Download PDF
Semin Liver Dis 2006; 26(2): 153-161
DOI: 10.1055/s-2006-939753
Copyright © 2006 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Hepatocellular Carcinoma and Hepatitis B Virus

Henry Lik-Yuen Chan1 , Joseph Jao-Yiu Sung1
  • 1Institute of Digestive Diseases and Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, China
Further Information

Publication History

Publication Date:
03 May 2006 (online)

    Permissions and Reprints

ABSTRACT

Chronic hepatitis B is the most common cause of hepatocellular carcinoma (HCC) in Asia. Integration of hepatitis B virus (HBV) genome is likely an early event of carcinogenesis. The integrated HBV genome may activate neighboring cellular genes directly to offer a selective growth advantage to the liver cells. Production of hepatitis B X protein can act as a transactivator on various cellular genes for tumor development. Hepatic inflammation and cirrhosis also favors the process of carcinogenesis. Various viral factors associated with hepatocellular carcinoma development include HBV genotype, basal core promoter mutations, and high viral load. Polymorphisms at the androgen receptor-regulating genes and cytokine genes are possible host factors associated with HCC. This review article summarizes the pathogenesis of HBV-related carcinogenesis and the viral and host factors that may increase the risk of HCC development.

KEYWORDS

Hepatitis B virus - hepatocellular carcinoma - gene - mutation - DNA

REFERENCES

  • 1 Beasley R P, Lin C C, Hwang L Y et al.. Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22707 men in Taiwan.  Lancet. 1981;  2 1129-1132
    PubMedGoogle Scholar
  • 2 Hwang S J, Tong M J, Lai P P et al.. Evaluation of hepatitis B and C viral markers: clinical significance in Asian and Caucasian patients with hepatocellular carcinoma in the United States of America.  J Gastroenterol Hepatol. 1996;  11 949-954
    PubMedGoogle Scholar
  • 3 Chan H LY, Hui A Y, Wong M L et al.. Genotype C hepatitis B virus infection is associated with increased risk of hepatocellular carcinoma.  Gut. 2004;  53 1494-1498
    CrossrefPubMedGoogle Scholar
  • 4 McMahon B J, Holck P, Bulkow L et al.. Serologic and clinical outcomes of 1536 Alaska natives chronically infected with hepatitis B virus.  Ann Intern Med. 2001;  135 759-768
    CrossrefPubMedGoogle Scholar
  • 5 Liaw Y F, Tai D I, Chu C M et al.. Early detection of hepatocellular carcinoma in patients with chronic type B hepatitis: a prospective study.  Gastroenterology. 1986;  90 263-267
    PubMedGoogle Scholar
  • 6 Sherman M, Peltekian K M, Lee C. Screening for hepatocellular carcinoma in chronic carriers of hepatitis B virus: incidence and prevalence of hepatocellular carcinoma in a North American urban population.  Hepatology. 1995;  22 432-438
    CrossrefPubMedGoogle Scholar
  • 7 Liaw Y F, Chu C M, Lin D Y et al.. Age-specific prevalence and significance of hepatitis B e antigen and antibody in chronic hepatitis B virus infection in Taiwan: a comparison among asymptomatic carriers, chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma.  J Med Virol. 1984;  13 385-391
    PubMedGoogle Scholar
  • 8 Lindh M, Andersson A S, Gusdal A. Genotypes, nt 1858 variants, and geographic origin of hepatitis B virus-large-scale analysis using a new genotyping method.  J Infect Dis. 1997;  175 1285-1293
    CrossrefPubMedGoogle Scholar
  • 9 Chang M H, Chen C J, Lai M S et al.. Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children.  N Engl J Med. 1997;  336 1855-1859
    CrossrefPubMedGoogle Scholar
  • 10 McMahon B J, Bulkow L, Harpster A et al.. Screening for hepatocellular carcinoma in Alaska natives infected with chronic hepatitis B: a 16-year population-based study.  Hepatology. 2000;  32 842-846
    CrossrefPubMedGoogle Scholar
  • 11 Yuen M F, Cheng C C, Lauder I J et al.. Early detection of hepatocellular carcinoma increases the chance of treatment: Hong Kong experience.  Hepatology. 2000;  31 330-335
    CrossrefPubMedGoogle Scholar
  • 12 Gust I D. Epidemiology of hepatitis B infection in the Western Pacific and South East Asia.  Gut. 1996;  38(suppl 2) S18-S23
    PubMedGoogle Scholar
  • 13 Brechot C. Hepatitis B virus (HBV) and hepatocellular carcinoma. HBV DNA status and its implications.  J Hepatol. 1987;  4 269-279
    CrossrefPubMedGoogle Scholar
  • 14 Yamamoto T, Kajino K, Kudo M et al.. Determination of the clonal origin of multiple human hepatocellular carcinomas by cloning and polymerase chain reaction of the integrated hepatitis B virus DNA.  Hepatology. 1999;  29 1446-1452
    CrossrefPubMedGoogle Scholar
  • 15 Brechot C, Hadchouel J, Scotto M et al.. State of hepatitis B virus DNA in hepatocytes of patients with HBsAg positive and HBeAg negative liver diseases.  Proc Natl Acad Sci USA. 1981;  78 3906-3910
    PubMedGoogle Scholar
  • 16 Kam W, Rall L B, Smuckler E A et al.. Hepatitis B viral DNA in liver and serum of asymptomatic carriers.  Proc Natl Acad Sci USA. 1982;  79 7522-7526
    PubMedGoogle Scholar
  • 17 Shafritz D A, Shouval D, Sherman H et al.. Integration of hepatitis B virus DNA into the genome of liver cells in chronic liver disease and hepatocellular carcinoma.  N Engl J Med. 1981;  305 1067-1073
    PubMedGoogle Scholar
  • 18 Yasui H, Hino O, Ohtake K et al.. Clonal growth of hepatitis B virus integrated hepatocytes in cirrhotic liver nodules.  Cancer Res. 1992;  52 6810-6814
    PubMedGoogle Scholar
  • 19 Lugassy C, Bernuau J, Thiers V et al.. Sequences of hepatitis B virus DNA in the serum and liver patients wit acute benign and fulminant hepatitis.  J Infect Dis. 1987;  155 64-71
    PubMedGoogle Scholar
  • 20 Murakami Y, Minami M, Daimon Y, Okanoue T. Hepatitis B virus DNA in liver, serum, and peripheral blood mononuclear cells after the clearance of serum hepatitis B virus surface antigen.  J Med Virol. 2004;  72 203-214
    CrossrefPubMedGoogle Scholar
  • 21 Pollicino T, Squadrito G, Cerenzia G et al.. Hepatitis B virus maintains its pro-oncogenic properties in the case of occult HBV infection.  Gastroenterology. 2004;  126 102-110
    CrossrefPubMedGoogle Scholar
  • 22 Slagle B L, Zhou Y Z, Butel J S. Hepatitis B virus integration event in human chromosome 17p near the p53 gene identifies the region of the chromosome commonly deleted in virus-positive hepatocellular carcinoma.  Cancer Res. 1991;  51 49-54
    PubMedGoogle Scholar
  • 23 Buetow K H, Sheffield V C, Zhu M et al.. Low frequency of p53 mutations observed in a diverse collection of primary hepatocellular carcinomas.  Proc Natl Acad Sci USA. 1992;  89 9622-9626
    PubMedGoogle Scholar
  • 24 Aguilar F, Harris C C, Sun T et al.. Geographic variation of p53 mutational profile in nonmalignant human liver.  Science. 1994;  264 1317-1319
    PubMedGoogle Scholar
  • 25 Fujimoto Y, Hamptom L L, Wirth P J et al.. Alterations of tumor suppressor genes and allelic losses in human hepatocellular carcinomas in China.  Cancer Res. 1994;  54 281-285
    PubMedGoogle Scholar
  • 26 Murakami Y, Hayashi K, Hirohashi S, Sekya T. Aberrations of tumor suppressor p53 and retinoblastoma genes in human hepatocellular carcinoma.  Cancer Res. 1991;  51 5520-5525
    PubMedGoogle Scholar
  • 27 Nishida N, Fukuda Y, Kokuryu H et al.. Role and mutational heterogeneity of the p53 gene in hepatocellular carcinoma.  Cancer Res. 1993;  53 368-372
    PubMedGoogle Scholar
  • 28 Pineau P, Marchio A, Mattei M G et al.. Extensive analysis of duplicated-inverted hepatitis B virus integrations in human hepatocellular carcinoma.  J Gen Virol. 1998;  79 591-600
    PubMedGoogle Scholar
  • 29 Minami M, Daimon Y, Mori K et al.. Hepatitis B virus-related insertional mutagenesis in chronic hepatitis B patients as an early drastic genetic change leading to hepatocarcinogenesis.  Oncogene. 2005;  24 4340-4348
    CrossrefPubMedGoogle Scholar
  • 30 Tamori A, Yamanishi Y, Kawashima S et al.. Alteration of gene expression in human hepatocellular carcinoma with integrated hepatitis B virus DNA.  Clin Cancer Res. 2005;  11 5821-5826
    CrossrefPubMedGoogle Scholar
  • 31 Wang J, Chenivesse X, Henglein B, Brechot C. Hepatitis B virus integration in a cyclin A gene in a hepatocellular carcinoma.  Nature. 1990;  343 555-557
    PubMedGoogle Scholar
  • 32 Dejean A, Bougueleret L, Grzeschik K H, Tiollais P. Hepatitis B virus DNA integration in a sequence homologous to v-erb-A and steroid receptor genes in a hepatocellular carcinoma.  Nature. 1986;  322 70-72
    PubMedGoogle Scholar
  • 33 Murakami Y, Saigo K, Takashima H et al.. Large scaled analysis of hepatitis B virus (HBV) DNA integration in HBV related hepatocellular carcinomas.  Gut. 2005;  54 1162-1168
    CrossrefPubMedGoogle Scholar
  • 34 Horikawa I, Barrett J C. Transcriptional regulation of the telomerase hTERT gene as a target for cellular and viral oncogenic mechanisms.  Carcinogenesis. 2003;  24 1167-1176
    CrossrefPubMedGoogle Scholar
  • 35 Kim J H, You K R, Kim I H et al.. Over-expression of the ribosomal protein 1.36a gene is associated with cellular proliferation in hepatocellular carcinoma.  Hepatology. 2004;  39 129-138
    CrossrefPubMedGoogle Scholar
  • 36 Poussin K, Dienes H, Sirma H et al.. Expression of mutated hepatitis B virus X genes in human hepatocellular carcinomas.  Int J Cancer. 1999;  80 497-505
    CrossrefPubMedGoogle Scholar
  • 37 Tu H, Bonura C, Giannini C et al.. Biological impact of natural COOH-terminal deletions of hepatitis B virus X protein in hepatocellular carcinoma tissues.  Cancer Res. 2001;  61 7803-7810
    PubMedGoogle Scholar
  • 38 Wang Y, Lau S H, Sham J S et al.. Characterization of HBV integrants in 14 hepatocellular carcinoma: association of truncated X gene and hepatocellular carcinogenesis.  Oncogene. 2004;  23 142-148
    CrossrefPubMedGoogle Scholar
  • 39 Benn J, Schneider R J. Hepatitis B virus HBx protein activates Ras-GTP complex formation and establishes a Ras, Raf, MAP kinase signaling cascade.  Proc Natl Acad Sci USA. 1994;  91 10350-10354
    PubMedGoogle Scholar
  • 40 Benn J, Su F, Doria M, Schneider R J. Hepatitis B virus HBx protein induces transcription factor AP-1 by activation of extracellular signal0-regulated and c-Jun N-terminal mitogen-activated protein kinases.  J Virol. 1996;  70 4978-4985
    PubMedGoogle Scholar
  • 41 Lee Y H, Yun Y. HBx protein of hepatitis B virus activates Jak1-STAT signaling.  J Biol Chem. 1998;  273 25510-25515
    CrossrefPubMedGoogle Scholar
  • 42 Lee Y I, Kang-Park S, Do S I, Lee Y I. The hepatitis B virus-X protein activates a phosphatidylinositol 3-kinase-dependent survival signaling cascade.  J Biol Chem. 2001;  276 16969-16977
    CrossrefPubMedGoogle Scholar
  • 43 Yen T S. Hepadnaviral X protein: review of recent progress.  J Biomed Sci. 1996;  3 20-30
    CrossrefPubMedGoogle Scholar
  • 44 Lara-Pezzi E, Majano P L, Gomez-Gonzalo M et al.. The hepatitis B virus X protein up-regulates tumor necrosis factor alpha gene expression in hepatocytes.  Hepatology. 1998;  28 1013-1021
    CrossrefPubMedGoogle Scholar
  • 45 Yoo Y D, Ueda H, Park K et al.. Regulation of transforming growth factor-beta 1 expression by the hepatitis B virus (HBV) X transactivator.  J Clin Invest. 1996;  97 388-395
    CrossrefPubMedGoogle Scholar
  • 46 Elmore L W, Hancock A R, Chang S F et al.. Hepatitis B virus X protein and p53 tumor suppressor interactions in the modulation of apoptosis.  Proc Natl Acad Sci USA. 1997;  94 14707-14712
    CrossrefPubMedGoogle Scholar
  • 47 Takada S, Kaneniwa N, Tsuchida N, Koide K. Cytoplasmic retention of the p53 tumor suppressor gene product is observed in the hepatitis B virus X gene-transfected cells.  Oncogene. 1997;  15 1895-1901
    CrossrefPubMedGoogle Scholar
  • 48 Terradillos O, de La Coste A, Pollicino T et al.. The hepatitis B virus X protein abrogates Bcl-2-mediated protection against Fas apoptosis in the liver.  Oncogene. 2002;  21 377-386
    CrossrefPubMedGoogle Scholar
  • 49 Chami M, Ferrari D, Nicotera P et al.. Caspase-dependent alterations of Ca2+ signaling in the induction of apoptosis by hepatitis B virus X protein.  J Biol Chem. 2003;  278 31745-31755
    CrossrefPubMedGoogle Scholar
  • 50 Lee T H, Elledge S J, Butel J S. Hepatitis B virus X protein interacts with a probable cellular DNA repair protein.  J Virol. 1995;  69 1107-1114
    PubMedGoogle Scholar
  • 51 Groisman I J, Koshy R, Henkler F et al.. Downregulation of DNA excision repair by the hepatitis B virus-x protein occurs in p53-proficient and p53-deficient cells.  Carcinogenesis. 1999;  20 479-483
    CrossrefPubMedGoogle Scholar
  • 52 Sirma H, Weil R, Rosmorduc O et al.. Cytosol is the prime compartment of hepatitis B virus where it colocalizes with the proteasome.  Oncogene. 1998;  16 2051-2063
    CrossrefPubMedGoogle Scholar
  • 53 Schluter V, Meyer M, Hofschneider P H et al.. Integrated hepatitis B virus X and 3′ truncated preS/S sequences derived from human hepatomas encode functionally active transactivators.  Oncogene. 1994;  9 3335-3344
    PubMedGoogle Scholar
  • 54 Luber B, Arnold N, Sturzl M et al.. Hepatoma-derived integrated HBV DNA causes multi-stage transformation in vitro.  Oncogene. 1996;  12 1597-1608
    PubMedGoogle Scholar
  • 55 Soussan P, Garreua F, Zylberberg H et al.. In vivo expression of a new hepatitis B virus protein encoded by a spliced RNA.  J Clin Invest. 2000;  105 55-60
    PubMedGoogle Scholar
  • 56 De Franchis R, Meucci G, Vecchi M et al.. The natural history of asymptomatic hepatitis B surface antigen carriers.  Ann Intern Med. 1993;  118 191-194
    PubMedGoogle Scholar
  • 57 Villeneuve J P, Desrochers M, Infante Rivard C et al.. A long-term follow-up study of asymptomatic hepatitis B surface antigen-positive carriers in Montreal.  Gastroenterology. 1994;  106 1000-1005
    PubMedGoogle Scholar
  • 58 Liaw Y F, Tai D, Chu C M et al.. Early detection of hepatocellular carcinoma in patients with chronic type B hepatitis: a prospective study.  Gastroenterology. 1986;  90 263-267
    PubMedGoogle Scholar
  • 59 Ikeda K, Saitoh S, Suzuki Y et al.. Disease progression and hepatocellular carcinogenesis in patients with chronic viral hepatitis: a prospective observation of 2215 patients.  J Hepatol. 1998;  28 930-938
    CrossrefPubMedGoogle Scholar
  • 60 Fattovich G, Giustina G, Christensen E et al.. Influence of hepatitis B delta virus infection on morbidity and mortality in compensated cirrhosis type B.  Gut. 2000;  46 420-426
    CrossrefPubMedGoogle Scholar
  • 61 Tsai J F, Jeng J E, Ho M S et al.. Effect of hepatitis C and B virus infection on risk of carcinoma: a prospective study.  Br J Cancer. 1997;  76 968-974
    PubMedGoogle Scholar
  • 62 Norder H, Courouce A M, Magnius L O. Complete genomes, phylogenetic relatedness, and structural proteins of six strains of the hepatitis B virus, four of which represent two new genotypes.  Virology. 1994;  198 489-503
    CrossrefPubMedGoogle Scholar
  • 63 Stuyver L, De Gendt S, Van Geyt C et al.. A new genotype of hepatitis B virus: complete genome and phylogenetic relatedness.  J Gen Virol. 2000;  81 67-74
    PubMedGoogle Scholar
  • 64 Arauz-Ruiz P, Norder H, Robertson B H, Magnius L O. Genotype H: a new Amerindian genotype of hepatitis B virus revealed in Central America.  J Gen Virol. 2002;  83 2059-2073
    PubMedGoogle Scholar
  • 65 Chu C J, Hussain M, Lok A SF. Hepatitis B virus genotype is associated with earlier HBeAg seroconversion compared with hepatitis B virus genotype C.  Gastroenterology. 2002;  122 1756-1762
    CrossrefPubMedGoogle Scholar
  • 66 Chan H LY, Wong M L, Hui A Y et al.. Hepatitis B virus genotype C takes a more aggressive disease course than hepatitis B virus genotype B in hepatitis B e antigen-positive patients.  J Clin Microbiol. 2003;  41 1277-1279
    CrossrefPubMedGoogle Scholar
  • 67 Sumi H, Yokosuka O, Seki N et al.. Influence of hepatitis B virus genotypes on the progression of chronic type B liver disease.  Hepatology. 2003;  37 19-26
    CrossrefPubMedGoogle Scholar
  • 68 Chan H LY, Tsang S WC, Liew C T et al.. Viral genotype and hepatitis B virus DNA levels are correlated with histological liver damage in HBeAg-negative chronic hepatitis B virus infection.  Am J Gastroenterol. 2002;  97 406-412
    CrossrefPubMedGoogle Scholar
  • 69 Kao J H, Chen P J, Lai M Y et al.. Hepatitis B genotypes correlate with clinical outcomes in patients with chronic hepatitis B.  Gastroenterology. 2000;  118 554-559
    CrossrefPubMedGoogle Scholar
  • 70 Fujie H, Moriya K, Shintani Y, Yotsuyanagi H. Hepatitis B virus genotypes and hepatocellular carcinoma in Japan.  Gastroenterology. 2001;  120 1564-1565
    PubMedGoogle Scholar
  • 71 Yu M W, Yeh S H, Chen P J et al.. Hepatitis B virus genotype and DNA level and hepatocellular carcinoma: a prospective study in men.  J Natl Cancer Inst. 2005;  97 265-272
    CrossrefPubMedGoogle Scholar
  • 72 Kao J H, Chen P J, Lai M Y, Chen D S. Basal core promoter mutations of hepatitis B virus increase the risk of hepatocellular carcinoma in hepatitis B carriers.  Gastroenterology. 2003;  124 327-334
    CrossrefPubMedGoogle Scholar
  • 73 Yuen M F, Sablon E, Yuan H J et al.. Significance of hepatitis B genotype in acute exacerbation, HBeAg seroconversion, cirrhosis-related complications, and hepatocellular carcinoma.  Hepatology. 2003;  37 562-567
    CrossrefPubMedGoogle Scholar
  • 74 Sugauchi F, Kumada H, Acharya S et al.. Epidemiology and sequence differences between two subtypes (Ae and Aa) of hepatitis B virus genotype A.  J Gen Virol. 2004;  85 811-820
    CrossrefPubMedGoogle Scholar
  • 75 Tanaka Y, Hasegawa I, Kato T et al.. A case-control study for differences among hepatitis B virus infections of genotypes A (subtypes Aa and Ae) and D.  Hepatology. 2004;  40 747-755
    CrossrefPubMedGoogle Scholar
  • 76 Sugauchi F, Orito E, Ichida T et al.. Epidemiology and virological characteristics of hepatitis B virus genotype B having the recombination with genotype C.  Gastroenterology. 2003;  124 925-932
    CrossrefPubMedGoogle Scholar
  • 77 Kobayashi M, Suzuki F, Akuta N et al.. Virological differences between patients infected with subtypes Ba and Bj of hepatitis B virus genotype B.  J Gastroenterol Hepatol. 2005;  20 570-576
    CrossrefPubMedGoogle Scholar
  • 78 Chan H LY, Tsui S KW, Tse C H et al.. Epidemiological and virological characteristics of two subgroups of genotype C hepatitis C virus.  J Infect Dis. 2005;  191 2022-2032
    CrossrefPubMedGoogle Scholar
  • 79 Baptista M, Kramvis A, Kew M C. 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. 1999;  29 946-953
    CrossrefPubMedGoogle Scholar
  • 80 Kuang S Y, Jackson P E, Wang J B et al.. Specific mutations of hepatitis B virus in plasma predict liver cancer development.  Proc Natl Acad Sci USA. 2004;  101 3575-3580
    CrossrefPubMedGoogle Scholar
  • 81 Buckwold V E, Xu Z, Chen M et al.. Effects of a naturally occurring mutation in the hepatitis virus basal core promoter on precore gene expression and viral replication.  J Virol. 1996;  70 5845-5851
    PubMedGoogle Scholar
  • 82 Scaglioni P P, Melegari M, Wands J R. Biological properties of hepatitis B viral genomes with mutations in the precore promoter and precore open reading frame.  Virology. 1997;  233 374-381
    CrossrefPubMedGoogle Scholar
  • 83 Chan H LY, Leung N WY, Hussain M et al.. Hepatitis B e antigen-negative chronic hepatitis B in Hong Kong.  Hepatology. 2000;  31 763-768
    CrossrefPubMedGoogle Scholar
  • 84 Sung J JY, Chan H LY, Wong M L et al.. Relationship of clinical and virological factors with hepatitis activity in hepatitis B e antigen-negative chronic hepatitis B virus-infected patients.  J Viral Hepat. 2002;  9 229-234
    CrossrefPubMedGoogle Scholar
  • 85 Iavarone M, Trabut J B, Delpuech O et al.. Characterisation of hepatitis B virus X protein mutants in tumor and non-tumor liver cells using laser capture microdissection.  J Hepatol. 2003;  39 253-261
    CrossrefPubMedGoogle Scholar
  • 86 Chan H LY, Hussain M, Lok A SF. Different hepatitis B virus genotypes are associated with different mutations in the core promoter and precore regions during Hepatitis B e antigen seroconversion.  Hepatology. 1999;  29 976-984
    CrossrefPubMedGoogle Scholar
  • 87 Lin X, Qian G S, Lu P X, Wen Y M. Full-length genomic analysis of hepatitis B virus isolates in a patient progressing from hepatitis to hepatocellular carcinoma.  J Med Virol. 2001;  64 299-304
    CrossrefPubMedGoogle Scholar
  • 88 Song B C, Kim H, Kim S H et al.. Comparison of full length sequences of hepatitis B virus isolates in hepatocellular carcinoma patients and asymptomatic carriers in Korea.  J Med Virol. 2005;  75 13-19
    CrossrefPubMedGoogle Scholar
  • 89 Sung J JY, Tsui S KW, Tse C H et al.. Viral genomic marker associated with the development of hepatocellular carcinoma: a complete genomic sequence of hepatitis B virus.  Gastroenterology. 2005;  128 A743
    PubMedGoogle Scholar
  • 90 Yang H I, Lu S N, Liaw Y F et al.. Hepatitis B e antigen and the risk of hepatocellular carcinoma.  N Engl J Med. 2002;  347 168-174
    PubMedGoogle Scholar
  • 91 Hsu Y S, Chien R N, Yeh C T et al.. Long-term outcome after spontaneous HBeAg seroconversion in patients with chronic hepatitis B.  Hepatology. 2002;  35 1522-1527
    CrossrefPubMedGoogle Scholar
  • 92 Di Marco V, Iacono O L, Camma C et al.. The long-term course of chronic hepatitis B.  Hepatology. 1999;  30 257-264
    CrossrefPubMedGoogle Scholar
  • 93 McMahon B J, Holck P, Bulkow L, Snowball M. Serologic and clinical outcomes of 1536 Alaska natives chronically infected with hepatitis B virus.  Ann Intern Med. 2001;  135 759-768
    CrossrefPubMedGoogle Scholar
  • 94 Chan H LY, Wong M L, Hui A Y et al.. The value of hepatitis B virus DNA quantitation to predict hepatitis B e antigen reversion in chronic hepatitis B.  J Clin Microbiol. 2003;  41 4793-4795
    CrossrefPubMedGoogle Scholar
  • 95 Manesis E K, Papatheodoridis G V, Hadziyannis S J. Serum HBV-DNA levels in inactive hepatitis B virus carriers.  Gastroenterology. 2002;  122 2092-2093
    PubMedGoogle Scholar
  • 96 Martinot-Peignoux M, Boyer N, Colombat M et al.. Serum hepatitis B virus DNA levels and liver histology in inactive HBsAg carriers.  J Hepatol. 2002;  36 543-546
    CrossrefPubMedGoogle Scholar
  • 97 Ohkubo K, Kato Y, Ichikawa T et al.. Viral load is a significant prognostic factor for hepatitis B virus-associated hepatocellular carcinoma.  Cancer. 2002;  94 2663-2668
    CrossrefPubMedGoogle Scholar
  • 98 Lin S M, Sheen I S, Chien R N et al.. Long-term beneficial effect of interferon therapy in patients with chronic hepatitis B virus infection.  Hepatology. 1999;  29 971-975
    CrossrefPubMedGoogle Scholar
  • 99 Van Zonneveld M, Honkoop P, Hansesn B E et al.. Long-term follow-up of alpha-interferon treatment of patients with chronic hepatitis B.  Hepatology. 2004;  39 804-810
    CrossrefPubMedGoogle Scholar
  • 100 Chan H LY, Hui A Y, Wong V WS et al.. Long-term follow-up of peginterferon and lamivudine combination treatment in HBeAg-positive chronic hepatitis B.  Hepatology. 2005;  41 1357-1364
    CrossrefPubMedGoogle Scholar
  • 101 Liaw Y F, Sung J J, Chow W C et al.. Lamivudine for patients with chronic hepatitis B and advanced liver disease.  N Engl J Med. 2004;  351 1521-1531
    CrossrefPubMedGoogle Scholar
  • 102 Yu M W, Chen C J. Elevated serum testosterone levels and risk of hepatocellular carcinoma.  Cancer Res. 1993;  53 790-794
    PubMedGoogle Scholar
  • 103 Tanaka K, Sakai H, Hashizume M, Hirohata T. Serum testosterone: estradiol ration and the development of hepatocellular carcinoma among male cirrhotic patients.  Cancer Res. 2000;  60 5106-5110
    PubMedGoogle Scholar
  • 104 Yu M W, Cheng S W, Lin M W et al.. Androgen-receptor gene CAG repeats, plasma testosterone levels, and risk of hepatitis B-related hepatocellular carcinoma.  J Natl Cancer Inst. 2000;  92 2023-2028
    CrossrefPubMedGoogle Scholar
  • 105 Yu M W, Yang Y C, Yang S Y et al.. Hormonal markers and hepatitis B virus-related hepatocellular carcinoma risk: a case-control study among men.  J Natl Cancer Inst. 2001;  93 1644-1651
    PubMedGoogle Scholar
  • 106 Makridakis N, Reichardt J, Pike M et al.. Genetic control of human androgen metabolism by the CYP17 and SRD5A2 genes.  Am J Hum Genet. 1997;  61(suppl) A257
    PubMedGoogle Scholar
  • 107 Lunn R M, Bell D A, Mohler J L, Taylor J A. Prostate cancer risk and polymorphism in 17 hydroxylase (CYP17) and steroid reductase (SRD5A2).  Carcinogenesis. 1999;  20 1727-1731
    CrossrefPubMedGoogle Scholar
  • 108 Lutz M, Knaus P. Integration of the TGF-beta pathway into cellular signaling network.  Cell Signal. 2002;  14 977-988
    CrossrefPubMedGoogle Scholar
  • 109 Cui W, Fowlis D J, Bryson S et al.. TFGbeta1 inhibits the formation of benign skin tumors, but enhances progression to invasive spindle carcinomas in transgenic mice.  Cell. 1996;  86 531-542
    CrossrefPubMedGoogle Scholar
  • 110 Cambien F, Ricard S, Troesch A et al.. Polymorphisms of the transforming growth factor-beta 1 gene in relation to myocardial infarction and blood pressure. The Etude Cas-Temoin de I'infactus du Myocarde (ECTIM) Study.  Hypertension. 1996;  28 881-887
    PubMedGoogle Scholar
  • 111 Kim Y J, Lee H J, Im J P et al.. Association of transforming growth factor-1β1 gene polymorphism with a hepatocellular carcinoma risk in patients with chronic hepatitis B virus infection.  Exp Mol Med. 2003;  35 196-202
    PubMedGoogle Scholar
  • 112 Migita K, Miyazoe S, Maeda Y et al.. Cytokine gene polymorphisms in Japanese patients with hepatitis B virus infection: association between TGF-β1 polymorphisms and hepatocellular carcinoma.  J Hepatol. 2005;  42 505-510
    CrossrefPubMedGoogle Scholar
  • 113 Yamada Y, Okuizumi H, Miyauchi A et al.. Association of transforming growth factor 1-beta genotype with spinal osteophytosis in Japanese women.  Arthritis Rheum. 2000;  43 452-460
    CrossrefPubMedGoogle Scholar
  • 114 Grainger D J, Heathcote K, Chiano M et al.. Genetic control of the circulating concentration of transforming growth factor type beta1.  Hum Mol Genet. 1999;  8 93-97
    CrossrefPubMedGoogle Scholar
  • 115 Yamada Y, Miyauchi A, Goto J et al.. Association of a polymorphism of the transforming growth factor beta-1 gene with genetic susceptibility to osteoporosis in postmenopausal Japanese women.  J Bone Miner Res. 1998;  13 1569-1576
    CrossrefPubMedGoogle Scholar
  • 116 Tanaka Y, Furuta T, Suzuki S et al.. Impact of interleukin-1β genetic polymorphisms on the development of hepatitis C virus-related hepatocellular carcinoma in Japan.  J Infect Dis. 2003;  187 1822-1825
    CrossrefPubMedGoogle Scholar
  • 117 Wang Y, Kato N, Hoshida Y et al.. Interleukin-1β gene polymorphisms associated with hepatocellular carcinoma in hepatitis C virus infection.  Hepatology. 2003;  37 65-71
    CrossrefPubMedGoogle Scholar
  • 118 Shin H D, Park B Y, Kin L H et al.. Interleukin 10 haplotype associated with increased risk of hepatocellular carcinoma.  Hum Mol Genet. 2003;  12 901-906
    CrossrefPubMedGoogle Scholar
  • 119 Heneghan M A, Johnson P J, Clare M, Ho S, Harrison P M, Donaldson P T. Frequency and nature of cytokine gene polymorphisms in hepatocellular carcinoma in Hong Kong Chinese.  Int J Gastrointest Cancer. 2003;  34 19-26
    PubMedGoogle Scholar
  • 120 Werle-Lapostolle B, Bowden S, Locarnini S et al.. Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy.  Gastroenterology. 2004;  126 1750-1758
    CrossrefPubMedGoogle Scholar
  • 121 Sung J JY, Wong M L, Bowden S et al.. Intrahepatic hepatitis B virus covalently closed circular DNA can be a predictor of sustained response to therapy.  Gastroenterology. 2005;  128 1890-1897
    CrossrefPubMedGoogle Scholar
  • 122 Poon T CW, Hui A Y, Chan H LY et al.. Prediction of liver fibrosis and cirrhosis in chronic hepatitis B infection by serum proteomic fingerprinting-a pilot study.  Clin Chem. 2005;  51 328-335
    CrossrefPubMedGoogle Scholar
  • 123 Hui A Y, Chan H LY, Wong V WS et al.. Identification of chronic hepatitis B patients without significant liver fibrosis by a simple noninvasive predictive model.  Am J Gastroenterol. 2005;  100 616-623
    CrossrefPubMedGoogle Scholar
  • 124 Chan H LY, Tsang S WC, Leung N WY et al.. Occult hepatitis B virus (HBV) infection in cryptogenic liver cirrhosis in an area with high prevalence of HBV infection.  Am J Gastroenterol. 2002;  97 1211-1215
    CrossrefPubMedGoogle Scholar
  • 125 Huo T I, Wu J C, Lee P C et al.. Sero-clearance of hepatitis B surface antigen in chronic carriers does not necessarily imply a good prognosis.  Hepatology. 1998;  28 231-236
    CrossrefPubMedGoogle Scholar

Joseph J.Y. SungM.D. Ph.D. 

Department of Medicine and Therapeutics, 9/F Prince of Wales Hospital

30-32 Ngan Shing Street, Shatin, Hong Kong, China

      >