Comparative study on proliferation activity in small hepatocellular carcinoma related to hepatitis virus B and C

AIM: To compare the proliferation activity of small hepatocellular carcinoma (HCC) related to hepatitis B virus (HBV) and hepatitis C virus (HCV).METHODS: Sixty liver biopsy specimens were obtained from patients with small HCC (≤3 cm in diameter) and examined immunohistochemically using anti-proliferating cell nuclear antigen monoclonal antibody. Of the 60 specimens, 30 were HBV-related and 30 were HCV-related. The 60 patients providing the samples for study were matched by sex and morphologic features of the HCC specimens.RESULTS: The labeling index of proliferating cell nuclear antigen was 7.9% in the HBV-related HCC specimens and 12.5% in the HCV-related HCC specimens. There was no statistically significant difference between the two groups (P > 0.05).CONCLUSION: In the early phase, or small stage, of HCC, HBV-related HCC shows similar proliferating activity to that of HCV-related HCC; this finding suggests that in the early phase, HBV-related HCC has similar malignancy to HCV-related HCC.     

Current status and clinical course of hepatitis C virus in Korea

The mortality due to chronic liver disease, including liver cirrhosis and hepatocellular carcinoma (HCC), ranks as one of the highest in Korea. The prevalence rates of hepatitis C virus (HCV) and hepatitis B virus (HBV) infections in the general Korean population are approximately 1 and 5%, respectively. Blood transfusion was the strongest risk factor for the transmission of HCV infection. Therefore, the evaluation of risk factors for HCV infection including blood transfusion, intravenous drug user, hemophilia, and hemodialysis, is important. The most prevalent HCV genotype is 1b followed by 2a. The annual incidence of HCC among HCV-related liver cirrhosis has been estimated at 5%, and approximately 12% of HCC is attributable to HCV and 68% to HBV in Korea. HCV infection is more closely associated with HCC in elderly patients than HBV-related HCC. Even though the prevalence of anti-HCV in Korea has been reduced and the risk of HCV transmission through blood transfusion has markedly decreased, public-health programs to prevent de novo infections should be developed. This review describes the HCV prevalence and risk factors among the general population, and the distribution of HCV genotypes as well as the clinical course of HCV in Korea.     

Relative Risk for the Development of Hepatocellular Carcinoma in Alcoholic Patients with Cirrhosis: A Multiple Logistic-Regression Coefficient Analysis

The hepatitis B virus (HBV) or hepatitis C virus (HVC) markers are frequently positive in alcoholic patients with hepatocellular carcinoma (HCC). However, the role of the relationship between HBV or HCV infection and alcohol drinking in the development of HCC has not been clearly documented. In the present study, the relative risk in 1200 cirrhotic patients with different etiologies who were admitted to five different hospitals in Japan was calculated using the multiple logistic-regression coefficient analysis. In the HCV+ alcohol group, HCC patients tended to be younger, and the odds ratio for the development of HCC was significantly higher compared with the HCV-alone group. Furthermore, the interaction coefficient of alcohol and HCV for the development of HCC was significant statistically. However, the interaction between HBV and alcohol was not significant. Because the proportion of male patients with HCC was significantly higher in the alcohol-alone and HBV-related groups than in the HCV-related group, the multiple logistic-regression analysis was also performed in male patients only. The results were nearly the same as those in male and female patients combined. These results suggest strongly that alcohol and HCV together accelerate the development of HCC. However, a similar relationship was not found between alcohol and HBV.     

Changing relative roles of hepatitis B and C viruses in the aetiology of hepatocellular carcinoma in Greece. Epidemiological and clinical observations

Summary. Chronic infection with hepatitis B virus (HBV) has been reported in two-thirds of cases of hepatocellular carcinoma (HCC) in Greece from 1973 to 1995, while chronic hepatitis C virus (HCV) infection in 10% of them. We studied the roles of HBV and HCV in HCC in Greece between 1996 and 2000 compared with the past, and possible differences in clinical and laboratory characteristics of HBV- and HCV-related HCC. Complete clinical and laboratory data from 306 patients with HCC, diagnosed from January 1996 to December 2000, were analyzed. Chronic HBV and HCV infection were detected in 52.3 and 21.6% of the patients, respectively. The ratio of HBV- to HCV-related HCC was 2.42. Compared with the data prior to 1996, there was a 101.8% increase in the relative frequency of HCV ( P  < 0.0001) and an 11.8% decrease in that of HBV ( P  = 0.033), with a −56.3% change in the ratio of HBV- to HCV-related HCC cases. Statistically significant differences in the male/female ratio, median age and frequency of multifocal lesions were found in HBV- vs HCV-related HCC. Although HBV still represents the major aetiological factor of HCC in Greece, its role has significantly decreased in the last 5 years, while a more significant increase has occurred in HCV-related HCC. The two aetiological types of HCC differ in Greece in demographic, epidemiological and other features.     

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.     

Risk factors and prevention of hepatocellular carcinoma in HCV infection

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors worldwide. Several risk factors for HCC development have been identified, including cirrhosis, hepatitis B virus (HBV) infection, and hepatitis C virus (HCV) infection. With regard to cirrhosis, multivariate analysis indicates that alcohol abuse, HBsAg positivity, and anti-HCV seropositivity are independent variables associated with an increased risk for HCC in the cirrhotic patient. A close relationship between chronic HBV infection and HCC has been established by epidemiological studies and laboratory investigations. Evidence indicates that HCV also plays a leading role in development of HCC. Most patients with HCV-related HCC develop the tumor as a consequence of long-standing infection accompanied by chronic and progressive liver damage. In our study of 290 consecutive patients with cirrhosis, patients with persistently elevated or fluctuating ALT levels had a significantly greater rate of HCC development. The mechanism of HCC development in HCV infection remains to be elucidated. The annual cumulative risk of developing HCC is approximately 1% in patients without cirrhosis at inclusion and 3–10% in those with cirrhosis, depending on the stage of cirrhosis and presence of etiological cofactors. Although some evidence suggests that patients infected with the HCV genotype 1b are at increased risk for development of more severe liver disease, including HCC, results of our prospective study do not support a difference between cirrhotic and noncirrhotic patients in terms of the natural course of cirrhosis and the rate of developing HCC based on genotype. Strategies to prevent HCV-related HCC include blood screening and treatment of chronic HCV infection with interferon-α. Recent studies suggest that interferon-α treatment may prevent the development of HCC in HCV infection. Further research is warranted.     

Hepatitis B virus infection and the risk of hepatocellular carcinoma

Epidemiological studies have provided overwhelming evidence for a causal role of chronic hepatitis B virus(HBV) infection in the development of hepatocellular carcinoma(HCC).However,the pathogenesis of HBV infection and carcinogenesis of HBV-associated HCC are still elusive.This review will summarize the current knowledge on the mechanisms involved in HBV-related liver carcinogenesis.The role of HBV in tumor formation appears to be complex,and may involve both direct and indirect mechanisms.Integration of H...     

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。     

Anti-viral therapy to reduce recurrence and improve survival in hepatitis B virus-related hepatocellular carcinoma

Hepatocellular carcinoma(HCC)is the most common malignancy and the third leading cause of cancer death worldwide.Chronic infection with hepatitis B virus(HBV)and hepatitis C virus accounts for approximately75%-80%of HCC cases worldwide.In particular,chronic HBV infection is a predominant risk factor for HCC in Asia and Africa.Hepatic resection and radiofrequency ablation are increasingly used for the curative treatment of HCC,and good local control can be achieved.However,the high rate of recurrence is a major obstacle to improving prognosis.A high viral load of HBV DNA is the most important correctable risk factor for recurrence.Furthermore,interferon and/or nucleotide analogues may decrease HBV DNA.Therefore,these drugs may decrease recurrence.In this article,treatment strategies for HBV-related HCC are described in order to reduce recurrence and improve survival.     

MicroRNAs as therapeutic strategy for hepatitis B virus-associated hepatocellular carcinoma: Current status and future prospects

Hepatocellular carcinoma (HCC) remains to be one of the top causing cancer-related deaths today. The majority of HCC cases are reported to be the result of chronic hepatitis B virus (HBV) infection. Current treatments for HBV-related HCC revolve around the use of drugs to inhibit viral replication, as a high level of viral load and antigen in circulation often presents a poor patient prognosis. However, existing therapies are inefficient in the complete eradication of HBV, often resulting in tumour recurrence. The involvement of microRNAs (miRNAs) in important processes in HBV-related HCC makes it an important player in the progression of HCC in chronic hepatitis B infected patients. In this review, we discuss the key aspects of HBV infection and the important viral products that may regulate cancer-related processes via their interaction with miRNAs or their closely related protein machinery. Conversely, we also look at how miRNAs may go about regulating the virus, especially in vital processes like viral replication. Apart from miRNAs acting as either oncogenes or tumour-suppressors, we also look at how miRNAs may function as biomarkers that may possibly serve as better candidates than those currently employed in the diagnosis of HBV infection or HBV-related HCC. A summary of the roles of miRNAs in HBV-related HCC will hopefully lead to a gain in understanding of the pathogenesis process and pave the way for new insights in medical therapy.     

The global epidemiology of hepatocellular carcinoma: present and future

The global risk of hepatocellular carcinoma (HCC) has been largely driven by hepatitis B virus (HBV) infection for the past century, along with hepatitis C virus (HCV), aflatoxin, excessive alcohol consumption, and obesity/diabetes. The dominant effect of HBV on global HCC risk should decline as the population vaccinated against HBV grows older. Infection with HCV is also expected to decline. Projections of HCV-related HCC rates remaining high for another 30 years may be overly pessimistic. Alcohol may be less of a factor in HCC in coming years. However, obesity and diabetes may become even more important risk factors for HCC.     

乙型与丙型肝炎病毒感染对小肝癌患者预后的影响

目的 探讨HBV、HCV感染对小肝癌的外科治疗策略及其预后的影响.方法 回顾性分析1997年1月-2003年12月天津医科大学附属肿瘤医院413例手术根治切除治疗的小肝痛(≤3 cm)患者的临床资料,将其分为4组:HCV感染组75例、HBV感染组251例、HCV、HBV混合感染组33例和尢HCV、HBV感染组54例,对可能影响预后的因素采用Kaplan-Meier生存分析、log-rank时序检验.结果 413例患者术后1、3、5年尢瘤生存率分别为83%、66%和58%,术后共有168(40.8%)例患者出现肝内复发,5年复发率HCV感染组最高(64.2%),其次为HBV/HCV感染组(48.4%),HBV感染组(37.8%)及无感染组(32.3%).肝内复发肿瘤为多发者在HCV感染组发生率最高(占肝内复发肿瘤的66.0%),其次为HBV/HCV感染组(28.6%),HBV感染组(23.3%)及无感染组(17.6%).413例小肝癌患者术后1、3、5年总生存率分别为89%、70%和61%,HCV感染组预后最差.和其他组相比,HCV感染组肝硬化程度严重,肿瘤细胞分化低,更易发生血管侵犯.在随访过程中,HCV感染组肝内复发率高,且复发类型常为多结节型.结论 HCV感染相关肝癌的临床肝硬化症状更重,而且术后复发率较高,预后更差.     

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 C infection and the increasing incidence of hepatocellular carcinoma: a population-based study

BACKGROUND AND AIMS: A significant increase in the incidence of hepatocellular carcinoma (HCC) has been reported in the United States. The risk factors underlying this increase remain unclear. METHODS: By using Surveillance, Epidemiology, and End-Results program (SEER)-Medicare-linked data, we conducted a population-based study to examine temporal changes in risk factors for patients 65 years and older diagnosed with HCC between 1993 and 1999. Only patients with continuous Medicare enrollment for 2 years before and up to 2 years after HCC diagnosis were examined. Univariate and multiple logistic regression analyses were used to evaluate changes in risk factors over time (January 1993-June 1996 and July 1996-December 1999). RESULTS: The age-adjusted incidence of HCC among persons 65 years of age and older significantly increased from 14.2 per 100,000 in 1993 to 18.1 per 100,000 in 1999. We identified 2584 patients with continuous Medicare enrollment 2 years before and up to 2 years after HCC diagnosis. The proportion of hepatitis C virus (HCV)-related HCC increased from 11% during January of 1993 to June of 1996 to 21% during July of 1996 to December of 1999, whereas hepatitis B virus (HBV)-related HCC increased from 6% to 11% ( P < .0001). In multiple logistic regression analyses that adjusted for age, sex, race, and geographic region, the risk for HCV-related HCC and HBV-related HCC increased by 226% and 67%, respectively. Idiopathic HCC decreased from 43% to 39%. This decrease did not fully account for the significant increases observed for HCV and HBV. No significant changes over time were observed for alcohol-induced liver disease, nonspecific cirrhosis, or nonspecific hepatitis. CONCLUSIONS: There has been a significant recent increase in HCV- and HBV-related HCC. Increasing rates of HCV-related HCC can explain a substantial proportion of the reported increase in HCC incidence during recent years.     

Hepatitis B Virus Vaccine for Patients with Hepatitis C Virus Infection

Summary Hepatitis C is a disease with varying rates of progression. The role of hepatitis B virus (HBV) as a cofactor in the development of hepatitis C virus (HCV)-related cirrhosis and hepatocellular carcinoma (HCC) has been suggested and the use of HBV vaccine in all HCV-infected patients has been advocated. This review presents the implications of HBV and HCV coinfection and addresses the issues of HBV vaccine immunogenicity and safety in patients with chronic HCV infection. Received: December, 1999 · Revision accepted: July 1, 2000     

Current therapy for hepatitis C or D or immunodeficiency virus concurrent infection with chronic hepatitis B

Concurrent hepatitis C virus (HCV), hepatitis delta virus (HDV), or human immunodeficiency virus (HIV) infection with chronic hepatitis B virus (HBV) appears to increase the risk of progressive liver disease including liver cirrhosis and hepatocellular carcinoma. There is a 10% prevalence of HCV infection in chronic HBV or HDV infection. Serological evidence of previous exposure to HBV is found in more than 80% of HIV-positive patients in the high risk group. Notably, the most recently acquired virus tends to suppress the pre-existing virus. In chronic HBV infection acquired perinatally or in early childhood, usually HCV is dominant and may suppress or even displace HBV and HDV. Less frequently, HBV or HDV suppresses HCV. It is generally agreed that the dominant virus should be identified in order to make appropriate treatment decisions. Studies with standard interferon (IFN) to treat patients with HCV dominantly dual HBV/HCV infection have showed only limited virological response. But high dose of IFN has been demonstrated with better response rate. Combined ribavirin with standard or pegylated IFN therapy could achieve a sustained HCV clearance rate comparable with those infected with HCV alone. On the contrary, patients with HBV dominantly dual viral infection might indicate more appropriate addition of lamivudine to IFN than ribavirin. Additionally, patients with concurrent infection of HBV and HDV, IFN seems to be the only effective agent. However, the efficacy of IFN is related to the dose. High dose of IFN [9 MU tiw (thrice per week)] and longer treatment duration (at least 2 years) have been shown to achieve adequate virological response. In patients with concurrently infected HBV and HIV, anti-HBV therapy should be considered for all patients with evidence of liver disease, irrespective of the CD4 cell count. In patients not requiring antiretroviral therapy, HBV therapy should be preferentially based on IFN, adefovir, or telbivudine. In contrast, in patients with CD4 cell counts <350 cells/μl or those already on antiretroviral therapy, agents with double anti-HBV and anti-HIV activity are preferred. At present, the evidence of therapeutic efficacy is not sufficient to make a recommendation in treating patients with dual HBV/HCV or HBV/HDV or HBV/HIV infection. Further studies of the well-designed, larger scale are needed to elucidate the role of different regimens or combination in the treatment of dual viral infection.     

Autophagy and microRNA in hepatitis B virus-related hepatocellular carcinoma

Approximately 350 million people worldwide are chronically infected by hepatitis B virus (HBV). HBV causes severe liver diseases including cirrhosis and hepatocellular carcinoma (HCC). In about 25% of affected patients, HBV infection proceeds to HCC. Therefore, the mechanisms by which HBV affects the host cell to promote viral replication and its pathogenesis have been the subject of intensive research efforts. Emerging evidence indicates that both autophagy and microRNAs (miRNAs) are involved in HBV replication and HBV-related hepatocarcinogenesis. In this review, we summarize how HBV induces autophagy, the role of autophagy in HBV infection, and HBV-related tumorigenesis. We further discuss the emerging roles of miRNAs in HBV infection and how HBV affects miRNAs biogenesis. The accumulating knowledge pertaining to autophagy and miRNAs in HBV replication and its pathogenesis may lead to the development of novel strategies against HBV infection and HBV-related HCC tumorigenesis.     

HBV/HCV重叠感染的抗病毒治疗

从全球范围看,乙型肝炎病毒(hepatitis B virus,HBV)和丙型肝炎病毒(hepatitis C virus,HCV)重叠感染估计约有700-2000万人口感染.重叠感染和单一HBV或HCV感染比较,更易发展为肝硬化、肝细胞癌甚至肝衰竭的比例也高,HBV和HCV重叠感染可有四种不同的临床模式,即HCV活动...     

Occult hepatitis B virus infection is not associated with disease progression of chronic hepatitis C virus infection

AIM To clarify the prevalence of occult hepatitis B virus(HBV) infection(OBI) and the association between OBI and liver disease progression, defined as development of liver cirrhosis or hepatocellular carcinoma(HCC), worsening of Child-Pugh class, or mortality in cases of chronic hepatitis C virus(HCV) infection. METHODS This prospective cohort study enrolled 174 patients with chronic HCV infection(chronic hepatitis, n = 83; cirrhosis, n = 47; HCC, n = 44), and evaluated disease progression during a mean follow-up of 38.7 mo. OBI was defined as HBV DNA positivity in 2 or moredifferent viral genomic regions by nested polymerase chain reaction using 4 sets of primers in the S, C, P and X open reading frame of the HBV genome. RESULTS The overall OBI prevalence in chronic HCV patients at enrollment was 18.4%, with 16.9%, 25.5% and 13.6% in the chronic hepatitis C, liver cirrhosis and HCC groups, respectively(P = 0.845). During follow-up, 52 patients showed disease progression, which was independently associated with aspartate aminotransferase 40 IU/L, Child-Pugh score and sustained virologic response(SVR), but not with OBI positivity. In 136 patients who were not in the SVR state during the study period, OBI positivity was associated with neither disease progression, nor HCC development. CONCLUSION The prevalence of OBI in chronic HCV patients was 18.4%, and OBI was not associated with disease progression in South Koreans.