Development Of HCV-related Hepatocellular Carcinoma Research Articles

Identification and Verification of Ubiquitin D as a Gene Associated with Hepatitis C Virus-Induced Hepatocellular Carcinoma.

Accumulated studies have suggested that hepatitis C virus (HCV) infection is one of the leading causes for hepatocellular carcinoma (HCC). However, the mechanisms underlying the effect of HCV on the occurrence of HCC are still poorly understood. HCV infection datasets (GSE82177 and GSE17856) and HCC datasets (The Cancer Genome Atlas Liver Hepatocellular Carcinoma and GSE89377) were downloaded from Gene Expression Omnibus or TCGA for analysis. The common differentially expressed genes in the above four datasets were identified by R software. The expression of ubiquitin D (UBD) in HCV-infected HepG2 cells was detected by RT-qPCR and Western blot, respectively. The interaction between NS3 and p53 was detected by co-immunoprecipitation. The influence of UBD on the proliferation and migration ability of HepG2 cells was evaluated by CCK-8 and wound healing assay, respectively. UBD was upregulated in both HCV-infected samples and HCC samples. HCV NS3 interacted with p53 and inhibited its expression. HCV NS3-induced UBD promoted the proliferation and migration of HepG2 cells. Our results suggest that HCV NS3-induced UBD is positively correlated with the development of HCV-related HCC during HCV infection. Targeting UBD could be a potential strategy for preventing and treating HCV-induced HCC.

Expression of cyclo-oxygenase-2 and yap/taz in hepatocellular carcinoma in untreated and treated hepatitis C virus patients.

The pathogenesis of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) differs according to whether prior treatment with interferon (IFN) vs. direct-acting antiviral agents (DAAs) was administered. Cyclo- oxygenase-2 (COX-2), yes-associated protein 1 (YAP), and transcriptional co-activator with PDZ-binding motif (TAZ) play acrucial role in hepatocarcinogenesis. However, their roles in untreated or treated HCV-related HCC development have not been clarified. Therefore, we performed an immunohistochemical study and stained tissue from 83 HCV-related HCC cases using antibodies against COX-2, YAP, and TAZ and correlated their expression with the clinicopathological characteri stics and survival data. The cases were subdivided into 3 groups based on prior HCV treatment. In the 3 groups, COX-2 was significantly higher in HCC tissue compared with adjacent non-tumour liver tissue. However, the expression of YAP/TAZ was not significantly different between HCC and adjacent non-tumour tissue. We further grouped HCC cases into YAP+/TAZ+ and YAP-/TAZ- cases. In the YAP+/TAZ+ cases, COX-2 was significantly associated with tumour size, tumour multifocality, and late pathologic stage. No significant difference was observed in COX-2 and TAZ expression as aresult of IFN or DAA treatment; however, YAP was significantly higher in IFN-treated HCC. Cyclo-oxygenase-2 overexpression may play arole in late HCC development, while YAP/TAZ could play an early role in HCC progression. Sustained expression of combined YAP/TAZ could mediate the poor prognostic role of COX-2.

Association of MTHFR and TYMS gene polymorphisms with the susceptibility to HCC in Egyptian HCV cirrhotic patients.

Identification of host genetic factors influencing the risk of developing hepatocellular carcinoma (HCC) in patients with chronic hepatitis C virus (HCV) infection may help to refine patients' selection to benefit from specific preventative measures and/or adapted screening policies. Thus, this study aimed to investigate the association of MTHFR c.677C > T and c.1298A > C in addition to TYMS 3'-UTR 6-bp ins/del polymorphisms with the susceptibility to HCV-related HCC in an Egyptian population. Polymerase chain reaction-restriction fragment length polymorphism was performed to genotype the polymorphisms in 194 HCV-infected patients subdivided into liver cirrhotic (LC, n = 104) and HCC (n = 90) patients as well as 100 healthy subjects. In healthy controls, the MTHFR c.677C > T polymorphism under the homozygous and recessive models (p = 0.005) and the c.1298A > C polymorphism under all the tested genetic models (p-values range from < 0.001 to 0.007) were associated with an increased risk of HCC. In LC patients, the MTHFR c.677C > T polymorphism under the homozygous, dominant, and recessive models (p-values range from 0.001 to 0.007), as well as MTHFR c.1298A > C under the homozygous model only (p = 0.014), increased the susceptibility to HCC. The C/C and T/C haplotypes of MTHFR c.677C > T and MTHFR c.1298A > C polymorphisms were contributed to an increased risk of healthy subjects to develop HCC (p-values range from < 0.001 to 0.015), while only the T/C haplotype was associated with the progression of HCC in LC patients (p = 0.001). In conclusion, MTHFR c.677C > T and c.1298A > C in addition to their haplotypes may contribute to the development of HCV-related HCC in an Egyptian population. These findings may aid in the early diagnosis and management of HCC.

Evaluation of toll-like receptor 4 polymorphism in patients with hepatitis c virus-induced hepatocellular carcinoma

Background: Liver related pathologies including Hepatocellular Carcinoma (HCC) is a universal problem. Innate immunity receptors were accused in the etiopathogenesis of HCC with many conflicts. TLR4 is one of pathogen recognition receptors involved in the pathogenesis of many diseases and malignancies. TLR4 receptor polymorphisms were investigated in HCV related morbidities along with inconclusive results Objectives: to study the role of TLR4 rs 2149356 and rs 1927914 genotypes polymorphisms in HCV related HCC development. Methodology: 200 Chronically infected HCV patients were enrolled in this study. they were divided according to lab and clinical data into 100 CHC group and 100 HCC patients who were compared to health individual. The blood samples obtained were further proceed to full lab and TLR4 genotyping by RFLP-PCR technique Results: GT genotype and T allele of TLR4 rs 2149356 at 95% CI of 0.38 (0.21-0.70) was significantly increased in control group than in HCC and CHC groups. At 0.32(0.17-0.63) TLR4 rs 1927914 C allele and CT genotype was significantly increased in Controls than diseased groups while T allele is significantly increased in HCC than control group. Conclusions: TLR4 genotypes may play a protective role against HCC development among chronic HCV patients.

Evaluation of VCAM-1 and sPCAM-1 as biomarkers for the detection of hepatocellular carcinoma in patients with Hepatitis C virus

Hepatocellular carcinoma (HCC), the third leading cause of cancer deaths worldwide. Early diagnosis of HCC remains a challenge and diagnosis is usually achieved by biomarkers, but up to date, there is not a perfect single biomarker for this tumor. The diagnostic and predictive abilities of the biomarkers are limited by the heterogeneous nature of the HCC and to improve the predicatively and sensitivity, combinations of biomarkers, or a panel of biomarker combinations and clinical parameters as well as laboratory test results, might be required The objective of the present study was to assess a combination of biomarkers that is reliable in the diagnose and the prognosis of HCV-related HCC. For this purpose, a group of biomarkers including two novel ones; the vascular adhesion molecule-1 (VCAM-1) and soluble platelet endothelial cell adhesion molecule 1(sPECAM-1) were measured in Egyptian patients with chronic HCV and HCC. The ROC analyses were applied to evaluate the specificity and sensitivity of the biomarkers and come up with a recommendation for the employment of these markers to predict early development of hepatitis C to hepatocellular carcinoma. In the present study, 120 individuals from the National Hepatology and Tropical Medicine Research Institute, enrolled during the period from September 2014 to March 2017, were divided into four major groups; the control group which comprised 20 individuals.HCV group comprising 50 patients with chronic hepatitis C genotype 4, HCC group comprising 25 patients with HCC without HCV, and finally the HCC+HCV group comprising 25 patients with proven chronic hepatitis C genotype 4 and hepatocellular carcinoma. All the study patients were subjected to laboratory investigations which included liver functions, oxidative stress, LDH, AFP, IL-10, IL-6, IL-8, TNF-α, IFN-γ, Caspase-3, MCP-1, VCAM-1 and sPECAM-1, to predict early development of hepatitis C to hepatocellular carcinoma. The results suggested that there were significant differences in most of the liver functions, LDH, oxidative stress, IL-8, TNF-α, MCP-1 and AFP between healthy individuals and the groups with the disease forms. There were no significant correlations between serum IL-6, IL-10, INF-γ, VCAM-1, sPECAM-1 and caspase-3 with HCV or HCC. The ROC curve analyses revealed that sPECAM-1 and sVCAM-1 were not sensitive biomarkers for HCC. AFP levels were highly specific, but insufficiently sensitive to detect HCC. Serum PECAM and serum VCAM were not sensitive indicators for HCC diagnosis because of their low discriminative power between groups. Consequently, they were passive with respect to their predictive power in the progression of HCV-related HCC development. In conclusion, relying on a single marker for the diagnosis of HCC is not possible by employing the nowadays widely used markers in diagnostic practice.

Circulating IL-13 Is Associated with De Novo Development of HCC in HCV-Infected Patients Responding to Direct-Acting Antivirals

Simple SummaryChronic hepatitis C virus infection is one of the major risk factors for the development of hepatocellular carcinoma. New direct-acting antivirals substantially improved the cure rate of hepatitis C, but the incidence of hepatitis C virus-related hepatocellular carcinoma remains high. To identify the immune profile associated with the risk for hepatocellular carcinoma, we investigated a cohort of patients who developed de novo hepatocellular carcinoma following direct-acting antiviral treatment in comparison to controls who did not develop hepatocellular carcinoma. Our results can improve clinical management prior to the development of hepatocellular carcinoma.Direct-acting antivirals (DAAs) are highly effective in targeting hepatitis C virus (HCV) infections, but the incidence of HCV-related hepatocellular carcinoma (HCC) remains still high. In this study, we investigated a cohort of HCV-infected patients treated with DAAs who were followed up for 4 years after sustained virological response (SVR) achievement. Patients who developed de novo HCC following DAA treatment were compared to matched controls who did not develop HCC. These control patients were selected based on DAA treatment, sex, age, fibrosis status, and platelet counts. We evaluated serum levels of 30 immune mediators before, during, at the end of, and three months after DAA treatment using Luminex technology. We identified the immune factors associated with de novo HCC occurrence following DAA treatment. Specifically, interleukin (IL)-4 and IL-13 levels were significantly higher before start of the DAA treatment in the serum of patients who later developed HCC than in controls and stayed higher at each subsequent time point. Least absolute shrinkage and selection operator (LASSO) regression revealed IL-13 as the only strong factor associated with HCC development in this cohort of HCV patients. The difference was observed already at baseline of DAA treatment, which confirms the existence of a specific immune profile in these patients who later develop HCC.

Association of MicroRNA 196a and 499 Polymorphisms with Development of Cirrhosis and Hepatocellular Carcinoma Post-HCV Infection in Egyptian Patients.

Hepatocellular carcinoma (HCC) is the commonest primary tumor of the liver. Chronic HCV infection is the leading cause of end-stage liver disease, HCC and liver-related death in Egypt. Single nucleotide polymorphisms (SNPs) in microRNAs were reported to increase susceptibility to tumorigenesis; affect prognosis and as promising biomarkers in virus-host interactions. This study was conducted to investigate the role of genetic variants of miR-196a2 (rs 11614913) C>T and miR-499 (rs 3746444) A>G in the development of cirrhosis and HCC in Egyptian HCV infected patients. Genotyping of the candidate SNPs was performed by Real Time PCR in 75 HCV-related HCC patients, 75 cirrhotic patients on top of HCV and 75 healthy controls. There was significant difference in miR-499 (rs3746444) genotypes frequency between the three studied groups as the GG genotype was significantly lower in HCC cases than other groups (P = 0.009) while the combined miR-499 (AA+AG) genotypes were significantly higher in HCC cases than other groups (P = 0.005). Also a significant difference was found in miR-499 genotypes frequency when compared between HCC and cirrhosis groups as the GG genotype was significantly lower in HCC cases than cirrhosis group (P = 0.006) while the combined miR-499 (AA+AG) genotypes were significantly higher in HCC cases than in cirrhosis group (P = 0.003) [OR (95% CI) = 0.131 (0.028-0.601)]. The frequency of the G allele was significantly lower in HCC than other groups (P = 0.024) and significantly lower in HCC than normal group (P = 0.006) [OR (95%CI) = 0.501 (0.304-0.825)]. For miR-196a2 (rs11614913) C>T polymorphisms, no significant association was found with HCC risk. Our study concluded that the G allele of miR-499 is associated with lower risk of HCV related HCC development. No significant association of miR-196a2 (rs 11614913), genotypes or alleles with risk for HCC development, could be detected.

Molecular Mechanisms of Hepatocarcinogenesis Following Sustained Virological Response in Patients with Chronic Hepatitis C Virus Infection.

Despite the success of direct-acting antiviral (DAA) agents in treating chronic hepatitis C virus (HCV) infection, the number of cases of HCV-related hepatocellular carcinoma (HCC) is expected to increase over the next five years. HCC develops over the span of decades and is closely associated with fibrosis stage. HCV both directly and indirectly establishes a pro-inflammatory environment favorable for viral replication. Repeated cycles of cell death and regeneration lead to genomic instability and loss of cell cycle control. DAA therapy offers >90% sustained virological response (SVR) rates with fewer side effects and restrictions than interferon. While elimination of HCV helps to restore liver function and reverse mild fibrosis, post-SVR patients remain at elevated risk of HCC. A series of studies reporting higher than expected rates of HCC development among DAA-treated patients ignited debate over whether use of DAAs elevates HCC risk compared to interferon. However, recent prospective and retrospective studies based on larger patient cohorts have found no significant difference in risk between DAA and interferon therapy once other factors are taken into account. Although many mechanisms and pathways involved in hepatocarcinogenesis have been elucidated, our understanding of drivers specific to post-SVR hepatocarcinogenesis is still limited, and lack of suitable in vivo and in vitro experimental systems has hampered efforts to examine etiology-specific mechanisms that might serve to answer this question more thoroughly. Further research is needed to identify risk factors and biomarkers for post-SVR HCC and to develop targeted therapies based on more complete understanding of the molecules and pathways implicated in hepatocarcinogenesis.

IL-28B rs12979860 polymorphism affect the course of chronic hepatitis and the development of HCC in Egyptian patients with hepatitis C type 4

ABSTRACTBackground: A single nucleotide polymorphism (SNP) in the interleukin 28B (IL28B) gene may alter the trajectory of hepatitis C virus (HCV) chronic infection. Several studies have sought to determine a link between IL28B rs12979860 SNP and the development of HCV-related hepatocellular carcinoma (HCC), but with variable results, and consensus is awaited. We hypothesised that IL28B rs12979860 SNP is linked to HCC in patients with HCV type 4.Methods: IL28B genotyping of 300 patients with HCV-related fibrosis (n = 100), cirrhosis (n = 100) and HCC (n = 100) was carried out and the results were analysed to determine the association between the IL28B genotype and clinical outcome.Results: In IL28B TT genotype carriers, the proportions of moderate/severe fibrosis, advanced cirrhosis (Child B-C) and HCC (50%, 84% and 60.2%, respectively) were higher (p < 0.05) than in CC/CT (4.3%, 46% and 23%, respectively). IL-28B SNP was linked significantly (p < 0.05) with cirrhosis progression and HCC advanced stages. Moreover, HCC advanced Child, Okuda and CLIP stages were associated with T allele carriage (73.9%, 82.6% and 78.3% vs. 44.2%, 50.6% and 46.8% in CC/CT). The percentage of large tumour size (> 3cm) increased (p = 0.028) in TT genotype carriers (81.8% vs.52.6% in CC/CT).Conclusion: IL-28B rs12979860 TT genotype is more prevalent in patients with advanced fibrosis, cirrhosis and HCC stages. Thus, it seems to be associated with poor outcomes in chronic HCV patients and to augment the risk of developing HCC.

Responsibility of hepatitis C virus in the development of hepatocellular carcinoma: From molecular alterations to possible solutions.

There are several causes of hepatocellular carcinoma (HCC), but certainly the hepatitis C virus (HCV) is one of the most common. The HCV is able to contribute, both directly and indirectly, to the development of HCC. Determining early HCV clearance before an advanced liver disease develops, is absolutely necessary as this prevents the initiation of the cascade of events induced by HCV that may result in the development of HCC. The early treatment of the infection and the clearance of HCV represents today, in the age of the direct antiviral agents (DAAs), an extraordinary opportunity for true prevention of the development of HCV-related HCC.

Polymorphisms of base-excision repair genes and the hepatocarcinogenesis

AimTo determine the possible association between polymorphisms of DNA repair genes, including XRCC1 Arg194Tryp, Arg280His, and Arg399Glu, APE1 Asp148Glu, and NEIL2 Arg257Leu, and the risk of developing hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). MethodsA total of 264 subjects were recruited in this retrospective case-control study and were categorized into four groups: 88 control subjects (CR), 53 chronic hepatitis C patients (CHC), 36 liver cirrhotic patients (LC), and 87 HCC patients. The XRCC1 Arg194Tryp, Arg280His, and Arg399Glu polymorphisms were detected using PCR-RFLP, while real-time PCR was used to genotype APE1 Asp148Glu and NEIL2 Arg257Leu. ResultsOur data revealed that, compared with the healthy controls, for those subjects with the XRCC1 Arg194Trp genotype, the risk of developing CHC, LC, and HCC was increased by 6.66- (odds ratio (OR) = 6.667; 95% confidence interval (CI) = 3.244–13.701; P > 0.01), 3.85- (OR = 3.852; 95% CI = 1.797–8.256; P > 0.01), and 2.14-fold (OR = 2.14; 95% CI = 1.13–4.06; P > 0.05), respectively. There was no association between the risk of HCC development and the XRCC1 Arg280His or XRCC1 Arg399Gln genotypes. Moreover, the analysis showed a lack of association between APE1 Asp148Glu and the risk of HCC development. The analysis of clinicopathological parameters showed that the HCC patients with the XRCC1 Arg280His polymorphism were 2.9 fold more likely to have hepatic lesions in both hepatic lobes (OR: 2.9; 95% CI: 1.15–7.29). Notably, in the HCC patients, the prevalence of the APE1 polymorphism in the males was four times higher than that in the females (OR = 4; 95% CI = 1.129–14.175; P > 0.05). ConclusionOur results indicate that the XRCC1 Arg194Trp polymorphism could be a risk factor for HCV-related HCC development in Egypt.

Autophagy, apoptosis, vitamin D, and vitamin D receptor in hepatocellular carcinoma associated with hepatitis C virus.

The aims of this study were to investigate the interplay between autophagy and apoptosis and to investigate the association between both of autophagy and apoptosis and vitamin D and its receptor in hepatitis C virus (HCV) viral infection and its implication in the progression into hepatocellular carcinoma (HCC).A cross-sectional study where serum levels of microtubule-associated protein 1A/1B-light chain 3 (LC3); marker of autophagy, caspase-3; marker of apoptosis, vitamin D3 and vitamin D receptor (VDR) were measured in healthy subjects as well as HCV and HCV-HCC patients using enzyme-linked immunosorbent assay technique.Collectively, the liver profile revealed hepatic dysfunctions in HCV patients with or without HCC. A significant reduction in the serum concentration levels LC3 and caspase-3 were observed referring to the down regulation of autophagy and host-mediated apoptosis in HCV patients with or without HCC. Deficiency of vitamin D and decreased levels of its receptor were observed in HCV and HCV-HCC patients.The perturbation in vitamin D/VDR axis, which modulates both of autophagy and apoptosis in HCV infection, may point out to its involvement and implication in the pathogenesis of HCV infection and the development of HCV-related HCC. Therefore, supplementation with vitamin D may not be the only solution to restore the vital biological functions of vitamin D but VDR-targeted therapy may be of great importance in this respect.

LncRNA-HEIH in serum and exosomes as a potential biomarker in the HCV-related hepatocellular carcinoma.

Chronic hepatitis C (CHC) is a contagious liver disease that results from infection with the hepatitis C virus (HCV). The most serious consequence of CHC is HCV-related hepatocellular carcinoma (HCC). To illustrate the clinical significance of lncRNA HEIH expression in serum and exosomes in the development of HCV-related HCC. Thirty-five CHC, twenty-two HCV-induced cirrhosis and ten HCV-related HCC patients in Huzhou Central Hospital from January 2016 to September 2016 were recruited in the present study. Basic patient information, clinical serological indicators, and clinical imaging data were investigated and analyzed. Serum samples were collected from patients after receiving informed consent. Exosomes were extracted from the serum, and electron microscopy was used to observe the ultrastructure of exosomes. Quantitative PCR was used to detect lncRNA HEIH gene expression in serum and exosomes. The changes in the ALT, GGT, HDL, INR, Alb and AFP levels in the patients with HCV-induced cirrhosis and HCV-related HCC were statistically significant. In patients with HCV-related HCC, lncRNA-HEIH expression in serum and exosomes was increased, but the ratio of lncRNA-HEIH expression in serum versus exosomes was decreased compared to patients with CHC.

Diabetes mellitus increases the risk of hepatocellular carcinoma in treatment-naïve chronic hepatitis C patients in China.

We investigated the link between diabetes mellitus (DM) and hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) risk in treatment-naïve chronic hepatitis C (CHC) patients in China.To examine the association between DM and HCC, we conducted a case–control study of 300 Chinese CHC patients with HCC, compared to an age- and sex-matched control group of 517 CHC patients not diagnosed with HCC.We found that DM was more prevalent in the HCC patient group (18.7%) than in the CHC-only patient group (10.8%). We conducted logistic regression analyses adjusting for demographics features and other HCC risk factors and found that DM increased the risk of HCC development nearly 2-fold [adjusted odds ratio (AOR), 95% confidence interval (95% CI), 1.80 (1.17–2.75)]. Meanwhile, the proportion of HCC patients and CHC-only patients with liver cirrhosis were 79.3% and 46.2%, respectively, yielding an AOR of 4.62 (95% CI, 3.31–6.46). Multivariate analyses comparing the risk of HCV-related HCC development in DM patients with and without liver cirrhosis revealed that the estimated AOR (95% CI) for those with liver cirrhosis was 5.60 (2.25–13.96). However, the HCC risk decreased significantly with a later age of diabetes onset (AOR [95% CI], 0.94 [0.89–0.99]).DM was associated with an increased risk for HCC development in treatment-naïve CHC patients in China. Furthermore, liver cirrhosis and an early DM diagnoses further increased the risks of HCC development in patients diagnosed with both CHC and DM.

From the Editor’s desk...: October 2016

Oral DAA therapy is a major breakthrough in the treatment of hepatitis C virus (HCV) infection. In this issue of the Journal, two articles raise concerns about this therapy while two other provide relatively good news. In the first of the two “alarming” studies, Reig et al. show an unexpected early tumor recurrence in patients with HCV-related hepatocellular carcinoma (HCC) undergoing DAA therapy. HCC recurrence coincides with HCV clearance. In the second study providing bad news, Conti et al. show that in patients with HCV-related cirrhosis, DAA-induced resolution of HCV infection does not seem to reduce occurrence of HCC, and patients previously treated for HCC have still a high risk of tumor recurrence, in the short term. In contrast, in a third study, Cheuk Men Cheung et al. find that DAA therapy in patients with decompensated cirrhosis leads to sustained improvement in liver function, with no evidence of increase in HCC development. Finally, The ANRS collaborative study group on hepatocellular carcinoma, by analyzing three distinct prospective cohorts, and a large number of patients, finds no increased risk of HCC recurrence after DAA therapy, in particular in those who underwent curative HCC treatment including liver transplantation. All these studies were performed in European countries. Together these studies indicate that there is an urgent need for large prospective studies, performed in different continents, evaluating the impact of DAA therapy on the risk of HCC, in particular, in patients with HCV-related cirrhosis.

Effect of peginterferon alfa-2b and ribavirin on hepatocellular carcinoma prevention in older patients with chronic hepatitis C.

The population of patients chronically infected with hepatitis C virus (HCV) is aging, and the number of older patients with HCV-related hepatocellular carcinoma (HCC) is increasing. The purpose of this study was to elucidate the effects of peginterferon and ribavirin combination therapy on prevention of HCC in older patients with chronic hepatitis C (CH-C). We compared the sustained virological response (SVR) and treatment discontinuation rates between older (≥ 65 years) and younger patients (< 65 years) among 1280 CH-C patients treated with peginterferon alfa-2b and ribavirin. Cumulative incidence of HCC was determined by Kaplan-Meier analysis, and factors associated with liver carcinogenesis were analyzed by Cox proportional hazards regression. Older patients had a significantly lower SVR rate and a significantly higher discontinuation rate of treatment than younger patients. Fifty patients developed HCC during median follow-up period of 47 months. Cox proportional hazards regression analysis indicated that the following were independent risk factors associated with the development of HCC: older age, male, advanced fibrosis, non-SVR in all patients: higher gamma-glutamyltranspeptidase, and non-SVR in older patients. Older patients who achieved SVR had a significantly reduced rate of HCC compared with those who did not achieve SVR, especially those who had gamma-glutamyltranspeptidase over 44 IU/L. The SVR rate was lower and the combination therapy discontinuation rate was higher in older CH-C patients than in younger patients. However, older patients who achieved SVR had a markedly lower rate of HCC development compared with older patients who did not achieve SVR.

Hepatic oxidative stress in ovariectomized transgenic mice expressing the hepatitis C virus polyprotein is augmented through suppression of adenosine monophosphate-activated protein kinase/proliferator-activated receptor gamma co-activator 1 alpha signali

Oxidative stress plays an important role in hepatocarcinogenesis of hepatitis C virus (HCV)-related chronic liver diseases. Despite the evidence of an increased proportion of females among elderly patients with HCV-related hepatocellular carcinoma (HCC), it remains unknown whether HCV augments hepatic oxidative stress in postmenopausal women. The aim of this study was to determine whether oxidative stress was augmented in ovariectomized (OVX) transgenic mice expressing the HCV polyprotein and to investigate its underlying mechanisms. OVX and sham-operated female transgenic mice expressing the HCV polyprotein and non-transgenic littermates were assessed for the production of reactive oxygen species (ROS), expression of inflammatory cytokines and antioxidant potential in the liver. Compared with OVX non-transgenic mice, OVX transgenic mice showed marked hepatic steatosis and ROS production without increased induction of inflammatory cytokines, but there was no increase in ROS-detoxifying enzymes such as superoxide dismutase 2 and glutathione peroxidase 1. In accordance with these results, OVX transgenic mice showed less activation of peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α), which is required for the induction of ROS-detoxifying enzymes, and no activation of adenosine monophosphate-activated protein kinase-α (AMPKα), which regulates the activity of PGC-1α. Our study demonstrated that hepatic oxidative stress was augmented in OVX transgenic mice expressing the HCV polyprotein by attenuation of antioxidant potential through inhibition of AMPK/PGC-1α signaling. These results may account in part for the mechanisms by which HCV-infected women are at high risk for HCC development when some period has passed after menopause.

Genetic analyses reveal a role for vitamin D insufficiency in HCV-associated hepatocellular carcinoma development.

BackgroundVitamin D insufficiency has been associated with the occurrence of various types of cancer, but causal relationships remain elusive. We therefore aimed to determine the relationship between genetic determinants of vitamin D serum levels and the risk of developing hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC).Methodology/Principal FindingsAssociations between CYP2R1, GC, and DHCR7 genotypes that are determinants of reduced 25-hydroxyvitamin D (25[OH]D3) serum levels and the risk of HCV-related HCC development were investigated for 1279 chronic hepatitis C patients with HCC and 4325 without HCC, respectively. The well-known associations between CYP2R1 (rs1993116, rs10741657), GC (rs2282679), and DHCR7 (rs7944926, rs12785878) genotypes and 25(OH)D3 serum levels were also apparent in patients with chronic hepatitis C. The same genotypes of these single nucleotide polymorphisms (SNPs) that are associated with reduced 25(OH)D3 serum levels were found to be associated with HCV-related HCC (P = 0.07 [OR = 1.13, 95% CI = 0.99–1.28] for CYP2R1, P = 0.007 [OR = 1.56, 95% CI = 1.12–2.15] for GC, P = 0.003 [OR = 1.42, 95% CI = 1.13–1.78] for DHCR7; ORs for risk genotypes). In contrast, no association between these genetic variations and liver fibrosis progression rate (P>0.2 for each SNP) or outcome of standard therapy with pegylated interferon-α and ribavirin (P>0.2 for each SNP) was observed, suggesting a specific influence of the genetic determinants of 25(OH)D3 serum levels on hepatocarcinogenesis.Conclusions/SignificanceOur data suggest a relatively weak but functionally relevant role for vitamin D in the prevention of HCV-related hepatocarcinogenesis.

613 Hepatitis C Virus (HCV) Diagnosis and Clinical Outcomes of Patients With HCV-Related Hepatocellular Carcinoma (HCC): A Comparative Study of Asians Versus Non-Asians

BACKGROUND AND AIMS: In addition to hepatitis B virus, HCV is also an important cause of HCC in Asians; however, it is often overlooked. This study aims to examine baseline characteristics, timing of HCV diagnosis and long-term survival of HCV-related HCC in Asians compared to non-Asian patients. METHODS: We conducted a retrospective cohort study of 798 consecutive Asian (n=220) and non-Asian (n=572) patients with HCV-related HCC who were identified via computer query using ICD-9 diagnosis at a U.S. university medical center between 7/1996 and 6/2012. Individual records were reviewed. RESULTS: Asians were much older (66 [38-88] vs. 56 [31-87] years, P ,0.0001) and more likely to be female (33% vs. 19%, P,0.0001). A significantly larger proportion of Asians were also diagnosed with HCC within only 2 years of HCV diagnosis compared to non-Asians (35% vs. 20%, p=0.001). Non-Asians were more likely to have decompensated liver disease and had higher median Child-Turcotte-Pugh score (6 [5-11] vs. 7 [5-13], P ,0.0001). Asian patients were more likely to undergo liver-directed palliative therapy (46% vs. 28%) and much less likely to be listed for liver transplantation(20% vs. 48%) (P ,0.001), despite similar rates of meeting Milan criteria for liver transplantation (52 vs.58%, P=0.16). Overall, there was a trend for higher median survival rates in Asians compared to non-Asians (30 vs. 21 months, P=0.091). Among those who were listed for liver transplantation, there was no statistically significant difference in survival between Asians and non-Asians in the first 2 years (72% vs. 68%) but there was divergence with Asians having higher survival afterwards (61% vs. 51%) (Figure 1). However, among those undergoing liver-directed palliative therapy, Asians had significantly higher long-term survival compared to non-Asians (5-year survival: 28% vs. 10%, P,0.0001) (Figure 2). On multivariate Cox proportional hazards model also inclusive of age, sex, BCLC staging, Child-Pugh score, meeting Milan criteria, liver transplantation listing, non-Asian ethnicity was an independent predictor for lower overall survival (HR=0.70 [0.52-0.86]). CONCLUSIONS: Despite being older and having a lower rate of liver transplantation listing, Asian HCV/HCC patients had higher median survival compared to non-Asian patients, particularly among those undergoing palliative therapy. Non-Asians were more likely to have decompensated liver disease and non-Asian ethnicity was an independent predictor for poorer long-term survival. Compared to non-Asians, Asians with HCV-related HCCwere also muchmore likely to have delayed HCV diagnosis. Improved strategies in HCV screening in Asians are needed as it may lead to earlier diagnosis and treatment of HCV infection and possible prevention of HCC development in this ethnic population with a disproportionate HCC disease burden.

Association between metabolic abnormalities and hepatitis C-related hepatocellular carcinoma

Background and aim. Metabolic syndrome is recognised as a potential risk factor for the development of hepatocellular carcinoma (HCC). The association between metabolic factors and hepatitis C (HCV)-related HCC has not yet been well clarified. This study was conducted to elucidate the role of metabolic factors in HCV-related HCC.Material and methods. We recruited 147 HCC patients and compared them with 147 matched CHC patients and 320 controls. The plasma levels of homeostasis model assessment-IR (HOMA-IR), adiponectin and lipids for all participants were assessed.Results. The HCC group showed significantly hig-her levels of insulin, glucose, HOMA-IR and adiponectin as well as lower levels of total cholesterol, HDL-C, LDL-C, and triglycerides compared with the matched CHC patients and controls. HOMA-IR did not correlate with pathologic features of HCC, whereas serum adiponectin levels correlated positively with the size of tumour nodules (P = 0.009). Based on stepwise logistic regression analysis, age (OR: 1.456, 95% CI: 1.0721.979, P < 0.01), HOMA-IR (OR: 2.50, 95% CI: 1.70-3.69, P = 0.001), and adiponectin (OR: 1.585, 95% CI: 1.2691.980, P = 0.001) were independently associated with HCC.Conclusions. Metabolic abnormalities are closely associated with the occurrence and development of HCV-related HCC. Patients with CHC and high serum adiponectin levels face a higher risk of developing liver cancer. Insulin resistance, as measured by HOMA-IR, is significantly associated with HCV-related HCC.