Susceptibility to hepatocellular carcinoma is associated with genetic variation in the enzymatic detoxification of aflatoxin B1.

Aflatoxin B1 (AFB1) has been postulated to be a hepatocarcinogen in humans, possibly by causing p53 mutations at codon 249. AFB1 is metabolized via the phase I and II detoxification pathways; hence, genetic variation at those loci may predict susceptibility to the effects of AFB1. To test this hypothesis, genetic variation in two AFB1 detoxification genes, epoxide hydrolase (EPHX) and glutathione S-transferase M1 (GSTM1), was contrasted with the presence of serum AFB1-albumin adducts, the presence of hepatocellular carcinoma (HCC), and with p53 codon 249 mutations. Mutant alleles at both loci were significantly overrepresented in individuals with serum AFB1-albumin adducts in a cross-sectional study. Mutant alleles of EPHX were significantly overrepresented in persons with HCC, also in a case-control study. The relationship of EPHX to HCC varied by hepatitis B surface antigen status and indicated that a synergistic effect may exist. p53 codon 249 mutations were observed only among HCC patients with one or both high-risk genotypes. These results indicate that individuals with mutant genotypes at EPHX and GSTM1 may be at greater risk of developing AFB1 adducts, p53 mutations, and HCC when exposed to AFB1. Hepatitis B carriers with the high-risk genotypes may be an even greater risk than carriers with low-risk genotypes. These findings support the existence of genetic susceptibility in humans to the environmental carcinogen AFB1 and indicate that there is a synergistic increase in risk of HCC with the combination of hepatitis B virus infection and susceptible genotype.     

Human hepatitis B virus and hepatocellular carcinoma II. Experimental induction of hepatocellular carcinoma in tree shrews exposed to hepatitis B virus and aflatoxin B1

On the basis of the successful establishment of an animal model in tree shrews experimentally infected with human hepatitis B virus (HBV), a study on the hepatocarcinogenic effects of HBV and/or aflatoxin B1 (AFB1) was conducted. The results showed that the incidence of hepatocellular carcinoma (HCC) was significantly higher in the animals both infected with HBV and exposed to AFB1 (52.94%) than in those solely infected with HBV (11.11%) or exposed to AFB1 (12.50%). No HCC of precancerous lesions were found in the controls that were neither HBV-infected nor AFB1-exposed. Precancerous lesions, including liver cell dysplasia and enzyme-altered hyperplastic hepatocyte foci, were observed before the occurrence of HCC, and the frequency of their appearance correlated well with the incidence of HCC. HBV DNA and the protein it encodes were detected in the cancer cells and/or the surrounding hepatocytes. Integration of HBV DNA inot the host liver genome was found during hepatocarcinogenesis among the animals infected by HBV. These results suggest that exposure to HBV and AFB1 may play a synergistic role in the development of HCC, and support the viewpoint of an aetiological relationship between HBV and HCC.Abbreviations HCC hepatocellular carcinoma - HBV human hepatitis B virus - AFB1 aflatoxin B1 - GGT foci hyperplastic hepatocyte foci positive for -glutamyltranspeptidase - LCD liver cell dysplasia     

Hepatic aflatoxin B1‐DNA adducts and TP53 mutations in patients with hepatocellular carcinoma despite low exposure to aflatoxin B1 in southern Japan

Background & aims: Hepatitis B or C virus infection is considered to be the main cause of hepatocellular carcinoma (HCC) in Japan. Aflatoxin B1 (AFB1) is a carcinogen associated with HCC in regions with high exposure. Mutations in codon 249, exon 7 are a hallmark of AFB1 exposure. Therefore, to clarify the role of AFB1 in hepatocarcinogenesis, we examined AFB1‐DNA in liver tissue and sequenced TP53 in Japanese patients with HCC. Methods: Hepatocyte AFB1‐DNA adducts were determined immunohistochemically and direct sequencing of TP53 was done to determine mutations in 188 of 279 patients who underwent hepatic resection for HCC. We assessed hepatitis C virus antibodies (HCV Ab) and HBSAg expression; patients without either were defined as having non‐B non‐C hepatocellular carcinoma (NBNC HCC). Results: AFB1‐DNA adducts were detected in hepatocyte nuclei in 18/279 patients (6%), including13/83 patients (16%) with NBNC HCC and 5/51 patients (10%) expressing hepatitis B surface antigen. None of the patients with HCV Ab (n=136) were positive for AFB1‐DNA. The incidence of the G–T transversion and mutations in exon 7 of TP53 in patients with AFB1‐DNA adducts were significantly higher in patients with than in patients without AFB1‐DNA adducts. All three patients with the codon 249 AGG–AGT mutation had AFB1‐DNA adducts. Conclusion: Although exposure to AFB1 is thought to be low in Japan, it is still associated with hepatocarcinogenesis, particularly in NBNC HCC and hepatitis B individuals.     

Prevention of hepatocellular carcinoma in chronic viral hepatitis B and C infection

Hepatocellular carcinoma(HCC)is a leading cause of cancer-related mortality worldwide,with the majority of cases associated with persistent infection from hepatitis B virus(HBV)or hepatitis C virus(HCV).Natural history studies have identified risk factors associated with HCC development among chronic HBV and HCV infection.High-risk infected individuals can now be identified by the usage of risk predictive scores.Vaccination plays a central role in the prevention of HBV-related HCC.Treatment of chronic HBV infection,especially by nucleoside analogue therapy,could also reduce the risk of HBV-related HCC.Concerning HCV infection,besides the advocation of universal precautions to reduce the rate of infection,pegylated interferon and ribavirin could also reduce the risk of HCV-related HCC among those achieving a sustained virologic response.Recently there has been mounting evidence on the role of chemopreventive agents in reducing HBV-and HCV-related HCC.The continued advances in the understanding of the molecular pathogenesis of HCC would hold promise in preventing this highly lethal cancer.     

The polymorphisms of GSTM1, GSTT1, HYL1*2, and XRCC1, and aflatoxin B1-related hepatocellular carcinoma in Guangxi population, China.

AIM: High incidence rates of hepatocellular carcinoma (HCC) in Guangxi, China, are primarily due to heavy aflatoxin B1 (AFB1) exposure via corn and groundnut consumption. This study was designed to examine the polymorphisms associated of three carcinogen-metabolizing genes (namely: GSTM1, GSTT1, and HYL1*2) and one DNA-repair gene (namely: XRCC1), and investigate their role as susceptibility markers for HCC. METHODS: We conducted a case-control study including 257 cases of cancer and 649 hospital-based age, sex, ethnicity, and hepatitis B virus infection-matched controls to examine the role of genetic polymorphisms of four genes (GSTM1, GSTT1, HYL1*2, and XRCC1) in the context of HCC risk for the Guangxi population. Genomic DNA isolated from 2ml whole blood was used to genotype GSTM1, GSTT1, HYL1*2, and XRCC1 by means of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. RESULTS: GSTT1-null genotype was not significantly associated with the risk of HCC, but GSTM1-null genotype [adjusted odds ratio (OR)=2.29, 95% confidence interval (CI)=1.59-3.31], HYL1*2 genotypes with 113 His allele (namely: YH/HH, adjusted OR=2.55, CI=1.78-3.65), and XRCC1 genotypes with 399 Gln allele (namely: AG/GG, adjusted OR=2.47, CI=1.72-3.54) increased the HCC risk. Compared with those individuals who did not express any putative risk genotypes as reference (OR=1), individuals featuring all of the putative risk genotypes [GSTM1-null, HYL1*2-YH/HH, and XRCC1-AG/GG] did experience a significantly greater cancer risk (adjusted OR=10.83, CI=5.44-21.59, P(interaction)<0.01). Additionally, the risk of HCC did appear to differ more significantly among individuals featuring risk genotypes and high-level or long-term AFB1 exposure, whose adjusted ORs (CIs) were 52.44 (17.51-157.08) and 326.93 (38.58-2770.52), respectively. CONCLUSIONS: The results suggest that carcinogen metabolism and DNA-repair pathways may simultaneously modulate the risk of HCC for Guangxi population, and, particularly for these having high-level or long-term AFB1 exposure.     

Hepatocellular carcinoma and the risk of occupational exposure

Hepatocellular carcinoma(HCC)is the most common type of liver cancer.The main risk factors for HCC are alcoholism,hepatitis B virus,hepatitis C virus,nonalcoholic steatohepatitis,obesity,type 2 diabetes,cirrhosis,aflatoxin,hemochromatosis,Wilson’s disease and hemophilia.Occupational exposure to chemicals is another risk factor for HCC.Often the relationship between occupational risk and HCC is unclear and the reports are fragmented and inconsistent.This review aims to summarize the current knowledge regarding the association of infective and non-infective occupational risk exposure and HCC in order to encourage further research and draw attention to this global occupational public health problem.     

Individualized hepatocellular carcinoma risk: The challenges for designing successful chemoprevention strategies

Hepatocellular carcinoma (HCC) develops in the context of environmental risk factors like chronic viral hepatitis, diabetes and alcohol exposure, often associated to an increased risk of cirrhosis. Antiviral treatments that are effective to counteract hepatitis B and C may also attenuate the risk of tumor development. However, since hepatitis B-related carcinogenesis is promoted independently of the onset of cirrhosis, such antiviral treatments as nucleo(t)side analogs can promote regression of cirrhosis, prevent clinical decompensation and variceal bleeding but not HCC. This means that in successfully treated patients with cirrhosis, HCC is often the consequence of their extended survival. In hepatitis C patients, a sustained virological response to interferon-based therapies can reduce the rate of HCC development, even in patients with cirrhosis who experience histological regression of their liver disease. Future therapies aimed at this endpoint in at risk populations should take into consideration pretreatment patient stratification for host, viral and environmental risk factors. In this context the recent discovery of single nucleotide polymorphisms involved in the immune system function and tumorigenesis, might permit enrollment of populations of patients enriched with HCC risk factors for targeted chemopreventive therapies. This could finally pave the way to personalized algorithms, as already seen in the diagnosis and treatment schemes for chemoprevention.     

Interaction of Hepatitis B Virus X Protein with the Pregnane X Receptor Enhances the Synergistic Effects of Aflatoxin B1 and Hepatitis B Virus on Promoting Hepatocarcinogenesis

Background and AimsHepatitis B virus (HBV) infection has been found to increase hepatocellular sensitivity to carcinogenic xenobiotics, by unknown mechanisms, in the generation of hepatocellular carcinoma. The pregnane X receptor (PXR) is a key regulator of the body’s defense against xenobiotics, including xenobiotic carcinogens and clinical drugs. In this study, we aimed to investigate the molecular mechanisms of HBV X protein (HBx)-PXR signaling in the synergistic effects of chemical carcinogens in HBV-associated hepatocarcinogenesis.MethodsThe expression profile of PXR-cytochrome p450 3A4 (CYP3A4) signaling was determined by PCR, western blotting, and tissue microarray. Cell viability and aflatoxin B1 (AFB1) cytotoxicity were measured using the cell counting kit-8 assay. Target gene expression was evaluated using transient transfection and real time-PCR. The genotoxicity of AFB1 was assessed in newborn mice with a single dose of AFB1.ResultsHBx enhanced the hepatotoxicity of AFB1 by activating CYP3A4 and reducing glutathione S-transferase Mu 1 (GSTM1) in cell lines. Activation of PXR by pregnenolone 16α-carbonitrile increased AFB1-induced liver tumor incidence by up-regulating oncogenic KRAS to enhance interleukin (IL)-11:IL-11 receptor subunit alpha-1 (IL11RA-1)-mediated inflammation in an HBx transgenic model.ConclusionsOur finding regarding AFB1 toxicity enhancement by an HBx-PXR-CYP3A4/ GSTM1-KRAS-IL11:IL11RA signaling axis provides a rational explanation for the synergistic effects of chemical carcinogens in HBV infection-associated hepatocarcinogenesis.     

Viral hepatitis and hepatocellular carcinoma: From molecular pathways to the role of clinical surveillance and antiviral treatment

Hepatocellular carcinoma (HCC) is a global health challenge. Due to the high prevalence in low-income countries, hepatitis B virus (HBV) and hepatitis C virus infections remain the main risk factors for HCC occurrence, despite the increasing frequencies of non-viral etiologies. In addition, hepatitis D virus coinfection increases the oncogenic risk in patients with HBV infection. The molecular processes underlying HCC development are complex and various, either independent from liver disease etiology or etiology-related. The reciprocal interlinkage among non-viral and viral risk factors, the damaged cellular microenvironment, the dysregulation of the immune system and the alteration of gut-liver-axis are known to participate in liver cancer induction and progression. Oncogenic mechanisms and pathways change throughout the natural history of viral hepatitis with the worsening of liver fibrosis. The high risk of cancer incidence in chronic viral hepatitis infected patients compared to other liver disease etiologies makes it necessary to implement a proper surveillance, both through clinical-biochemical scores and periodic ultrasound assessment. This review aims to outline viral and microenvironmental factors contributing to HCC occurrence in patients with chronic viral hepatitis and to point out the importance of surveillance programs recommended by international guidelines to promote early diagnosis of HCC.     

Study on the association of Helicobacter species with viral hepatitis-induced hepatocellular carcinoma

Helicobacter species are important pathogens and previous studies in mice suggested a link between colonization by Helicobacter hepaticus (H. hepaticus) and hepatocellular carcinoma (HCC). This study aimed at corroborating this potential link in human patients. We used a sensitive and specific Helicobacter ssp PCR assay to screen stool samples from a collective of patients with viral-induced HCC (hepatitis B or hepatitis C) and a control group for presence of Helicobacter ssp DNA. Although retrieving DNA of H. pylori and H. canadensis from stool samples of non-HCC patients, we found no evidence indicating the presence of H. hepaticus in HCC-patients with chronic hepatitis B or hepatitis C. Interestingly we found H. canadensis in a stool sample of a patient presenting with diarrhea. Taken together, our data argue against a pathogenic role of H. hepaticus in viral-induced HCC. Yet, our results do not exclude a role of H. hepaticus in those HCC cases caused by other carcinogens, such as aflatoxin. Moreover, we speculate that H. canadensis might be a novel gastrointestinal pathogen.     

酒精合并病毒性肝损伤与肝癌的关系

病毒性肝炎和酒精均是肝细胞癌(肝癌)致病的主要病因, 慢性乙型肝炎病毒(hepatitis Bvirus, HBV)和丙型肝炎病毒(hepatitis C virus,HCV)感染引起肝癌的危险性为正常人10倍以上, 饮酒引起肝癌危险性近2倍, 病毒性肝炎伴饮酒危险性进一步增大. 病毒和酒精协同作用的机制尚未完全清楚, 在多数患者, 两种因素均先通过肝硬化再进展为肝癌. 预防肝炎病毒感染和控制饮酒是预防肝癌的最好手段, 普及乙型肝炎疫苗接种已取得非常好的成绩. 对慢性HBV和HCV感染者应抗病毒治疗, 早期戒酒对预防肝癌的肯定有益, 但尚没有足够证据支持戒酒可减低肝硬化向肝癌发展的风险.     

Expression of IGF- II, p53, p21 and HBxAg in precancerous events of hepatocarcinogenesis induced by AFB1 and/or HBV in tree shrews

INTRODUCTION In order to study the relationship between oncogene expression and HCC generation, we observed the precancerous hepatic GGT foci, IGF-Ⅱ, p53 and p21 expression during hepatocarcinogenesis of tree shrew induced by hepatitis B virus (HBV) and/or aflatoxin B1 (AFB1).     

Current impact of viral hepatitis on liver cancer development: The challenge remains

Chronic infections due to hepatitis B and hepatitis C viruses are responsible for most cases of hepatocellular carcinoma (HCC) worldwide, and this association is likely to remain during the next decade. Moreover, viral hepatitis-related HCC imposes an important burden on public health in terms of disability-adjusted life years. In order to reduce such a burden, some major challenges must be faced. Universal vaccination against hepatitis B virus, especially in the neonatal period, is probably the most relevant primary preventive measure against the development of HCC. Moreover, considering the large adult population already infected with hepatitis B and C viruses, it is also imperative to identify these individuals to ensure their access to treatment. Both hepatitis B and C currently have highly effective therapies, which are able to diminish the risk of development of liver cancer. Finally, it is essential for individuals at high-risk of HCC to be included in surveillance programs, so that tumors are detected at an early stage. Patients with hepatitis B or C and advanced liver fibrosis or cirrhosis benefit from being followed in a surveillance program. As hepatitis B virus is oncogenic and capable of leading to liver cancer even in individuals with early stages of liver fibrosis, other high-risk groups of patients with hepatitis B are also candidates for surveillance. Considerable effort is required concerning these strategies in order to decrease the incidence and the mortality of viral hepatitis-related HCC.     

HCV HBV感染与肝细胞性肝癌

调查了肝癌高发地区不同肝病患者中丙型肝炎病毒(HCV)感染率。慢性肝病患者绝大多数已被乙型肝炎病毒(HBV)感染。HCV第二代抗体阳性率,肝癌7.3％,肝硬化6.6％,慢性肝炎6.6％和急性肝炎3.4％。两种病毒的复合感染率,肝癌5.1％,肝硬化1.7％,慢性肝炎3.9％和急性肝炎1.1％。在38例HCV抗体阳性的慢性肝病患者中,ALT异常84.2％,有输血史者占57.9％,HCV-RNA阳性率为71.1％。本研究的资料分析提示,在肝癌高发地区尽管HCV抗体阳性率较低,但HCV感染也是肝癌发生的重要病因之一。     

Enhanced duck hepatitis B virus gene expression following aflatoxin B1 exposure

Epidemiological studies have suggested synergistic interactions between chronic hepatitis B virus (HBV) infection and aflatoxin B1 (AFB1) exposure in the etiology of hepatocellular carcinoma (HCC), although the molecular mechanisms of their interactions are still not understood. The aim of this study was to use the Pekin duck model to investigate the impact of AFB1 exposure on duck hepatitis B virus (DHBV) replication during the early stages of virus-carcinogen interactions. Six-week-old chronic DHBV-carrier or uninfected ducks were exposed to AFB1 for 5 weeks or treated with dimethylsulfoxide (DMSO) as a control. Animals were observed for 6 to 13 weeks after AFB1 treatment to study the influence of AFB1 exposure on DHBV replication and liver pathologies. Histological analysis showed more marked changes in the livers of AFB1-treated ducks, and these were enhanced by DHBV infection. A significant increase in serum and liver DHBV DNA level was observed in AFB1-treated ducks as compared with DMSO-treated controls. In addition, viral RNAs, in particular the pregenomic RNA that is the template of viral replication, and intrahepatic DHBV DNA replicative intermediates, were significantly increased by AFB1 treatment. Moreover, an overexpression and accumulation of DHBV large envelope (L) protein was observed in the hepatocytes of AFB1-exposed animals. The in vitro study has further confirmed an increase in intracellular viral DNA and in virus release in AFB1-treated primary duck hepatocytes. Taken together, our results indicate that AFB1 exposure leads to an increase in virus gene expression associated with intrahepatic accumulation of DHBV L protein and enhanced liver pathology.     

Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma

Chronic infection with viral hepatitis affects half a billion individuals worldwide and can lead to cirrhosis, cancer, and liver failure. Liver cancer is the third leading cause of cancer-associated mortality, of which hepatocellular carcinoma (HCC)represents 90%of all primary liver cancers. Solid tumors like HCC are complex and have heterogeneous tumor genomic profiles contributing to complexity in diagnosis and management. Chronic infection with hepatitis B virus (HBV),hepatitis delta virus (HDV), and hepatitis C virus (HCV) are the greatest etiological risk factors for HCC. Due to the significant role of chronic viral infection in HCC development, it is important to investigate direct (viral associated) and indirect (immune-associated) mechanisms involved in the pathogenesis of HCC. Common mechanisms used by HBV, HCV, and HDV that drive hepatocarcinogenesis include persistent liver inflammation with an impaired antiviral immune response, immune and viral protein-mediated oxidative stress, and deregulation of cellular signaling pathways by viral proteins.DNA integration to promote genome instability is a feature of HBV infection, and metabolic reprogramming leading to steatosis is driven by HCV infection. The current review aims to provide a brief overview of HBV, HCV and HDV molecular biology, and highlight specific viral-associated oncogenic mechanisms and common molecular pathways deregulated in HCC, and current as well as emerging treatments for HCC.     

Prevention of hepatocellular carcinoma in patients with chronic hepatitis B

Patients with chronic hepatitis B are at significant risk for hepatocellular carcinoma(HCC). Globally,over half a million people each year are diagnosed with HCC,with marked geographical variations. Despite overwhelming evidence for a causal role of hepatitis B virus(HBV) infection in the development of HCC and a well-established relationship between high baseline hepatitis B viral load and cumulative risk of HCC,the molecular basis for this association has not been fully elucidated. In addition,a beneficial role for antiviral therapy in preventing the development of HCC has been difficult to establish. This review examines the biological and molecular mechanisms of HBV-related hepatocarcinogenesis,recent results on the effect of modern nucleos(t)ides on the rate of HCC development in high risk HBV cohorts and the potential mechanisms by which long-term antiviral therapy with potent inhibitors of HBV replication might reduce the risk of HCC in patients with chronic hepatitis B. Although evidence from randomized controlled trials shows the favourable effects of antiviral agentsin achieving profound and durable suppression of HBV DNA levels while improving liver function and histology,robust evidence of other long-term clinical outcomes,such as prevention of HCC,are limited.     

Hepatitis B virus x gene and cyanobacterial toxins promote aflatoxin B1-induced hepatotumorigenesis in mice

AIM: To assess the combinative role of aflatoxin B1 (AFB1), cyanobacterial toxins (cyanotoxins), and hepatitis B virus (HBV) x gene in hepatotumorigenicity. METHODS: One-week-old animals carrying HBV x gene and their wild-type littermates were intraperitoneally (ip) injected with either single-dose AFB1 [6 mg/kg body weight (bw)], repeated-dose cyanotoxins (microcystin-LR or nodularin, 10μg/kg bw once a week for 15 wk), DMSO (vehicle control) alone, or AFB1 followed by cyanotoxins a week later, and were sacrificed at 24 and 52 wk post-treatment. RESULTS: AFB1 induced liver tumors in 13 of 29 (44.8%) transgenic mice at 52 wk post-treatment, significantly more frequent than in wild-type mice (13.3%). This significant difference was not shown in the 24-wk study. Compared with AFB1 exposure alone, MC-LR and nodularin yielded approximately 3-fold and 6-fold increases in the incidence of AFB1-induced liver tumors in wild-type animals at 24 wk, respectively. HBV x gene did not further elevate the risk associated with co-exposure to AFB1 and cyanotoxins. With the exception of an MC-LR-dosed wild-type mouse, no liver tumor was observed in mice treated with cyanotoxins alone at 24 wk. Neither DMSO-treated transgenic mice nor their wild-type littermates had pathologic alterations relevant to hepatotumorigenesis in even up to 52 wk. CONCLUSION: HBV x gene and nodularin promote the development of AFB1-induced liver tumors. Co-exposure to AFB1 and MC-LR tends to elevate the risk of liver tumors at 24 wk relative to exposure to one of them. The combinative effect of AFB1, cyanotoxins and HBVx on hepatotumorigenesis is weak at 24 wk.     

Host nucleotide polymorphism in hepatitis B virusassociated hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is etiologically linked with hepatitis B virus(HBV) and is the leading cause of death amongst 80% of HBV patients. Among HBV affected patients, genetic factors are also involved in modifying the risk factors of HCC. However, the genetic factors that regulate progression to HCC still remain to be determined. In this review, we discuss several single nucleotide polymorphisms(SNPs) which were reportedly associated with increased or reduced risk of HCC occurrence in patients with chronic HBV infection such as cyclooxygenase(COX)-2 expression specifically at COX-2-1195G/A in Chinese, Turkish and Egyptian populations, tumor necrosis factor α and the three most commonly studied SNPs: PAT-/+, Lys939Gln(A33512C, rs2228001) and Ala499Val(C21151T, rs2228000). In genome-wide association studies, strong associations have also been found at loci 1p36.22, 11q22.3, 6p21(rs1419881, rs3997872, rs7453920 and rs7768538), 8p12(rs2275959 and rs37821974) and 22q11.21. The genes implicated in these studies include HLA-DQB2, HLA-DQA1, TCF19, HLA-C, UBE2L3, LTL, FDX1, MICA, UBE4 B and PG. The SNPs found to be associated with the above-mentioned genes still require validation in association studies in order to be considered good prognostic candidates for HCC. Screening of these polymorphisms is very beneficial in clinical experiments to stratify the higher or lower risk for HCC and may help in designing effective and efficient HCC surveillance programs for chronic HBV-infected patients if further genetic vulnerabilities are detected.     

Environmental Exposures and Hepatocellular Carcinoma

Infection with hepatitis B and/or hepatitis C virus is a well-established risk factor for the development of hepatocellular carcinoma (HCC). However, it is now clear that certain occupational, environmental, and lifestyle factors also play a role in cancer development. Among these factors are smoking, alcohol consumption, workplace exposure to vinyl chloride, and exposure to polycylic aromatic hydrocarbons and aflatoxins. There is also evidence that several other chemical and infectious agents have a role in inducing HCC in humans. Epidemiologic studies and the use of biomarkers have provided essential data to demonstrate the importance of some of these factors in human risk, while animal studies have suggested that other chemicals may also play a role. Although immunization against hepatitis B virus infection remains the primary method of preventing HCC in regions of the world where this virus is a primary etiologic agent, there is currently no vaccine for hepatitis C virus. Thus, limiting exposure to other known risk factors remains an important mechanism in preventing HCC.