中文English
ISSN 1001-5256
CN 22-1108/R

留言板

尊敬的读者、作者、审稿人, 关于本刊的投稿、审稿、编辑和出版的任何问题, 您可以本页添加留言。我们将尽快给您答复。谢谢您的支持!

姓名
邮箱
手机号码
标题
留言内容
验证码

慢性乙型肝炎患者发生肝细胞癌的危险因素分析

刘龙 时克 张群 冉崇平 侯杰 张艺 王宪波

刘龙, 时克, 张群, 等. 慢性乙型肝炎患者发生肝细胞癌的危险因素分析[J]. 临床肝胆病杂志, 2021, 37(7): 1591-1593. DOI: 10.3969/j.issn.1001-5256.2021.07.022
引用本文: 刘龙, 时克, 张群, 等. 慢性乙型肝炎患者发生肝细胞癌的危险因素分析[J]. 临床肝胆病杂志, 2021, 37(7): 1591-1593. DOI: 10.3969/j.issn.1001-5256.2021.07.022
LIU L, SHI K, ZHANG Q, et al. Risk factors for hepatocellular carcinoma in patients with chronic hepatitis B[J]. J Clin Hepatol, 2021, 37(7): 1591-1593. DOI: 10.3969/j.issn.1001-5256.2021.07.022
Citation: LIU L, SHI K, ZHANG Q, et al. Risk factors for hepatocellular carcinoma in patients with chronic hepatitis B[J]. J Clin Hepatol, 2021, 37(7): 1591-1593. DOI: 10.3969/j.issn.1001-5256.2021.07.022

慢性乙型肝炎患者发生肝细胞癌的危险因素分析

DOI: 10.3969/j.issn.1001-5256.2021.07.022
基金项目: 

首都卫生发展科研专项 2018-1-2172

北京市科学技术委员会资助 Z191100006619033

国家中医药管理局重大疑难疾病中西医临床协作试点项目 2018-6-4

国家中医药管理局区域中医诊疗中心 2019-3-18

详细信息
    通讯作者:

    王宪波,wangxianbo638@163.com

  • 中图分类号: R512.62; R735.7

Risk factors for hepatocellular carcinoma in patients with chronic hepatitis B

Funds: 

Capital Health Development Research Project 2018-1-2172

Beijing Municipal Commission of Science and Technology Z191100006619033

National Administration of Traditional Chinese Medicine Clinical Cooperation Pilot Project of Traditional Chinese and Western Medicine for Major and Difficult Diseases 2018-6-4

Regional TCM Diagnosis and Treatment Center of State Administration of Traditional Chinese Medicine 2019-3-18

  • 摘要:   目的  探究慢性乙型肝炎(CHB)患者发生肝细胞癌(HCC)的危险因素。  方法  收集2013年1月—2015年6月北京地坛医院确诊的CHB且随访超过3年的患者,共1239例。其中非肝硬化患者1108例,肝硬化患者131例。收集患者的一般资料及实验室检查指标并计算APRI、FIB-4及mFZB-4评分。符合正态分布的计量资料2组间比较采用t检验;非正态分布的计量资料2组间比较采用Mann-Whitney U检验。计数资料2组间比较采用χ2检验。影响HCC发生的独立危险因素采用Cox回归分析。采用受试者工作特征曲线下面积(AUC)比较3种评分对CHB患者发生HCC的预测能力,采用DeLong检验对各个评分的AUC进行比较。通过拟合优度检验分析mFIB-4评分校准能力。使用Kalplan-Merier法对HCC发生进行分析,log-rank法进行比较。  结果  中位随访时间为4.6年,37例(3.0%)患者发生HCC。多因素Cox回归分析显示,年龄(HR=1.046,95%CI:1.018~1.074,P=0.001)、ALT (HR=0.995,95%CI:0.992~0.999,P=0.008)、AST (HR=0.994,95%CI:0.990~0.998,P=0.020)和PLT (HR=0.988,95%CI:0.981~0.994,P=0.001)是影响HCC发生的独立危险因素。mFIB-4、FIB-4、APRI评分的AUC分别为0.771、0.658、0.676,其中mFIB-4评分的AUC大于FIB-4评分(Z=5.629, P<0.000 1)及APRI评分(Z=4.243, P<0.000 1)。与mFIB-4<2.68的患者相比,mFIB-4 ≥2.68的患者HCC发生风险更高(Z=37.840, P<0.000 1)。  结论  年龄、ALT、AST和PLT是CHB患者发生HCC的独立危险因素。与FIB-4,APRI评分相比,mFIB-4评分对CHB患者发生HCC的预测价值更高。mFIB-4 ≥2.68的CHB患者是发生HCC的高危人群。

     

  • 图  1  各评分ROC曲线及mFIB-4评分校准直方图

    图  2  不同mFIB-4评分患者肝癌发生情况

    表  1  患者基线特征

    指标 全部患者(n=1239) 非肝硬化组(n=1108) 肝硬化组(n=131) 统计值 P
    年龄(岁) 39.4±11.8 38.3±11.5 48.3±10.8 t=9.506 <0.001
    男/女(例) 912/327 809/299 103/28 χ2=2.228 0.522
    HCC家族史[例(%)] 74 (6.0) 61 (5.5) 13 (9.9) χ2=3.997 0.046
    饮酒史[例(%)] 285 (23.0) 280 (25.3) 28 (21.4) χ2=0.234 0.628
    高血压[例(%)] 107 (8.6) 87 (7.9) 20 (15.3) χ2=12.621 <0.001
    糖尿病[例(%)] 87 (7.0) 66 (6.0) 21 (16.0) χ2=12.425 <0.001
    ALT(U/L) 112.4 (39.9~403.3) 129.0(44.7~442.3) 44.6 (27.3~106.2) Z=-5.010 <0.001
    AST(U/L) 62.0 (30.8~191.1) 67.4 (32.3~204.0) 34.6 (26.2~85.3) Z=-3.541 <0.001
    TBil(μmol/L) 16.1 (11.3~27.6) 15.9 (11.1~27.3) 18.6(13.4~29.0) Z=-0.337 0.736
    Alb(g/L) 30.6(27.5~33.9) 41.5(37.8~45.4) 39.5(35.9~42.8) Z=-3.256 0.003
    GGT(U/L) 59.7 (27.3~124.1) 61.0 (27.1~126.8) 50.6 (28.0~110.9) Z=-0.706 0.480
    WBC(×109/L) 5.1 (4.2~6.1) 5.1 (4.2~6.2) 4.7 (3.1~5.7) Z=-2.882 0.004
    PLT(×109/L) 153.0(115.5~197.5) 160.6(122.0~200.1) 100.6(76.0~129.0) Z=-9.572 0.001
    BUN(mmol/L) 4.4 (3.5~5.4) 4.4 (3.7~5.3) 4.9 (4.2~5.9) Z=0.271 0.786
    Cr(μmoI/L) 68.7 (59.0~77.0) 68.3 (58.8~77.0) 70.0 (59.8~77.0) Z=-0.002 0.998
    PT(s) 12.2 (11.5~13.1) 12.1 (11.4~13.0) 12.7 (11.7~14.1) Z=2.922 0.004
    INR 1.0 (0.9~1.1) 1.1 (1.0~1.1) 1.1 (1.0~1.2) Z=-0.195 0.846
    AFP(ng/ml) 5.7 (2.6~25.9) 5.6 (2.9~24.9) 6.5 (3.3~29.4) Z=-0.634 0.405
    HBV DNA(log10拷贝/ml) 5.5 (3.3~7.1) 5.7 (3.5~7.1) 3.9 (2.7~6.1) Z=-5.374 0.001
    mFIB-4 1.6(0.8~2.9) 1.5(0.8~2.5) 3.6(2.3~7.3) Z=10.827 <0.001
    FIB-4 1.6 (0.9~3.3) 1.5 (0.8~3.1) 3.2 (1.8~5.4) Z=3.194 0.001
    APRI 1.5(1.1~2.2) 1.5(1.1~2.1) 2.1(1.5~2.8) Z=5.124 <0.001
    抗病毒治疗[例(%)]
      恩替卡韦 1239(100.0) 1108(100.0) 131(100.0)
      之前服用抗病毒药物 312(25.2) 86(6.9) 226(18.3)
      聚乙二醇化干扰素 35(2.8) 35(2.8) 0
    下载: 导出CSV

    表  2  CHB患者发生HCC风险的单因素分析

    因素 HR(95%CI) P
    年龄 1.067(0.041~1.094) <0.001
    男性 1.361(0.658~2.823) 0.407
    HCC家族史 1.443(0.444~4.720) 0.540
    饮酒史 1.222(0.591~2.525) 0.588
    高血压 1.270(0.454~3.555) 0.660
    糖尿病 0.374(0.051~2.734) 0.332
    ALT 0.994(0.990~0.998) 0.003
    AST 0.994(0.989~0.999) 0.014
    TBil 0.984(0.966~1.003) 0.102
    Alb 0.966(0.923~1.011) 0.139
    GGT 0.996(0.991~1.001) 0.183
    WBC 0.978(0.840~1.139) 0.978
    PLT 0.984(0.978~0.990) <0.001
    BUN 1.004(0.991~1.018) 0.530
    Cr 1.009(0.999~1.019) 0.054
    PT 1.049(0.938~1.114) 0.400
    INR 0.991(0.803~1.222) 0.935
    AFP 0.997(0.991~1.003) 0.361
    HBV DNA 0.827(0.699~1.078) 0.271
    下载: 导出CSV
  • [1] SINGAL AG, El-SERAG HB. Hepatocellular carcinoma from epidemiology to prevention: Translating knowledge into practice[J]. Clin Gastroenterol Hepatol, 2015, 13(12): 2140-2151. DOI: 10.1016/j.cgh.2015.08.014.
    [2] HEIMBACH JK, KULIK LM, FINN RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma[J]. Hepatology, 2018, 67(1): 358-380. DOI: 10.1002/hep.29086.
    [3] ARENDS P, SONNEVELD MJ, ZOUTENDIJK R, et al. Entecavir treatment does not eliminate the risk of hepatocellular carcinoma in chronic hepatitis B: Limited role for risk scores in Caucasians[J]. Gut, 2015, 64(8): 1289-1295. DOI: 10.1136/gutjnl-2014-307023.
    [4] European Association for the Study of the Liver. EASL clinical practice guidelines: Management of chronic hepatitis B virus infection[J]. J Hepatol, 2012, 57(1): 167-185. DOI: 10.1016/j.jhep.2012.02.010.
    [5] JUNG KS, KIM SU, SONG K, et al. Validation of hepatitis B virus-related hepatocellular carcinoma prediction models in the era of antiviral therapy[J]. Hepatology, 2015, 62(6): 1757-1766. DOI: 10.1002/hep.28115.
    [6] VALLET-PICHARD A, MALLET V, NALPAS B, et al. FIB-4: An inexpensive and accurate marker of fibrosis in HCV infection. comparison with liver biopsy and fibrotest[J]. Hepatology, 2007, 46(1): 32-36. DOI: 10.1002/hep.21669.
    [7] WAI CT, GREENSON JK, FONTANAL RJ, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C[J]. Hepatology, 2003, 38(2): 518-526. DOI: 10.1053/jhep.2003.50346.
    [8] PAIK N, SINN DH, LEE JH, et al. Non-invasive tests for liver disease severity and the hepatocellular carcinoma risk in chronic hepatitis B patients with low level viremia[J]. Liver Int, 2018, 38(1): 68-75. DOI: 10.1111/liv.13489.
    [9] WANG HW, PENG CY, LAI HC, et al. New noninvasive index for predicting liver fibrosis in Asian patients with chronic viral hepatitis[J]. Sci Rep, 2017, 7(1): 3259. DOI: 10.1038/s41598-017-03589-w.
    [10] Chinese Society of Infectious Diseases and Chinese Society of Hepatology Chinese, Medical Association. The guideline of prevention and treatment for chronic hepatitis B: A 2019 update[J]. J Clin Hepatol, 2019, 35 (12): 2648-2669. DOI: 1001-5256(2019)12-2648-22.

    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: 1001-5256(2019) 12-2648-22.
    [11] Chinese Society of Infectious Diseases Chinese, Medical Association. Chinese guidelines on the management of liver cirrhosis[J]. J Clin Hepatol, 2019, 35(11): 2408-2425. DOI: 1001-5256(2019)11-2408-18.

    中华医学会肝病学分会. 肝硬化诊治指南[J]. 临床肝胆病杂志, 2019, 35 (11): 2408-2425. DOI: 1001-5256(2019) 11-2408-18.
    [12] OMATA M, CHENG AL, KOKUDO N, et al. Asia-Pacific clinical practice guidelines on the management of hepatocellular carcinoma, a 2017 update[J]. Hepatol Int, 2017, 11(4): 317-370. DOI: 10.1007/s12072-017-9799-9.
    [13] CHAN SL, WONG VW, QIN S, et al. Infection and cancer: The case of hepatitis B[J]. J Clin Oncol, 2016, 34(1): 83-90. DOI: 10.1200/JCO.2015.61.5724.
    [14] CHAN HLY. Okuda lecture: Challenges of hepatitis B in the era of antiviral therapy[J]. J Gastroenterol Hepatol, 2019, 34(3): 501-506. DOI: 10.1111/jgh.14534.
    [15] PAPATHEODORIDIS GV, IDILMAN R, DALEKOS GN, et al. The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B[J]. Hepatology, 2017, 66(5): 1444-1453. DOI: 10.1002/hep.29320.
    [16] PAPATHEODORIDIS GV, MANOLAKOPOULOS S, TOULOUMI G, et al. Hepatocellular carcinoma risk in HBeAg-negative chronic hepatitis B patients with or without cirrhosis treated with entecavir: HepNet. Greece cohort[J]. J Viral Hepat, 2015, 22(2): 120-127. DOI: 10.1111/jvh.12283.
    [17] CHEN CF, LEE WC, YANG HI, et al. Changes in serum levels of HBV DNA and alanine aminotransferase determine risk for hepatocellular carcinoma[J]. Gastroenterology, 2011, 141(4): 1240-1248, 1248. e1-e2. DOI: 10.1053/j.gastro.2011.06.036.
    [18] TSENG TC. Risk factors of liver cancer progression in patients with chronic hepatitis B virus infection[J/CD]. Chin J Exp Clin Infect Dis (Electronic Edition), 2019, 13(5): 440. DOI: 10.3877/cma.j.issn.1674-1358.2019.05.017.

    TSENG TC. 慢性乙型肝炎病毒感染者进展为肝癌的危险因素[J/CD]. 中华实验和临床感染病杂志(电子版), 2019, 13(5): 440. DOI: 10.3877/cma.j.issn.1674-1358.2019.05.017.
    [19] KIM JH, KIM YD, LEE M, et al. Modified PAGE-B score predicts the risk of hepatocellular carcinoma in Asians with chronic hepatitis B on antiviral therapy[J]. J Hepatol, 2018, 69(5): 1066-1073. DOI: 10.1016/j.jhep.2018.07.018.
    [20] BERZIGOTTI A, SEIJO S, ARENA U, et al. Elastography, spleen size, and platelet count identify portal hypertension in patients with compensated cirrhosis[J]. Gastroenterology, 2013, 144(1): 102-111. e101. DOI: 10.1053/j.gastro.2012.10.001.
    [21] THOMOPOULOS KC, LABROPOULOU-KARATZA C, MIMIDIS KP, et al. Non-invasive predictors of the presence of large oesophageal varices in patients with cirrhosis[J]. Dig Liver Dis, 2003, 35(7): 473-478. DOI: 10.1016/s1590-8658(03)00219-6.
    [22] TANDON P, GARCIA-TSAO G. Portal hypertension and hepatocellular carcinoma: Prognosis and beyond[J]. Clin Gastroenterol Hepatol, 2006, 4(11): 1318-1319. DOI: 10.1016/j.cgh.2006.09.009.
    [23] SUH B, PARK S, SHIN DW, et al. High liver fibrosis index FIB-4 is highly predictive of hepatocellular carcinoma in chronic hepatitis B carriers[J]. Hepatology, 2015, 61(4): 1261-1268. DOI: 10.1002/hep.27654.
    [24] KIM MN, KIM SU, KIM BK, et al. Increased risk of hepatocellular carcinoma in chronic hepatitis B patients with transient elastography-defined subclinical cirrhosis[J]. Hepatology, 2015, 61(6): 1851-1859. DOI: 10.1002/hep.27735.
    [25] BAGLIERI J, BRENNER DA, KISSELEVA T. The role of fibrosis and liver-associated fibroblasts in the pathogenesis of hepatocellular carcinoma[J]. Int J Mol Sci, 2019, 20(7): 1723. DOI: 10.3390/ijms20071723.
    [26] GABELE E, BRENNER DA, RIPPE RA. Liver fibrosis: Signals leading to the amplification of the fibrogenic hepatic stellate cell[J]. Front Biosci, 2003, 8: d69-d77. DOI: 10.2741/887.
    [27] SAKURAI T, HE G, MATSUZAWA A, et al. Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis[J]. Cancer Cell, 2008, 14(2): 156-165. DOI: 10.1016/j.ccr.2008.06.016.
    [28] FARAZI PA, DEPINHO RA. Hepatocellular carcinoma pathogenesis: From genes to environment[J]. Nat Rev Cancer, 2006, 6(9): 674-87. DOI: 10.1038/nrc1934.
  • 加载中
图(2) / 表(2)
计量
  • 文章访问数:  132
  • HTML全文浏览量:  13
  • PDF下载量:  45
  • 被引次数: 0
出版历程
  • 收稿日期:  2021-01-02
  • 修回日期:  2021-02-10
  • 刊出日期:  2021-07-20
  • 分享
  • 用微信扫码二维码

    分享至好友和朋友圈

目录

    /

    返回文章
    返回