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.     

Comparison of serum and liver hepatitis C virus quasispecies in HCV-related hepatocellular carcinoma

Background/Aims: The hepatitis C virus (HCV) genome consists of quasispecies populations of heterogeneous variants, especially in the hypervariable region. To assess the profiles of viral quasispecies in HCV-related hepatocellular carcinoma, we studied the viral population patterns in serum and liver tissues of 13 HCV-positive patients with hepatocellular carcinoma developed on cirrhotic and non-cirrhotic livers (5 and 8 cases, respectively).Methods: HCV genome heterogeneity was analyzed by polymerase chain reaction-mediated single-strand conformation polymorphism analysis, which showed multiple DNA bands representing different hypervariable region sequences.Results: The HCV populations were different between tumorous and nontumorous tissues in hepatocellular carcinomas with cirrhosis and in without cirrhosis. At least one or more than one common band was detected in both compartments in all but one case. No significant differences in the complexity of HCV quasispecies were found in hepatocellular carcinoma with or without underlying cirrhosis. Comparison of the HCV quasispecies profiles in serum and liver tissues showed a different distribution of HCV variants between these two compartments in patients. In four cases, both common and compartmentalized sequences were detected, whereas in two cases, both without cirrhosis, the HCV population in serum was completely different from that found in the liver.Conclusions: These results suggest that the complexity of HCV populations is influenced by the presence of hepatocellular carcinoma rather than by the severity of the underlying chronic liver disease. The different quasispecies patterns found in serum and liver may reflect different biological properties of circulating and intrahepatic HCV particles or the existence of extrahepatic sites of replication.     

Dermatomyositis associated with hepatocellular carcinoma in an elderly female patient with hepatitis C virus-related liver cirrhosis

A 79-year-old female patient with hepatitis C virus-related liver cirrhosis was diagnosed as having hepatocellular carcinoma (HCC) with a diameter of 2.0 cm. She refused therapy for HCC. Nine months after the diagnosis, she developed dermatomyositis when the HCC enlarged to a diameter of 6.0 cm. She underwent therapy for dermatomyositis, and then transcatheter arterial chemoembolization for HCC. Although the manifestations of dermatomyositis improved and entire tumor necrosis was achieved, she died of pneumonia 2 mo after the treatment of HCC. HCC and/or chronic hepatitis C virus infection might be involved in the pathogenesis of dermatomyositis.     

Insulin resistance is associated with hepatocellular carcinoma in chronic hepatitis C infection

AIM:To elucidate the role of insulin resistance(IR) and serum adiponectin level in hepatocellular carcinoma(HCC) associated with chronic hepatitis C.METHODS:Clinical and biochemical characteristics were collected from 165 consecutive patients with newly diagnosed HCC.Homeostasis model assessment of IR(HOMA-IR) and serum adiponectin level were investigated in 188 patients with different stages of hepatitis C virus(HCV) infection.RESULTS:Among HCC patients,type 2 diabetics(DM) was more prevalent in HCV subjec...     

Significance of plasma osteopontin in diagnosis of hepatitis C virus-related hepatocellular carcinoma

Background and study aimsAlfa fetoprotein (AFP) is widely used as a surveillance test for hepatocellular carcinoma (HCC) among patients with liver cirrhosis (LC). However, the clinical use of AFP has been shown to present some important limitations in sensitivity and specificity. Osteopontin (OPN) is a secreted matrix glycoprotein that is emerging as a significant protein in the biology of HCC. The aim of this study was to assess the diagnostic value of plasma OPN compared with that of AFP in the diagnosis of HCC among hepatitis C virus (HCV)-related LC.Patients and methodsPlasma levels of OPN and AFP were measured in 69 Egyptian patients with HCV-related LC (35 with HCC and 34 without HCC) and 20 healthy controls.ResultsBoth median AFP and OPN levels were significantly higher in the HCC group compared to LC and healthy control groups (p < 0.001 in each) and in LC compared to the control group (p < 0.001). In the HCC group, both OPN and AFP levels were significantly higher in patients with Child–Pugh class C and B compared to class A (p < 0.05 in each). There was no correlation between OPN and AFP levels. The OPN level was significantly higher in patients with multiple focal lesions than in those with single lesions (p < 0.05) and in patients with portal vein invasion compared to patients without portal vein invasion (p < 0.05). Receiver operator characteristic (ROC) curves showed that the area under the curve (AUC) for OPN and AFP was 0.824 and 0.730, respectively.ConclusionOPN is a promising tumour marker which could be used as a screening test for the diagnosis of HCC in patients with LC and, hence, improves the prognosis and survival rate of these patients. The association of OPN with the multiplicity of focal lesions and portal vein invasion suggests an additional prognostic value.     

肝癌和慢性肝炎患者丙型肝炎病毒核心蛋白基因表达及其核苷酸序列分析

目的：为探讨丙型肝炎病毒（HCV）感染在肝癌发生中的作用。方法：从HCV第二代抗体阳性的肝癌和慢性肝炎患者血清中提取HCV-RNA，经随机引物逆转录合成cDNA，再以病毒5’-末端至E1区间的多对引物进行巢式PCR扩增，其最终产物（425bp和621bp）分别连接p-GEM－T载体，在大肠杆菌中表达后进行测序。结果：所有患者均为HCV－Ⅱ型感染，完整的核心蛋白基因（573bp）与已报道的其它株比较，其核苷酸同源性为：慢性肝炎株89．0％～95.5％，肝癌株88．7％～92.3％；氨基酸同源性为：前者91.1％～96.6％，后者87．4％～92．1％。且发现该段基因中核苷酸置换肝癌患者较明显地高于慢性肝炎患者。结论：本文资料提示核心蛋白基因的变异，可能与HCV的慢性持续感染及肝癌的发生有关。     

Latent hepatitis B is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C

AIM:To study the potential association between hepatocellular carcinoma(HCC)in patients with chronic hepatitis C(CHC),cirrhosis and latent hepatitis B(LHB)infection,defined as the absence of detectable serum hepatitis B surface antigen(HBsAg)and the presence of hepatitis B core antibody(HBcAb).METHODS:This retrospective analysis is comprised of 185 cirrhotic patients with HCC who were hepatitis C virus antibody(HCV Ab)(+)and HBsAg(-)at Wayne State University between 1999 and 2008.From these,108 patients had HCV polymerase chain reaction confirmation of viremia while the remaining(77)were considered to have CHC on the basis of a positive HCV Ab and the absence of any other cause of liver disease.Controls were drawn from our institutional database from the same time period and consisted of 356 HBsAg(-)age,race and gender matched patients with HCV RNA-confirmed CHC and without evidence of HCC.A subgroup of controls included 118matched patients with liver cirrhosis.χ2test and t test were used for data analysis.RESULTS:Seventy-seven percent of patients in all3 groups were African Americans.Patients with HCC had a significantly higher body mass index(P=0.03),a higher rate of co-infection with human immunodeficiency virus(HIV)(P=0.05)and a higher prevalence of alcohol abuse(P=0.03)than the controls.More patients with HCC had LHB than controls(78%vs39%,P=0.01).Sixty three percent of patients with HCC were both hepatitis B surface antigen(HBsAb)(-)and HBcAb(+)compared to 23%of controls(P<0.01).When compared to cirrhotic controls,the frequency of HBcAb(+)remained higher in patients with HCC(78%vs 45%,P=0.02).Patients with HCC were more likely to be both HBsAb(-)and HBcAb(+)than the cirrhotic controls(63%vs 28%,P=0.01).Although not statistically significant,100%of CHC and HIV coinfected patients with HCC(n=11)were HBcAb(+)when compared to controls(44%;n=9).CONCLUSION:These data suggest that LHB occurs at a significantly increased frequency in patients with CHC and HCC than in patients with CHC without HCC.     

Increasing hepatitis C virus-associated hepatocellular carcinoma mortality and aging: Long term trends in Japan.

BACKGROUND: The incidence of hepatocellular carcinoma (HCC) in Japan has been increasing. The aim of the study was to determine the epidemiological trends in HCC mortality in Japan. METHODS: We reviewed the medical records of all patients whose death was caused by liver disease between 1981 and 2000 at two hospitals. The courses of death were separated based on presence or absence of HCC when death ensued. Additionally, cohorts of patients with HCC were analyzed in 5-year time periods. RESULTS: The number of deaths from hepatitis C virus (HCV)-associated HCC steadily increased 2.6 times from 49 to 128 during observation period. The mean age at death from HCV-associated HCC from 1996 to 2000 was significantly higher than that in the period from 1981 to 1985 (p<0.0001). INTERPRETATION: Deaths from HCV-associated HCC increased from 1981 to 2000, consistent with the aging of the population in Japan.     

Chemoprevention of hepatocellular carcinoma in patients with hepatitis C virus related cirrhosis

Interferon(IFN) therapy has been reported to decrease the risk of hepatocellular carcinoma(HCC) and improve survival by preventing liver-related deaths in patients with chronic hepatitis C virus(HCV) infection, while the role of IFN therapy on the natural history of hepatitis C related cirrhosis is still under debate. The ideal goal of therapy is to prevent the progression into end-stage disease. The use of IFN in patients with HCV compensated cirrhosis reduces the negative clinical evolution independently of the type of laboratoristic and virological response. In our experience, IFN therapy in HCV compensated cirrhosis is barely useful in prevention of HCC, as cirrhosis itself represents a risk of cancer.Some authors noted that IFN treatment reduces the risk of HCC independently of the virological response. It would probably be interesting to evaluate the efficacy of weekly low-dose pegylated(PEG)-IFN therapy in patients with HCV cirrhosis and to assess potential benefits of long-term PEG-IFN plus Ribavirin treatment.     

应用SELDI-TOF-MS技术建立肝癌筛选血清蛋白质指纹图谱模型

目的:建立肝癌筛选血清蛋白质指纹图谱模型．方法:用表面加强激光解析电离飞行时间质谱技术(SELDI-TOF-MS)及WCX2蛋白芯片获得新发肝癌、肝硬化患者和正常人血清的蛋白质指纹图谱,用计算机软件进行比较分析,建立肝癌的筛选模型．结果:肝癌患者与健康对照组血清蛋白质指纹图谱之间有5个标志蛋白(4477,8943,5181, 8617,13 761 Da)在肝癌患者血清中高表达,肝癌患者与肝硬化患者血清蛋白质指纹图谱之间2个标志蛋白(4477,13 761 Da)在肝癌患者血清中高表达,1个标志蛋白(4097 Da)在肝癌患者血清中低表达．SELDI-TOF-MS技术的特异性(60／60,100％);敏感度(18／20,90％)．分析系统筛选出4477,8943,13 761,4097 Da标志蛋白建立的肝癌诊断模型．结论:建立的血清蛋白质指纹图谱模型能够区分肝癌与非肝癌患者,SELDI-TOF-MS在肝癌的诊断及肿瘤特异性蛋白质生物标志分子的筛选等方面具有一定价值．     

Risk of hepatocellular carcinoma after hepatitis C virus cure

Hepatitis C virus(HCV)is a significant cause of hepatocellular carcinoma(HCC).The direct-acting antivirals marked a new era of HCV therapy and are associated with greater than 95%cure rate.Successful treatment of chronic hepatitis C greatly reduces the risk of HCC.A proportion of patients,especially those with pre-existing cirrhosis,remain at risk for HCC despite sustained virologic response(SVR).Diabetes mellitus,hepatic steatosis,alcohol consumption and lack of fibrosis regression are associated with risks of HCC after HCV cure.Noninvasive modalities such as aspartate aminotransferase to platelet ratio index and fibrosis-4 index and transient elastography have been used to monitor hepatic fibrosis.More recently,various fibrosis scores have been combined with clinical parameters and other novel biomarkers to predict risks of HCC for patients who achieved SVR.These models still need to be validated and standardized prior to applying to routine clinical care.     

Association of interferon lambda-4 rs12979860 polymorphism with hepatocellular carcinoma in patients with chronic hepatitis C infection

BACKGROUND Hepatitis C virus(HCV) infection is a public health concern worldwide.Several factors,including genetic polymorphisms,may be evolved in the progression of HCV infection to liver diseases.Interferon lambdas(IFNLs) modulate the immune response during viral infections.IFNLs induce antiviral activity,interfering in the viral replication by promoting the expression of several genes that regulate immunological functions.The interferon lambda-4(IFNL4) rs12979860 polymorphism,which is characterized by a C to T transition in intron 1,is associated with spontaneous and treatment-induced clearance of HCV infection and may play a role in the development of HCV-associated liver diseases,including hepatocellular carcinoma(HCC).AIM To investigate the association of IFNL4 rs12979860 polymorphism with fibrosis,cirrhosis,and HCC in patients with chronic HCV infection.METHODS This study was comprised of 305 chronic HCV-infected patients(53 fibrosis,154 cirrhosis,and 98 HCC cases).The control group was comprised of 260 HCVnegative healthy individuals.The IFNL4 rs12979860 polymorphism was genotyped using the TaqMan assay.Fibrosis was diagnosed based on liver biopsy findings,while cirrhosis was diagnosed through clinical,laboratory,anatomopathological,and/or imaging data.HCC was diagnosed through imaging tests,tumor,and/or anatomopathological markers.RESULTS The T allele was observed in the three groups of patients(fibrosis,cirrhosis,and HCC) at a significantly higher frequency when compared with the control group(P=0.047,P 0.001,and P=0.01,respectively).Also,genotype frequencies presented significant differences between the control group and cirrhosis patients(P 0.001) as well as HCC patients(P=0.002).The risk analysis was performed using the codominant and dominant T allele models.In the codominant model,it was observed that the CT genotype showed an increased risk of developing cirrhosis in comparison with the CC genotype [odds ratio(OR)=2.53;95%confidence interval(CI):1.55-4.15;P 0.001] as well as with HCC(OR=2.54;95%CI:1.44-4.56;P=0.001).A similar result was observed in the comparison of the TT vs CC genotype between the control group and cirrhosis group(OR=2.88;95 % CI:1.44-5.77;P=0.001) but not for HCC patients.In the dominant T allele model,the CT+TT genotypes were associated with an increased risk for progression to cirrhosis(OR=2.60;95%CI:1.63-4.19;P 0.001) and HCC(OR=2.45;95%CI:1.42-4.31;P=0.001).CONCLUSION These findings suggest that the T allele of IFNL4 rs12979860 polymorphism is associated with the development of cirrhosis and HCC in chronic HCV-infected patients.     

Hepatocellular carcinoma in patients with hepatitis C virus-related chronic liver disease

Hepatitis C virus (HCV) is a major cause of hepatocellular carcinoma (HCC) worldwide due to the high prevalence of HCV infection and the high rate of HCC occurrence in patients with HCV cirrhosis. A striking increase in HCC incidence has been observed during the past decades in most industrialized countries, partly related to the growing number of patients infected by HCV. HCC is currently the main cause of death in patients with HCV-related cirrhosis, a fact that justifies screening as far as curative treatments apply only in patients with small tumors. As a whole, treatment options are similar in patients with cirrhosis whatever the cause. Chemoprevention could be also helpful in the near future. It is strongly suggested that antiviral treatment of HCV infection could prevent HCC occurrence, even in cirrhotic patients, mainly when a sustained virological response is obtained.     

Hepatocellular carcinoma in patients with chronic hepatitis C virus infection without cirrhosis

AIM:To investigate and characterise patients with chronic hepatitis C virus(HCV) infection presenting with hepatocellular carcinoma(HCC) in the absence of cirrhosis.METHODS:Patients with chronic hepatitis C infection without cirrhosis presenting with HCC over a 2-year period were identified.The clinical case notes,blood test results and histological specimens were reviewed to identify whether additional risk factors for the development of HCC were present.RESULTS:Six patients(five male,one female) with chro...     

乙型肝炎自然病程中不同纤维化分期及癌变时乙型肝炎病毒的复制状态

目的为了阐明慢性乙型肝炎自然病程中不同纤维化分期及癌变时乙型肝炎病毒(HBV)e系统状态和HBV DNA载量的变化状态。方法使用酶联免疫吸附试验和荧光多聚酶链反应分别检测并比较了慢性乙型肝炎不同纤维化分期和癌变病人血清的HBVe系统状态和HBVDNA载量。结果慢性乙型肝炎肝纤维化Ⅰ、Ⅱ、Ⅲ、Ⅳ期和癌变时的年龄分别为27·1±7·8、29·3±7·1、35·5±7·4、39·1±9·3和50·8±9·6岁。HBeAg的阳性率分别为80%(20/25)、70.9%(22/31)、47·8%(11/23)、25%(7/28)和17·5%(11/63);抗-HBe阳性率分别为8%(2/25)、16.1%(5/31)、30·4%(7/23)、53·6%(15/28)和71·4%(45/63)。HBVDNA载量分别为2·3×107±0·2×102、7·1×106±1·2×102、5·7×105±1·9×102、1·2×105±0·7×102和4·7×104±4·1×102(copies/m1)。年龄,HBeAg和抗-HBe阳性率以及HBVDNA载量在肝纤维化Ⅰ、Ⅱ、Ⅲ、Ⅳ期和癌变五组之间的两两比较存在统计学差异。结论随着慢性乙型肝炎肝纤维化从Ⅰ期向Ⅳ期发展以及部分病人发生癌变,病人的年龄逐渐地增加。HBeAg的阳性率逐渐降低,抗-HBe阳性率逐渐升高,可能与部分病人由于长期受到机体的免疫压力,HBV相继发生HBV前C区或基本核心区启动子双变异有关;另外,HBVDNA载量也呈逐渐下降的趋向,可能与肝纤维化逐步的加重造成肝实质细胞逐渐的减少,导致提供HBV复制的场所进行性减少有关。     

Influence of interferon therapy on outcome after surgery for hepatitis C virus-related hepatocellular carcinoma.

Influence of interferon (IFN) therapy on postoperative outcomes in patients with hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) is still inconclusive. Of 518 patients who underwent hepatic resection for HCV-related HCC, 312 patients with Japan integrated staging score 0-2 were included in this study. Of 50 patients underwent IFN therapy, 29 patients who obtained a normalized alanine aminotransferase (ALT) activity irrespective of disappearance of serum HCV RNA were classified as the response group, while 21 patients were classified as the non-response group because their ALT activities were not normalized and serum HCV RNA persisted. The non-IFN group included 262 patients who had not received IFN therapy. The tumor-free and the overall survival rates for patients in the response group were significantly higher than those in other groups. Only one patient in the response group died of HCC recurrence, and the proportion of deaths associated with liver disease (HCC recurrence or cirrhosis) was significantly lower in the response group than other two groups. IFN therapy can improve postoperative outcomes in patients with HCV-related HCC because of suppression of recurrence and preventing progress of cirrhosis, especially when IFN therapy has controlled their active hepatitis.     

Prevention of cancer recurrence after treatment for hepatitis C virus-related hepatocellular carcinoma by interferon therapy

The outcome of treatment for hepatitis C virus-related hepatocellular carcinoma is still unsatisfactory because of the high rate of recurrence of cancer, including intrahepatic metastasis and multicentric carcinogenesis after treatment. The rate of recurrence, especially that of multicentric carcinogenesis, is affected by persistent active hepatitis and hepatic fibrosis caused by chronic hepatitis C. Interferon therapy improves the outcome after treatment of hepatocellular carcinoma by decreasing recurrence and preserving or improving liver function when treatment is successful. Radical treatment by anatomic resection and interferon therapy can markedly improve the outcome in patients with hepatitis C virus-related hepatocellular carcinoma.     

Postoperative adjuvant antiviral therapy for hepatitis B/C virus-related hepatocellular carcinoma:A meta-analysis

AIM:To investigate the impact of postoperative antiviral treatment on tumor recurrence and survival of patients with chronic hepatitis B virus(HBV) or hepatitis C virus(HCV) infection-related primary hepatocellular carcinoma(HCC) after curative therapy.METHODS:We performed a meta-analysis of randomized and non-randomized control trials from electronic search and manual search.The fixed effect model of Mantel-Haenszel method and the random effect model of Der Simonian and Laird method were used for homogeneo...