Hepatitis B viremia is associated with increased risk of hepatocellular carcinoma in chronic carriers

Tang, Baiqing; Kruger, Warren D.; Chen, Gang; Shen, Fumin; Lin, Wen; Mboup, Souleymane; London, W. Thomas; Evans, Alison A.

doi:10.1002/jmv.10559

Cited by 79 publications

(73 citation statements)

References 13 publications

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“…This higher replication efficiency of HBV in males provides an explanation as to why there are more male HBV carriers than female HBV carriers. It also provides an explanation as to the gender discrepancy in the incidence of HCC, as HBV viral load has been shown to be a major risk factor for HCC (2,4,11).…”

Section: Discussionmentioning

confidence: 99%

Enhancement of Hepatitis B Virus Replication by Androgen and Its Receptor in Mice

Tian

Kuo

Chen

et al. 2012

J Virol

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Hepatitis B virus (HBV) is an important pathogen that chronically infects more men than women. To understand the molecular mechanism of this gender disparity, we analyzed HBV replication in transgenic mice that carried the HBV genome with or without the ability to express the HBV X protein (HBx). We found that gender had no effect on HBV surface antigen (HBsAg), DNA, and RNA levels in mice before puberty, but its effect on HBV after puberty was apparent, with HBV replicating approximately twice more efficiently in male mice than in female mice whether or not HBx was expressed. The castration of male mice resulted in a reduction of HBV HBsAg, DNA, and RNA levels, which could be partially restored by the injection of the androgen agonist R1881, indicating a positive role of androgen in HBV replication. The introduction of HBV genomic DNA and androgen receptor (AR) short hairpin RNA (shRNA) into the liver of naïve mice by hydrodynamic injection revealed that the effect of androgen on HBV was dependent on its receptor, which apparently could also stimulate HBV replication via an androgen-independent pathway. Further studies indicated that the two previously identified androgen response elements (AREs) in the HBV genome could indeed mediate the effect of androgen on HBV RNA transcription and DNA replication in vivo. These effects of androgen and its receptor on HBV thus provide an explanation for why men have a higher risk of HBV infection than women. H epatitis B virus (HBV) is a hepatotropic virus that chronically infects approximately 350 million people in the world.Chronic infection by this virus can lead to severe liver diseases, including liver cirrhosis and hepatocellular carcinoma (HCC) (7). HBV has a small DNA genome of about 3.2 kb. This genome carries four genes: the C, S, P, and X genes. The C gene codes for the viral core protein and a related protein named e antigen, the S gene codes for the three viral envelope proteins known as HBV surface antigens (HBsAgs), the P gene codes for the viral DNA polymerase, and the X gene codes for a 17-kDa regulatory protein. The expression of the HBV genes is controlled by four different promoters and two enhancer elements (for a review, see reference 9).HBV pathogenesis is affected by many factors, such as viral load, viral genotypes, and viral variants (1). In addition, gender has also been found to affect HBV replication and pathogenesis (19). Men are three to seven times more likely to become HBV carriers than women, and male HBV carriers are more likely to develop HCC than are female HBV carriers (19). This effect of gender on HBV replication and carcinogenesis appears to be associated with the male sex hormone, as the incidence of HBVassociated HCC is positively correlated with serum androgen levels and inversely correlated with the number of CAG trinucleotide repeats in the androgen receptor (AR) gene, which inversely affects the activity of the AR (10,18,19). The AR is a member of the nuclear receptor superfamily. It consists of several functional domains respo...

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Section: Discussionmentioning

confidence: 99%

Enhancement of Hepatitis B Virus Replication by Androgen and Its Receptor in Mice

Tian

Kuo

Chen

et al. 2012

J Virol

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“…Recent studies have indicated that serum level of HBV DNA may be a risk factor for HCC [13][14][15][16] . Tang et al [17] have previously reported that adult HBV carriers who maintain high-titer serum HBV DNA are at higher risk for development of HCC. In Taiwan, a 12-year follow-up study of 4841 men who were Hepatitis B surface antigen (HBsAg) positive has demonstrated that the risk of HCC is 2.7-10.7-fold higher in patients with baseline HBV DNA levels of 4.0 log10 copies/mL to ≥ 6.0 log10 copies/mL [18] .…”

Section: Introductionmentioning

confidence: 99%

A case-control study of the relationship between hepatitis B virus DNA level and risk of hepatocellular carcinoma in Qidong, China

Liu¹,

Fāng²,

Xiong³

et al. 2008

WJG

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AIM:To investigate the role of hepatitis B virus (HBV) replication in the development of hepatocellular carcinoma (HCC), a nested case-control study was performed to study the relationship between HBV DNA level and risk of HCC. METHODS:One hundred and seventy cases of HCC and 276 control subjects free of HCC and cirrhosis were selected for this study. Serum HBV DNA level was measured using fluorescein quantitative polymerase chain reaction at study entry and the last visit. RESULTS:In a binary unconditional logistic regression analysis adjusted for age, cigarette smoking, alcohol consumption and family history of chronic liver diseases, the adjusted odds ratios (95% confidence intervals) of HCC in patients with increasing HBV DNA level were 2.834 (1.237-6.492), 48.403 (14.392-162.789), 42.252 (14.784-120.750), and 14.819 (6.992-31.411) for HBV DNA levels ≥ 10 4 to < 10 5 ; ≥ 10 5 to < 10 6 ; ≥ 10 6 to < 10 7 ; ≥ 10 7 copies/mL, respectively. Forty-six HCC cases were selected to compare the serums viral loads of HBV DNA at study entry with those at the last visit. The HBV DNA levels measured at the two time points did not differ significantly.

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“…At the same time, the virus levels decrease and hepatitis abates. Some patients, however, remain positive for HBeＡｇ, and in those patients the hepatitis virus persists at high levels, resulting in the progression to hepatic cirrhosis and the onset of hepatocellular carcinoma (HCC) in a high percentage of such patients [3,4,5]. The number of HBV carriers is decreasing in Japan and some other countries as a result of the prevention of mother-child transmission through the use of HBV vaccines and/or high-potency antibody to hepatitis B surface antigen (HBsAb) human immunoglobulin (HBIG) [6].…”

Section: Introductionmentioning

confidence: 99%

Efficacy of lamivudine for preventing hepatocellular carcinoma in chronic hepatitis B: A multicenter retrospective study of 2795 patients

Matsumoto

Tanaka

Rokuhara

et al. 2005

Hepatology Research

186

162

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A retrospective survey of Japanese patients histologically diagnosed with chronic hepatitis B was conducted to determine the effectiveness of lamivudine in preventing hepatocellular carcinoma (HCC). Of the 2,795 patients who satisfied criteria for analysis after treatment from any of 30 medical institutions, 657 had received lamivudine and the remaining 2,138 had not. A Cox regression model with liver biopsy as the starting point revealed seven factors related to HCC: lamivudine therapy, gender, family clustering of hepatitis B, age at liver biopsy, hepatic fibrosis stage, serum albumin level, and platelet count. In a matched case-controlled study, 377 patients in a lamivudine-treated group and 377 matched patients in a non-treated group were selected based on their propensity scores. The mean follow-up period was 2.7 years in the lamivudine group and 5.3 years in the control group. In the lamivudine group, HCC occurred in 4 patients (1.1%) with an annual incidence rate of 0.4%/patient/year, whereas in the control group HCC occurred in 50 patients (13.3%) for a rate of 2.5%/patient/year. A comparison of the cumulative HCC incidence between the two groups by the Kaplan-Meier method showed a significantly lower incidence of HCC in the lamivudine group (p<0.001). These findings suggest that lamivudine effectively reduces the incidence of HCC in patients with chronic hepatitis B.

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Hepatitis B viremia is associated with increased risk of hepatocellular carcinoma in chronic carriers

Cited by 79 publications

References 13 publications

Enhancement of Hepatitis B Virus Replication by Androgen and Its Receptor in Mice

Enhancement of Hepatitis B Virus Replication by Androgen and Its Receptor in Mice

A case-control study of the relationship between hepatitis B virus DNA level and risk of hepatocellular carcinoma in Qidong, China

Efficacy of lamivudine for preventing hepatocellular carcinoma in chronic hepatitis B: A multicenter retrospective study of 2795 patients

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