Hepatocellular Carcinoma In Hepatitis B Virus Carriers Research Articles

Protective effect of N-acetylcysteine against hepatocellular carcinoma in hepatitis B virus carriers.

Hepatitis B virus (HBV) infection is a leading risk factor for hepatocellular carcinoma (HCC), contributing to cancer development through direct genomic integration and chronic inflammation. N-acetylcysteine (NAC), known for its antioxidant properties, is widely utilized in cancer prevention. However, clinical evidence regarding its protective effect against HCC in HBV carriers remains sparse. In this retrospective cohort study spanning 2008 to 2018, we utilized Taiwan's National Health Insurance Research Database (NHIRD) to include 1,061,174 chronic HBV carriers. Participants were stratified into NAC users and non-users using Propensity Score Matching. We assessed the incidence of HCC in both cohorts, examining the relationship between NAC usage duration and HCC incidence, and evaluating the dose-response effect. NAC users exhibited a significantly lower risk of developing HCC (adjusted hazard ratio [aHR]: 0.38; 95% confidence interval [CI]: 0.36-0.40; P < 0.0001). A dose-response relationship was evident, with higher cumulative defined daily doses (cDDDs) of NAC correlating with reduced HCC risk, revealing a significant trend (P < 0.0001). Notably, a daily NAC intensity of > 1.4 DDDs was associated with a decreased risk of HCC in HBV patients. Our results demonstrate that the use of NAC, in a dose-dependent manner, is intricately linked with a diminished incidence of HCC in individuals chronically infected with the HBV.

Dual hepatitis B and C-associated hepatocellular carcinoma: clinical characteristics, outcome, and prognostic role of albumin-bilirubin grade.

Albumin-bilirubin (ALBI) grade is used to evaluate the outcome of patients with hepatocellular carcinoma (HCC) which is often associated with chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. This study aimed to investigate the clinical characteristics, outcome, and prognostic role of ALBI grade in dual HBV/HCV-related HCC. A total 3341 HCC patients with viral etiology were prospectively enrolled and retrospectively analyzed. Multivariate Cox proportional hazards model was used to identify independent prognostic predictors. Of all patients, 2083 (62%), 1068 (32%), and 190 (6%) patients had HBV, HCV, and dual HBV/HCV infection, respectively. The mean age of HBV, HCV, and dual virus group was 60, 68, and 64years (p < 0.001), respectively. There was no significant survival difference between HBV, HCV, and dual HBV/HCV-related HCC group (p = 0.712). Multivariate Cox analysis in dual HBV/HCV-related HCC showed that multiple tumors [hazard ratio (HR): 1.537, p = 0.044], tumor size >3cm (HR 2.014, p = 0.044), total tumor volume (TTV) >50 cm3 (HR 3.050, p < 0.001), vascular invasion (HR 3.258, p < 0.001), performance status 2-4 (HR 2.232, p < 0.001), ALBI grade 2-3 (HR 2.177, p < 0.001), and BCLC stage B-D (HR 2.479, p < 0.001) were independent predictors of poor survival. Dual viral infection does not accelerate the development of HCC in HBV carriers. Patient survival is similar between dual HBV/HCV-related HCC and single HBV- or HCV-related HCC group. The ALBI grade is a robust prognostic model in dual virus-related HCC to discriminate patient long-term survival.

A genetic variant in microRNA-122 regulatory region confers risk for chronic hepatitis B virus infection and hepatocellular carcinoma in Han Chinese.

miR-122 plays a vital role in the development of chronic hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). Based on data from the Encyclopedia of DNA Elements (ENCODE), two single nucleotide polymorphisms (SNPs), rs4309483 and rs4503880, were identified in the upstream regulatory region of miR-122. A case-control study consisting of 1,300 HBV-positive HCC cases, 1,344 HBV carriers, and 1,344 persons who cleared HBV naturally was carried out to test the association between the two SNPs and the risk for chronic HBV infection and HCC. The CA/AA genotypes of rs4309483 were associated with significantly increased risk for HCC [adjusted odds ratio (OR) = 1.21, 95% confidence intervals (CIs) = 1.02-1.43, P = 0.025] compared with HBV carriers, but decreased risk for chronic HBV infection (adjusted OR = 0.82, 95% CIs = 0.70-0.97, P = 0.017) compared with persons who cleared HBV naturally. The genotype-expression correlation between rs4309483 and the expression of primary or mature miR-122 expression was investigated in 29 pairs of HBV positive HCC and noncancerous liver tissues. In noncancerous liver tissues, subjects carrying the CA genotype exhibited significantly lower expression level of pri-miR-122 than those carrying the CC genotype. In addition, positive or inverse correlation between the expression levels of pri-miR-122 and mature miR-122 were observed in HCC tissues or noncancerous tissues, respectively. These findings indicate that the C to A base change of rs4309483 may alter the expression of miR-122, thus providing protective effect from chronic HBV infection but an increased risk for HCC in HBV carriers.

Fine mapping of hepatitis B virus pre‐S deletion and its association with hepatocellular carcinoma

Naturally occurring pre-S deletion mutants have been identified in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). This study investigated whether specific deletions within the pre-S region were associated with HCC development. The virologic characteristics of 56 HBV chronic carriers and 112 age-matched patients with HBV-related HCC were examined. The HCC patients had a significantly higher frequency of high viral load, basal core promoter mutation and pre-S deletion than chronic carriers. Sequencing analysis showed that the deleted regions were clustered mainly in the C terminus of pre-S1 (70.5%) and the N terminus of pre-S2 (72.7%) in HCC patients. Immuno-epitope mapping of these pre-S deletion sequences showed that all the deletion regions encompassed T- and B- cell epitopes and the B-cell epitope at amino acid 1-6 of pre-S2 was significantly deleted in HCC patients (60.0% vs. 0.0%; P = 0.036). Functional mapping of these deletion mutants showed that most of HCC patients lost one or more functional sites and the deletion of site for viral secretion (aa 1-5 of pre-S2 domain) was significantly detected in HCC patients than chronic carriers (62.5% vs. 0.0%; P = 0.029). Computational protein function prediction indicated that these mutants may have different molecular functions and participate in other biological processes compared with wild-type pre-S. Deletion of B-cell epitope at amino acid 1-6 of pre-S2 region and the site for virion secretion are significantly associated with the development of HCC in HBV carriers.

Molecular characterisation of the genotypes and mutants of hepatitis B virus from South Africa

Genotypes A, D and E of hepatitis B virus (HBV) circulate in southern Africa. The prevalence of subgenotype A1, a segment of genotype A, and its high mean nucleotide divergence suggest that this subgenotype is endemic in South African blacks. We have fully characterized subgenotype A1 sequences and identified mutations or variations that could account for the high HBeAg-negativity and low HBV DNA levels, seen in carriers of the virus. These mutations or variations can reduce HBeAg expression at three levels. Firstly, at the transcriptional level, the core promoter mutations 1762T1764A, highly prevalent in isolates from hepatocellular carcinoma (HCC) patients reduce HBeAg expression. Secondly, at the translational level, mutations at 1809-1812 that alter the Kozak sequence of the precore/core open reading frame are stable traits of subgenotype A1 and affect HBeAg expression, at a level comparable to 1762T1764A. The presence of 1762T1764A, together with 1809-1812 mutations, reduced HBeAg expression in an additive manner. Thirdly, a G to T transversion at 1862 of the precore region affects HBeAg expression at the post-translational level, by interfering with signal peptide cleavage. Unique sequence alterations in the transcriptional regulatory elements and the HBV polymerase coding region were found in subgenotype A1. These, together with the mutations affecting HBeAg expression, may contribute to the pathogenesis of HBV-induced HCC, which has a high incidence in southern African blacks. In fact, we have shown a 4.5-fold increased risk of HCC in HBV carriers infected with genotype A, which is entirely attributable to subgenotype A1.

Hepatitis B virus pre‐S mutants, endoplasmic reticulum stress and hepatocarcinogenesis

Although hepatitis B virus (HBV) has been documented to cause hepatocellular carcinoma (HCC), the exact role of HBV in the development of HCC remains enigmatic. Several hypotheses have been proposed to explain the potential mechanism, including insertional mutagenesis of HBV genomes and transcriptional activators of HBV gene products such as hepatitis B x protein (HBx) and truncated middle S mutants. In the past few years, we have identified two types of large HBV surface antigens (LHBs) with deletions at the pre-S1 (DeltaS1-LHBs) and pre-S2 (DeltaS2-LHBs) regions in ground glass hepatocytes. The pre-S mutant LHBs are retained in the endoplasmic reticulum (ER) and escape from immune attack. The pre-S mutants, particularly DeltaS2-LHBs, are increasingly prevalent in patients with hepatitis B e antigen (HBeAg)-positive chronic HBV infection, ranging from 6% before the 3rd decade to 35% in the 6th decade. In HCC patients, the two pre-S mutants were detected in 60% of HCC patients, in the serum and in HCC tissues. Pre-S mutant LHBs can initiate ER stress to induce oxidative DNA damage and genomic instability. Furthermore, pre-S mutant LHBs can upregulate cyclooxygenase-2 and cyclin A to induce cell cycle progression and proliferation of hepatocytes. In transgenic mice, the pre-S mutants can induce dysplasia of hepatocytes and development of HCC. In a nested control study, the presence of pre-S mutants carried a high risk of developing HCC in HBV carriers. In summary, the findings we describe in this review suggest a potential role for HBV pre-S mutants in HBV-related hepatocarcinogenesis, providing a model of viral carcinogenesis associated with ER stress.

Usefulness of acute phase proteins for monitoring development of hepatocellular carcinoma in hepatitis B virus carriers

Serum levels of acute phase proteins (APP) have been used to diagnose and follow up treatment of liver diseases. This study was carried out to determine the usefulness of APP to predict development of hepatocellular carcinoma (HCC) among Hepatitis B virus (HBV) carriers. In a prospective study, serum haptoglobin, transferrin and alpha 2 macroglobulin levels of 55 subjects consisting of 20 HBV carriers, 18 HBV-positive HCC patients and 17 controls were determined using single radial immunodiffusion. The mean levels of haptoglobin were 141.75mg/dl+/-133.76, 97.11mg/dl+/-92.62,161.59mg/dl+/-146.86 for HBV carriers, HBV-positive HCC and controls respectively. The mean transferrin levels for HBV carriers, HBV-positive HCC and controls were 166.4mg/ dl+/-88.31, 140.0mg/dl+/-68.73 and 270.35mg/dl+/-122.79 respectively while similar values for alpha 2 macroglobulin were 195.4mg/dl+/-93.86, 189.83mg/dl+/-77.19 and 127.53mg/dl+/-43.29. No significant difference in the mean serum haptoglobin levels of HBV carriers and HBV-positive HCC (p=0.526), HBV carriers and controls (p= 0.883) and HBV-positive HCC and controls (p=0.295). The difference between the mean serum transferrin levels was insignificant between HBV carriers and HBV-positive HCC, p= 0.671, but was significant between HBV carriers, and HBV-positive HCC compared with controls, (p=0.005 and 0.000 respectively). No significant difference in alpha 2 macroglobulin between HBV carriers and HBV-positive HCC, (p=0.972), but the differences were significant between HBV carriers, and HBV-positive HCC and controls, (p=0.024 and 0.048 respectively). Haptoglobin, alpha 2 macroglobulin and transferrin lack predictive value for development of HCC in HBV carriers. Reduced transferrin and increased alpha 2 macroglobulin in HBV carriers might suggest active liver disease.

An intensive screening program detected high incidence of hepatocellular carcinoma (HCC) in hepatitis B virus carriers (HBVC) with abnormal alfa-fetoprotein (AFP) or abdominal ultrasongraphy (AUS)

4002 Background: Screening holds the promise to early detection and treatment of HCC. However, the efficacy in terms of decreasing disease-specific mortality and its cost-effectiveness remain controversial. Intensity of screening and selection of target patient group contribute to the success of such program. In this study we subjected hepatitis B virus carriers (HBVC) with at least 1 abnormal AFP or AUS to an intensive screening program and determine their prevalence and incidence of HCC. Methods: Enrollment criteria: age 40–70 years, HBsAg positive, Child-Pugh Liver Classification A or B. All patients were screened by serum AFP and AUS at enrollment. Patients with either AFP>20ng/dl or abnormal AUS were enrolled to an intensive program that screened patient with one or more hepatic angiogram plus lipiodol CT scan, followed by AFP/AUS every 3 months for 2 years then every 6 months. Patients with normal AFP/AUS were followed with AFP every 6 months and AUS repeated at the end of 2 years. Histology is the gold standard for diagnosis of HCC. Results: Between 10/97 and 11/00 we screened 1018 patients (m:f 688:330; mean age 48.4) and enrolled 171 patients (AFP+/AUS- 126; AFP-/AUS+ 38; AFP+/AUS+ 7) to the intensive screening program. After a median follow-up of 4.4 years we detected 47 HCCs (15 at enrollment and 32 during follow-up), giving a prevalence of 1473/100,000 (95%CI 858 to 2477 per 100,000) and annual incidence of 794/100,000 (95% CI 562 to 1122 per 100,000). 9 HCC were detected from 847 pts with normal AFP/AUS over 2 years giving an incidence of 223/100,000 (95% CI 116 to 429 per 100,000). Surgical resection: 17 cases. Main reasons for inoperability: poor liver function and multi-centric disease. Conclusion: An intensive screening program detects a high prevalence and incidence of HCC in HBVC with at least one abnormal AFP or AUS. Incidence of HCC is significantly lower in the population with normal screening AFP and AUS for 2 years. Survival data will be available for presentation. We acknowledge the Hong Kong Cancer Fund for support towards this project. No significant financial relationships to disclose.

Activation of Protooncogene C-jun by the X Protein of Hepatitis B Virus

A specific viral oncogenic mechanism has not been shown for hepatitis B virus (HBV), although persistent HBV infection has been strongly associated with the development of hepatocellular carcinoma (HCC). Most HCCs in HBV carriers contain integrated viral sequences in host DNA and this raises the question of whether such integrations ever contribute to oncogenesis. HBV does contain a gene (designated the hbx gene) which encodes a transcriptional trans-activator protein capable of activating homologous and heterologous regulatory sequences. Hbx has been detected in some human HCC with HBV integrations and the expressed hbx protein appears to have transcriptional transactivating activity. These findings raise the possibility that hbx expression could contribute to hepatocarcinogenesis by activating cellular genes that could contribute to oncogenicity. The possibility that the hbx protein may activate certain protooncogenes was investigated and we found that hbx can activate the protooncogene c-jun promoter. c-Jun was found to be expressed at a very low level in normal liver tissue but at high levels in HCCs of HBV-infected patients.

The protooncogene c‐jun is transactivated by the X protein of hepatitis B virus and highly expressed in liver cancer

AbstractA specific viral oncogenic mechanism has not been shown for hepatitis B virus (HBV), although persistent HBV infection has been strongly associated with the development of hepatocellular carcinoma (HCC). Most HCC in HBV carriers contain integrated viral sequences in host DNA and this raises the question of whether such integrations ever contribute to oncogenesis. HBV contains a gene (designated the hbx gene), which encodes a transcriptional transactivator protein capable of activating homologous and heterologous cis‐acting regulatory sequences. Among the regulatory sequences that are responsive to hbx are those of HBV and heterologous regulatory sequences in the long terminal repeat (LTR) of human immunodeficiency virus type 1 (HIV‐1) and Rous sarcoma virus, and regulatory sequences of simian virus 40 and the human β interferon gene. The diversity of regulatory sequence that appear to be activated by hbx suggests that the hbx protein acts by a general mechanism that is not DNA sequence specific and other cellular genes may be similarly transactivated. This property of hbx raises the question of whether hbx expression in infected hepatocytes may activate cellular genes that could play a role in HCC, and hbx has been shown to be expressed from integrated viral genomic DNA in some HCC. In this regard, hbx was found to activate transcription regulated by the promoter of the protooncogene c‐jun. c‐jun was found to be expressed at a very low level in normal liver tissue but at high levels in HCC of HBV‐infected patients.