunol,2013,13(9):649-665.
[15]Pineda JA.Combined use of aspartate aminotransferase,platelet count and matrix metalloproteinase 2 measurements to predict liver fibrosis in HIV/hepatitis C virus-coinfected patients.HIVMed,2015,12(1):14-21.
[16]Julio C,Eulalia VG,Tomás SZ,et al.Matrix metalloproteases and their tissue inhibitors in non-alcoholic liver fibrosis of human immunodeficiency virus-infected patients.J Med Virol,2017,6(2):18-27.
[17]Kurzepa J,Madro A,Czechowska G,et al.Role of MMP-2 and MMP-9 and their natural inhibitors in liver fibrosis,chronic pancreatitis and non-specific inflammatory bowel diseases.Hepatobiliary Pancreat Dis Int,2014,13(6):570-579.
[18]Okazaki I,Noro T,Tsutsui N,et al.Fibrogenesis and carcinogenesis in nonalcoholic steatohepatitis(NASH):involvement of matrix metalloproteinases(MMPs)and tissue inhibitors of metalloproteinase(TIMPs).Cancers(Basel),2014,6(3):1220-1255.
[19]Munsterman ID,Kendall TJ,Khelil N,et al.Extracellular matrix components indicate remodelling activity in different fibrosis stages of human non-alcoholic fatty liver disease.Histopathology,2018,73(4):612-621.
[20]Toyoda H,Kumada T,Kiriyama S,et al.Higher hepatic gene expression and serum levels of matrix metalloproteinase-2 are associated with steatohepatitis in non-alcoholic fatty liver diseases.Biomarkers,2013,18(1):82-87.