慢性乙型肝炎患者血清血管生成素样蛋白2和高尔基体蛋白73水平变化及其诊断显著肝纤维化的效能分析
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摘要
目的评价血清血管生成素样蛋白2(ANGPTL2)和高尔基体蛋白73(GP73)诊断慢性乙型肝炎(CHB)患者肝纤维化程度的价值。方法 2015年3月～2017年10月我院收治的117例CHB患者,采用ELISA法检测血清ANGPTL2和GP73水平,采用受试者工作特征曲线(ROC)下面积(AUC)评价血清ANGPTL2和GP73诊断CHB患者肝纤维化和肝硬化的效能。结果 15例CHBS3～S4期患者血清ANGPTL2和GP73水平分别为(9.1±2.4)ng/ml和(84.9±15.2) ng/ml,显著高于78例S1～S2期[分别为(6.7±2.3) ng/ml和(65.1±14.8) ng/ml,P<0.05]或24例S0期患者[分别为(4.4±1.4) ng/ml和(53.7±14.3) ng/ml,P<0.05];以肝组织纤维化大于等于S3为严重肝纤维化,分别以血清ANGPTL2水平等于8.6 ng/mL和9.6 ng/ml或血清GP73水平等于75.6 ng/ml和103.5 ng/ml为诊断严重肝纤维化和肝硬化的截断点,结果 ANGPTL2诊断慢性乙型肝炎患者严重肝纤维化和肝硬化的AUC与GP73比,差异无统计学意义(Z=1.872,P=0.061;Z=0.328,P=0.743);ANGPTL2与GP73联合诊断慢性乙型肝炎患者严重肝纤维化的效能显著高于单指标诊断,即AUC联合检测>AUCANGPTL2(Z=3.310,P=0.001)或AUC联合检测>AUCGP73(Z=2.004,P=0.045),血清ANGPTL2与GP73联合诊断乙型肝炎肝硬化的效能与单指标诊断的效能比,差异无统计学意义(Z=1.471,P=0.141;Z=1.575,P=0.115);采用血清ANGPTL2与GP73联合诊断肝纤维化的效能与基于4因子模型(FIB-4)或天门冬氨酸氨基转移酶/血小板指数(APRI)比,差异无统计学意义(Z=0.869,P=0.386;Z=0.492,P=0.623);血清ANGPTL2与GP73联合诊断肝硬化的效能与FIB-4或APRI比,差异也无统计学意义(Z=1.834,P=0.067;Z=0.610,P=0.512)。结论慢性乙型肝炎患者血清ANGPTL2和GP73水平有一些变化规律,应用两者诊断肝纤维化分期有一些有意义的苗头,值得进一步探讨。
Objective To evaluate the value of serum angiopoietin-like protein 2(ANGPTL2) and Golgi protein 73(GP73) levels in the diagnosis of liver fibrosis in patients with chronic hepatitis B(CHB). Methods 117 patients with CHB were recruited in our hospital between March 2015 and October 2017,and serum ANGPTL2 and GP73 levels were detected by enzyme-linked immunosorbent assay. The efficacy of serum ANGPTL2 and GP73 levels in the diagnosis of significant hepatic fibrosis and cirrhosis were evaluated by the area under receiver operating characteristic curve(ROC). Results Serum levels of ANGPTL 2 and GP73 in 15 CHB patients with S3-S4 were(9.1±2.4) ng/ml and(84.9±15.2) ng/ml,significantly higher than(6.7±2.3) ng/ml and(65.1±14.8) ng/ml(P<0.05) in 78 patients with S1-S2 or(4.4±1.4) ng/ml and(53.7±14.3) ng/ml in 24 patients with S0(P<0.05);based on serum ANGPTL2 levels equal to 8.6 ng/mL and equal to 9.6 ng/mL or serum GP73 level equal to 75.6 ng/ml and equal to 103.5 ng/mL as the cut-off-value for the diagnosis of significant hepatic fibrosis(equal to or greater than S3) and liver cirrhosis,the diagnostic efficacy of serum ANGPTL2 levels was not superior to serum GP73(Z=1.872,P=0.061;Z=0.328,P=0.743);the diagnostic value of combination serum ANGPTL2 and GP73 levels for significant hepatic fibrosis was superior to either serum ANGPTL2 level or serum GP73 level alone,e.g. AUCcombination >AU CANGPTL2(Z =3.310,P =0.001) or AUCcombination >AUCGP73(Z =2.004,P=0.045),while the diagnostic efficacy of combination serum ANGPTL2 and GP73 levels for liver cirrhosis was not superior to either serum ANGPTL2 or GP73 alone(Z=1.471,P=0.141;Z=1.575,P=0.115);the efficacy of combination of serum ANGPTL2 and GP73 levels in diagnosis of liver fibrosis was not superior to FIB-4 or APRI(Z=0.869,P=0.386;Z=0.492,P=0.623) and it also not better than FIB-4 or APRI in diagnosis of liver cirrhosis(Z=1.834,P=0.067;Z=0.610,P=0.512). Conclusion Serum levels of ANGPTL2 and GP73 change obviously in patients with CHB,which might hint hepatic fibrosis and be applied to evaluate the liver fibrosis staging.
Objective To evaluate the value of serum angiopoietin-like protein 2(ANGPTL2) and Golgi protein 73(GP73) levels in the diagnosis of liver fibrosis in patients with chronic hepatitis B(CHB). Methods 117 patients with CHB were recruited in our hospital between March 2015 and October 2017,and serum ANGPTL2 and GP73 levels were detected by enzyme-linked immunosorbent assay. The efficacy of serum ANGPTL2 and GP73 levels in the diagnosis of significant hepatic fibrosis and cirrhosis were evaluated by the area under receiver operating characteristic curve(ROC). Results Serum levels of ANGPTL 2 and GP73 in 15 CHB patients with S3-S4 were(9.1±2.4) ng/ml and(84.9±15.2) ng/ml,significantly higher than(6.7±2.3) ng/ml and(65.1±14.8) ng/ml(P<0.05) in 78 patients with S1-S2 or(4.4±1.4) ng/ml and(53.7±14.3) ng/ml in 24 patients with S0(P<0.05);based on serum ANGPTL2 levels equal to 8.6 ng/mL and equal to 9.6 ng/mL or serum GP73 level equal to 75.6 ng/ml and equal to 103.5 ng/mL as the cut-off-value for the diagnosis of significant hepatic fibrosis(equal to or greater than S3) and liver cirrhosis,the diagnostic efficacy of serum ANGPTL2 levels was not superior to serum GP73(Z=1.872,P=0.061;Z=0.328,P=0.743);the diagnostic value of combination serum ANGPTL2 and GP73 levels for significant hepatic fibrosis was superior to either serum ANGPTL2 level or serum GP73 level alone,e.g. AUCcombination >AU CANGPTL2(Z =3.310,P =0.001) or AUCcombination >AUCGP73(Z =2.004,P=0.045),while the diagnostic efficacy of combination serum ANGPTL2 and GP73 levels for liver cirrhosis was not superior to either serum ANGPTL2 or GP73 alone(Z=1.471,P=0.141;Z=1.575,P=0.115);the efficacy of combination of serum ANGPTL2 and GP73 levels in diagnosis of liver fibrosis was not superior to FIB-4 or APRI(Z=0.869,P=0.386;Z=0.492,P=0.623) and it also not better than FIB-4 or APRI in diagnosis of liver cirrhosis(Z=1.834,P=0.067;Z=0.610,P=0.512). Conclusion Serum levels of ANGPTL2 and GP73 change obviously in patients with CHB,which might hint hepatic fibrosis and be applied to evaluate the liver fibrosis staging.
引文
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[2]郝洁,田小军,段树鹏,等.慢性乙型肝炎患者肝纤维化的危险因素分析.实用肝脏病杂志,2017,20(5):538-541.
[3]何志颖,赵新颜.肝组织病理学检查在不明原因肝病诊治中的应用.实用肝脏病杂志,2018,21(1):10-13.
[4]Kadomatsu T,Endo M,Miyata K,et al.Diverse roles of ANGPTL2in physiology and pathophysiology.Trends Endocrinol Metab,2014,25(5):245-254.
[5]Yao M,Wang L,PSC L,et al.The clinical significance of GP73in immunologically mediated chronic liver diseases:experimental data and literature review.Clin Rev Allergy Immunol,2018,54(2):282-294.
[6]中华医学会肝病学分会.慢性乙型肝炎防治指南(2015更新版).中华传染病杂志,2015,33(11):321-340.
[7]Zhang G,Xia Y.Reference intervals of fibrosis index based on four indicators in healthy elderly Chinese.J Clin Lab Anal,2016,30(5):645-648.
[8]杨晴,刘东屏,李鲁平,等.慢性乙型肝炎肝纤维化非创伤性诊断模型的建立与评价.中华肝脏病杂志,2017,25(1):15-20.
[9]Huang R,Xia J,Liu Y,et al.Acoustic radiation force impulse in the diagnosis of liver fibrosis in patients with chronic hepatitis B.Eur J Gastroenterol Hepatol,2017,29(8):980-981.
[10]Wang ZF,Wang MY,Yu DH,et al.Therapeutic effect of chitosan on CCl4induced hepatic fibrosis in rats.Mol Med Rep,2018,18(3):3211-3218.
[11]Huber A,Ebner L,Heverhagen JT,et al.State-of-the-art imaging of liver fibrosis and cirrhosis:A comprehensive review of current applications and future perspectives.Eur J Radiol Open,2015,2(c):90-100.
[12]Serai SD,Trout AT,Miethke A,et al.Putting it all together:established and emerging MRI techniques for detecting and measuring liver fibrosis.Pediatr Radiol,2018,48(9):1256-1272.
[13]Yang W,Liu W,Yu W,et al.Angptl2 deficiency attenuates paraquat(PQ)-induced lung injury in mice by altering inflammation,oxidative stress and fibrosis through NF-κB pathway.Biochem Biophys Res Commun,2018,503(1):94-101.
[14]Gao G,Dong F,Xu X,et al.Diagnostic value of serum Golgi protein 73 for HBV-related primary hepatic carcinoma.Int JClin Exp Pathol,2015,8(9):11379-11385.
[15]Sasaki H,Suzuki A,Shitara M,et al.Angiopoietin-like protein ANGPTL2 gene expression is correlated with lymph node metastasis in lung cancer.Oncol Letters,2012,4(6):1325-1328.
[16]Xu Z,Liu L,Pan X,et al.Serum Golgi protein 73(GP73)is a diagnostic and prognostic marker of chronic HBV liver disease.Medicine,2015,94(12):e659.
[17]Yang SL,Zeng C,Fang X,et al.Hepatitis B virus upregulates GP73 expression by activating the HIF-2αsignaling pathway.Oncol Lett,2018,15(4):5264-5270.
[18]Yin Z,Zou J,Li Q,et al.Diagnostic value of FIB-4 for liver fibrosis in patients with hepatitis B:a meta-analysis of diagnostic test.Oncotarget,2017,8(14):22944-22953.
[19]Suh B,Yun JM,Park S,et al.Prediction of future hepatocellular carcinoma incidence in moderate to heavy alcohol drinkers with the FIB-4 liver fibrosis index.Cancer,2015,121(21):3818-3825.
[20]Taneja S,Tohra S,Duseja A,et al.Noninvasive assessment of liver fibrosis by transient elastography and FIB4/APRI for prediction of treatment response in chronic hepatitis C-an experience from a tertiary care hospital.J Clin Exp Hepatol,2016,6(4):282-290.
[2]郝洁,田小军,段树鹏,等.慢性乙型肝炎患者肝纤维化的危险因素分析.实用肝脏病杂志,2017,20(5):538-541.
[3]何志颖,赵新颜.肝组织病理学检查在不明原因肝病诊治中的应用.实用肝脏病杂志,2018,21(1):10-13.
[4]Kadomatsu T,Endo M,Miyata K,et al.Diverse roles of ANGPTL2in physiology and pathophysiology.Trends Endocrinol Metab,2014,25(5):245-254.
[5]Yao M,Wang L,PSC L,et al.The clinical significance of GP73in immunologically mediated chronic liver diseases:experimental data and literature review.Clin Rev Allergy Immunol,2018,54(2):282-294.
[6]中华医学会肝病学分会.慢性乙型肝炎防治指南(2015更新版).中华传染病杂志,2015,33(11):321-340.
[7]Zhang G,Xia Y.Reference intervals of fibrosis index based on four indicators in healthy elderly Chinese.J Clin Lab Anal,2016,30(5):645-648.
[8]杨晴,刘东屏,李鲁平,等.慢性乙型肝炎肝纤维化非创伤性诊断模型的建立与评价.中华肝脏病杂志,2017,25(1):15-20.
[9]Huang R,Xia J,Liu Y,et al.Acoustic radiation force impulse in the diagnosis of liver fibrosis in patients with chronic hepatitis B.Eur J Gastroenterol Hepatol,2017,29(8):980-981.
[10]Wang ZF,Wang MY,Yu DH,et al.Therapeutic effect of chitosan on CCl4induced hepatic fibrosis in rats.Mol Med Rep,2018,18(3):3211-3218.
[11]Huber A,Ebner L,Heverhagen JT,et al.State-of-the-art imaging of liver fibrosis and cirrhosis:A comprehensive review of current applications and future perspectives.Eur J Radiol Open,2015,2(c):90-100.
[12]Serai SD,Trout AT,Miethke A,et al.Putting it all together:established and emerging MRI techniques for detecting and measuring liver fibrosis.Pediatr Radiol,2018,48(9):1256-1272.
[13]Yang W,Liu W,Yu W,et al.Angptl2 deficiency attenuates paraquat(PQ)-induced lung injury in mice by altering inflammation,oxidative stress and fibrosis through NF-κB pathway.Biochem Biophys Res Commun,2018,503(1):94-101.
[14]Gao G,Dong F,Xu X,et al.Diagnostic value of serum Golgi protein 73 for HBV-related primary hepatic carcinoma.Int JClin Exp Pathol,2015,8(9):11379-11385.
[15]Sasaki H,Suzuki A,Shitara M,et al.Angiopoietin-like protein ANGPTL2 gene expression is correlated with lymph node metastasis in lung cancer.Oncol Letters,2012,4(6):1325-1328.
[16]Xu Z,Liu L,Pan X,et al.Serum Golgi protein 73(GP73)is a diagnostic and prognostic marker of chronic HBV liver disease.Medicine,2015,94(12):e659.
[17]Yang SL,Zeng C,Fang X,et al.Hepatitis B virus upregulates GP73 expression by activating the HIF-2αsignaling pathway.Oncol Lett,2018,15(4):5264-5270.
[18]Yin Z,Zou J,Li Q,et al.Diagnostic value of FIB-4 for liver fibrosis in patients with hepatitis B:a meta-analysis of diagnostic test.Oncotarget,2017,8(14):22944-22953.
[19]Suh B,Yun JM,Park S,et al.Prediction of future hepatocellular carcinoma incidence in moderate to heavy alcohol drinkers with the FIB-4 liver fibrosis index.Cancer,2015,121(21):3818-3825.
[20]Taneja S,Tohra S,Duseja A,et al.Noninvasive assessment of liver fibrosis by transient elastography and FIB4/APRI for prediction of treatment response in chronic hepatitis C-an experience from a tertiary care hospital.J Clin Exp Hepatol,2016,6(4):282-290.