Occult hepatitis B virus infection is associated with the development of hepatocellular carcinoma in chronic hepatitis C patients

Squadrito, Giovanni; Pollicino, Teresa; Cacciola, Irene; Caccamo, Gaia; Villari, Daniela; Masa, Tiziana La; Restuccia, Tea; Cucinotta, Eugenio; Scisca, Claudio; Magazzù, Domenico; Raimondo, Giovanni

doi:10.1002/cncr.21702

Cited by 122 publications

(158 citation statements)

References 27 publications

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“…Although the interaction between occult HBV and HCV infection could not be assessed properly, the study showed that the OR for HCC was about threefold higher for dual occult HBV and HCV infection compared to HCV infection alone, which is in line with the 2.9 OR for occult HBV infection for having HCC (cases) compared to having chronic hepatitis or cirrhosis (controls) among HCV RNA-positive subjects in a multicentre Italian study (Pollicino et al, 2004). In the Messina study (Squadrito et al, 2006), a strong interaction was evident between occult HBV infection and HCV infection: among 124 patients with HCV chronic hepatitis, seven of the 50 with concurrent occult HBV and HCV infection developed HCC (incidence rate: 2.18/100 person-years) compared to one of the 74 without occult HCV infection (incidence rate: 0.19/100 person-years).…”

Section: Occult Hepatitis B Virus Infectionmentioning

confidence: 55%

“…In addition, other studies found a high proportion of occult HBV infections among HCV-positive HCC cases (Brechot et al, 2001) and that, in subjects with chronic HCV hepatitis, cirrhosis was more common among those with than those without occult HBV infection (Cacciola et al, 1999). In the Messina study, eight of nine HCC cases which developed in subjects with HCV-related chronic hepatitis were co-infected with occult HBV (Squadrito et al, 2006). In the Brescia HCC study, 37.4% of the HCV RNApositive and HBsAg-negative cases with HCC had HBV DNA in their sera, and 42.4% had a history of heavy alcohol intake, leaving a minority of HCC cases with HCV infection alone.…”

Section: Cirrhosis and Hepatocellular Carcinoma F Donato Et Almentioning

confidence: 88%

“…The overall impact of occult HBV infection as a cause of HCC by itself, however, seems modest in the area, since only 14 of 574 total HCC cases (2.3%) did not have evident risk factors ('cryptogenic') and may have been caused by 'pure' occult HBV infection. The role of occult HBV was also evaluated in an Italian cohort study performed in Messina, Sicily (Squadrito et al, 2006), with HBV DNA search performed in liver samples. The study found that, among 134 HBsAg-negative patients with chronic liver disease, mostly caused by HCV, nine developed HCC, eight of which had occult HBV infection as well (seven HCV positive, one with cryptogenic liver disease), during the follow-up (median: 83 months).…”

Section: Occult Hepatitis B Virus Infectionmentioning

confidence: 99%

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Southern Europe as an example of interaction between various environmental factors: a systematic review of the epidemiologic evidence

et al. 2006

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Hepatitis B virus (HBV), hepatitis C virus (HCV) and alcohol consumption are major causes of hepatocellular carcinoma (HCC) worldwide. We performed a systematic review of epidemiologic studies carried out on HCC aetiology in Southern Europe, an area with an intermediatehigh prevalence of these agents as well as of putative risk factors such as tobacco smoking, diabetes and obesity. To retrieve the articles, we performed a Medline search for titles and abstracts of articles. After the Medline search, we reviewed the papers and reference lists to identify additional articles. A synergism between HCV infection and HBV infection, overt (hepatitis B virus antigen (HbsAg) positivity) or occult (HBsAg negativity with presence of HBV DNA in liver or serum), is suggested by the results of some studies. The pattern of the risk for HCC due to alcohol intake shows a continuous dose-effect curve without a definite threshold, although most studies found that HCC risk increased only for alcohol consumption above 40-60 g of ethanol per day. Some evidence supports a positive interaction of alcohol intake probably with HCV infection and possibly with HBV infection. A few studies found that coffee has a protective effect on HCC risk due to various risk factors. Some data also support a role of tobacco smoking, diabetes and obesity as single agents or preferably cofactors in causing HCC. In countries with a relatively high alcohol consumption and intermediate levels of HCV and HBV infections (1-3% of population infected by each virus), such as Mediterranean countries, the three main risk factors together account for about 85% of the total HCC cases, leaving little space to other known risk factors, such as haemochromatosis, and to new, still unrecognised, factors as independent causes of HCC.

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Section: Occult Hepatitis B Virus Infectionmentioning

confidence: 55%

Section: Cirrhosis and Hepatocellular Carcinoma F Donato Et Almentioning

confidence: 88%

Section: Occult Hepatitis B Virus Infectionmentioning

confidence: 99%

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Southern Europe as an example of interaction between various environmental factors: a systematic review of the epidemiologic evidence

et al. 2006

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“…27,28 In addition, a cohort study also found that, among HBsAg-negative patients, HCC mostly developed in carriers of occult HBV. 29 One limitation of this study was the absence of HBV DNA assays for liver tissue. Most studies of occult HBV infection have reported higher HBV DNA detection rates in liver or peripheral blood mononuclear cells than in serum or plasma.…”

Section: Discussionmentioning

confidence: 99%

A study on sequence variations in pre‐S/surface, X and enhancer II/core promoter/precore regions of occult hepatitis B virus in non‐B, non‐C hepatocellular carcinoma patients in Taiwan

Chen

Changchien

Lee

et al. 2009

Intl Journal of Cancer

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This study was to investigate the clinical significance and virologic factors of occult hepatitis B virus (HBV) infection in hepatocellular carcinoma (HCC) patients without hepatitis B surface antigen (HBsAg) or anti-hepatitis C virus (non-B, non-C) in Taiwan. Serum HBV DNA (occult HBV) was detected in 90 of 222 non-B, non-C HCC patients and 24 of 300 non-B, non-C controls without HCC. Of 90 occult HBV-infected HCC patients, the sequences of HBV pre-S/surface, X and enhancer II/core promoter/precore genes were analyzed from 40 patients. Direct sequencing of such genes was also performed in 24 non-B, non-C controls without HCC and 40 HBsAg-positive HCC controls. Compared with non-B, non-C controls without HCC, non-B, non-C subjects with HCC had significantly higher prevalence of occult HBV (p < 0.0001). Moreover, M1I and Q2K in pre-S2 gene and G1721A were more common in occult HBV-infected patients with HCC than in those without HCC. Compared with the HBsAg-positive HCC controls, occult HBV-infected HCC patients had higher frequencies of M1I and Q2K in pre-S2 gene, G185R and S210N in surface gene, A36T and A44L in X gene, and G1721A in enhancer II gene, and had lower rates of pre-S deletions and A1762T/G1764A, A1846T, G1896A and G1899A in core promoter/precore genes. Multivariate analysis showed Q2K in pre-S2 gene, G1721A and A1846T were independent factors for occult HBV-infected HCC. Our study suggested that the virological factors of HBV related to HCC were different between occult HBV-infected and HBsAgpositive patients. The G1721A, M1I and Q2K in pre-S2 gene may be useful viral markers for HCC in occult HBV carriers. ' UICCKey words: hepatitis B virus; occult hepatitis B virus; hepatocellular carcinoma; precore mutation; core promoter mutation Hepatitis B virus (HBV) infection is a major health problem associated with 1 million deaths annually worldwide. 1 A wide range of clinical manifestations has been established for chronic HBV infection from asymptomatic carriers to severe chronic liver disease, including those with cirrhosis and hepatocellular carcinoma (HCC). 2-4 Chronic HBV infection is characterized by persistent hepatitis B surface antigen (HBsAg) and viremia. 1,2 Early studies revealed that the clearance of HBsAg in HBV patients is associated with undetectable serum HBV DNA and disease remission. However, accumulating data indicate that a low level of HBV DNA remains detectable in serum and liver tissues in some patients cleared of HBsAg from either acute self-limited or chronic HBV infection. Occult HBV infection was detected even among family members of HBV carriers. 5 This so-called occult HBV infection has been identified by sensitive polymerase chain reaction (PCR) assays that detect low levels of HBV DNA in serum and/or liver tissue of HBsAg-negative subjects. [6][7][8] Since the early 1980s, several studies have reported the detection of HBV DNA in both tumorous and non-tumorous liver tissue of HBsAg-negative HCC patients. 9,10 However, whether occult HBV infection also contributes to the...

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“…Most studies indicate an increased frequency of cirrhosis in occult HBVinfected patients, particularly if HCV co-infected (Torbenson and Thomas, 2002). Cryptic HBV infection is an important risk factor for the development of the HCC in patients with HCV-related cirrhosis (Pollicino et al, 2004;Squadrito et al, 2006). As occult HBV may persist in the infected livers both in integrated and episomal forms (Pollicino et al, 2004), it may contribute to hepatocellular transformation through the same mechanisms traditionally considered the basis of the tumorigenic properties of the HBV, including the capacity of the integrated virus to rearrange the host genome and the potential pro-oncogenic activity of the X protein that shares many molecular targets with HCV core and NS5A, including the ERK kinases, the b-catenin pathway, NF-kB and p53.…”

Section: Occult Hbv Infectionmentioning

confidence: 99%

Viral hepatitis and liver cancer: the case of hepatitis C

2006

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Chronic infection with the hepatitis C virus (HCV) is a major risk factor for the development of hepatocellular carcinoma (HCC) worldwide. The pathogenesis of HCC in HCV infection has extensively been analysed. Hepatitis C virus-induced chronic inflammation and the effects of cytokines in the development of fibrosis and liver cell proliferation are considered as one of the major pathogenic mechanisms. Increasing experimental evidence suggests that HCV contributes to HCC by directly modulating pathways that promote the malignant transformation of hepatocytes. Hepatitis C virus is an RNA virus that does not integrate into the host genome but HCV proteins interact with many host-cell factors well beyond their roles in the viral life cycle and are involved in a wide range of activities, including cell signaling, transcription, cell proliferation, apoptosis, membrane rearrangements, vesicular trafficking and translational regulation. At least four of the HCV gene products, namely HCV core, NS3, NS4B and NS5A, have been shown to exhibit transformation potential in tissue culture and several potentially oncogenic pathways have been shown to be altered by the expression of HCV proteins. Both HCV core and NS5A induce the accumulation of wild-type b-catenin and the Wnt-b-catenin pathway emerges as a common target for HCV (and HBV) in human HCCs, also independently from axin/b-catenin gene mutations. Induction of both endoplasmic reticulum stress and oxidative stress by HCV proteins might also contribute to HCV transformation. Most of the putative transforming functions of the HCV proteins have been defined in artificial cellular systems, which may not be applicable to HCV infection in vivo, and still need to be established in relevant infection and disease models.

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Occult hepatitis B virus infection is associated with the development of hepatocellular carcinoma in chronic hepatitis C patients

Cited by 122 publications

References 27 publications

Southern Europe as an example of interaction between various environmental factors: a systematic review of the epidemiologic evidence

Southern Europe as an example of interaction between various environmental factors: a systematic review of the epidemiologic evidence

A study on sequence variations in pre‐S/surface, X and enhancer II/core promoter/precore regions of occult hepatitis B virus in non‐B, non‐C hepatocellular carcinoma patients in Taiwan

Viral hepatitis and liver cancer: the case of hepatitis C

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