J Korean Med Sci.  2006 Apr;21(2):279-283. 10.3346/jkms.2006.21.2.279.

The Degrees of Hepatocyte Cytoplasmic Expression of Hepatitis B Core Antigen correlate with Histologic Activity of Liver Disease in the Young Patients with Chronic Hepatitis B Infection

• Kim TH
• Cho EY
• Oh HJ
• Choi CS
• Kim JW
• Moon HB
• Kim HC

• KMID: 1781835
• DOI: http://doi.org/10.3346/jkms.2006.21.2.279

Abstract

Subcellular localizaton of HBcAg have been found to be related to the activity of liver disease and HBV replication. The aim of this study was to determine whether the degree of expression of HBcAg in the hepatocyte nucleus and cytoplasm reflects the level of viral replication and histological activity in chronic HBV infection. A total of 102 patients with biopsy proven chronic hepatitis B were included. There was a highly significant correlation between the levels of HBV DNA in serum and the degree of expression of HBcAg in the nucleus for HBeAg-positive(p=0.000) and negative patients(p=0.04). There was a highly significant, correlation between the degrees of expression of HBcAg in hepatocyte cytoplasm and histologic activities (p<0.01) for HBeAg-positive patients. The degrees of expression of HBcAg in the hepatocyte cytoplasm correlated positively with the lobular activities (p<0.01), but not correlated with the portal activity and fibrosis for HBeAg-negative patients. In conclusion, in the young patients with chronic B viral hepatitis, the degree of expression of HBcAg in the hepatocyte nucleus may affect viral load, and the degree of expression of HBcAg in the hepatocyte cytoplasm may affect histologic activities of liver disease.

Keyword

Hepatitis B Core Antigen; Hepatitis Be Antigens; HBV DNA; Hepatitits B virus

MeSH Terms

Male
Liver/pathology/virology
Humans
Hepatocytes/pathology/*virology
Hepatitis B, Chronic/*pathology/*virology
Hepatitis B e Antigens/metabolism
Hepatitis B Core Antigens/*metabolism
DNA, Viral/blood
Cytoplasm/virology
Cell Nucleus/virology
Adult
Adolescent

Reference

1. Lee WM. Hepatitis B virus infection. N Engl J Med. 1997. 337:1733–1745.

2. Okada K, Kamiyama I, Inomata M, Imai M, Miyakawa Y. e antigen and anti-e in the serum of asymptomatic carrier mothers as indicators of positive and negative transmission of hepatitis B virus to their infants. N Engl J Med. 1976. 294:746–749.

3. Stevens CE, Neurath RA, Beasley RP, Szmuness W. HBeAg and anti-HBe detection by radioimmunoassay: Correlation with vertical transmission of hepatitis B virus in Taiwan. J Med Virol. 1979. 3:237–241.

4. Hadziyannis SJ, Lieberman HM, Karvountzis GG, Shafritz DA. Analysis of liver disease, nuclear HBcAg, viral replication, and hepatitis B virus DNA in liver and serum of HBeAg Vs. anti-HBe positive carriers of hepatitis B virus. Hepatology. 1983. 3:656–662.

5. Chu CM, Liaw YF. Membrane staining for hepatitis B surface antigen on hepatocytes: a sensitive and specific marker of active viral replication in hepatitis B. J Clin Pathol. 1995. 48:470–473.

6. Chu CM, Liaw YF. Intrahepatic distribution of hepatitis B surface and core antigens in chronic hepatitis B virus infection. Hepatocyte with cytoplasmic/membranous hepatitis B core antigen as a possible target for immune hepatocytolysis. Gastroenterology. 1987. 92:220–225.

7. Hsu HC, Su IJ, Lai MY, Chen DS, Chang MH, Chang SM, Sung JL. Biologic and prognostic significance of hepatocyte hepatitis B core antigen expressions in the natural course of chronic hepatitis B virus infection. J Hepatol. 1987. 5:45–50.

8. ter Borg F, ten Kate FJ, Cuypers HT, Leentvaar-Kuijpers A, Oosting J, Wertheim-van Dillen PM, Honkoop P, Rasch MC, de Man RA, van Hattum J, Chamuleau RA, Reesink HW, Jones EA. Relation between laboratory test results and histological hepatitis activity in individuals positive for hepatitis B surface antigen and antibodies to hepatitis B e antigen. Lancet. 1998. 351:1914–1918.

9. Chan HL, Hui Y, Leung NW, Ching JY, Chan FK, Sung JJ. Risk factors for active liver disease in HBeAg-negative chronic hepatitis B virus-infected patients. Am J Gastroenterol. 2000. 95:3547–3551.

10. Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology. 1994. 19:1513–1520.

11. Mangia A, Chung YH, Hoofnagle JH, Birkenmeyer L, Mushahwar I, Di Bisceglie AM. Pathogenesis of chronic liver disease in patients with chronic hepatitis B virus infection without serum HBeAg. Dig Dis Sci. 1996. 41:2447–2452.

12. Chu CM, Yeh CT, Sheen IS, Liaw YF. Subcellular localization of hepatitis B core antigen in relation to hepatocyte regeneration in chronic hepatitis B. Gastroenterology. 1995. 109:1926–1932.

13. Chu CM, Yeh CT, Chien RN, Sheen IS, Liaw YF. The degrees of hepatocyte nuclear but not cytoplasmic expression of hepatitis B core antigen reflects the level of viral replication in chronic hepatitis B virus infection. J Clin Microbiol. 1997. 35:102–105.

14. Thomas HC, Carman WF. The host immune response may be responsible for selection of envelope and precore/core variants of HBV. Prog Liver Dis. 1992. 10:239–251.

15. Yeh CT, Liaw YF, Ou JH. The arginine-rich domain of hepatitis B virus precore and core proteins contains a signal for nuclear transport. J Virol. 1990. 64:6141–6147.

16. Bock CT, Schranz P, Schroder CH, Zentgraf H. Hepatitis B virus genome is organized into nucleosomes in the nucleus of the infected cell. Virus Genes. 1994. 8:215–229.

17. Hirsch RC, Loeb DD, Pollack JR, Ganem D. cis-Acting sequences required for encapsidation of duck hepatitis B virus pregenomic RNA. J Virol. 1991. 65:3309–3316.

18. Tuttleman JS, Pourcel C, Summers J. Formation of the pool of covalently closed circular viral DNA in hepadnavirus-infected cells. Cell. 1986. 47:451–460.

19. Wu TT, Coates L, Aldrich CE, Summers J, Mason WS. In hepatocytes infected with duck hepatitis B virus, the template for viral RNA synthesis is amplified by an intracellular pathway. Virology. 1990. 175:255–261.

20. Hsu YS, Chien RN, Yeh CT, Sheen IS, Chiou HY, Chu CM, Liaw YF. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B. Hepatology. 2002. 35:1522–1527.

21. Yuen MF, Yuan HJ, Hui CK, Wong DK, Wong WM, Chan AO, Wong BC, Lai CL. A large population study of spontaneous HBeAg seroconversion and acute exacerbation of chronic hepatitis B infection: implications for antiviral therapy. Gut. 2003. 52:416–419.

22. Lindh M, Horal P, Dhillon AP, Norkrans G. Hepatitis B virus DNA levels, precore mutations, genotypes and histological activity in chronic hepatitis B. J Viral Hepat. 2000. 7:258–267.

23. Karayiannis P, Fowler MJ, Lok AS, Greenfield C, Monjardino J, Thomas HC. Detection of serum HBV-DNA by molecular hybridisation. Correlation with HBeAg/anti-HBe status, racial origin, liver histology and hepatocellular carcinoma. J Hepatol. 1985. 1:99–106.

24. Lindh M, Gustavson C, Mardberg K, Norkrans G, Dhillon AP, Horal P. Mutation of nucleotide 1762 in the core promoter region during hepatitis B e seroconversion and its relation to liver damage in hepatitis B e antigen carriers. J Med Virol. 1998. 55:185–190.

25. Kidd-Ljunggren K, Oberg M, Kidd AH. Hepatitis B virus X gene 1751-1764 mutations: implications for HBeAg status and disease. J Gen Virol. 1997. 78:1469–1478.

26. Li J, Buckwold VE, Hon MW, Ou JH. Mechanism of suppression of hepatitis B virus precore RNA transcription by a frequent double mutation. J Virol. 1999. 73:1239–1244.

27. Buckwold VE, Xu Z, Chen M, Yen TS, Ou JH. Effects of a naturally occurring mutation in the hepatitis B virus basal core promoter on precore gene expression and viral replication. J Virol. 1996. 70:5845–5851.

28. Wu PC, Lau JY, Lau TK, Lau SK, Lai CL. Relationship between intrahepatic expression of hepatitis B viral antigens and histology in Chinese patients with chronic hepatitis B virus infection. Am J Clin Pathol. 1993. 100:648–653.