HBV相关肝细胞癌的危险因素、早期筛查和预防策略
|
摘要
肝细胞癌(HCC)是全球癌症死亡的主要原因之一,HBV感染是HCC最重要的危险因素之一。HBV相关HCC的发生是宿主与病毒相互作用的复杂过程,危险因素包括HBV病毒载量、HBeAg、宿主易感性等。HCC筛查方式包括超声等影像学检查和AFP等血清标志物,血清异常凝血酶原Ⅱ和AFP异质体有助于诊断AFP阴性HCC。如果采取接种乙型肝炎疫苗、抗病毒治疗等合理措施,可以预防HCC发生。慢性乙型肝炎抗病毒治疗的长远目标在于减少并发症发生,包括肝硬化甚至HCC。核苷类药物抗病毒治疗可有效抑制病毒复制,但无法根除肝细胞核内的cccDNA,治愈乙型肝炎仍然迫在眉睫。综述了HBV相关HCC的流行病学、危险因素、筛查方法和预防策略。
Hepatocellular carcinoma( HCC) is a leading cause of cancer-related death worldwide and hepatitis B virus( HBV) infection isone of most important risk factors for HCC. The development of HBV-related HCC involves a complex interaction between host and virus,and related risk factors include HBV viral load,HBeAg,and host susceptibility. Screening methods for HCC include radiological examina-tion such as ultrasound and serological markers such as α-fetoprotein,and protein induced by vitamin K antagonist-II and alpha-fetopro-tein( AFP) variants may help with the diagnosis of AFP-negative HCC. Appropriate measures such as HBV vaccination and antiviral thera-py can help to prevent HCC. The long-term goal of antiviral therapy for chronic hepatitis B is to reduce complications such as liver cirrhosisand HCC. nucleos( t) ide analogues can effectively inhibit replication of virus,but they cannot eradicate covalently closed circular DNA inthe nucleus of hepatocytes. There is still an urgent need for a cure for hepatitis B. This article reviews the epidemiology,risk factors,screening methods,and preventive strategies for HBV-related HCC.
Hepatocellular carcinoma( HCC) is a leading cause of cancer-related death worldwide and hepatitis B virus( HBV) infection isone of most important risk factors for HCC. The development of HBV-related HCC involves a complex interaction between host and virus,and related risk factors include HBV viral load,HBeAg,and host susceptibility. Screening methods for HCC include radiological examina-tion such as ultrasound and serological markers such as α-fetoprotein,and protein induced by vitamin K antagonist-II and alpha-fetopro-tein( AFP) variants may help with the diagnosis of AFP-negative HCC. Appropriate measures such as HBV vaccination and antiviral thera-py can help to prevent HCC. The long-term goal of antiviral therapy for chronic hepatitis B is to reduce complications such as liver cirrhosisand HCC. nucleos( t) ide analogues can effectively inhibit replication of virus,but they cannot eradicate covalently closed circular DNA inthe nucleus of hepatocytes. There is still an urgent need for a cure for hepatitis B. This article reviews the epidemiology,risk factors,screening methods,and preventive strategies for HBV-related HCC.
引文
[1] LIN CL,KAO JH. Hepatitis B virus genotypes and variants[J]. Cold Spring Harb Perspect Med,2015,5(5):a021436.
[2] MACLACHLAN JH,COWIE BC. Hepatitis B virus epidemiolo-gy[J]. Cold Spring Harb Perspect Med,2015,5(5):a021410.
[3] SCHWEITZER A,HORN J,MIKOLAJCZYK RT,et al. Estima-tions of worldwide prevalence of chronic hepatitis B virus infec-tion:A systematic review of data published between 1965 and2013[J]. Lancet,2015,386(10003):1546-1555.
[4] PETRUZZIELLO A. Epidemiology of hepatitis B Virus(HBV)and hepatitis C virus(HCV)related hepatocellular carcinoma[J]. Open Virol J,2018,12:26-32.
[5] WANG SH,YEH SH,LIN WH,et al. Estrogen receptor alpharepresses transcription of HBV genes via interaction with hepa-tocyte nuclear factor 4alpha[J]. Gastroenterology,2012,142(4):989-998.
[6] FENG H,CHENG ASL,TSANG DP,et al. Cell cycle-relatedkinase is a direct androgen receptor-regulated gene thatdrivesβ-catenin/T cell factor-dependent hepatocarcinogen-esis[J]. J Clin Invest,2011,121(8):3159-3175.
[7] CHEN DS. Fighting against viral hepatitis:Lessons from Tai-wan[J]. Hepatology,2011,54(2):381-392.
[8] MARENGO A,ROSSO C,BUGIANESI E. Liver cancer:Con-nections with obesity,fatty liver,and cirrhosis[J]. Annu RevMed,2016,67:103-117.
[9] FORNER A,REIG M,BRUIX J. Hepatocellular carcinoma[J].Lancet,2018,391(10127):1301-1314.
[10] FRANCESCHI S,MONTELLA M,POLESEL J,et al. Hepatitisviruses,alcohol,and tobacco in the etiology of hepatocellularcarcinoma in Italy[J]. Cancer Epidemiol Biomarkers Prev,2006,15(4):683-689.
[11] BALOGH J,VICTOR D 3rd,ASHAM EH,et al. Hepatocellularcarcinoma:A review[J]. J Hepatocell Carcinoma,2016,3:41-53.
[12] Crissien AM,Frenette C. Current management of hepatocellu-lar carcinoma[J]. Gastroenterol Hepatol,2014,10(3):153-161.
[13] CHEN CJ,YANG HI,SU J,et al. Risk of hepatocellular carci-noma across a biological gradient of serum hepatitis B virusDNA level[J]. JAMA,2006,295(1):65-73.
[14] MCMAHON BJ. The natural history of chronic hepatitis B virusinfection[J]. Hepatology,2009,49(5 Suppl):s45-s55.
[15] SUNG WK,ZHENG H,LI S,et al. Genome-wide survey ofrecurrent HBV integration in hepatocellular carcinoma[J]. NatGenet,2012,44(7):765-769.
[16] PARK YM,JANG JW,YOO SH,et al. Combinations of eightkey mutations in the X/preC region and genomic activity ofhepatitis B virus are associated with hepatocellular carcinoma[J]. J Viral Hepat,2014,21(3):171-177.
[17] DONATO F,TAGGER A,GELATTI U,et al. Alcohol and hep-atocellular carcinoma:The effect of lifetime intake and hepatitisvirus infections in men and women[J]. Am J Epidemiol,2002,155(4):321-323.
[18] XU HZ,LIU YP,GULENG B,et al. Hepatitis B virus-relatedhepatocellular carcinoma:Pathogenic mechanisms and noveltherapeutic interventions[J]. Gastrointest Tumors,2014,1(3):135-145.
[19] TOYODA H,KUMADA T,TADA T,et al. Risk factors of hepa-tocellular carcinoma development in non-cirrhotic patientswith sustained virologic response for chronic hepatitis C virusinfection[J]. J Gastroenterol Hepatol,2015,30(7):1183-1189.
[20] ZHANG XM,WEI MJ,XU ZJ,et al. Pattern of serumα-fetalprotein,intereleukin-6 and Golgi protein 73 expressed in liverdiseases and their diagnostic value on hepatocellular carcino-ma[J/CD]. Chin J Exp Clin Infect Dis:Electronic Edition,2017,11(4):339-344.(in Chinese)张小曼,魏梅娟,许正锯,等.血清甲胎蛋白、白细胞介素-6和高尔基体蛋白73在肝脏疾病中的表达特点及其对肝细胞癌的诊断价值[J/CD].中华实验和临床感染病杂志:电子版,2017,11(4):339-344.
[21] MCMAHON BJ,BULKOW L,HARPSTER A,et al. Screeningfor hepatocellular carcinoma in Alaska Natives infected withchronic hepatitis B:A 16-year population-based study[J].Hepatology,2000,32(4):842-846.
[22] JANG ES,JEONG SH,KIM JW,et al. Diagnostic perform-ance of alpha-fetoprotein,protein induced by vitamin K ab-sence,osteopontin,dickkopf-1 and its combinations for hep-atocellular carcinoma[J]. PLo S One, 2016, 11(3):e0151069.
[23] KANG XY,YIN ZF,QIAN HH,et al. Correlation between ser-um alpha-fetoprotein variantlevels in patients with hepatocel-lular carcinoma and the presence of alpha-fetoprotein mR-NAin the circulating blood[J]. Chin J Hepatol,2003,11(1):17-19.(in Chinese)康晓燕,殷正丰,钱海华,等.肝癌患者外周血甲胎蛋白异质体和转录物含量的相关分析[J].中华肝脏病杂志,2003,11(1):17-19.
[24] ZHU R,YANG J,XU L,et al. Diagnostic performance of des-γ-carboxy prothrombin for hepatocellular carcinoma:Ameta-analysis[J]. Gastroenterol Res Pract,2014,2014:529314.
[25] SONG P,FENG X,INAGAKI Y,et al. Clinical utility of simultane-ous measurement of alpha-fetoprotein and des-γ-carboxyprothrombin for diagnosis of patients with hepatocellular carcino-ma in China:A multi-center case-controlled study of 1,153subjects[J]. Biosci Trends,2014,8(5):266-273.
[26] LU FM. Serological diagnosis of hepatocellular carcinoma:Chal-lenges and opportunities[J]. J Clin Hepatol,2017,33(7):1262-1265.(in Chinese)鲁凤民.肝细胞癌的血清学诊断———挑战与希望同在[J].临床肝胆病杂志,2017,33(7):1262-1265.
[27] MOSSAD NA,MAHMOUD EH,OSMAN EA,et al. Evaluationof squamous cell carcinoma antigen-immunoglobulin M com-plex(SCCA-IGM)and alpha-L-fucosidase(AFU)as no-vel diagnostic biomarkers for hepatocellular carcinoma[J].Tumour Biol,2014,35(11):11559-11564.
[28] PARK SJ,LEE SK,LIM CR,et al. Heme oxygenase-1/car-bon monoxide axis suppresses transforming growth factor-beta1-induced growth inhibition by increasing ERK1/2-me-diated phosphorylation of Smad3 at Thr-179 in human hepa-tocellular carcinoma cell lines[J]. Biochem Biophys Res Com-mun,2018,498(3):609-615.
[29] BOLONDI L,SOFIA S,SIRINGO S,et al. Surveillance pro-gramme of cirrhotic patients for early diagnosis and treatmentof hepatocellular carcinoma:A cost effectiveness analysis[J].Gut,2001,48(2):251-259.
[30] ZHANG BH,YANG BH,TANG ZY. Randomized controlled tri-al of screening for hepatocellular carcinoma[J]. J Cancer ResClin Oncol,2004,130(7):417-422.
[31] CHANG MH,YOU SL,CHEN CJ,et al. Long-term effects ofhepatitis B immunization of infants in preventing liver cancer[J]. Gastroenterology,2016,151(3):472-480.
[32] LIN CL,KAO JH. Review article:Novel therapies for hepatitisB virus cure-advances and perspectives[J]. Aliment Phar-macol Ther,2016,44(3):213-222.
[33] YUAN G,HU AR,HU YR,et al. Clinical effect of entecavirand adefovir dipivoxil in treatment of compensated hepatitis Bcirrhosis and long-term prognosis[J]. Chin J Clin PharmacolTher,2018,23(2):170-174.(in Chinese)袁刚,胡爱荣,胡耀仁,等.恩替卡韦和阿德福韦酯治疗代偿期乙肝肝硬化临床疗效及远期预后[J].中国临床药理学与治疗学,2018,23(2):170-174.
[34] ZHANG QQ,AN X,LIU YH,et al. Long-term nucleos(t)ideanalogues therapy for adults with chronic hepatitis B reducesthe risk of long-term complications:A meta-analysis[J].Virol J,2011,8:72.
[35] LAI CL,YUEN MF. Prevention of hepatitis B virus-relatedhepatocellular carcinoma with antiviral therapy[J]. Hepatolo-gy,2013,57(1):399-408.
[36] DARGAN A,WONG SY,COBEN R,et al. Persistent risk forhepatocellular carcinoma after more than a decade of suc-cessful hepatitis B virus suppression[J]. Minerva Gastroen-terol Dietol,2017,63(1):74-76.
[37] TAVAKOLPOUR S,MIRSAFAEI HS,ELKAEI BEHJATI S,et al.Toward cure chronic hepatitis B infection and hepatocellularcarcinoma prevention:Lessons learned from nucleos(t)ideanalogues therapy[J]. Immunol Lett,2017,190:206-212.
[38] SU TH,TSENG TC,KAO JH. HCC risk in patients with HBV-related cirrhosis receiving NA therapy:Is HCC prevented ordelayed?[J]. Hepatology,2018,67(4):1634-1635.
[39] SASAKI K,SHINDOH J,NISHIOKA Y,et al. Impact of viral e-tiology on postoperative de novo recurrence after hepatectomyfor hepatocellular carcinoma in cirrhotic patients[J]. J Gas-trointest Surg,2017,21(3):487-495.
[40] SUN P,DONG X,CHENG X,et al. Nucleot(s)ide analoguesfor hepatitis B virus-related hepatocellular carcinoma aftercurative treatment:A systematic review and meta-analysis[J]. PLo S One,2014,9(7):e102761.
[41] LEE PC,YEH CM,HU YW,et al. Antiplatelet therapy is asso-ciated with a better prognosis for patients with hepatitis B virus-related hepatocellular carcinoma after liver resection[J].Ann Surg Oncol,2016,23(Suppl 5):874-883.
[2] MACLACHLAN JH,COWIE BC. Hepatitis B virus epidemiolo-gy[J]. Cold Spring Harb Perspect Med,2015,5(5):a021410.
[3] SCHWEITZER A,HORN J,MIKOLAJCZYK RT,et al. Estima-tions of worldwide prevalence of chronic hepatitis B virus infec-tion:A systematic review of data published between 1965 and2013[J]. Lancet,2015,386(10003):1546-1555.
[4] PETRUZZIELLO A. Epidemiology of hepatitis B Virus(HBV)and hepatitis C virus(HCV)related hepatocellular carcinoma[J]. Open Virol J,2018,12:26-32.
[5] WANG SH,YEH SH,LIN WH,et al. Estrogen receptor alpharepresses transcription of HBV genes via interaction with hepa-tocyte nuclear factor 4alpha[J]. Gastroenterology,2012,142(4):989-998.
[6] FENG H,CHENG ASL,TSANG DP,et al. Cell cycle-relatedkinase is a direct androgen receptor-regulated gene thatdrivesβ-catenin/T cell factor-dependent hepatocarcinogen-esis[J]. J Clin Invest,2011,121(8):3159-3175.
[7] CHEN DS. Fighting against viral hepatitis:Lessons from Tai-wan[J]. Hepatology,2011,54(2):381-392.
[8] MARENGO A,ROSSO C,BUGIANESI E. Liver cancer:Con-nections with obesity,fatty liver,and cirrhosis[J]. Annu RevMed,2016,67:103-117.
[9] FORNER A,REIG M,BRUIX J. Hepatocellular carcinoma[J].Lancet,2018,391(10127):1301-1314.
[10] FRANCESCHI S,MONTELLA M,POLESEL J,et al. Hepatitisviruses,alcohol,and tobacco in the etiology of hepatocellularcarcinoma in Italy[J]. Cancer Epidemiol Biomarkers Prev,2006,15(4):683-689.
[11] BALOGH J,VICTOR D 3rd,ASHAM EH,et al. Hepatocellularcarcinoma:A review[J]. J Hepatocell Carcinoma,2016,3:41-53.
[12] Crissien AM,Frenette C. Current management of hepatocellu-lar carcinoma[J]. Gastroenterol Hepatol,2014,10(3):153-161.
[13] CHEN CJ,YANG HI,SU J,et al. Risk of hepatocellular carci-noma across a biological gradient of serum hepatitis B virusDNA level[J]. JAMA,2006,295(1):65-73.
[14] MCMAHON BJ. The natural history of chronic hepatitis B virusinfection[J]. Hepatology,2009,49(5 Suppl):s45-s55.
[15] SUNG WK,ZHENG H,LI S,et al. Genome-wide survey ofrecurrent HBV integration in hepatocellular carcinoma[J]. NatGenet,2012,44(7):765-769.
[16] PARK YM,JANG JW,YOO SH,et al. Combinations of eightkey mutations in the X/preC region and genomic activity ofhepatitis B virus are associated with hepatocellular carcinoma[J]. J Viral Hepat,2014,21(3):171-177.
[17] DONATO F,TAGGER A,GELATTI U,et al. Alcohol and hep-atocellular carcinoma:The effect of lifetime intake and hepatitisvirus infections in men and women[J]. Am J Epidemiol,2002,155(4):321-323.
[18] XU HZ,LIU YP,GULENG B,et al. Hepatitis B virus-relatedhepatocellular carcinoma:Pathogenic mechanisms and noveltherapeutic interventions[J]. Gastrointest Tumors,2014,1(3):135-145.
[19] TOYODA H,KUMADA T,TADA T,et al. Risk factors of hepa-tocellular carcinoma development in non-cirrhotic patientswith sustained virologic response for chronic hepatitis C virusinfection[J]. J Gastroenterol Hepatol,2015,30(7):1183-1189.
[20] ZHANG XM,WEI MJ,XU ZJ,et al. Pattern of serumα-fetalprotein,intereleukin-6 and Golgi protein 73 expressed in liverdiseases and their diagnostic value on hepatocellular carcino-ma[J/CD]. Chin J Exp Clin Infect Dis:Electronic Edition,2017,11(4):339-344.(in Chinese)张小曼,魏梅娟,许正锯,等.血清甲胎蛋白、白细胞介素-6和高尔基体蛋白73在肝脏疾病中的表达特点及其对肝细胞癌的诊断价值[J/CD].中华实验和临床感染病杂志:电子版,2017,11(4):339-344.
[21] MCMAHON BJ,BULKOW L,HARPSTER A,et al. Screeningfor hepatocellular carcinoma in Alaska Natives infected withchronic hepatitis B:A 16-year population-based study[J].Hepatology,2000,32(4):842-846.
[22] JANG ES,JEONG SH,KIM JW,et al. Diagnostic perform-ance of alpha-fetoprotein,protein induced by vitamin K ab-sence,osteopontin,dickkopf-1 and its combinations for hep-atocellular carcinoma[J]. PLo S One, 2016, 11(3):e0151069.
[23] KANG XY,YIN ZF,QIAN HH,et al. Correlation between ser-um alpha-fetoprotein variantlevels in patients with hepatocel-lular carcinoma and the presence of alpha-fetoprotein mR-NAin the circulating blood[J]. Chin J Hepatol,2003,11(1):17-19.(in Chinese)康晓燕,殷正丰,钱海华,等.肝癌患者外周血甲胎蛋白异质体和转录物含量的相关分析[J].中华肝脏病杂志,2003,11(1):17-19.
[24] ZHU R,YANG J,XU L,et al. Diagnostic performance of des-γ-carboxy prothrombin for hepatocellular carcinoma:Ameta-analysis[J]. Gastroenterol Res Pract,2014,2014:529314.
[25] SONG P,FENG X,INAGAKI Y,et al. Clinical utility of simultane-ous measurement of alpha-fetoprotein and des-γ-carboxyprothrombin for diagnosis of patients with hepatocellular carcino-ma in China:A multi-center case-controlled study of 1,153subjects[J]. Biosci Trends,2014,8(5):266-273.
[26] LU FM. Serological diagnosis of hepatocellular carcinoma:Chal-lenges and opportunities[J]. J Clin Hepatol,2017,33(7):1262-1265.(in Chinese)鲁凤民.肝细胞癌的血清学诊断———挑战与希望同在[J].临床肝胆病杂志,2017,33(7):1262-1265.
[27] MOSSAD NA,MAHMOUD EH,OSMAN EA,et al. Evaluationof squamous cell carcinoma antigen-immunoglobulin M com-plex(SCCA-IGM)and alpha-L-fucosidase(AFU)as no-vel diagnostic biomarkers for hepatocellular carcinoma[J].Tumour Biol,2014,35(11):11559-11564.
[28] PARK SJ,LEE SK,LIM CR,et al. Heme oxygenase-1/car-bon monoxide axis suppresses transforming growth factor-beta1-induced growth inhibition by increasing ERK1/2-me-diated phosphorylation of Smad3 at Thr-179 in human hepa-tocellular carcinoma cell lines[J]. Biochem Biophys Res Com-mun,2018,498(3):609-615.
[29] BOLONDI L,SOFIA S,SIRINGO S,et al. Surveillance pro-gramme of cirrhotic patients for early diagnosis and treatmentof hepatocellular carcinoma:A cost effectiveness analysis[J].Gut,2001,48(2):251-259.
[30] ZHANG BH,YANG BH,TANG ZY. Randomized controlled tri-al of screening for hepatocellular carcinoma[J]. J Cancer ResClin Oncol,2004,130(7):417-422.
[31] CHANG MH,YOU SL,CHEN CJ,et al. Long-term effects ofhepatitis B immunization of infants in preventing liver cancer[J]. Gastroenterology,2016,151(3):472-480.
[32] LIN CL,KAO JH. Review article:Novel therapies for hepatitisB virus cure-advances and perspectives[J]. Aliment Phar-macol Ther,2016,44(3):213-222.
[33] YUAN G,HU AR,HU YR,et al. Clinical effect of entecavirand adefovir dipivoxil in treatment of compensated hepatitis Bcirrhosis and long-term prognosis[J]. Chin J Clin PharmacolTher,2018,23(2):170-174.(in Chinese)袁刚,胡爱荣,胡耀仁,等.恩替卡韦和阿德福韦酯治疗代偿期乙肝肝硬化临床疗效及远期预后[J].中国临床药理学与治疗学,2018,23(2):170-174.
[34] ZHANG QQ,AN X,LIU YH,et al. Long-term nucleos(t)ideanalogues therapy for adults with chronic hepatitis B reducesthe risk of long-term complications:A meta-analysis[J].Virol J,2011,8:72.
[35] LAI CL,YUEN MF. Prevention of hepatitis B virus-relatedhepatocellular carcinoma with antiviral therapy[J]. Hepatolo-gy,2013,57(1):399-408.
[36] DARGAN A,WONG SY,COBEN R,et al. Persistent risk forhepatocellular carcinoma after more than a decade of suc-cessful hepatitis B virus suppression[J]. Minerva Gastroen-terol Dietol,2017,63(1):74-76.
[37] TAVAKOLPOUR S,MIRSAFAEI HS,ELKAEI BEHJATI S,et al.Toward cure chronic hepatitis B infection and hepatocellularcarcinoma prevention:Lessons learned from nucleos(t)ideanalogues therapy[J]. Immunol Lett,2017,190:206-212.
[38] SU TH,TSENG TC,KAO JH. HCC risk in patients with HBV-related cirrhosis receiving NA therapy:Is HCC prevented ordelayed?[J]. Hepatology,2018,67(4):1634-1635.
[39] SASAKI K,SHINDOH J,NISHIOKA Y,et al. Impact of viral e-tiology on postoperative de novo recurrence after hepatectomyfor hepatocellular carcinoma in cirrhotic patients[J]. J Gas-trointest Surg,2017,21(3):487-495.
[40] SUN P,DONG X,CHENG X,et al. Nucleot(s)ide analoguesfor hepatitis B virus-related hepatocellular carcinoma aftercurative treatment:A systematic review and meta-analysis[J]. PLo S One,2014,9(7):e102761.
[41] LEE PC,YEH CM,HU YW,et al. Antiplatelet therapy is asso-ciated with a better prognosis for patients with hepatitis B virus-related hepatocellular carcinoma after liver resection[J].Ann Surg Oncol,2016,23(Suppl 5):874-883.