Hepatitis B Virus-Associated Hepatocellular Carcinoma

Hepatitis B virus (HBV) is DNA-based virus, member of the Hepadnaviridae family, which can cause liver disease and increased risk of hepatocellular carcinoma (HCC) in infected individuals, replicating within the hepatocytes and interacting with several cellular proteins. Chronic hepatitis B can progressively lead to liver cirrhosis, which is an independent risk factor for HCC. Complications as liver decompensation or HCC impact the survival of HBV patients and concurrent HDV infection worsens the disease. The available data provide evidence that HBV infection is associated with the risk of developing HCC with or without an underlying liver cirrhosis, due to various direct and indirect mechanisms promoting hepatocarcinogenesis. The molecular profile of HBV-HCC is extensively and continuously under study, and it is the result of altered molecular pathways, which modify the microenvironment and lead to DNA damage. HBV produces the protein HBx, which has a central role in the oncogenetic process. Furthermore, the molecular profile of HBV-HCC was recently discerned from that of HDV-HCC, despite the obligatory dependence of HDV on HBV. Proper management of the underlying HBV-related liver disease is fundamental, including HCC surveillance, viral suppression, and application of adequate predictive models. When HBV-HCC occurs, liver function and HCC characteristics guide the physician among treatment strategies but always considering the viral etiology in the treatment choice.     

The Biomarkers for Predicting Viral Hepatitis-Associated Hepatocellular Carcinoma

BackgroundHepatocellular carcinoma (HCC) is the fifth most common cancer in the world, and more than half of the newly diagnosed cases are chronic hepatitis B patients. Due to the lack of specific clinical manifestations, many patients are already at an advanced stage at the time of diagnosis and therefore have missed the best time for treatment. Organs in a pathological state usually secrete specific substances into the blood, which can indirectly indicate the pathological state of the organ, so some biological markers in the blood can be used as a tool to predict the incidence of HCC.MethodsThe Research articles related to HCC were collected by searching PubMed databases with the keywords “hepatocellular carcinoma”, “serum biomarker”, “hepatitis B”, “prediction” and “prognosis”, and Additional articles were identified by manual search of references found in the primary articles, followed by a summary and review.ResultsViral hepatitis is the main cause of HCC worldwide, and this phenomenon is particularly prominent in Asian and African populations. A variety of serological markers including M2BPGi, IL-6 and COMP can be used to predict the incidence of long-term HCC in patients. The risk of HCC is dynamic rather than constant, and dynamic detection will help improve prediction accuracy. For hepatitis B patients, HBV DNA load and HBcr Ag are important predictive markers of HCC.ConclusionFor a high-risk population of HCC, early risk prediction is helpful to guide clinical work, and timely adjustments of the screening frequency and treatment plan are helpful to prolong the survival time of HCC patients.     

Hepatocellular Carcinoma inAutoimmune Hepatitis

To determine if hepatocellular carcinoma can develop in autoimmune hepatitis in the absence of viral infection and to assess its frequency, liver tissue removed at hepatectomy was tested for HBV DNA and HCV RNA in one patient and the frequency of hepatocellular carcinoma was determined in 212 other uniformly followed individuals. The liver tissue from the propositus was uninfected and only one patient (0.5%) in the cohort undergoing routine follow-up developed malignancy during 1732 patient-years of observation. Only one of 88 patients with cirrhosis (1%) developed hepatocellular carcinoma during 1002 patient-years of observation after cirrhosis (mean, 123 ± 9 months) and of the 65 patients with histological cirrhosis for at least five years, only one developed carcinoma during 162 ± 8 months (incidence, 1 per 965 patient-years). We conclude that hepatocellular carcinoma can develop in autoimmune hepatitis in the absence of viral infection. Its occurrence is rare and only in long-standing cirrhosis.     

Tenofovir vs. Entecavir on Outcomes of Hepatitis B Virus-Related Hepatocellular Carcinoma after Radiofrequency Ablation

For patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) treated with curative radiofrequency ablation (RFA), the effect of entecavir (ETV) vs. tenofovir disoproxil fumarate (TDF) on recurrence-free survival (RFS) and overall survival (OS) remains unclear. We aimed to compare the outcomes of patients receiving ETV or TDF after RFA. This study consecutively collected patients who were treated with ETV (n = 202) or TDF (n = 102) for chronic hepatitis B (CHB) after curative RFA of HCC from December 2015 to January 2021 at Sun Yat-sen University Cancer Center. There were 130 patients in the ETV group and 77 patients in the TDF group after we performed 1-to-n propensity score matching. Kaplan–Meier and Cox regression analyses were performed to validate possible risk factors for RFS and OS. In addition, we estimated the curative effect of ETV and TDF for HBV-related hepatitis by recording the change in serum HBV DNA and ALBI grade after RFA. During the study period (median 34.1 (interquartile range: 19.6–47.4 months) months), 123 (40.5%) patients suffered HCC recurrence, and 15 (4.9%) died. In the full cohort, the probability of HCC recurrence (41.6% vs. 37.3%, p = 0.49) and overall survival (95% vs. 95.1%, p = 0.39) at 5 years were similar between the ETV and TDF groups. In the matched cohort, HCC recurrence (40.8% vs. 40.3%, p = 0.35) and overall survival (96.9% vs. 93.5%, p = 0.12) at 5 years were similar between the ETV and TDF groups. Furthermore, the early RFS (<2 years) did not differ significantly between the two groups in the full and matched cohorts (p = 0.26, p = 0.13). Compared with the ALBI grade before RFA, the ALBI grade of 80 patients (41%) remained stable or improved in the ETV group and 64 patients (64%) in the TDF group (p < 0.001). The mean time of serum HBV DNA reduction to 0 was 9.13 (95% CI: 5.92–12.33) and 2.75 (95% CI: 2.01–3.49) months in the ETV and TDF groups, respectively (p = 0.015). The RFS and OS of patients after curative RFA for HCC were not significantly different between the ETV and TDF groups. TDF therapy was associated with a better effect of protecting liver function and reducing the load of HBV. Further validation studies are needed.     

Hepatitis B Virus Gene in Liver Tissue Promotes Hepatocellular Carcinoma Development in Chronic Hepatitis C Patients

The hepatitis B virus (HBV) gene has been detected in hepatocellular carcinoma (HCC) tissue negative for the hepatitis B surface antigen and positive for the hepatitis C virus (HCV) antibody, but the precise role of the HBV gene in hepatocarcinogenesis has yet to be clarified. We studied the HBV gene in liver tissue several years before the emergence of HCC. Eleven patients diagnosed with HCV-positive chronic liver disease and who developed HCC were assigned to group A. HBV DNA was detected in 8 of the 11 patients (73%). Twenty-five patients, who did not develop HCC, were selected as group B. Six of the group B patients were classified as DNA-positive (24%). The HBV DNA in liver tissue was found to be significantly related to HCC development (P < 0.01). Thus, the presence of the HBV gene in patients with chronic HCV associated-liver injury appears to promote hepatocarcinogenesis, although prospective studies are needed to confirm this result.     

Previous or Occult Hepatitis B Virus Infection in Hepatitis C Virus-Associated Hepatocellular Carcinoma Without Hepatic Fibrosis

We investigated the role of hepatitis B virus infection in development of hepatocellular carcinoma in hepatitis C virus-infected patients without hepatic fibrosis. Of 253 patients, 8 lacked hepatic fibrosis (group 1); group 2 included the remaining 245 patients. Clinicopathologic findings were compared between the groups. Hepatitis B x gene was sought in cancers and adjoining noncancerous liver. Group 1 showed better liver function parameters and milder active hepatitis than group 2. The proportion of patients with anti-hepatitis B virus antibody tended to be higher in group 1 than in group 2. The proportion of patients with hepatitis B x RNA in cancers was significantly higher in group 1 than in group 2. All group 1 patients had previous or occult hepatitis B virus infection. Previous or occult hepatitis B virus infection may be critical in development of hepatocellular carcinomas in hepatitis C virus-infected patients without hepatic fibrosis.     

Significance of Prior Hepatitis B Virus Infection in the Development of Hepatocellular Carcinoma in Patients with Chronic Hepatitis C

To clarify the clinical significance of prior hepatitis B virus (HBV) infection in the development of C-viral hepatocellular carcinoma (HCC), we conducted two studies: (1) Two hundred thirty-four patients with C-viral HCC and 320 patients with C-viral chronic liver disease without HCC admitted to our hospital between 1990 and 1994 were analyzed for the association of hepatitis B core antibody (HBcAb) positivity with HCC by multivariate logistic regression analysis, and this revealed HBcAb positivity as an independent risk factor for development of HCC adjusted for age and sex. (2) Four hundred fifty-nine patients with biopsy-proven hepatitis C virus-related chronic liver disease between 1986 and 1998 were enrolled in the cohort study and followed for the development of HCC. During an average follow-up of 6.6 ± 3.3 years, HCC developed in 63 patients, 37 of 160 patients positive for HBcAb and 26 of 299 patients negative for HBcAb. Multivariate Cox proportional regression analysis showed that the incidence of HCC increased by age, advanced stage of liver fibrosis, mean alanine aminotransferase value of more than 80 IU/liter, and positivity of HBcAb. Sustained virological responders after interferon therapy revealed a reduced risk for HCC development. In conclusion, prior HBV infection was shown to be one of the independent risk factors for development of HCC in C-viral chronic liver disease.     

乙肝病毒e抗原系统与肝癌的关系

本文报道了98例肝癌患者和70倒慢性肝病患者 HBV 抗原抗体系统的检测情况检查结果表明。①HCC 患者,HBeAg 阳性率为11.2％,慢性肝病组为34.3％(P<0.01);②抗-HBe 阳性率:慢性肝病组为38.5％而中晚期 HCC 为50％,小肝癌为61.1％(P<0.01),揭示肝癌患者 HBeAs 转为抗-HBe 阳性才增加,故慢性肝病患者 HBekAg 转为抗-HBe 阳性之后,必须定期随访,作 AFP 及 B 超监测,警惕 HCC。     

Identification of Hub Genes and Analysis of Prognostic Values in Hepatocellular Carcinoma by Bioinformatics Analysis

BackgroundHepatocellular carcinoma (HCC) is one of the most frequent cancers in the world. In this study, differentially expressed genes (DEGs) between tumor tissues and normal tissues were identified using the comprehensive analysis method in bioinformatics.Materials and MethodsWe downloaded 3 mRNA expression profiles from the Gene Expression Omnibus database to identify DEGs between tumor tissues and adjacent normal tissues. The Gene Ontology, Kyoto Encyclopedia of Genes and Genomes pathway analysis, protein-protein interaction network was performed to understand the function of DEGs. OncoLnc, which was linked to The Cancer Genome Atlas survival data, was used to investigate the prognostic values of hub genes. The expression of selected hub genes was validated by the quantitative real-time polymerase chain reaction.ResultsA total of 235 DEGs, consisting of 36 upregulated and 199 downregulated genes, were identified between tumor tissue and normal tissue. The Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analysis results showed the upregulated DEGs to be significantly enriched in cell division, mid-body, ATP binding and oocyte meiosis pathways. The downregulated DEGs were mainly involved in epoxygenase P450 pathway, extracellular region, oxidoreductase activity and metabolic pathways. Ten hub genes, including Aurora kinase A, Cell division cycle 20, formiminotransferase cyclodeaminase, UBE2C, Cyclin B2, pituitary tumor-transforming gene 1, CDKN3, CKS1B, Topoisomerase-II alpha and KIF20A, were identified as the key genes in HCC. Survival analysis found the expression of hub genes to be significantly correlated with the survival of patients with HCC.ConclusionsThe present study identified hub genes and pathways in HCC that may be potential targets for diagnosis, treatment and prognostic prediction.     

Identification and Validation of an Immune-related Prognostic Signature for Hepatocellular Carcinoma

Background and AimsThe immune system plays vital roles in hepatocellular carcinoma (HCC) initiation and progression. The present study aimed to construct an immune-gene related prognostic signature (IRPS) for predicting the prognosis of HCC patients.MethodsGene expression data were retrieved from The Cancer Genome Atlas database. The IRPS was established via least absolute shrinkage and selection operator (LASSO) and multivariate Cox regression analysis. The prognostic values of the IRPS were further validated using the International Cancer Genome Consortium (ICGC) dataset.ResultsA total of 62 genes were identified as candidate immune-related prognostic genes. According to the results of Lasso and multivariate Cox regression analysis, we established an IRPS and confirmed its stability and reliability in the ICGC dataset. The IRPS was significantly associated with advanced clinicopathological characteristics. Both Cox regression analyses revealed that the IRPS could be independent risk factors influencing prognosis of HCC patients. The relationships between the IRPS and infiltration of immune cells demonstrated that the IRPS was associated with immune cell infiltration. Furthermore, a nomogram was constructed to estimate the survival probability of HCC patients.ConclusionsThe IRPS was effective for predicting prognosis of HCC patients, which might serve as novel prognostic and therapeutic biomarkers for HCC.     

Lamivudine versus Entecavir for Newly Diagnosed Hepatitis B Virus-Related Hepatocellular Carcinoma

Background/AimsAntiviral therapy is a key component in the management of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) patients. However, whether the potent drug entecavir is more effective than a less potent drug, such as lamivudine, in HBV-related HCC is not clear.MethodsA retrospective cohort of 451 newly diagnosed, HBV-related HCC patients without antiviral therapy at diagnosis, who started antiviral therapy with either entecavir (n=249) or lamivudine (n=202), were enrolled.ResultsThe median survival was longer for the entecavir group than for the lamivudine group, and lamivudine use (vs entecavir) was an independent factor for mortality (hazard ratio [HR], 1.49; p=0.002). Lamivudine use (vs entecavir) was an independent risk factor for new-onset hepatic decompensation (HR, 1.67; p=0.010) in 318 patients without previous hepatic decompensation, and it was also an independent risk factor for recurrence after curative therapy (HR, 1.84; p=0.002) in 117 patients who received curative therapy. The findings were similar in a propensity score-matched cohort.ConclusionsOverall survival, decompensation-free survival, and recurrence-free survival were better in the entecavir-treated patients than in the lamivudine treated-patients, indicating that the potent antiviral drug should be the preferred choice in HBV-related HCC patients.     

Hepatitis C Virus Infection in African Patients with Liver Cirrhosis or Primary Hepatocellular Carcinoma

We have studied the prevalence of hepatitis C virus (HCV) infection in Rwandan patients with histologically proven liver cirrhosis (LC) or primary hepatocellular carcinoma (HCC). Anti-HCV antibodies were determined by using a second-generation test, with a line immunoassay for structural and non-structural antigens as confirmation. Seventy-nine patients with LC, 26 with HCC, and 54 voluntary blood donors as controls were evaluated. Anti-HCV antibodies were more prevalent in LC patients (48%) and in HCC patients (38%) than in the controls (17%; difference, p = 0.0001 and p = 0.03, respectively). Eighty-four per cent of LC patients and 54% of HCC patients were HBsAg-negative. The prevalence of anti-HCV antibodies was significantly higher for LC and HCC patients who had been in contact with HBV but who had no persistent HBV infection (p < 0.05). We conclude that HCV infection is common in Rwanda and is linked to LC and HCC.     

Evaluation of the Hepatocellular Carcinoma Predictive Scores PAGE-B and mPAGE-B among Brazilian Patients with Chronic Hepatitis B Virus Infection

Hepatitis B virus (HBV) is intrinsically oncogenic and related to hepatocellular carcinoma (HCC). Predictive scores of HCC have been developed but have been poorly studied in admixed populations. Therefore, we aimed to evaluate the performance of PAGE-B and mPAGE-B scores for HCC prediction in HBV Brazilian patients and factors related to HCC occurrence. This is a retrospective study that evaluated patients followed at a tertiary university center. A total of 224 patients were included, with a median follow-up period of 9 years. The mean age at HBV diagnosis was 38.71 ± 14.19 years, predominantly males (66.1%). The cumulative incidence of HCC at 3, 5, and 7 years was 0.993%, 2.70%, and 5.25%, respectively, being related in the univariate logistic regression analysis to male sex (p = 0.0461), older age (p = 0.0001), cirrhosis at HBV diagnosis (p < 0.0001), and higher values of PAGE-B and mPAGE-B scores (p = 0.0002 and p < 0.0001, respectively). Older age, male sex, and cirrhosis at HBV diagnosis were independently associated with HCC occurrence. The AUROCs of PAGE-B and mPAGE-B were 0.7906 and 0.7904, respectively, with no differences between them (p = 0.9767). In conclusion, both PAGE-B and mPAGE-B showed a correct prediction of HCC above 70% in this cohort.     

Hepatitis D Virus and Hepatocellular Carcinoma

Hepatitis D virus (HDV) is a small, defective RNA virus that depends on hepatitis B virus (HBV) for virion assembly and transmission. It replicates within the nucleus of hepatocytes and interacts with several cellular proteins. Chronic hepatitis D is a severe and progressive disease, leading to cirrhosis in up to 80% of cases. A high proportion of patients die of liver decompensation or hepatocellular carcinoma (HCC), but the lack of large prospective studies has made it difficult to precisely define the rate of these long-term complications. In particular, the question of whether HDV is an oncogenic virus has been a matter of debate. Studies conducted over the past decade provided evidence that HDV is associated with a significantly higher risk of developing HCC compared to HBV monoinfection. However, the mechanisms whereby HDV promotes liver cancer remain elusive. Recent data have demonstrated that the molecular profile of HCC-HDV is unique and distinct from that of HBV-HCC, with an enrichment of upregulated genes involved in cell-cycle/DNA replication, and DNA damage and repair, which point to genome instability as an important mechanism of HDV hepatocarcinogenesis. These data suggest that HBV and HDV promote carcinogenesis by distinct molecular mechanisms despite the obligatory dependence of HDV on HBV.