Virologic Analysis of Non‐B, Non‐C Hepatocellular Carcinoma in Japan: Frequent Involvement of Hepatitis B Virus

Yotsuyanagi, Hiroshi; Shintani, Yoshizumi; Moriya, Kyoji; Fujie, Hajime; Tsutsumi, Takeshi; Kato, Tomohiro; Nishioka, Kusuki; Takayama, Tadatoshi; Makuuchi, Masatoshi; Iino, Shiro; Kimura, Satoshi; Koike, Kazuhiko

doi:10.1086/315512

Cited by 94 publications

(95 citation statements)

References 40 publications

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“…Other patients may have chronic HBV infection for decades leading to liver damage but HBsAg is no longer detectable when cirrhosis or HCC is diagnosed. [19][20][21] The role of occult HBV infection in the etiology of liver disease in seronegative individuals is less clear. Data are scanty and based on case reports or case series.…”

mentioning

confidence: 99%

Occult Hepatitis B Virus Infection: A Hidden Menace?

2001

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Recovery from an acute hepatitis B virus (HBV) infection is associated with loss of HBV DNA from serum, hepatitis B e antigen seroconversion, hepatitis B surface antigen (HBsAg) seroconversion, and normalization of serum aminotransferases. These changes generally imply clearance of virus, but clinical observations have shown that reactivation of HBV infection can occur either spontaneously or after immunosuppression. [1][2][3] Recent studies showed that immune response to HBV remains vigorous long after an acute infection. In addition, HBV DNA can be detected by polymerase chain reaction (PCR) assays in serum, liver, and peripheral blood mononuclear cells more than a decade after an apparent recovery from HBV infection. [4][5][6] These findings suggest that recovery from acute hepatitis B may not result in complete virus elimination, but rather the immune system keeps the virus at very low levels. There is, however, no clear evidence that patients who have persistently low levels of HBV after recovery from acute hepatitis B develop progressive liver disease.The availability of PCR assays for HBV DNA allows the detection of 10 2 copies/mL compared with 10 6 copies/mL using hybridization assays. Using PCR assays, HBV DNA has been detected in some subjects who are HBsAg negative including those with no serologic markers of HBV infection. In this issue of the HEPATOLOGY, Bréchot et al. review the prevalence, virologic basis, and clinical significance of occult HBV infection. 7 For the clinician, several issues regarding occult HBV infection are pertinent: Does it exist? How common is it? What is the risk of transmission? What is the risk of progressive liver disease? How can it be diagnosed? Is antiviral therapy indicated? Before these issues can be addressed, it must be recognized that there is currently no standardized definition or diagnostic criteria of occult HBV infection. A simple definition would be the detection of HBV DNA in HBsAg-negative subjects. However, more specific information must be provided, as occult HBV infection is a heterogeneous clinical entity.Bréchot et al. provide very strong evidence that occult HBV infection exists and that most cases are related to very low levels of HBV rather than to HBV mutants that do not express or produce aberrant surface proteins and therefore are undetected by standard testing. 7 Because HBV-DNA detection is the key to diagnosis of occult HBV infection, the type of assay used and its sensitivity must be specified. The sensitivity of PCR assays for HBV DNA in studies on occult HBV infection varies from 10 1 to 10 3 copies/mL. 8 However, most PCR assays including commercially available assays are not standardized. 9 Other factors that may affect the detection rates of HBV DNA include the volume of sample used and the material tested. Thus, the limit of detection can be increased by using a larger volume of serum as in the case of the hybrid capture assay. Most studies on occult HBV infection have reported higher rates of HBV-DNA detection in liver or peripheral b...

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confidence: 99%

Occult Hepatitis B Virus Infection: A Hidden Menace?

2001

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“…No patients were double-positive for HCV antibody and HBs antigen. Although three patients were double-negative for HCV antibody and HBs antigen, the presence of HBV mRNA was confirmed using the previously reported RT-PCR method (15). These patients were considered to have HBV-positive HCC for further analysis.…”

Section: Methodsmentioning

confidence: 55%

“…These patients were considered to have HBV-positive HCC for further analysis. For the remaining 20 non-B, non-C patients who were double-negative for HCV antibody and HBs antigen, the absence of viral genomes was confirmed by RT-PCR as reported to rule out possible cryptic HCV or HBV infection (15,16). In total, 80 cases were in the HCV group, 19 in the HBV group, and 20 in the non-B, non-C group.…”

Section: Methodsmentioning

confidence: 96%

Central genetic alterations common to all HCV-positive, HBV-positive and non-B, non-C hepatocellular carcinoma: A new approach to identify novel tumor markers

et al. 2006

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Abstract. Hepatocellular carcinoma (HCC) is a common malignancy, but the prognosis remains poor due to the lack of sensitive diagnostic markers. To gain insight into the central molecular features common to all types of HCC, and to identify novel diagnostic markers or therapeutic targets for HCC, we performed a gene expression profiling analysis using a high throughput RT-PCR system. After examining the mRNA expression of 3,072 genes in 204 (119 tumor and 85 nontumor) liver samples, we identified differential gene expression between the HCV group (n=80), HBV group (n=19) and non-B, non-C group (n=20) with a principal component analysis and a correlation spectrum analysis. After selection of genes differentially expressed between tumor and non-tumor tissues (p<0.01) within each HCC group, a total of 51 differentially expressed genes (23 upregulated and 28 downregulated genes) were found to be common to the three HCC groups. Gene Ontology grouping analysis revealed that genes with functions related to cell proliferation or differentiation and genes encoding extracellular proteins were found to be significantly enriched in these 51 common genes. Using an Atelocollagenbased cell transfection array for functional analysis of eight upregulated genes, five (CANX, FAM34A, PVRL2, LAMR1, and GBA) significantly inhibited cellular apoptosis by two independent assays. In conclusion, we identified 51 differentially expressed genes, common to all HCC types. Among these genes, there was a high incidence of anti-apoptotic activity. This combination approach with the advanced statistical methods and the bioinformatical analysis may be useful for finding novel molecular targets for diagnosis and therapy.

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“…It was reported that the frequency of HCC due to chronic HCV infection is higher in Japan than in any other country (4). Several studies have reported that occult HBV infection may also be one of the causative factors of HCC (5,6). The presence of occult HBV infection is diagnosed based on the fact that HBV DNA still exists in serum and liver tissue after hepatitis B surface antigen (HBsAg) disappears in acute or chronic HBV infection (7)(8)(9), or even after antiviral treatment is successful.…”

Section: Introductionmentioning

confidence: 98%

Antibody to hepatitis B core antigen is associated with the development of hepatocellular carcinoma in hepatitis C virus-infected persons: A 12-year prospective study

Tanaka

Nagao²,

Ide³

et al. 2006

Int J Mol Med

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Abstract. Several studies have reported that antibody to hepatitis B core antigen (anti-HBc) positivity may influence the development of hepatocellular carcinoma (HCC) in chronic hepatitis C patients, but the evidence is still not conclusive. In this study, we examined whether the presence of antiHBc positive was associated with the development of HCC in hepatitis C virus (HCV)-infected subjects among the residents in an HCV hyperepidemic area who were followed up for 12 years. In an HCV hyperendemic area (positive rate of anti-HCV: 23.4%), 509 residents were examined by health screening in 1990. After 12 years of follow-up, we evaluated the risk factors for HCC. The incidence of HCC was compared between anti-HBc positive and anti-HBc negative subjects after 12 years of prospective observation. Univariate and multivariate analyses were conducted to determine risk factors for the development of HCC. The incidence of HCC was significantly higher in the anti-HBc positive group (13 subjects) than in the anti-HBc negative group (0 subjects) (P=0.012). Multivariate analysis identified positivity for antiHBc and HCV RNA, history of icterus, and female gender as independent determinants of the development of HCC. Our findings provide clear evidence in a prospective study that presence of anti-HBc, that is, past hepatitis B virus (HBV) infection, is a risk factor for the development of HCC in HCVinfected people.

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Virologic Analysis of Non‐B, Non‐C Hepatocellular Carcinoma in Japan: Frequent Involvement of Hepatitis B Virus

Cited by 94 publications

References 40 publications

Occult Hepatitis B Virus Infection: A Hidden Menace?

Occult Hepatitis B Virus Infection: A Hidden Menace?

Central genetic alterations common to all HCV-positive, HBV-positive and non-B, non-C hepatocellular carcinoma: A new approach to identify novel tumor markers

Antibody to hepatitis B core antigen is associated with the development of hepatocellular carcinoma in hepatitis C virus-infected persons: A 12-year prospective study

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