丙型肝炎病毒相关性原发性肝癌危险因素的回顾性研究
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摘要
目的：探讨丙型肝炎病毒相关性原发性肝癌的危险因素,以尽早在HCV感染者中筛选出高危人群,并进行追踪、随访。
方法：选择2007年1月～2011年1月中日联谊医院HCV相关性原发性肝癌患者56例(以下简称肝癌组),其中男性44例,女性12例,年龄39～83岁,平均年龄65.0±8.2岁；随机选取66例HCV感染者(不合并原发性肝癌)作为对照组(以下简称非肝癌组),其中男性26例,女性40例,年龄19～77岁,平均年龄55.5±13.1岁。所有研究对象共计122例,其中男性70例,女性52例。年龄19～83岁,平均年龄60.4±10.8岁。所有患者均进行肝功能、血脂、血糖,乙肝三对、丙肝抗体检查,以及肝、脾彩超、上腹部CT检查；其中92例患者行外周血HCV RNA定量检查,104例患者行病毒基因分型检查。采用Beckman全自动生化分析仪检测血清生化指标。采用实时荧光定量FQ-PCR方法检测血清HCV RNA含量。
结果：肝癌组男性患者44例,占78.6%；非肝癌组男性患者29例,占39.4%。肝癌组中肝硬化患者40例,占71.4%；非肝癌组肝硬化患者28例,占42.4%。肝癌组HBcAb阳性者37例,占72.5%；非肝癌组HBcAb阳性者21例,占33.9%。肝癌组患者的平均年龄为65.0±8.2岁；非肝癌组为55.5±13.1岁。肝癌组年龄≥65岁者占51.8%,共计29例；非肝癌组年龄≥65岁者占21.2%,共计14例。肝癌组基因1型病毒感染者占70%,共计28例；非肝癌组基因1型病毒感染者占53.1%,共计34例。在肝癌组,男性、肝硬化、HBcAb阳性及老年(年龄≥65岁)患者的比例均高于非肝癌组,且有显著性差异(P<0.05)。多因素Logistic回归模型中,危险因素依次为男性(OR=4.846,95%CI,1.905-12.329)、肝硬化(OR=3.915,95%CI,1.542-9.942)、HBcAb阳性(OR=2.806,95%CI,1.140-6.907)、年龄≥65岁(OR=1.080,95%CI,1.024-1.139)。
结论：男性、肝硬化、HBcAb阳性、老年(年龄≥65岁)均是慢性HCV感染者肝癌发生的独立危险因素。慢性丙型肝炎进展至肝硬化阶段后,其癌变几率较慢性丙型肝炎升高,基因1型HCV感染同肝癌发生率升高间的确切关系尚需大样本流行病学调
AIMS:The aim of the study was to assess the risk factors for the development of PLC among hepatitis C, so as to promote the screening in the high risk populations。
METHORDS:A total of 122 patients (70 male,52 female, age 39～83 years old, the average of age 59.9±12.0 years old) were incorporated in this program. This study contains 56 patients with HCV related PLC(the group of PLC),and 66 patients with HCV infection as control(the group of non-PLC).In the group of PLC, there were 44 male and 12 female patients whose average of age was 65.0±8.2 years old. In the group of non-PLC, there were 26 male and 40 female patients whose average of age were 55.5±13.1 years old. All patients underwent Liver function, triglyceride and total cholesterol, blood glucose. HBV and HCV markers test, and the liver, upper spleen ultrasonography.abdominal CT examination.Beckman automatic Automatic biochemical analyzer was used to detect serum biochemical parameters; Quantitative real-time FQ-PCR method was used for detection of serum HCV RNA levels.Unconditional logistic regression was performed to analyze the risk factors by using SPSS 16.0 software.
RESULTS:In the group of PLC the porproation of male,age≥65 years old,HBcAb positive and liver cirrhosis were 78.6%,51.8%,72.5% and 71.4%, which were higher than the porproation in the group of non-PLC. In Univariate analysis, the following four factors influenced carcinogenesis with statistical significance:male (p=0.001), age (p=0.005), HBcAb positive (p=0.025), liver cirrhosis (p=0.004).Other factors including HCV load,blood glucose,triglyceride and total cholesterol have already been proven that there not be significant differences between the two groups. With logistic analysis using these four factors, male, age, HBcAb, liver cirrhosis were independent significant risk factors for predicting PLC.The OR of the male patients was 4.846(95%CI,1.905-12.329) compared with female patients;the OR of the patients older than 65 years old is 1.080(95%CI,1.024-1.139) compared with those who were younger than 65 years old;the OR of patients with HBcAb positive was 2.806(95%CI,1.140-6.907) compared with those who were HBcAb negative,and the OR of patients with liver cirrhosis was 3.915(95%CI, 1.542-9.942) compared with those who were only hepatitis but not liver cirrhosis.
CONCLUSIONS:Male, liver cirrhosis, HBcAb posotive, elderly(age≥65 years old) are risk factors for development of PLC in Hepatitis C patients.The proporation of genotype 1 hepatitis C virus is the largest among all the patients. The incidence of genotype 1 HCV infection in the group of PLC is higher compared with the group of non-PLC,however,there were no significant difference between the two groups.The relationship between genotype of HCV and PLC in Hepatitis C need futher large sample study.
方法：选择2007年1月～2011年1月中日联谊医院HCV相关性原发性肝癌患者56例(以下简称肝癌组),其中男性44例,女性12例,年龄39～83岁,平均年龄65.0±8.2岁；随机选取66例HCV感染者(不合并原发性肝癌)作为对照组(以下简称非肝癌组),其中男性26例,女性40例,年龄19～77岁,平均年龄55.5±13.1岁。所有研究对象共计122例,其中男性70例,女性52例。年龄19～83岁,平均年龄60.4±10.8岁。所有患者均进行肝功能、血脂、血糖,乙肝三对、丙肝抗体检查,以及肝、脾彩超、上腹部CT检查；其中92例患者行外周血HCV RNA定量检查,104例患者行病毒基因分型检查。采用Beckman全自动生化分析仪检测血清生化指标。采用实时荧光定量FQ-PCR方法检测血清HCV RNA含量。
结果：肝癌组男性患者44例,占78.6%；非肝癌组男性患者29例,占39.4%。肝癌组中肝硬化患者40例,占71.4%；非肝癌组肝硬化患者28例,占42.4%。肝癌组HBcAb阳性者37例,占72.5%；非肝癌组HBcAb阳性者21例,占33.9%。肝癌组患者的平均年龄为65.0±8.2岁；非肝癌组为55.5±13.1岁。肝癌组年龄≥65岁者占51.8%,共计29例；非肝癌组年龄≥65岁者占21.2%,共计14例。肝癌组基因1型病毒感染者占70%,共计28例；非肝癌组基因1型病毒感染者占53.1%,共计34例。在肝癌组,男性、肝硬化、HBcAb阳性及老年(年龄≥65岁)患者的比例均高于非肝癌组,且有显著性差异(P<0.05)。多因素Logistic回归模型中,危险因素依次为男性(OR=4.846,95%CI,1.905-12.329)、肝硬化(OR=3.915,95%CI,1.542-9.942)、HBcAb阳性(OR=2.806,95%CI,1.140-6.907)、年龄≥65岁(OR=1.080,95%CI,1.024-1.139)。
结论：男性、肝硬化、HBcAb阳性、老年(年龄≥65岁)均是慢性HCV感染者肝癌发生的独立危险因素。慢性丙型肝炎进展至肝硬化阶段后,其癌变几率较慢性丙型肝炎升高,基因1型HCV感染同肝癌发生率升高间的确切关系尚需大样本流行病学调
AIMS:The aim of the study was to assess the risk factors for the development of PLC among hepatitis C, so as to promote the screening in the high risk populations。
METHORDS:A total of 122 patients (70 male,52 female, age 39～83 years old, the average of age 59.9±12.0 years old) were incorporated in this program. This study contains 56 patients with HCV related PLC(the group of PLC),and 66 patients with HCV infection as control(the group of non-PLC).In the group of PLC, there were 44 male and 12 female patients whose average of age was 65.0±8.2 years old. In the group of non-PLC, there were 26 male and 40 female patients whose average of age were 55.5±13.1 years old. All patients underwent Liver function, triglyceride and total cholesterol, blood glucose. HBV and HCV markers test, and the liver, upper spleen ultrasonography.abdominal CT examination.Beckman automatic Automatic biochemical analyzer was used to detect serum biochemical parameters; Quantitative real-time FQ-PCR method was used for detection of serum HCV RNA levels.Unconditional logistic regression was performed to analyze the risk factors by using SPSS 16.0 software.
RESULTS:In the group of PLC the porproation of male,age≥65 years old,HBcAb positive and liver cirrhosis were 78.6%,51.8%,72.5% and 71.4%, which were higher than the porproation in the group of non-PLC. In Univariate analysis, the following four factors influenced carcinogenesis with statistical significance:male (p=0.001), age (p=0.005), HBcAb positive (p=0.025), liver cirrhosis (p=0.004).Other factors including HCV load,blood glucose,triglyceride and total cholesterol have already been proven that there not be significant differences between the two groups. With logistic analysis using these four factors, male, age, HBcAb, liver cirrhosis were independent significant risk factors for predicting PLC.The OR of the male patients was 4.846(95%CI,1.905-12.329) compared with female patients;the OR of the patients older than 65 years old is 1.080(95%CI,1.024-1.139) compared with those who were younger than 65 years old;the OR of patients with HBcAb positive was 2.806(95%CI,1.140-6.907) compared with those who were HBcAb negative,and the OR of patients with liver cirrhosis was 3.915(95%CI, 1.542-9.942) compared with those who were only hepatitis but not liver cirrhosis.
CONCLUSIONS:Male, liver cirrhosis, HBcAb posotive, elderly(age≥65 years old) are risk factors for development of PLC in Hepatitis C patients.The proporation of genotype 1 hepatitis C virus is the largest among all the patients. The incidence of genotype 1 HCV infection in the group of PLC is higher compared with the group of non-PLC,however,there were no significant difference between the two groups.The relationship between genotype of HCV and PLC in Hepatitis C need futher large sample study.
引文
[1]中华医学会肝病学分会、传染病与寄生虫病学分会.丙型肝炎防治指南.中国.2004.
[2]王吉耀.内科学第二版人民卫生出版社.2010.
[3]A. SMEDILE EB. Steatosis and hepatocellular carcinoma risk. European Review for Medical and Pharmacological Sciences.2005;9:291-3.
[4]Yasuhiro A. KT, Nobuharu TI, Itsuko HA,et al. Effect of Aging on Risk for Hepatocellular Carcinoma in Chronic Hepatitis C Virus Infection. HEPATOLOGY.2010; 52.
[5]Benvegnu L. Pontisso P, Cavalletto D. Lack of correlation between hepatitis C virus genotypes and clinical course of hepatitis C virus-related cirrhosis. Hepatology. 1997;25:211-5.
[6]Toru IT, Satoshi YA, Satoshi SA. High viral loads, serum alanine aminotransferase and gender are predictive factors for the development of hepatocellular carcinoma from viral compensated liver cirrhosis. Journal of Gastroenterology and Hepatology.2001:1274-81.
[7]Yu MC. Elevated serum testosterone levels and risk of hepatocellular carcinoma. 730-94. Cancer Res.1993;53.
[8]Naugler WE, Sakurai T, Kim S, et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science.2007;317:121.
[9]Kudo M, Sakaguchi Y, Chung H, et al. Long-Term Interferon Maintenance Therapy Improves Survival in Patients with HCV-Related Hepatocellular Carcinoma after Curative Radiofrequency Ablation. Oncology.2007;72:132-8.
[10]Bruno S, Crosignani A, Maisonneuve P, et al. Hepatitis C virus genotype lb as a major risk factor associated with hepatocellular carcinoma in patients with cirrhosis:a seventeen-year prospective cohort study. Hepatology.2007;46:1350-6.
[11]Fishman SL, Factor SH, Balestrieri C, et al. Mutations in the hepatitis C virus core gene are associated with advanced liver disease and hepatocellular carcinoma. Clin Cancer Res. 2009;15:3205-13.
[12]Wang Y, Kato N, Hoshida Y, et al. Interleukin-lbeta gene polymorphisms associated with hepatocellular carcinoma in hepatitis C virus infection. Hepatology.2003;37:65-71.
[13]El-Chennawi FA, Auf FA, Metwally SS,et al. HLA-class II alleles in Egyptian patients with hepatocellular carcinoma. Immunol Invest.2008;37:661-74.
[14]Castera L H. Roudot-Thoraval.Effect of antiviral treatment on evolution of over steatosis in patients with chronic hepatitis C:evidence for a role of hcv genotype 3 in steatosis. EASL Conference Summary of Asbtracts on Hepatitis C.2003.
[15]Catera L CP, Hezode C,Zafrani ES,et al. Changes in lipid metabolism in chronic hepatitis C. world J Gastroenterol 2005; 11:6422-8.
[16]Jiang J, Zhang X, Wu C, et al. Increased plasma apoM levels in the patients suffered from hepatocellular carcinoma and other chronic liver diseases. Lipids in health and disease. 2008;7:25.
[17]Chisari SB. Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids. PANS.2005; 102.
[18]Wei Yang BLH, Sara L. CK,et al. Fatty Acid Synthase Is Up-Regulated During Hepatitis C Virus Infection and Regulates Hepatitis C Virus Entry and Production. HEPATOLOGY. 2008;48:1396-403.
[19]M. Soresi, S. Tripi VF, Giannitrapani.L, et al. Impact of liver steatosis on the antiviral response in the hepatitis C virus-associated chronic hepatitis. Liver International 2006;26:1119-25.
[20]Marcela Salomao M, Woojin M. Yu, MD, et al. Steatohepatitic Hepatocellular Carcinoma (SH-HCC).A Distinctive Histological Variant of HCC in Hepatitis C Virus-related Cirrhosis With Associated NAFLD/NASH. Am J Surg Pathol. 2010;2010:1630-6.
[21]Tanaka H, Fujita N, Sugimoto R, et al. Hepatic oxidative DNA damage is associated with increased risk for hepatocellular carcinoma in chronic hepatitis C. British journal of cancer.2008;98:580-6.
[22]Lonardo A.AL, Loria P, Carulli N. Steatosis and hepatitis C virus:mechanisms and significance for hepatic and extrahepatic disease. Gastroenterology 2004;26:586-97.
[23]Sarah L. Fishman SHF, Cinzia Balestrieri,et al. Mutations in the Hepatitis C Virus core GeneAreAssociated with Advanced Liver Disease and Hepatocellular Carcinoma. Clin Cancer Res 2009; 15.
[24]Moriya K.YH. Shintani Y, Fujie H, et al. Hepatitis C virus core protein induces hepatic steatosis in transgenic mice. J Gen Virol 1997;78:1527-31.
[25]Moriya K.FH, Shintani Y, Yotsuyanagi H, et al. Hepatitis C virus core protein induces hepatocellular carcinoma in transgenic mice. Nature Med.1998; 1065-8.
[26]Tanaka N, Moriya K, Kiyosawa K, et al. PPARalpha activation is essential for HCV core protein-induced hepatic steatosis and hepatocellular carcinoma in mice. J Clin Invest. 2008; 118:683-94.
[27]M J Walsh JRJ, M M Richardson, G M Lipka, et al. Non-response to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signalling 3 (SOCS-3) in patients with chronic hepatitis C, viral geno. GUT.2006;55:529-35.
[28]L Caste'ra CHz, F Roudot-Thoraval, I Lonjon, et al. Effect of antiviral treatment on evolution of liver steatosis in patients with chronic hepatitis C:indirect evidence of a role of hepatitis C virus genotype 3 in steatosis. GUT.2004;53::420-4.
[29]Yu Jian Wu, LSCaW, Qiang G. Effects of fatty liver and related factors on the efficacy of combination antiviral therapy in patients with chronic hepatitis C. Liver International 2006;26:166-72.
[30]Chou CL, Ting LP, et al. Selective suppression of insulin-induced proliferation of cultured human hepatoma cells by somatostatin. J Clin Invest J Clin Invest.1987;79:175-8.
[31]H L. Correlation between anti-HBc titers and HBV DNA in blood units without detectable HBsAg. Vox Sanguinus 1992;;63::107-11.
[32]B R. The hepatitis B virus persists for decades after patients recovery from acute viral hepatitis despite active mainternance of a cytotoxic T-lymphocyte response. Nature Med. 1996;2:1104-8.
[33]Haruhiko Imai RLO, Kendo Kiyosawa tSF, Robert M. Nakamura aEMT. Nucleolar Antigens and Autoantibodies in Hepatocellular Carcinoma and Other Malignancies. Americwn Journal of Pathology.1992;140:859-70.
[34]Xiaohong Chen, Songbin FU, Feng Chen,et al. Identification of tumor-associated antigens in human hepatocellular carcinoma by autoantibodies. Oncology REPORTS 2008;20:979-85.
[2]王吉耀.内科学第二版人民卫生出版社.2010.
[3]A. SMEDILE EB. Steatosis and hepatocellular carcinoma risk. European Review for Medical and Pharmacological Sciences.2005;9:291-3.
[4]Yasuhiro A. KT, Nobuharu TI, Itsuko HA,et al. Effect of Aging on Risk for Hepatocellular Carcinoma in Chronic Hepatitis C Virus Infection. HEPATOLOGY.2010; 52.
[5]Benvegnu L. Pontisso P, Cavalletto D. Lack of correlation between hepatitis C virus genotypes and clinical course of hepatitis C virus-related cirrhosis. Hepatology. 1997;25:211-5.
[6]Toru IT, Satoshi YA, Satoshi SA. High viral loads, serum alanine aminotransferase and gender are predictive factors for the development of hepatocellular carcinoma from viral compensated liver cirrhosis. Journal of Gastroenterology and Hepatology.2001:1274-81.
[7]Yu MC. Elevated serum testosterone levels and risk of hepatocellular carcinoma. 730-94. Cancer Res.1993;53.
[8]Naugler WE, Sakurai T, Kim S, et al. Gender disparity in liver cancer due to sex differences in MyD88-dependent IL-6 production. Science.2007;317:121.
[9]Kudo M, Sakaguchi Y, Chung H, et al. Long-Term Interferon Maintenance Therapy Improves Survival in Patients with HCV-Related Hepatocellular Carcinoma after Curative Radiofrequency Ablation. Oncology.2007;72:132-8.
[10]Bruno S, Crosignani A, Maisonneuve P, et al. Hepatitis C virus genotype lb as a major risk factor associated with hepatocellular carcinoma in patients with cirrhosis:a seventeen-year prospective cohort study. Hepatology.2007;46:1350-6.
[11]Fishman SL, Factor SH, Balestrieri C, et al. Mutations in the hepatitis C virus core gene are associated with advanced liver disease and hepatocellular carcinoma. Clin Cancer Res. 2009;15:3205-13.
[12]Wang Y, Kato N, Hoshida Y, et al. Interleukin-lbeta gene polymorphisms associated with hepatocellular carcinoma in hepatitis C virus infection. Hepatology.2003;37:65-71.
[13]El-Chennawi FA, Auf FA, Metwally SS,et al. HLA-class II alleles in Egyptian patients with hepatocellular carcinoma. Immunol Invest.2008;37:661-74.
[14]Castera L H. Roudot-Thoraval.Effect of antiviral treatment on evolution of over steatosis in patients with chronic hepatitis C:evidence for a role of hcv genotype 3 in steatosis. EASL Conference Summary of Asbtracts on Hepatitis C.2003.
[15]Catera L CP, Hezode C,Zafrani ES,et al. Changes in lipid metabolism in chronic hepatitis C. world J Gastroenterol 2005; 11:6422-8.
[16]Jiang J, Zhang X, Wu C, et al. Increased plasma apoM levels in the patients suffered from hepatocellular carcinoma and other chronic liver diseases. Lipids in health and disease. 2008;7:25.
[17]Chisari SB. Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids. PANS.2005; 102.
[18]Wei Yang BLH, Sara L. CK,et al. Fatty Acid Synthase Is Up-Regulated During Hepatitis C Virus Infection and Regulates Hepatitis C Virus Entry and Production. HEPATOLOGY. 2008;48:1396-403.
[19]M. Soresi, S. Tripi VF, Giannitrapani.L, et al. Impact of liver steatosis on the antiviral response in the hepatitis C virus-associated chronic hepatitis. Liver International 2006;26:1119-25.
[20]Marcela Salomao M, Woojin M. Yu, MD, et al. Steatohepatitic Hepatocellular Carcinoma (SH-HCC).A Distinctive Histological Variant of HCC in Hepatitis C Virus-related Cirrhosis With Associated NAFLD/NASH. Am J Surg Pathol. 2010;2010:1630-6.
[21]Tanaka H, Fujita N, Sugimoto R, et al. Hepatic oxidative DNA damage is associated with increased risk for hepatocellular carcinoma in chronic hepatitis C. British journal of cancer.2008;98:580-6.
[22]Lonardo A.AL, Loria P, Carulli N. Steatosis and hepatitis C virus:mechanisms and significance for hepatic and extrahepatic disease. Gastroenterology 2004;26:586-97.
[23]Sarah L. Fishman SHF, Cinzia Balestrieri,et al. Mutations in the Hepatitis C Virus core GeneAreAssociated with Advanced Liver Disease and Hepatocellular Carcinoma. Clin Cancer Res 2009; 15.
[24]Moriya K.YH. Shintani Y, Fujie H, et al. Hepatitis C virus core protein induces hepatic steatosis in transgenic mice. J Gen Virol 1997;78:1527-31.
[25]Moriya K.FH, Shintani Y, Yotsuyanagi H, et al. Hepatitis C virus core protein induces hepatocellular carcinoma in transgenic mice. Nature Med.1998; 1065-8.
[26]Tanaka N, Moriya K, Kiyosawa K, et al. PPARalpha activation is essential for HCV core protein-induced hepatic steatosis and hepatocellular carcinoma in mice. J Clin Invest. 2008; 118:683-94.
[27]M J Walsh JRJ, M M Richardson, G M Lipka, et al. Non-response to antiviral therapy is associated with obesity and increased hepatic expression of suppressor of cytokine signalling 3 (SOCS-3) in patients with chronic hepatitis C, viral geno. GUT.2006;55:529-35.
[28]L Caste'ra CHz, F Roudot-Thoraval, I Lonjon, et al. Effect of antiviral treatment on evolution of liver steatosis in patients with chronic hepatitis C:indirect evidence of a role of hepatitis C virus genotype 3 in steatosis. GUT.2004;53::420-4.
[29]Yu Jian Wu, LSCaW, Qiang G. Effects of fatty liver and related factors on the efficacy of combination antiviral therapy in patients with chronic hepatitis C. Liver International 2006;26:166-72.
[30]Chou CL, Ting LP, et al. Selective suppression of insulin-induced proliferation of cultured human hepatoma cells by somatostatin. J Clin Invest J Clin Invest.1987;79:175-8.
[31]H L. Correlation between anti-HBc titers and HBV DNA in blood units without detectable HBsAg. Vox Sanguinus 1992;;63::107-11.
[32]B R. The hepatitis B virus persists for decades after patients recovery from acute viral hepatitis despite active mainternance of a cytotoxic T-lymphocyte response. Nature Med. 1996;2:1104-8.
[33]Haruhiko Imai RLO, Kendo Kiyosawa tSF, Robert M. Nakamura aEMT. Nucleolar Antigens and Autoantibodies in Hepatocellular Carcinoma and Other Malignancies. Americwn Journal of Pathology.1992;140:859-70.
[34]Xiaohong Chen, Songbin FU, Feng Chen,et al. Identification of tumor-associated antigens in human hepatocellular carcinoma by autoantibodies. Oncology REPORTS 2008;20:979-85.