Viral Hepatitis and Hepatocellular Carcinoma Prevention Strategy in Japan

The study of human hepatitis, particularly in Asia, where the incidence rate has been the highest in the world, has contributed greatly to the understanding of carcinogenesis of the liver and related diseases. In this article, the history of research on hepatitis viruses and hepatocellular carcinoma (HCC) and the successful prevention of vertical transmission of hepatitis B virus (HBV) in Japan are reviewed, focusing on the studies that resulted in the identification of vertical transmission of HBV infection and the association of HBV-sustained infection and HCC. The vaccination trials for preventing HBV vertical transmission and the fruitful outcome of the nationwide vaccination strategy in Japan, on the basis of'selective'immunization by using anti-HBs immunoglobulin (HBIG) and HB vaccine, are highlighted. Ongoing studies on the mechanisms underlying hepatocarcinogenesis induced by viruses, e.g., the roles of viral proteins and inflammation, are also reviewed, and prospects for the control of HCC are discussed.     

A model of interaction: Aflatoxins and hepatitis viruses in liver cancer aetiology and prevention

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide and has an extremely poor prognosis. The majority of cases occur in south-east Asia and sub-Saharan Africa where the major risk factors are chronic infection with hepatitis B and C viruses (HBV and HCV) as well as dietary exposure to aflatoxins. Aflatoxin B1, the most commonly occurring and potent of the aflatoxins is associated with a specific AGG to AGT transversion mutation at codon 249 of the p53 gene in human HCC, providing mechanistic support to a causal link between exposure and disease. Prospective epidemiological studies have shown a more than multiplicative interaction between HBV and aflatoxins in terms of HCC risk. However, the biology underlying this statistical interaction is not fully understood. There are a number of potential mechanisms including, among others: the fixation of AFB1-induced mutations in the presence of liver regeneration and hyperplasia induced by chronic HBV infection; the predisposition of HBV-infected hepatocytes to aflatoxin-induced DNA damage; an increase in susceptibility to chronic HBV infection in aflatoxin-exposed individuals; and oxidative stress exacerbated by co-exposure to aflatoxins and chronic hepatitis infection. Priorities for prevention are global HBV vaccination, primary and secondary prevention strategies against aflatoxin and the avoidance of transmission of HCV through good hygiene practices.     

Molecular mechanism of viral hepatocarcinogenesis

Overwhelming lines of epidemiological evidence have indicated that chronic infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) is a major risk for the development of hepatocellular carcinoma (HCC). In the pathogenesis of HCC associated with HBV or HCV, it remains controversial whether these hepatitis viruses play a direct role or merely an indirect role. By virtue of transgenic mice established by us, it has become evident that the product of the HBV X gene (HBx protein) and the core protein of HCV have an oncogenic potential, although the pathways through which these two viral proteins operate may differ. The findings in our studies indicate that HBV and HCV are directly involved in hepatocarcinogenesis, albeit other factors such as continued cell death and regeneration associated with chronic hepatitis may play a role as well. Combined, our results suggest that there might be a mechanism in the development of HCC in persistent infection with hepatitis viruses that is distinct from that in other cancers. Similarly to the pathogenesis of other malignancies represented by colorectal cancer, the accumulation of a set of genetic aberrations may also be necessary for a multistage development of HCC. However, HBx protein and HCV core protein, to which an oncogenic potential is attributed, may allow some of the multiple stages skipped in hepatocarcinogenesis. Unlike for the other cancers, therefore, infection with HBV or HCV may be capable of inducing HCC in the absence of a complete set of genetic aberrations. Such a scenario would explain an unusually high incidence and multicentric nature of HCC developing in chronic hepatitis B or C.     

Breakthrough in human hepatocellular carcinogenesis--from hepatitis B virus to hepatitis C virus]

Since demonstration of causative relationship of hepatocellular carcinoma (HCC) and persistent hepatitis B virus (HBV) infection, nation-wide preventive measures have made remarkable progress in Japan. This will contribute to minimizing the probability to create new sources for HBV infection resulting in reduction of the incidence with liver cirrhosis and HCC due to HBV infection in the next generation. Currently, however, HCC not due to HBV increased twice in the pastdecade up to three quarters of total HCC cases and 30-40% of them had previous history of blood transfusion. Hepatitis C virus (HCV) antibody test revealed that at least three quarters of them are due to HCV infection. Seroepidemiological studies demonstrated that transmission route of HCV in mainly blood borne horizontal infection and partly by sexual contact. Transfusion of blood or blood products is major route in Japan. Elimination of HCV infected blood for blood transfusion and improvement of sanitary condition especially in health care system will be most effective counter measures for prevention of HCV infection. Antiviral therapy specially with interferon will be the most promising measure to intervene clinical progression of HCV infected cases to HCV related liver cirrhosis or HCC.     

Etiology of hepatocellular carcinoma in Africa

The important factors in the causation of hepatocellular carcinoma (HCC) in Africa include hepatitis B virus (HBV), aflatoxin and possibly malnutrition. The evidence in support of an association of HBV with HCC is mainly epidemiological and includes: (a) the similarity between the geographical distribution of chronic carriers of hepatitis B surface antigen (HBsAg) and that of HCC; (b) the increased prevalence of HBV markers in the serum of patients with HCC when compared with the general population; and (c) the observation that HBV infection precedes the general development of the tumour and that HBV infection increases the risk of HCC over 200-fold. Laboratory evidence has shown that HBV DNA is integrated in the host tissue in patients with HCC. A vaccination programme in Senegal showed that hepatitis B vaccine reduced HBV infection and it is hoped that it will eventually lead to a reduction in HCC. Studies in East Africa have shown a correlation between aflatoxin contamination and the incidence of HCC. The possible roles of malnutrition and/or alcohol are discussed.     

Viral Hepatitis and Liver Cancer in Korea: an Epidemiological Perspective

In the past, hepatitis B virus (HBV) infection was endemic in the general Korean population. The associationof HBV infection with the occurrence of liver cancer has been well demonstrated in several epidemiologic studies.While the mortality rates of liver cancer in Korea have decreased steadily over the last decade, the presenceof hepatitis B surface antigen (HBsAg) in mothers remains high at 3-4%, and 25.5% of these HBsAg positivemothers are positive for hepatitis B e antigen (HBeAg). HBV infection caused almost a quarter of hepatocellularcarcinoma (HCC) cases and one-third of deaths from HCC. These aspects of HBV infection prompted the Koreangovernment to create a vaccination program against HBV in the early 1980s. In 1995, the Communicable DiseasePrevention Act (CDPA) was reformed, and the government increased the number of HBV vaccines in the NationalImmunization Program (NIP), driving the vaccination rate up to 95%. In 2000, the National Health InsuranceAct (NHIA) was enacted, which provided increased resources for the prevention of perinatal HBV infection.Then in 2002, the Korean government, in conjunction with the Korean Medical Association (KMA), launchedan HBV perinatal transmission prevention program. The prevalence of HBsAg in children had been high (4-5%)in the early 1980s, but had dropped to below 1% in 1995, and finally reached 0.2% in 2006 after the NIP hadbeen implemented. After the success of the NIP, Korea finally obtained its first certification of achievement fromthe Western Pacific Regional Office of the World Health Organization (WPRO-WHO) for reaching its goal forHBV control. An age-period-cohort analysis showed a significant reduction in the liver cancer mortality ratein children and adolescents after the NIP had been implemented. In addition to its vaccination efforts, Korealaunched the National Cancer Screening Program (NCSP) for 5 leading sites of cancer, including the liver, in1999. As a consequence of this program, the 5-year liver cancer survival rate increased from 13.2% (1996-2000)to 23.3% (2003-2008). The development of both the primary and secondary prevention for liver cancer includingHBV immunization and cancer screening has been of critical importance.     

Hepadnaviruses and hepatocellular carcinoma (HCC)

Members of the hepadnavirus family share properties of virion structure, genome structure and replication, epidemiologic behavior, and pathogenic effects. Persistent infections with hepatitis B virus (HBV) in man, woodchuck hepatitis virus (WHV) in Marmota monax, ground squirrel hepatitis virus (GSHV) in Spermophilus beecheyi, and duck hepatitis B virus (DHBV) in domestic ducks of China are associated with development of hepatocellular carcinoma (HCC). Epidemiological evidence implicating hepadnavirus infection in HCC includes the observation that the geographic distributions of HBV infection and HCC are similar, that the incidence of HCC is much higher in hepadnavirus-infected than uninfected hosts, and that viral DNA sequences are integrated in the cellular DNA of most (e.g., 80 to 90%), but not all, hepadnavirus-associated HCC. Cirrhosis further increases the risk of HCC in HBV-infected humans. The precise role of hepadnaviruses in development of most HCC is unclear, although the finding of viral integrations within or near protooncogenes in a few cases suggests the possibility that these integrations may play a direct role in these HCC. However, in the great majority of HCC, viral integrations are in different cellular DNA sites in different HCC, integrations are not within domains of known protooncogenes, and integrations are not found in some 10 to 15% hepadnavirus-associated HCC, suggesting that persisting viral sequences are not directly involved in the development of these HCC as viral sequences are for tumors caused by viruses with oncogenes or viruses that act by a "promoter-insertion" mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hepatocellular carcinoma associated with hepatitis C virus infection in Japan: projection to other countries in the foreseeable future

During the turmoil after the end of World War II some 50 years ago, in Japan intravenous methamphetamine was widespread and penetrated the young generation aged 15-25 years and remunerated blood donors. The vicious cycle gave an enormous thrust to the spread of hepatitis C virus (HCV) infection among drug users and blood donors. Their HCV infection was transmitted to the general population through transfusions, folk medicine involving the breaking of the integument and tattooing. Indiscreet and widespread treatment with intravenous injection using contaminated syringes and needles at that time accelerated the transmission of HCV further. An overall result was the outbreak of HCV infection in restricted subpopulations in Japan, which inevitably involved the general population. Abrogation of paid blood donation in 1968, the exclusion of blood units contaminated with hepatitis B virus (HBV) in 1973 and that of HCV since November 1989 (by the second generation tests after February 1992) decreased the risk of posttransfusion hepatitis from >50% in the 1960s to infinitely close to zero at present. Now the incidence of HCV infection in Japan is decreased to 1.8-3.5/100,000 person-years. Mother-to-baby transmission of HBV has been prevented since 1986 by a combined passive and active immunoprophylaxis of the babies at risk with hepatitis B immune globulin and vaccine. What we see today in Japan, however, is an ever-increasing incidence of hepatocellular carcinoma (HCC) that has reached almost 40/100,000 population, with males >50 years accounting for the great majority. Of the HCC cases in Japan, approximately 16% is caused by HBV infection and approximately 80% by HCV infection. The growing incidence of HCC is expected to reach a plateau around the year 2015, and then to start to decrease. The ordeal we have gone through, with special reference to the increasing incidence of HCV-associated HCC, is expected elsewhere in the world with a current profile of age-specific HCV infection like ours a few decades back. For worse or better (probably in this order), Japan is a country far advanced as regards the HCC associated with HCV infection. Our long-term experience related in detail here is hoped to help plan strategies to contain HCV infection and cope with its long-term sequelae in many other countries worldwide.     

Hepatocellular carcinoma: paradigm of preventive oncology

Morbidity and mortality from hepatocellular carcinoma (HCC), which is primarily caused by hepatitis B virus or hepatitis C virus, can be prevented. Public health interventions have eliminated transfusion transmission of these viruses and, in endemic countries with effective hepatitis B virus vaccination programs, have greatly reduced incident hepatitis B virus infections (and HCC) in children. Antiviral treatment can eliminate detectable hepatitis C virus in 50%-80% of chronically infected patients, presumably reducing their risk of cancer. HCC survival rates remain universally poor, but early detection and treatment in developed countries has improved survival in selected patients. Despite these advances, worldwide HCC rates remain high, and additional preventive efforts are needed. The most important opportunity is wider distribution of hepatitis B virus vaccine in endemic areas. Development of an HCV vaccine, improved antiviral therapies, and better methods for HCC detection would also help decrease morbidity and mortality from HCC. HCC prevention efforts provide a paradigm for preventive oncology in cancers of viral etiology.     

The role of hepatitis B and C viruses in hepatocellular carcinoma in a hepatitis B endemic area. A case-control study.

To investigate the role of hepatitis B (HBV) and C viruses (HCV) in hepatocellular carcinoma (HCC) in an HBV endemic area and elucidate the interaction of these two viruses, a case-control study of 128 patients with HCC and 384 age-matched and sex-matched control subjects was done. The positive rates of hepatitis B surface antigen (HBsAg, 77.3%, 99 of 128) and anti-HCV (19.5%, 25 of 128) in patients with HCC were significantly higher than in control subjects (P less than 0.001). Both HBsAg and anti-HCV were important risk factors for HCC (relative risks, 13.96 and 27.12, respectively), and the risk for HCC was elevated significantly to 40.05 (95% confidence interval, 12.57 to 127.6) when HBsAg and anti-HCV were considered simultaneously. These results suggested that HBV and HCV were associated highly with HCC in an HBV endemic area and that these two viruses might contribute independent but synergistic effects to the pathogenesis of HCC.     

Hepatitis B and C virus hepatocarcinogenesis: lessons learned and future challenges

Worldwide, hepatocellular carcinoma (HCC) is one of the most common cancers. It is thought that 80% of hepatocellular carcinomas are linked to chronic infections with the hepatitis B (HBV) or hepatitis C (HCV) viruses. Chronic HBV and HCV infections can alter hepatocyte physiology in similar ways and may utilize similar mechanisms to influence the development of HCC. There has been significant progress towards understanding the molecular biology of HBV and HCV and identifying the cellular signal transduction pathways that are altered by HBV and HCV infections. Although the precise molecular mechanisms that link HBV and HCV infections to the development of HCC are not entirely understood, there is considerable evidence that both inflammatory responses to infections with these viruses, and associated destruction and regeneration of hepatocytes, as well as activities of HBV- or HCV-encoded proteins, contribute to hepatocyte transformation. In this review, we summarize progress in defining mechanisms that may link HBV and HCV infections to the development of HCC, discuss the challenges of directly defining the processes that underlie HBV- and HCV-associated HCC, and describe areas that remain to be explored.     

Application of the woodchuck animal model for the treatment of hepatitis B virus-induced liver cancer

This review describes woodchucks chronically infected with the woodchuck hepatitis virus (WHV) as an animal model for hepatocarcinogenesis and treatment of primary liver cancer or hepatocellular carcinoma (HCC) induced by the hepatitis B virus (HBV). Since laboratory animal models susceptible to HBV infection are limited, woodchucks experimentally infected with WHV, a hepatitis virus closely related to HBV, are increasingly used to enhance our understanding of virus-host interactions, immune response, and liver disease progression. A correlation of severe liver pathogenesis with high-level viral replication and deficient antiviral immunity has been established, which are present during chronic infection after WHV inoculation of neonatal woodchucks for modeling vertical HBV transmission in humans. HCC in chronic carrier woodchucks develops 17 to 36 mo after neonatal WHV infection and involves liver tumors that are comparable in size, morphology, and molecular gene signature to those of HBV-infected patients. Accordingly, woodchucks with WHV-induced liver tumors have been used for the improvement of imaging and ablation techniques of human HCC. In addition, drug efficacy studies in woodchucks with chronic WHV infection have revealed that prolonged treatment with nucleos(t)ide analogs, alone or in combination with other compounds, minimizes the risk of liver disease progression to HCC. More recently, woodchucks have been utilized in the delineation of mechanisms involved in innate and adaptive immune responses against WHV during acute, self-limited and chronic infections. Therapeutic interventions based on modulating the deficient host antiviral immunity have been explored in woodchucks for inducing functional cure in HBV-infected patients and for reducing or even delaying associated liver disease sequelae, including the onset of HCC. Therefore, woodchucks with chronic WHV infection constitute a well-characterized, fully immunocompetent animal model for HBV-induced liver cancer and for preclinical evaluation of the safety and efficacy of new modalities, which are based on chemo, gene, and immune therapy, for the prevention and treatment of HCC in patients for which current treatment options are dismal.     

Hospital- and community-based screenings for hepatocellular carcinoma in Taiwan

In Taiwan, hepatocellular carcinoma (HCC) has been the leading cause of cancer incidence and mortality in recent decades. The majority of patients have hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. The HBV carrier rate and incidence of HCC in children have declined with the implementation of a hepatitis B vaccination program for newborns since 1984. A combination of α-fetoprotein and ultrasonography (US) has been used for surveillance in patients with chronic HBV and HCV infection in intervals of 3-6 and 6-12 months for cirrhosis and chronic liver disease, respectively. A secular survival improvement in HCC patients has been demonstrated. A reasonable screening protocol should include two stages. The first stage is identification of high-risk subjects and the second stage is US screening of high-risk subjects. Community-based HCC screening programs have been conducted for more than two decades in Taiwan. The commonly used first-stage markers are HBsAg and anti-HCV, while the platelet count should be a useful marker in HCV-endemic communities. The benefit of HCC screening was shown by a prolonged overall survival. However, this was limited to the early curable stage in elderly subjects. Prevention and control of HCC have multiple modalities. Identification of a high-risk group for active surveillance, effective antiviral treatment for chronic HBV and HCV infection, and early detection and prompt treatment of HCC should decrease the sequelae of HCC in Taiwan.     

Burden of Hepatocellular Carcinoma in Asian

Hepatocellular carcinoma (HCC), the sixth most prevalent cancer worldwide, continues to have high prevalence in many countries of Asia. The main challenge is the high prevalence of chronic hepatitis and aflatoxin, for example in China. HBV vaccination should be the major preventive tactic in Asian countries. The burden of HCC is low in Iran because most cases are due to HBV and this infection was less common. Although in Iran, a mass vaccination program started in 1993, its impact on decreasing the burden of HCC due to HBV can onlybe expected in future decades.     

Replication efficiency and sequence analysis of full-length hepatitis B virus isolates from hepatocellular carcinoma tissues

Prolonged replication of hepatitis B virus (HBV) in liver tissues of hepatitis B patients has been considered as an important risk factor for the development of malignancy. Few studies on full-length HBV sequencing in association with the replication efficiency of isolates from HCC tissues have been reported. To study the structural and functional genomics of HBV isolates from Chinese hepatocellular carcinoma (HCC) patients, full-length HBV genomes were amplified from 6 HBV-marker positive HCC tissues and used to transfect HepG2 cells. Five of 6 isolates showed high replicative efficiency. All isolates were of genotype C and "hot-spots" mutations were detected in the B cell and T helper (Th) cell epitopes of the envelope and the core region. In addition, the X region of 2 isolates contained a stop-codon mutation that was predicted to result in a truncated X protein. High replicative HBV immune escape mutants that persist in infected hepatocytes could be 1 of the important factors to initiate pathological processes for the development of HCC in Chinese patients.     

Natural history of hepatitis B and C virus infections

Thirty-five years have already elapsed since the discovery of hepatitis B virus (HBV), and 10 years since that of hepatitis C virus (HCV). Nonetheless, the natural history of HBV and HCV infections has not been fully defined, partly because they do not have subjective symptoms in most cases. Even when liver disease is induced by these hepatitis viruses, the clinical course is slow and mostly insidious. HBV and HCV are much alike in that they both cause a spectrum of clinical conditions ranging from the symptom-free carrier state through chronic hepatitis and liver cirrhosis to eventual hepatocellular carcinoma. Despite a close similarity, infections with HBV and HCV are very different in many aspects, from the early to end stage. Large-scale unbiased studies to sort out the natural history of HBV and HCV infections are lacking, however. Understandably, in view of the fact that only a few decades have passed since these hepatitis viruses were discovered. My personal account on the natural history of HBV and HCV infections is given here, which is based on my experience of over 40 years as a clinical and research hepatologist in Japan, although I am aware that it invites more questions than it answers.     

Epidemiology of primary liver cancer in Japan

In Japan, more than 90% of primary liver cancers consist of hepatocellular carcinoma (HCC), 80% of which is caused by chronic hepatitis C virus (HCV) infection, and the remaining 15% of which is caused by chronic hepatitis B virus (HBV) infection. The proportion of older patients among patients with HCC has been increasing in recent years because of the aging of the HCV-prevalent birth cohort born between 1925 and 1935. The cumulative risk of developing HCC among HCV carriers was estimated as 30% for males and 6% for females. Older age, being male, having a low platelet count, higher histological stage, genotype 1b, co-infection with HBV, heavy drinking and smoking increase the risk of developing HCC among patients with chronic HCV infection. Recent reports on the efficacy of interferon therapy on the incidence of HCC in Japanese patients with chronic hepatitis C demonstrate the importance of providing a screening system for chronic HCV infection and establishing a medical referral system so that patients undergo the appropriate therapy for the Japanese HCV carriers.