血清HBV DNA与肝动脉化疗栓塞术后肝癌复发的相关性研究

目的观察肝癌患者血清HBV DNA载量与肝动脉化疗栓塞术(TACE)后肿瘤复发的关系。方法检测193例乙型肝炎病毒标记物阳性的肝癌患者在TACE治疗前血清HBV DNA载量,分析患者血清HBV DNA载量与栓塞术后肿瘤复发的关系。结果在193例患者中,介入治疗术后2年内共有169例(87.6%)患者肿瘤复发;血清HBV DNA阳性(≥5×102copies/ml)138例,平均血清病毒载量为6.20±1.12lg copies/ml;单因素及多因素分析显示,肝功能Child-Pugh B级或C级、多发肿瘤、肿瘤最长径大于3cm、血清HBV DNA≥5×102copies/ml患者肿瘤复发的相对危险性较高,无肿瘤复发生存期较短。结论肝癌患者血清HBV DNA≥5×102copies/ml是TACE治疗后肿瘤复发的危险因素之一。     

乙型肝炎病毒致肝细胞癌发生机制研究进展

肝细胞癌（HCC）的发生与乙型肝炎病毒（HBV）感染密切相关。HBV感染所致的炎症反应、HBV X基因及其产物X蛋白、核心启动子突变、前S2区突变、剪接特异性蛋白等均可能参与HCC的发生发展。     

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...     

Hepatitis B virus and hepatocellular carcinoma at the miRNA level

AIM: To study Hepatitis B virus (HBV) infection and its association with hepatocellular carcinoma (HCC) at the miRNA level.METHODS: Three cellular models were used to investigate miRNA expression changes during HBV infection: human HepG2 hepatoblastoma cell line as a model without HBV infection;HepG2 cell line transfected with a 1.3-fold full-length HBV genome as an acute infection model;and HepG2.2.15 cell line,which is derived from HepG2 and stably transfected with a complete HBV genome,as a chronic infec...     

乙型肝炎病毒X基因突变与肝细胞癌

原发性肝细胞癌是世界上最常见的恶性肿瘤之一,慢性HBV感染是导致肝细胞癌的主要病因。HBV诱发肝细胞癌的确切机制仍不十分清楚。目前在HBV相关肝细胞癌病人血清和肝癌组织中发现了许多HBV X基因突变体,一些与肝细胞癌发生发展密切相关。本文主要就HBV X基因突变与肝细胞癌研究进展进行综述。     

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

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

Occult hepatitis B virus and hepatocellular carcinoma

Occult hepatitis B virus (HBV) infection (OBI) is a challenging pathobiological and clinical issue that has been widely debated for several decades. By definition, OBI is characterized by the persistence of HBV DNA in the liver tissue (and in some cases also in the serum) in the absence of circulating HBV surface antigen (HBsAg). Many epidemiological and molecular studies have indicated that OBI is an important risk factor for hepatocellular carcinoma (HCC) development. OBI may exert direct pro-oncogenic effects through the activation of the same oncogenic mechanisms that are activated in the course of an HBsAg-positive infection. Indeed, in OBI as in HBV-positive infection, HBV DNA can persist in the hepatocytes both integrated into the host genome as well as free episome, and may maintain the capacity to produce proteins-mainly X protein and truncated preS-S protein - provided with potential transforming properties. Furthermore, OBI may indirectly favor HCC development. It has been shown that the persistence of very low viral replicative activity during OBI may induce mild liver necro-inflammation continuing for life, and substantial clinical evidence indicates that OBI can accelerate the progression of liver disease towards cirrhosis that is considered the most important risk factor for HCC development.     

Clinical features of hepatitis B virus-related hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a major cause of cancer death,and chronic hepatitis B is a serious worldwide problem.The epidemiology of HCC is distinctive.Hepatitis B virus (HBV) plays a major role in hepatocarcinogenesis.Prevention of HBV-related HCC is a key issue in current hepatology.This paper describes the prevention and clinical features of HBVrelated HCC,along with a short review of the disease.     

Genotypes, mutations, and viral load of hepatitis B virus and the risk of hepatocellular carcinoma: HBV properties and hepatocarcinogenesis

Chronic infection with hepatitis B virus (HBV) is the major risk factor for hepatocellular carcinoma (HCC) worldwide. Ten HBV genotypes (A-J) have been discovered so far. Genotypes B and C are endemic in East and Southeast Asia. Genotype C HBV is associated with increased risks of cirrhosis and HCC. Genotype B (B2) is associated with the development of HCC in non-cirrhotic patients younger than 50 years and with relapse of HCC after surgical treatment. It is also associated with earlier hepatitis B e antigen seroconversion than genotype C. High HBV load is independently associated with the occurrence and post-treatment recurrence of HCC. Different genotypes have distinct patterns of mutations. Viral mutations in the core promoter region and in the preS region are frequently found to be significantly associated with an increased risk of HCC. These mutations often occur before the onset of HCC and accumulate during the progression of chronic HBV infection. Multiple such mutations are more frequent in patients with HCC and are specific for HCC. HBV subgenotypes, viral mutations, and viral load can be used for the prediction of HCC. Early identification of HBV-infected individuals who will eventually develop HCC will help to develop active prophylactic protocols to reduce or delay the occurrence of HCC.     

Hepatitis B virus reactivation in patients with hepatocellular carcinoma undergoing anti-cancer therapy

Patients with hepatocellular carcinoma(HCC)often experience hepatic morbidity.Hepatitis B virus(HBV)reactivation is well documented as a serious hepatic morbidity during anti-cancer therapy.Reported rates of HBV reactivation in chronic carriers with HCC undergoing chemotherapy range from 4%-67%.Apart from chemotherapy,HBV reactivation has been increasingly identified in settings of hepatectomy and local ablation therapies.The rates of HBV reactivation vary with different levels of immunosuppression and depend on treatment,viral factors,and patient characteristics.The principal concern relating to reactivation is that a substantial proportion of patients with reactivation suffer from liver dysfunction during therapy,which often leads to disruption of planned,potentially life-prolonging treatments,adversely affecting the patients’final outcome.The first step in the management of HBV reactivation is identification of patients at risk of reactivation by testing for HBV serology prior to commencing anticancer therapy.Although it is a serious complication,HBV reactivation is preventable with prophylactic antiHBV drugs.Multiple publications have shown the benefit of prophylactic or preemptive antiviral therapy in this setting and justified such an approach before the start of therapy.Given the tumors and underlying cirrhosis,long-term use of antivirals with high potency and low risk of resistance is recommended in patients with HCC.This topic review will summarize the epidemiology,pathogenesis,and clinical issues related to HBV reactivation in HCC patients,and will discuss proper management against HBV reactivation during anti-cancer therapy for HCC.     

Coexistence of low levels of HBsAg and high levels of anti-HBs may increase risk of hepatocellular carcinoma in chronic hepatitis B patients with high HBV load

ObjectiveThe clinical significance of coexistence of HBsAg/anti-HBs in chronic hepatitis B (CHB) patients remains controversial. This study was aimed to assess the association of this serological pattern with hepatocellular carcinoma (HCC) in patients with CHB.MethodsIn this cross-section study, 206 CHB patients with coexistence of HBsAg/anti-HBs and 206 CHB patients with HBsAg alone were included to evaluate the risk of HCC development by logistic regression analysis. In addition, a retrospective cohort of 260 patients with CHB was recruited to estimate the cumulative incidence of HCC by Kaplan–Meier analysis.ResultsThe serological pattern of coexistence of HBsAg/anti-HBs, with high levels of (“High”) HBsAg/low levels of (“Low”) anti-HBs, were considered as independent risk factors for HCC. In particular, patients with “High” HBsAg/“High” anti-HBs [odds ratio (OR), 4.295; 95% confidence interval (CI), 1.104–16.699; p = 0.035] and “Low” HBsAg/ “High” anti-HBs (OR, 3.207; 95%CI, 1.299–7.919; p = 0.012) exhibited significantly higher risk for HCC development. However, only “Low” HBsAg /“High” anti-HBs might increase risk of HCC in CHB patients with high HBV load (logrank p < 0.001) in our cohort study.ConclusionThe coexistence of “Low” HBsAg /“High” anti-HBs might increase the risk of HCC development in CHB patients with high HBV load, which reflected that the long-term interaction between immune response and virus might lead to the development of HCC. The identification of the patients with poor prognosis will help clinicians to refine the therapeutic decisions and individualize follow-up strategies.     

乙型和丙型肝炎病毒感染与肝细胞癌

为探讨乙型和丙型肝炎病毒（ＨＢＶ和ＨＣＶ）感染与肝细胞癌（肝癌）发生的关系，采用ＥＬＩＳＡ和聚合酶链反应（ＰＣＲ）对沈阳地区１１７例肝癌、１０７例肝硬化和４５例血液透析患者血清进行了ＨＢＶ和ＨＣＶ血清标志及ＨＢＶＤＮＡ和ＨＣＶＲＮＡ检测，并采用限制性片段长度多态性对其中７３例ＨＣＶＲＮＡ阳性血清进行了ＨＣＶ基因分型。结果，肝癌组ＨＢＶ感染率（６０７％）显著高于ＨＣＶ感染率（３３３％，Ｐ＜００１），肝硬化组ＨＢＶ感染率（４３９％）明显高于ＨＣＶ感染率（２９０％，Ｐ＜００５）；血液透析组ＨＢＶ和ＨＣＶ重叠感染率（２６７％）明显高于肝硬化组（１０３％，Ｐ＜００５）；各组均以ＨＣＶⅡ型为主（６５２％～８００％），ＨＣＶⅢ型次之（２００％～３１４％）。结果提示：沈阳地区肝癌的诱发因素仍以ＨＢＶ为主，血液透析患者ＨＢＶ和ＨＣＶ重叠感染的机会更大，ＨＣＶⅡ型感染在本地区ＨＣＶ相关性肝癌和肝硬化的发生中可能起主要作用。     

Dermatomyositis associated with hepatitis B virus-related hepatocellular carcinoma

Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) with typical cutaneous manifestations. It has been proposed that DM may be caused by autoimmune responses to viral infections, and previous studies have also shown that an association between DM and malignancy. However, chronic hepatitis B virus (HBV) infection associated with DM and hepatocellular carcinoma (HCC) is rarely encountered. The authors report a case of DM and HCC in a patient with a HBV infection. A 58-year-old man presented erythematous skin rashes on a sun-exposed area of 2 year’s duration, and recent proximal muscle weakness. His medical history revealed that he had a chronic HBV infection. A diagnosis of DM relies on proximal muscle weakness, elevated muscle enzymes, myopathic changes (demonstrated by electromyography), muscle biopsy evidence of myositis, and its characteristic cutaneous findings. A Liver mass in the left lobe visualized by abdominal computed tomography was confirmed histologically as HCC. This case suggests that DM associated with HCC might be caused by a HBV infection.     

HBx致肝细胞癌分子机制的研究进展

乙型肝炎病毒(HBV)慢性感染是我国肝细胞肝癌(HCC)发生的主要原因之一.一些体内外研究发现,乙型肝炎病毒x(HBx)可诱导肝细胞的恶性转化及癌变,成为目前研究乙肝相关性肝细胞癌发生机制的热点.近来在HBx与抑癌基因,如p53的新成员p73以及p16,p21等之间的相互作用及其对肝细胞恶性转化与癌变的影响等方面的研究也取得初步成果,但其关系错综复杂,这方面不断的深入研究将有助于进一步揭示HBx致肝细胞癌发生的分子机制,对探寻乙肝相关性肝癌新的防治策略具有重要意义.     

Expression of B7-H4 and hepatitis B virus X in hepatitis B virus-related hepatocellular carcinoma

AIM: To investigate the expression and clinical significance of B7-H4 and hepatitis B virus X(HBx) protein in hepatitis B virus-related hepatocellular carcinoma(HBV-HCC).METHODS: The expression of B7-H4 in the human HCC cell lines Hep G2 and Hep G2.2.15 were detected by western blot, flow cytometry, and immunofluorescence. The expression of B7-H4 and HBx in 83 HBV-HCC was detected by immunohistochemistry, and the relationship with clinicopathological features was analyzed. Paraffin sections were generated from 83 HBV-HCC patients(22 females and 61 males) enrolled in this study. The age of these patients ranged from 35 to 77 years, with an average of 52.5 ± 11.3 years. All experiments were approved by the Ethics Committees of the Second Affiliated Hospital, Zhejiang University School of Medicine.RESULTS: B7-H4 was significantly upregulated in Hep G2.2.15 cells compared to Hep G2 cells. Specifically, the protein expression of B7-H4 in the lysates of Hep G2 cells was more than that in Hep G2.2.15 cells. In addition, HBx was expressed only in Hep G2.2.15 cells. Similar data were obtained by flow cytometry. The positive rates of B7-H4 and HBx in the tissues of 83 HBV-HCC patients were 68.67%(57/83) and 59.04%(49/83), respectively. The expression of HBx was correlated with tumor node metastases(TNM) stage, and the expression of B7-H4 was positively correlated with HBx(rs = 0.388; p 0.01). The expression level of B7-H4 in HBx-positive HBV-HCC tissues was substantially higher than that in HBx-negative HBV-HCC tissues. The expression level of B7H4 was negatively related to tumor TNM stage.CONCLUSION: Higher expression of HBx and B7-H4 was correlated with tumor progression of HBV-HCC, suggesting that B7-H4 may be involved in facilitating HBV-related hepatocarcinogenesis.     

Practical efficacy of sorafenib monotherapy for advanced hepatocellular carcinoma patients in a Hepatitis B virus-endemic area

Background  This study was conducted to assess the efficacy and safety of sorafenib monotherapy in clinical practice settings for Korean patients with hepatocellular carcinoma (HCC) related primarily to HBV infection. Methods  Medical records of 57 consecutive patients with unresectable or metastatic HCC treated with 400 mg bid sorafenib at the National Cancer Center, Korea between June 2007 and March 2008, were retrospectively reviewed. Results  The median patient age was 55 years (range, 28–76 years), and all patients had performance status 0–2 and Child–Pugh class A or B disease. HCC was etiologically related to HBV in 79.0% of patients. Eleven patients (19.3%) had modified UICC stage III tumors, 11 (19.3%) had stage IVa, and 35 (61.4%) had stage IVb. Following sorafenib monotherapy, 3 patients (5.3%) achieved a partial response and 18 (35.1%) achieved stable disease, with a disease control rate of 40.4%. The median times to progression (TTP) was 9.1 weeks (95% CI 3.4–14.8 weeks). Multivariate analyses showed that serum alpha-fetoprotein (α-FP) ≥400 ng/mL (HR, 2.810; P = 0.023) and the presence of massive intrahepatic tumors (HR, 7.633; P = 0.033) were independent predictors of shorter TTP. The most common grade 3/4 adverse events were hand-foot syndrome (8.8%), diarrhea (7.0%), and skin rash (7.0%). Exacerbation of underlying chronic hepatitis B was not found. Conclusion  Sorafenib monotherapy showed better outcomes with tolerable toxicity in Korean advanced HCC patients, who had intrahepatic nodular tumors and/or metastatic tumors, coupled with low levels of serum α-FP.     

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

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

Hepatitis B and alcohol affect survival of hepatocellular carcinoma patients

AIM: In the USA, Hawaii has the highest incidence of hepatocellular carcinoma (HCC) and a diverse population. It is an ideal place to characterize HCC in the context of ethnicity/risk factors. METHODS: A total of 262 cases of HCC (1992-2003) were retrospectively reviewed for demographics, ethnicity, birthplace, viral hepatitis, alcohol use, diabetes, smoking and risk factors for viral hepatitis such as intravenous drug abuse (IVDA), transfusions, tattoos and vertical transmission. Tumor stage, Child‘s class, Cancer of the Liver Italian Program (CLIP) score, α-fetoprotein level, treatment and survival were recorded. RESULTS: Gender, age, viral hepatitis, alcohol, IVDA, and diabetes differed significantly in Asians, non-Asians and Pacific Islanders. There were also specific differences within Asian subgroups. Alpha-fetoprotein, smoking, transfusions, stage and resectability did not differ between groups. Asians were more likely to have hepatitis B, while non-Asians were more likely to have hepatitis C. Factors that decreased survival included hepatitis B, alcohol, elevated alpha-fetoprotein, CLIP&gt;2 and increased Child‘s class. When Asians were combined with Pacific Islanders, median survival (1.52 years vs 3.54 years), 1-and 3-year survival was significantly worse than those for non-Asians. After Cox regression analysis for hepatitis B and alcohol, there was no difference in survival by ethnicity.CONCLUSION: Various ethnicities have different risk factors for HCC. Hepatitis B, alcohol, and α-fetoprotein are more important factors for survival than ethnicity.     

High viral load is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis B virus infection

BACKGROUND AND AIMS: Hepatitis B virus (HBV) is considered a major risk factor for the progression to liver cirrhosis and hepatocellular carcinoma (HCC). The serum level of HBV-DNA is correlated with progression of the disease. The aim of the present study was to determine the relationship between the level of HBV-DNA and hepatocarcinogenesis in patients with chronic HBV infection. METHODS: The authors studied 73 patients who were diagnosed with chronic HBV infection at Nagasaki University Hospital (Nagasaki, Japan) between January 1980 and December 1999. The significance of age, sex, habitual drinking, serum alanine aminotransferase level, HBV viral load, interferon treatment, hepatic fibrosis and hepatic inflammation on the development of HCC were examined using univariate and multivariate analyses. RESULTS: The cumulative incidence rates of HCC were 14%, 29% and 48% at 5, 10 and 15 years after liver biopsy, respectively. Multivariate analysis identified high viral load, together with age and severe fibrosis, as independent and significant risk factors (P = 0.045, 0.047 and 0.013, respectively) for HCC. CONCLUSIONS: The present findings indicate that high viral load is a risk factor for HCC in patients with chronic HBV infection. Patients with a high HBV viral load should be carefully monitored for HCC.