본문 바로가기
KERD
논문KCI 등재

Three heads are better than two: Hepatitis B core-related antigen as a new predictor of hepatitis B virus-related hepatocellular carcinoma

Jia-Horng Kao|Tai-Chung Tseng|Jer-Wei Wu
대한간학회 (The korean Association for the Study of the Liver)|2021.10|Clinical and Molecular Hepatology|제27권 제4호|pp. 524-534|DOI 10.3350/cmh.2021.0012

2

조회

0

다운로드

7

인용

0

참고문헌

키워드

BiomarkerHepatocellular carcinomaHepatitis B virus

초록

Patients with chronic hepatitis B virus (HBV) infection are at risk of developing hepatocellular carcinoma (HCC), and serum markers reflecting viral replication are potential predictors for HCC development. Besides the levels of serum HBV DNA and hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg) quantification is an emerging serological marker for viral replication. Unlike HBV DNA and HBsAg, HBcrAg is a covalently closed circular DNA-derived protein marker, consisting of hepatitis B e antigen (HBeAg), p22cr, and hepatitis B core antigen. In treatment-naïve HBV patients, higher HBcrAg levels are shown to be associated with an increased risk of HCC in several studies. More importantly, HBcrAg may complement HBV DNA level to predict HCC development. For example, an Asian treatmentnaïve cohort study’s data showed that HBcrAg level of 4 log U/mL was effective to stratify HCC risk in HBeAg-negative patients with intermediate viral loads, who may not need antiviral therapy because of the low to moderate risk of HCC. In patients receiving prolonged nucleos(t)ide analogue with profound viral suppression, most data indicated that HBV DNA and HBsAg levels no longer serve as HCC predictors. However, several studies suggested on-treatment HBcrAg levels may remain as an HCC predictor. In summary, HBcrAg level can be a useful biomarker for treatment-naïve patients, but its value in on-treatment patients needs validation. The next challenge is how to combine HBcrAg with the other viral markers to construct a better HCC prediction model, optimizing the management of HBV patients.

Abstract

Patients with chronic hepatitis B virus (HBV) infection are at risk of developing hepatocellular carcinoma (HCC), and serum markers reflecting viral replication are potential predictors for HCC development. Besides the levels of serum HBV DNA and hepatitis B surface antigen (HBsAg), hepatitis B core-related antigen (HBcrAg) quantification is an emerging serological marker for viral replication. Unlike HBV DNA and HBsAg, HBcrAg is a covalently closed circular DNA-derived protein marker, consisting of hepatitis B e antigen (HBeAg), p22cr, and hepatitis B core antigen. In treatment-naïve HBV patients, higher HBcrAg levels are shown to be associated with an increased risk of HCC in several studies. More importantly, HBcrAg may complement HBV DNA level to predict HCC development. For example, an Asian treatmentnaïve cohort study’s data showed that HBcrAg level of 4 log U/mL was effective to stratify HCC risk in HBeAg-negative patients with intermediate viral loads, who may not need antiviral therapy because of the low to moderate risk of HCC. In patients receiving prolonged nucleos(t)ide analogue with profound viral suppression, most data indicated that HBV DNA and HBsAg levels no longer serve as HCC predictors. However, several studies suggested on-treatment HBcrAg levels may remain as an HCC predictor. In summary, HBcrAg level can be a useful biomarker for treatment-naïve patients, but its value in on-treatment patients needs validation. The next challenge is how to combine HBcrAg with the other viral markers to construct a better HCC prediction model, optimizing the management of HBV patients.

참고문헌 (44)

  1. World Health Organization(WHO), "Global Hepatitis Report 2017" (2017), WHO
  2. Tseng TC, "Elimination of hepatitis B : is it a mission possible?", BMC Med, 15, pp.53~ (2017)
  3. Chen CJ, "Risk of hepatocellular carcinoma across a biological gradient of serum hepatitis B virus DNA level", JAMA, 295, pp.65~73 (2006)
  4. Tseng TC, "High levels of hepatitis B surface antigen increase risk of hepatocellular carcinoma in patients with low HBV load", Gastroenterology, 142, pp.1140~1149 (2012)
  5. Liu J, "Serum levels of hepatitis B surface antigen and DNA can predict inactive carriers with low risk of disease progression", Hepatology, 64, pp.381~389 (2016)
  6. Tada T, "HBcrAg predicts hepatocellular carcinoma development : an analysis using time-dependent receiver operating characteristics", J Hepatol, 65, pp.48~56 (2016)
  7. To WP, "Hepatitis B core-related antigen levels after HBeAg seroconversion is associated with the development of hepatocellular carcinoma", J Viral Hepat, 26, pp.1473~1480 (2019)
  8. Tseng TC, "High level of hepatitis B core-related antigen associated with increased risk of hepatocellular carcinoma in patients with chronic HBV infection of intermediate viral load", Gastroenterology, 157, pp.1518~1529 (2019)
  9. Takako Inoue, "Novel biomarkers for the management of chronic hepatitis B", Clinical and Molecular Hepatology, 26(3), pp.261~279 (2020), 대한간학회[DOI]
  10. Dandri M, "New insight in the pathobiology of hepatitis B virus infection", Gut, 61(Suppl 1), pp.i6~i17 (2012)
  11. Kimura T, "Hepatitis B virus DNA-negative dane particles lack core protein but contain a 22-kDa precore protein without C-terminal argininerich domain", J Biol Chem, 280, pp.21713~21719 (2005)
  12. Ganem D, "Fields Virology", pp.2923~2970 (2001), Lippincott Williams & Wilkins
  13. Lok AS, "Predictive value of precore hepatitis B virus mutations in spontaneous and interferon-induced hepatitis B e antigen clearance", Hepatology, 21, pp.19~24 (1995)
  14. Chang MH, "Precore stop codon mutant in chronic hepatitis B virus infection in children : its relation to hepatitis B e seroconversion and maternal hepatitis B surface antigen", J Hepatol, 28, pp.915~922 (1998)
  15. Chan HL, "Different hepatitis B virus genotypes are associated with different mutations in the core promoter and precore regions during hepatitis B e antigen seroconversion", Hepatology, 29, pp.976~984 (1999)
  16. Yuen MF, "Relationship between the development of precore and core promoter mutations and hepatitis B e antigen seroconversion in patients with chronic hepatitis B virus", J Infect Dis, 186, pp.1335~1338 (2002)
  17. Chu CJ, "Prevalence of HBV precore", core promoter variants in the United States, 2003, pp.38, 619~628
  18. Maasoumy B, "Hepatitis B core-related antigen(HBcrAg)levels in the natural history of hepatitis B virus infection in a large European cohort predominantly infected with genotypes A and D", Clin Microbiol Infect, 21, pp.606~ (2015)
  19. Wong DK, "Hepatitis B virus core-related antigen as a surrogate marker for covalently closed circular DNA", Liver Int, 37, pp.995~1001 (2017)
  20. Kimura T, "Sensitive enzyme immunoassay for hepatitis B virus corerelated antigens and their correlation to virus load", J Clin Microbiol, 40, pp.439~445 (2002)
  21. Yoshida K, "Hepatitis B core-related antigen to indicate high viral load : systematic review and meta-analysis of 10, 397 individual participants", Clin Gastroenterol Hepatol, 19, pp.46~60 (2021)
  22. Wooddell CI, "RNAi-based treatment of chronically infected patients and chimpanzees reveals that integrated hepatitis B virus DNA is a source of HBsAg", Sci Transl Med, 9, pp.eaan0241~ (2017)
  23. Suzuki F, "Correlation between serum hepatitis B virus core-related antigen and intrahepatic covalently closed circular DNA in chronic hepatitis B patients", J Med Virol, 81, pp.27~33 (2009)
  24. Matsuzaki T, "Significance of hepatitis B virus core-related antigen and covalently closed circular DNA levels as markers of hepatitis B virus re-infection after liver transplantation", J Gastroenterol Hepatol, 28, pp.1217~1222 (2013)
  25. Testoni B, "Serum hepatitis B core-related antigen(HBcrAg)correlates with covalently closed circular DNA transcriptional activity in chronic hepatitis B patients", J Hepatol, 70, pp.615~625 (2019)
  26. Kumada T, "Effect of nucleos(t)ide analogue therapy on hepatocarcinogenesis in chronic hepatitis B patients : a propensity score analysis", J Hepatol, 58, pp.427~433 (2013)
  27. Lam YF, "Sevenyear treatment outcome of entecavir in a real-world cohort : effects on clinical parameters, HBsAg and HBcrAg levels", Clin Transl Gastroenterol, 8, pp.e125~ (2017)
  28. Hosaka T, "Impact of hepatitis B core-related antigen on the incidence of hepatocellular carcinoma in patients treated with nucleos(t)ide analogues", Aliment Pharmacol Ther, 49, pp.457~471 (2019)
  29. Honda M, "Hepatitis B virus(HBV)core-related antigen during nucleos(t)ide analog therapy is related to intra-hepatic HBV replication and development of hepatocellular carcinoma", J Infect Dis, 213, pp.1096~1106 (2016)
  30. Ando Y, "Cumulative incidence and risk factors for the development of hepatocellular carcinoma in patients with chronic hepatitis B who achieved sustained disappearance of viremia by nucleos(t)ide analog treatment", Hepatol Res, 48, pp.E240~ (2018)
  31. Liang LY, "Serum hepatitis B core-related antigen predicts hepatocellular carcinoma in hepatitis B e antigen-negative patients", J Gastroenterol, 55, pp.899~908 (2020)
  32. Yang HI, "Associations between hepatitis B virus genotype and mutants and the risk of hepatocellular carcinoma", J Natl Cancer Inst, 100, pp.1134~1143 (2008)
  33. Baptista M, "High prevalence of 1762(T)1764(A)mutations in the basic core promoter of hepatitis B virus isolated from black Africans with hepatocellular carcinoma compared with asymptomatic carriers", Hepatology, 29, pp.946~953 (1999)
  34. Kao JH, "Basal core promoter mutations of hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis B carriers", Gastroenterology, 124, pp.327~334 (2003)
  35. Liu CJ, "Role of hepatitis B viral load and basal core promoter mutation in hepatocellular carcinoma in hepatitis B carriers", J Infect Dis, 193, pp.1258~1265 (2006)
  36. Liu S, "Associations between hepatitis B virus mutations and the risk of hepatocellular carcinoma : a meta-analysis", J Natl Cancer Inst, 101, pp.1066~1082 (2009)
  37. Tseng TC, "Serum hepatitis B core-related antigen level stratifies risk of disease progression in chronic hepatitis B patients with intermediate viral load", Aliment Pharmacol Ther, 53, pp.908~918 (2021)
  38. Tada T, "Hepatitis B virus core-related antigen levels predict progression to liver cirrhosis in hepatitis B carriers", J Gastroenterol Hepatol, 33, pp.918~925 (2018)
  39. Papatheodoridis G, "PAGE-B predicts the risk of developing hepatocellular carcinoma in Caucasians with chronic hepatitis B on 5-year antiviral therapy", J Hepatol, 64, pp.800~806 (2016)
  40. Tseng TC, "Baseline mac-2 binding protein glycosylation isomer level stratifies risks of hepatocellular carcinoma in chronic hepatitis B patients with oral antiviral therapy", Liver Cancer, 9, pp.207~220 (2020)
  41. Di Bisceglie AM, "Determination of hepatitis B phenotype using biochemical and serological markers", J Viral Hepat, 24, pp.320~329 (2017)
  42. Zhou K, "Phase transition is infrequent among north American adults with e-antigen-negative chronic hepatitis B and low-level viremia", Am J Gastroenterol, 114, pp.1753~1763 (2019)
  43. Bonacci M, "Anti-viral therapy can be delayed or avoided in a significant proportion of HBeAg-negative Caucasian patients in the grey zone", Aliment Pharmacol Ther, 47, pp.1397~1408 (2018)
  44. Lee HW, "Progression of untreated minimally active chronic HBV infection compared to inactive infection", Clin Gastroenterol Hepatol, 17, pp.2808~2810 (2019)

이 간행물의 다른 논문 (11건)

Update on liver disease management during the pandemic of coronavirus disease 2019 (COVID-19): 2021 KASL guidelineJu-Yeon Cho, Young-Sun Lee, Ji Hoon Kim, Soon Sun Kim, Do Seon Song, Jeong-Hoon Lee, Korean Association for the Study of the Liverpp. 515-523Treatment of direct oral anticoagulants in patients with liver cirrhosis and portal vein thrombosisHo Soo Chun, 이민종, Hwi Young Kim, A Reum Choe, Kwon Yoo, Tae Hun Kim, 조유리pp. 535-552Recent advances in nonalcoholic fatty liver disease metabolomicsHwi Young Kimpp. 553-559Microwave thermosphere versus radiofrequency ablation for hepatocellular carcinoma: Are we approaching the time to end the debate?Man-Deuk Kimpp. 560-561Can hepatocellular carcinoma recurrence be prevented after liver transplantation?Jong Man Kimpp. 562-563
원문 보기