Hepatitis C and hepatocellular carcinoma

Abstract Hepatitis C virus (HCV) infection is aetiologically very closely associated with hepatocellular carcinoma (HCC). World-wide, hepatitis B virus infection is the predominant aetiological factor in developing countries, whereas in industrialized countries, HCV has a far more important role in hepatocarcinogenesis. The varying weights of the aetiological role of HCV infection are compared among countries. The speed of progression of chronic hepatitis C to cirrhosis, thenceforth to HCC, and certain discrepancies between an American study and the Japanese experience are described. The reason for the recent surge of HCV infection and subsequent increase in the incidence of HCC is also discussed. The genetic mechanism of HCV-induced hepatocarcinogenesis is still poorly understood.     

New hepatitis viruses: contenders and pretenders

Following the development of tests for hepatitis C virus and hepatitis E virus infection, it became clear that there remained cases of hepatitis that were non-A-E. Such cases provided impetus for the search for additional hepatitis viruses and, by using molecular techniques, several candidates were identified. An enteric agent responsible for sporadic non-A and non-E hepatitis was tentatively called hepatitis F virus. However, the lack of any corroborating reports has cast doubt on its status as a true hepatitis virus. Two groups independently reported the isolation of a blood-borne virus, designated as hepatitis G virus (HGV) and GB virus C (GBV-C) by their respective discoverers. They were later shown to be isolates of the same virus. While the virus has a high prevalence in cases of non-A-E hepatitis, it also has a high prevalence in the appropriate control groups and convincing evidence for its replication in the liver is lacking. Another possible hepatitis virus, TT virus, was discovered in the blood of a patient with post-transfusion non-A-E hepatitis. By using PCR primers designed to overcome the high nucleotide sequence divergence, TT virus was found to be ubiquitous with a worldwide distribution. A disease association is thus unlikely. Most recently, a DNA virus designated as SEN-V has been announced as a major cause of non-A-E hepatitis. Based on limited data available to researchers, SEN-V is the most convincing contender for the new hepatitis virus title. However, the lessons learnt from the hepatitis virus pretenders will need to be applied to SEN-V and any future contenders.     

Hepatitis B virus markers and antibodies to hepatitis C virus in Japanese patients with hepatocellular carcinoma

Sera from Japanese patients with chronic liver disease were tested for hepatitis B virus (HBV) markers and antibodies to hepatitis C virus (anti-HCV), and the results were correlated to the presence of hepatocellular carcinoma. In chronic non-A, non-B liver disease, anti-HCV prevalence was high both in patients with hepatocellular carcinoma (78/89, 88%) and without it (66/84, 79%), while previous HBV infection was more common in patients with hepatocellular carcinoma (65/89, 73%) than in those without it (46/84, 55%) (P<0.05). Coexistence of anti-HCV and antibodies to HBV was observed frequently in patients with hepatocellular carcinoma (56/89, 63%) compared with patients without it (39/84, 46%) (P<0.05). In chronic HBV carriers, anti-HCV was more common in patients with hepatocellular carcinoma (12/38, 32%) than in those without it (3/62, 5%) (P<0.01). These results suggest that infection with the two viruses may be a risk factor for more serious liver disease.This work was supported by a Grant-in-Aid from the Ministry of Education, Science and Culture, Japan.     

HBsAg-negative hepatitis B virus infections in hepatitis C virus-associated hepatocellular carcinoma

This study was conducted to evaluate reports that hepatitis B virus (HBV) DNA sequences can be found in the serum and/or tumour tissue from some hepatocellular carcinoma (HCC) patients who have no detectable hepatitis B surface antigen (HBsAg) in their sera. Such HBV infections would be highly atypical, because prospective studies have shown a clear succession of specific serologic markers during and after most HBV infections. As most HBsAg-negative HCC patients in Japan have hepatitis C virus (HCV) infections, the present study was conducted to determine whether some of these patients actually have unrecognized HBV infections. Thirty newly diagnosed HCC patients from Kurume, Japan, with antibody to the hepatitis C virus (anti-HCV) were studied. None of the 30 had HBsAg detectable in their serum. Of 22 for whom test results for antibodies to the hepatitis B core antigen (anti-HBc) and antibodies to HBsAg (anti-HBs) were available, 14 (64%) had anti-HBc and anti-HBs, four (18%) had anti-HBc alone, and four (18%) had no HBV markers. Nested polymerase chain reaction was used to detect the HBV surface (S), core (C), polymerase (P) and core promoter gene sequences in the HCC tissues and in the adjacent nontumorous liver tissues. HBV DNA was detected in HCC and/or adjacent nontumorous liver in 22 of 30 (73%) patients [detected in both HCC and nontumorous liver in 19/30 patients (63%)]. Among the 22 patients with detectable HBV DNA, more than one HBV gene was detected in 10 (46%). Among the four patients whose sera were negative for all HBV markers, three had HBV DNA in either HCC and nontumorous liver (two cases) or only in the nontumorous liver (one case); HBV DNA could not be detected in tissues from the fourth patient. In 18 of 21 (86%) patients with detectable HBV core promoter sequences, mutations at both nucleotides 1762 (A-GT) and 1764 (G-A) in the core promoter region were found. No deletions were detected in the core promoter gene region of the type reported to be associated with some cases of HBsAg-negative HBV infection. Thus, HBV DNA was detectable in 22 (73%) HBsAg-negative, anti-HCV-positive HCCs, including three (10%) who were also negative for anti-HBc and anti-HBs. HBV mutations at both nucleotides 1762 (A-GT) and 1764 (G-A) in the core promoter region were found in the majority of cases, mutations that have previously been reported in HBV that is integrated in HCC DNA. In serologic surveys to determine etiologic associations of HCC, patients such as those in this study would have been incorrectly designated as having 'HCV-associated HCC,' whereas the data in this study suggest that HBV could have played a role in the development of their HCCs.     

Hepatitis C virus and hepatocellular carcinoma

The sequential development of cirrhosis and hepatocellular carcinoma (HCC) in patients with transfusion-associated hepatitis was a clue leading to the identification of hepatitis C virus (HCV) as a risk factor for HCC. The incidence of HCV-related liver cancer is increasing in many developed countries: tumours arise in older patients, are almost invariably associated with cirrhosis and often have a less aggressive course than is seen in HCC related to other aetiological factors. Most HCCs grow as a single hepatic nodule for several years before generating satellite or distant tumour nodules. Tumour progression and hepatic failure are the leading causes of death. HCV might promote cancer through cirrhosis, which is per se an important risk factor for this tumour. HCV might also have oncogenic properties by interacting with cellular genes that regulate cell growth and differentiation. The primary prevention of HCC through vaccination against HCV is not yet available. The treatment of patients with chronic hepatitis C with interferon might attenuate the risk of HCC.     

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.     

Hepatitis B and C virus infection as risk factors for liver cirrhosis and cirrhotic hepatocellular carcinoma: a case-control study

To investigate whether hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are risk factors for liver cirrhosis and hepatocellular carcinoma (HCC), a case-control study of 102 cirrhotic HCC patients, 102 sex-matched and age-matched patients with liver cirrhosis, and 102 matched patients with non-hepatic disease controls was performed. The prevalences of hepatitis B surface antigen (HBsAg) and antibody to HCV (anti-HCV) in HCC (70.5%, 39.2%) and liver cirrhosis (74.5%, 27.4%) were higher than controls (16.6%, 10.5%) (P = 0.0001). In HBsAg-negative patients, the prevalence of anti-HCV in cirrhotic HCC (66.6%) and liver cirrhosis (46.1%) was higher than in controls (10.5%; P = 0.0001). There was no such difference in HBsAg-positive patients. Multivariate analysis revealed that both HBsAg and anti-HCV were important risk factors for HCC (odds ratio, 6.52 and 4.59, respectively) and liver cirrhosis (odds ratio, 4.22 and 2.29, respectively). There was no difference in odds ratio when HCC and liver cirrhosis were compared. Our result implies that both HBV and HCV are independent risk factors for cirrhotic HCC and liver cirrhosis in Taiwan.     

Pathogenesis of hepatitis B and C-induced hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is estimated to have an annual worldwide incidence of 0.25 to 1.2 million new cases per year. Both the prevalence and incidence of HCC vary markedly as a function of geography and the local prevalence of chronic viral hepatitis. Both chronic hepatitis B and chronic hepatitis C are recognized as risk factors for HCC. The prevalence of cirrhosis in individuals with HCC and chronic hepatitis B or C is reported to be 80.9% and 75.8%, respectively. HCC occurs at a lower rate in chronic viral hepatitis in the absence of cirrhosis. Moreover, hepatitis C virus (HCV) rather than hepatitis B virus (HBV) is associated with the majority of non-cirrhotic cases of HCC. It is probable that the ongoing process of hepatocyte necrosis and liver cell renewal coupled with inflammation, which is characteristic of chronic viral hepatitis, causes not only nodular regeneration and cirrhosis but also progressive genomic errors in hepatocytes as well as unregulated growth and repair mechanisms leading to hepatocyte dysplasia and, in some cases, hepatic carcinoma. Current concepts concerning virus-induced HCC are reported and discussed in the following review.     

HBV/HCV相关性肝细胞癌抗病毒治疗专家共识

正1前言乙型肝炎病毒(HBV)和丙型肝炎病毒(HCV)感染在肝细胞癌(HCC)的发生发展中起重要作用。我国近年发布的《慢性乙型肝炎防治指南(2010版)》和《原发性肝癌诊疗规范(2011版)》都强调了肝癌患者抗病毒治疗的重要性,《丙型肝炎防治指南(2004版)》也注意到抗病毒治疗可延缓HCC的发生。目前国内外对肝癌抗病毒治疗的具体实施和评价尚无统一认识。有鉴于此,中华医学会肝病学     

De novo hepatitis B virus infection in hepatocellular carcinoma following eradication of hepatitis C virus by interferon therapy

Epidemiological studies have revealed that hepatocellular carcinoma (HCC) is still observed in hepatitis C virus (HCV)‐positive patients with a sustained response to interferon (IFN) treatment, although a substantial decrease in the incidence of hepatocellular carcinoma (HCC) has been achieved in those patients. Why HCC develops in patients who have a complete clearance of HCV remains unclear. Here, we provided evidence of latent hepatitis B virus (HBV) infection in an initially HCV‐positive chronic hepatitis patient who developed HCC after the complete eradication of HCV by IFN therapy. Although he was initially negative for anti‐hepatitis B surface antigen (HBsAg) or circulating HBV DNA but positive for anti‐hepatitis B core antigen (anti‐HBc) in his sera, he developed HBsAg and HBV DNA during the course of the management of a series of cancers. HBV DNA was detectable in the liver tissues before HBV reactivation and the viral sequences derived from his anti‐HBc‐positive liver showed 100% homology to that from the serum after HBsAg appearance. These findings indicates that HCV‐positive individuals who are positive for anti‐HBc in the absence of HBsAg could have latent HBV infection in their liver tissues and intrahepatic HBV infection may play a pivotal role in the development of HCC after the IFN‐mediated eradication of HCV.     

SEN virus infection in patients with hepatocellular carcinoma

Although most cases of hepatocellular carcinoma (HCC) are associated with either the hepatitis B or C viruses (HBV, HCV), about 10-20% of HCCs occur in patients with chronic hepatitis that is aetiologically undefined. The aim of the present study was to determine the prevalence of the transfusion-transmitted SEN virus (SEN-V) in patients with HCC, including those patients who do not otherwise appear to be infected with HBV or HCV. Fragments of SEN-V subtypes D and H were amplified separately by PCR from the sera of 50 patients with HCC (31 from Canada and 19 from Japan) as well as from HCC and adjacent nontumourous liver tissues from eight of the Canadian patients. SEN-V DNA was found in the serum of 10 of 31 (32%) Canadian patients and eight of 19 (42%) Japanese patients [overall, 18 of 50 (36%) HCC patients]. SEN-V DNA was detected in the serum of 10 of 23 (43%) HCC patients with antibody to HCV (anti-HCV), six of 11 (55%) with hepatitis B surface antigen (HBsAg), and two of 16 (12%) without detectable anti-HCV or HBsAg. Twenty-three HCC patients in this study had 'silent HBV,' characterized by the detection of HBV DNA in the absence of HBsAg; eight of these (35%) also had SEN-V infections. SEN-V DNA was detected in HCC patients most typically in those with coexistent HBV or HCV infection. SEN-V was found in only one of seven HCC patients without HBV (without HBsAg or HBV DNA) or HCV and thus does not appear to be an important cause of 'cryptogenic' HCC.     

Different viral aetiology of hepatocellular carcinoma between two hepatitis B and C endemic townships in Taiwan

In Taiwan, we found two hepatitis B virus (HBV)- and hepatitis C virus (HCV)-endemic townships, Paisha and Tzukuan, with an anti-HCV prevalence of 19 and 37% in men, and 26 and 38% in women, respectively. The hepatitis B surface antigen (HBsAg)-positive rates were 25 and 18%, for men and women in Paisha, and 25 and 22% in Tzukuan, respectively. According to the national death certification database (1982 to 1991), the annual age-adjusted mortality rates per 100 000 population for liver cancer among men and women were 83.0 and 13.8, respectively, in Paisha, and 55.9 and 17.0 in Tzukuan compared with 30.9 and 9.1 in Taiwan as a whole. The male-to-female ratios were 6.0 in Paisha and 3.3 in Tzukuan. Aetiology of 11 cases of hepatocellular carcinoma (HCC) from Paisha and 14 cases from Tzukuan were analysed. All HCC cases from Paisha were HBsAg positive, while 13/14 HCC cases from Tzukuan were anti-HCV positive. The endemic duration of HCV in Tzukuan seemed long enough to induce HCC, but the HCV appeared to be a newly introduced infection in Paisha.     

Hepatocellular carcinoma: role of hepatitis B and hepatitis C viruses proteins in hepatocarcinogenesis

Hepatocellular carcinoma (HCC) is the most important primary hepatic cancer, being a common cancer type worldwide. Many aetiological factors have been related with HCC development, such as cirrhosis, hepatitis viruses and alcohol. Chronic infection with hepatitis B (HBV) and C viruses (HCV) often results in cirrhosis and enhances the probability of developing HCC. The underlying mechanisms that lead to malignant transformation of infected cells, however, remain unclear. HBV is a DNA virus that integrates into the host genome, and this integration is believed, in part, to be carcinogenic. Besides, the virus encodes a 17 kDa protein, HBx, which is known to be a causative agent in the formation of HCC. On the contrary, HCV is a RNA virus that does not integrate into the host genome but likely induces HCC through host protein interactions or via the inflammatory response to the virus. Products encoded in the HCV genome interfere with and disturb intracellular signal transduction. Some HCV proteins, such as the core protein, NS3 and NS5A, have seen to have a regulatory effect on cellular promoters, to interact with a number of cellular proteins, and to be involved in programmed-cell death modulation under certain conditions. The identification of these proteins functions in HCC development and the subsequent development of strategies to inhibit protein-protein interactions may be the first step towards reducing the chronicity and/or of the carcinogenicity of these two viruses.     

HBV/HCV相关性肝细胞癌抗病毒治疗专家共识

<正>(2014年3月29日)1前言乙型肝炎病毒(HBV)和丙型肝炎病毒(HCV)感染在肝细胞癌(HCC)的发生发展中起重要作用。我国近年发布的《慢性乙型肝炎防治指南(2010版)》和《原发性肝癌诊疗规范(2011版)》都强调了肝癌患者抗病毒治疗的重要性,《丙型肝炎防治指南(2004版)》也注意到抗病毒治疗可延缓HCC的发生。目     

Occurrence of hepatocellular carcinoma after hepatoblastoma resection in an adult with hepatitis C virus

Hepatoblastoma is a rare malignancy in adults. It is often diagnosed after the appearance of symptoms, therefore, the tumor size tends to be larger. In patients with no indication for a hepatic resection, the prognosis of adult hepatoblastoma is quite poor. A 54-year-old man with hepatitis C virus-associated liver cirrhosis was initially treated with a hepatic resection for a hepatic tumor, 3 cm in diameter. The tumor consisted of osteoid-like and cartilaginous foci, myxomatous stroma, and poorly differentiated hepatocellular carcinomatous cells and was diagnosed as a mixed epithelial and mesenchymal hepatoblastoma. Two years after the first operation, multicentric hepatocellular carcinomas developed in the remnant liver and were successfully treated with a secondary hepatic resection combined with radio-frequency ablation. The patient is now alive with no recurrence at 5 years after the initial hepatectomy. To the best of our knowledge, the primary hepatoblastoma was the smallest such tumor reported and this is the first report of a metachronous hepatoblastoma and hepatocellular carcinoma in an adult hepatitis patient.     

Clinicopathological features and natural history of acute sporadic non-(A-E) hepatitis

Aim:  The aim of the present study was to describe the clinicopathological characteristics and the natural history of acute non-(A-E) hepatitis and to assess the possible role of hepatitis G virus (HGV), TT virus (TTV) and mainly SEN virus (SENV).
Methods:  A cohort of 55 patients with sporadic acute non-(A-E) hepatitis with a mean follow up of 31 (6–55) months was studied.
Results:  The clinical presentation was fulminant in one (1.8%), protracted with impaired regeneration in seven (12.7%) and benign in the remaining 47 (85.5%) cases. Progression to chronic hepatitis was observed in 15 (27.3%) patients; it was more frequent in clinically severe than in non-severe cases (five of eight patients or 62.5% vs 10 of 47 patients or 21.3%, P  = 0.028). Six of 10 biopsied chronic non-(A-E) cases developed cirrhosis within 10–33 months. Serum HGV-RNA was detected in 16 of 55 (29.1%) patients, TTV in 20 of 38 (52.6%) patients and SENV-D/H DNA in 20 of 55 (36.4%) cases. HGV-RNA was detected more frequently in clinically severe than in non-severe cases (five of eight or 62.5% vs 11 of 47 or 23.4%, P  = 0.038). There was no other association between the presence of HGV, TTV, or SENV infection and patient characteristics or severity and outcome of disease.
Conclusions:  HGV, TTV, and SENV do not seem to be responsible for the majority of sporadic acute non-(A-E) hepatitis cases. Our cohort further supports the existence of new, unknown hepatitis agent(s) with uncertain mode of transmission. The non-(A-E) agent(s) can also cause chronic hepatitis, which often has an aggressive course with rapid development of cirrhosis.