Detection of mutant p53 in hepatocellular cancer from Turkey and its correlation with clinicopathologic parameters

The samples of hepatocellular carcinoma from Turkey, a country with a high prevalence of hepatitis B virus and hepatitis C virus, but low dietary exposure to aflatoxin B1, were examined in order to detect the frequency of mutant p53 and its association with clinical and pathological data. Fifty-two samples of hepatocellular cancer from the patients who were diagnosed in our clinic were included in this study. The mutant p53 protein was searched for by specific enzyme-linked immunosorbent assay. Of 52 patients with hepatocellular carcinoma, 26 (50%) had the mutant p53. The incidence of p53 mutation in hepatocellular cancer patients with chronic liver disease due to hepatitis B virus infection was significantly higher than in those with chronic liver disease due to alcohol, indicating that not alcohol but hepatitis B virus, in fact induces the mutations in p53 gene. In addition, it has been shown that the p53 mutation was significantly associated with the diameter of tumor nodule and the degree of cellular differentiation in hepatocellular cancer. The p53 mutation rate found in our study is concordant for a geography where hepatitis B virus and hepatitis C virus are common. Hepatitis B virus and possibly hepatitis C virus, but not alcohol, should be responsible, to a degree, for the mutational change in p53 protein in hepatocellular cancer patients with chronic liver disease. The p53 mutation is a late event in hepatocarcinogenesis because it is related with cellular differentiation and tumor diameter. The specific ELISA can be a useful screening test in future studies to select the patients for gene therapy using wild-type p53.     

Hepatitis B today

Hepatitis B remains a major problem for public health worldwide and represents a challenging disease for practicing physicians. Of the 2 billion people who have been infected with the hepatitis B virus, more than 350 million have chronic infections. These chronically infected individuals are at high risk of death from cirrhosis and liver cancer. The use of new antiviral drugs, such us nucleotides analogues, offer good hope in the prognosis of patients suffering from chronic hepatitis B.     

Chronic hepatitis B and hepatitis C in Asian Americans

Both chronic hepatitis B and hepatitis C are prevalent among the 12 million Asians and Pacific Islanders living in the United States. Significant epidemiological and clinical differences exist between Asian Americans and the general U.S. population, most notably the higher rate of primary liver cancer and the differential response to various antiviral therapies. Perinatal and childhood transmission is common for hepatitis B virus. Transmission of hepatitis C virus probably also occurs early in life and results from nosocomial transmission and person-to-person spread. Asian patients with chronic hepatitis B commonly have hepatitis B e antigen-negative hepatitis B with either the precore or core-promoter mutant hepatitis B virus, which may require long-term antiviral viral therapy because of high rates of relapse following therapy. Asian patients with chronic hepatitis C may have a substantially higher risk of liver cancer but a better response to interferon-based therapy, both in terms of sustained virological response and reduced future incidence of liver cancer. Understanding these differences will lead to improved care for Asian Americans with viral hepatitis and better disease control for hepatitis B and hepatitis C for the entire U.S. population. This review briefly summarizes the major issues in the clinical care of patients with chronic viral hepatitis and focuses on pertinent epidemiological and clinical differences between Asian-American and Caucasian patients.     

Hepatitis B and C virus infections in the immune compromised

PURPOSE OF REVIEW: This review compares and contrasts the natural history and treatment of hepatitis B and C virus infections in three principal populations of immune compromised individuals: (1) patients co-infected with HIV; (2) patients with liver failure secondary to hepatitis B or C virus infection who undergo liver transplantation, and (3) patients with hepatitis B or C virus infection who undergo anticancer chemotherapy. RECENT FINDINGS: Chronic liver disease resulting from hepatitis B or C virus infection progresses more rapidly in patients co-infected with HIV than in HIV negative patients. Treatment protocols for antiviral therapy are, however, similar to those used in immunocompetent individuals and although few long-term results are available, the efficacy of interferon and ribavirin therapy in hepatitis C virus/HIV infection and lamivudine in HIV/hepatitis B virus infection has been proven in the short-term. Perhaps the most important consideration is the timing of administering treatments to co-infected patients. For patients with well preserved CD4 counts and hepatitis C virus/HIV co-infection, the hepatitis infection should be treated as early as possible to avoid drug interactions of hepatitis C virus antivirals with antiretroviral therapy. Also, response to hepatitis C virus treatment appears better when treatment is administered in the context of preserved immune function. Conversely, in hepatitis B virus/HIV co-infection, hepatitis B virus antivirals are best administered with anti-retroviral therapy, thus preventing the selection of HIV viral species which may be resistant to the drugs used for hepatitis B virus. Improved graft and patient survival after liver transplant and with anticancer chemotherapy in hepatitis B virus infected patients has been proven using lamivudine prophylaxis. However, although therapy for hepatitis C virus recurrence after liver transplantation would seem rational, limited success with current treatment protocols has been achieved. SUMMARY: Although the prognosis of hepatitis B and C virus infections in the immune compromised may be inferior to that of immunocompetent individuals, such patients should have full evaluation of their viral hepatitis, and antiviral therapy should be considered.     

Treatments for HBV: A Glimpse into the Future

The hepatitis B virus is responsible for most of the chronic liver disease and liver cancer worldwide. As actual therapeutic strategies have had little success in eradicating the virus from hepatocytes, and as lifelong treatment is often required, new drugs targeting the various phases of the hepatitis B virus (HBV) lifecycle are currently under investigation. In this review, we provide an overview of potential future treatments for HBV.     

世居藏族患者乙肝病毒基因型及其临床特点分析

目的对世居藏族乙肝病毒(HBV)的基因型及其临床特点进行分析。方法对78例世居藏族患者的乙肝病毒基因分型、乙肝病毒DNA定量及其肝功能、两对半、肝纤维化指标、AFP、CEA、腹部B超等进行了检测,并对其临床特点进行分析。结果世居藏族乙肝患者乙肝病毒基因型主要以B型和C型为主,78例患者中B型41例,C型37例,B型和C型构成无统计学差异。C型患者HBVDNA定量、肝功能各指标、肝纤维化指标、AFP、HBe-Ag阳性率、CEA阳性率、肝硬化发生率、肝癌发生率、脾大发生率均显著高于B型患者(P<0.05～0.01)。结论世居藏族乙肝病毒基因型以B型及C型为主,C型患者肝硬化、肝癌发生率及肝纤维化和肝功能损害程度明显要高于B型患者,故在临床对C型世居藏族乙肝患者应加强针对性的防治。     

Hepatitis B virus infection: current status

Hepatitis B virus currently infects more than 400 million people worldwide. Despite the availability of hepatitis B vaccine, the overall prevalence of hepatitis B virus infection has declined little in recent years. Hepatitis B virus causes liver injury by an immune response against the virus-infected liver cells and is not directly cytopathic, although immunosuppression appears to enhance replication and lead to direct cytotoxicity. The interplay of the host immune response and the virus’s ability to replicate is a prime determinant of the likelihood of liver injury, its intensity, and progression to cirrhosis. A series of stages evolve in the life cycle of each patient’s infection, with associated decreases in viral load at each successive stage. Viral mutations in the polymerase or the core gene affect replication and may enhance liver injury. Recently, genotypes have been identified that are linked to clinical outcomes, drug responses, and mutations. Four drugs (interferon alpha, lamivudine, adefovir, and entecavir) have been approved by the US Food and Drug Administration for treatment of hepatitis B virus; they effectively decrease replication and reduce inflammation and fibrosis. Treatment of hepatitis B virus in complex situations such as co-infection with human immunodeficiency virus or immunosuppressive therapy remains challenging. The use of hepatitis B vaccine has been shown to reduce the incidence of new infection in many regions. A decline in the prevalence of hepatitis B infection worldwide will require changes in high-risk behavior and the wider use of vaccination.     

Is there a downgrading in the alert about the hepatitis B virus infection in Italy?

BACKGROUND AND AIM: There is suspicion of a decrease in warning regarding the hepatitis B virus as a health problem both by the infected individuals and their doctors. The aim of this study was to investigate whether the clinical/virology investigation of chronic hepatitis B virus infected individuals is at present accurate. METHODS: The chronic hepatitis B virus surface antigen carriers consecutively attending 13 different hospital divisions in Calabria from July to December 2005 were evaluated to investigate the available information on the grade of their liver disease, their virologic profile and the hepatitis B virus status of their family members. RESULTS: Four-hundred-thirty hepatitis B virus surface antigen positive individuals were enrolled, 417 of whom were Calabrians. Most of them had a diagnosis of chronic liver disease, but a liver biopsy had been performed only in 13.5% of the cases, whereas more than 1/3 of them had not been tested for hepatitis Delta virus co-infection. The majority of these individuals were unaware of the hepatitis B virus status of their family members. Moreover, anti-hepatitis B virus vaccination procedures were not performed in most of the hepatitis B virus surface antigen carrier families. CONCLUSIONS: This study revealed that fundamental clinical, virological, and epidemiological aspects of chronic hepatitis B virus infection are not investigated in many hepatitis B virus surface antigen carriers, suggesting that the general knowledge as regards hepatitis B virus is mostly inadequate.     

NIH conference. Hepatocellular carcinoma

Hepatocellular carcinoma is the most frequent cancer worldwide, responsible for approximately 1,000,000 deaths annually, most of them in the Far East and in sub-Saharan Africa. It usually presents at an advanced stage and has a poor prognosis. There is evidence of an etiologic role for hepatitis B virus infection in the etiology of hepatocellular carcinoma. Carriers of the virus are 94 times more at risk for hepatocellular carcinoma than noncarriers. In many cases hepatitis B virus DNA is integrated within the cellular genome of the tumor. Programs have been established to detect hepatocellular carcinoma at an early stage; persons at high risk are regularly screened by measurement of serum alpha-fetoprotein levels and ultrasound examination of the liver. Surgical resection offers the only hope of cure at present, as chemotherapy, radiotherapy, and immunotherapy have not shown promise. Ideally, surgery should be done on small asymptomatic tumors.     

Human hepatitis viruses-associated cutaneous and systemic vasculitis

Human hepatitis viruses (HHVs) include hepatitis A virus, hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis delta virus, and hepatitis E virus and can cause liver inflammation in their common human host. Usually, HHV is rapidly cleared by the immune system, following acute HHV invasion. The morbidities associated with hepatitis A virus and hepatitis E virus infection occur shortly after their intrusion, in the acute stage. Nevertheless, the viral infectious process can persist for a long period of time, especially in HBV and HCV infection, leading to chronic hepatitis and further progressing to hepatic cirrhosis and liver cancer. HHV infection brings about complications in other organs, and both acute and chronic hepatitis have been associated with clinical presentations outside the liver. Vascular involvement with cutaneous and systemic vasculitis is a well-known extrahepatic presentation; moreover, there is growing evidence for a possible causal relationship between viral pathogens and vasculitis. Except for hepatitis delta virus, other HHVs have participated in the etiopathogenesis of cutaneous and systemic vasculitis via different mechanisms, including direct viral invasion of vascular endothelial cells, immune complex-mediated vessel wall damage, and autoimmune responses with stimulation of autoreactive B-cells and impaired regulatory T-cells. Cryoglobulinemic vasculitis and polyarteritis nodosa are recognized for their association with chronic HHV infection. Although therapeutic guidelines for HHV-associated vasculitis have not yet been established, antiviral therapy should be initiated in HBV and HCV-related systemic vasculitis in addition to the use of corticosteroids. Plasma exchange and/or combined cyclophosphamide and corticosteroid therapy can be considered in patients with severe life-threatening vasculitis manifestations.     

Current impact of viral hepatitis on liver cancer development: The challenge remains

Chronic infections due to hepatitis B and hepatitis C viruses are responsible for most cases of hepatocellular carcinoma (HCC) worldwide, and this association is likely to remain during the next decade. Moreover, viral hepatitis-related HCC imposes an important burden on public health in terms of disability-adjusted life years. In order to reduce such a burden, some major challenges must be faced. Universal vaccination against hepatitis B virus, especially in the neonatal period, is probably the most relevant primary preventive measure against the development of HCC. Moreover, considering the large adult population already infected with hepatitis B and C viruses, it is also imperative to identify these individuals to ensure their access to treatment. Both hepatitis B and C currently have highly effective therapies, which are able to diminish the risk of development of liver cancer. Finally, it is essential for individuals at high-risk of HCC to be included in surveillance programs, so that tumors are detected at an early stage. Patients with hepatitis B or C and advanced liver fibrosis or cirrhosis benefit from being followed in a surveillance program. As hepatitis B virus is oncogenic and capable of leading to liver cancer even in individuals with early stages of liver fibrosis, other high-risk groups of patients with hepatitis B are also candidates for surveillance. Considerable effort is required concerning these strategies in order to decrease the incidence and the mortality of viral hepatitis-related HCC.     

Tissue and organ culture studies of hepatitis B virus.

Techniques have been developed for the cultivation of human and nonhuman primate liver cells in tissue and organ culture. Progressive non-cytocidal involvement of the normal cytoplasmic and nuclear components of cultured liver cells has been demonstrated by specific attachment of fluorescent antibody to hepatitis B core and surface antigens after inoculation of the cultures of human origin with known infective sera and with clinical material. Hepatitis B surface antigen may be produced, although infrequently, in inoculated liver organ cultures but serial passage has not been achieved. Serial passage of hepatitis B virus has been reported with fragments of human embryo liver cultivated on the chorioallantoic membrane of the developing chick embryo. Intranuclear virus-like particles have been localized in hepatocytes of cultured explants of liver biopsies obtained from infants with chronic hepatitis B antigenemia. Further studies are urgently required to determine whether cultivation of hepatitis B virus can be firmly established in readily available cell and organ cultures.     

Hepatitis viruses (other than hepatitis B and C viruses) as causes of hepatocellular carcinoma: an update

Chronic hepatitis B and C virus infections are universally accepted as causes of hepatocellular carcinoma in humans. Hepatitis A and E viruses cause only acute self‐limiting infections of the liver. Of the remaining hepatitis viruses ‐ Delta hepatitis, hepatitis G (GB‐C), TT and SEN ‐ all have at some time been incriminated as causes of hepatocellular carcinoma. Delta hepatitis virus requires helper functions from hepatitis B virus to become invasive. Chronic Delta/hepatitis B viral co‐infection runs a more severe course than that resulting from chronic hepatitis B virus infection alone, with progression to cirrhosis being more likely and more rapid. A substantial majority of the early studies did not find an increased incidence of hepatocellular carcinoma in co‐infected individuals. But more recently, an increased incidence of the tumour has been recorded more often than no increase. Further studies are needed to draw a firm conclusion with regard to the hepatocarcinogenic effect of dual Delta/hepatitis B virus co‐infection. With one exception, no published study (of 13) has incriminated chronic infection with hepatitis G virus as a cause of hepatocellular carcinoma. The dissenting study, published in 1999, was the only one performed in the United States. Fewer studies of the hepatocarcinogenic effect of TT virus have been performed. Apart from one study, published in 1999, no convincing evidence is available that supports a causal role for TT virus in hepatocarcinogenesis. The exception was in Japanese patients with high hepatitis C viral loads but independent of chronic hepatitis C virus infection. No evidence has been produced to indicate that SEN virus causes hepatocellular carcinoma.     

Risk factors for the rising rates of primary liver cancer in the United States

BACKGROUND: A recent increase in the incidence of hepatocellular carcinoma was reported in the United States. The cause of this witnessed rise remains unknown. METHODS: We examined the temporal changes in both age-specific and age-standardized hospitalization rates of primary liver cancer associated with hepatitis C, hepatitis B, and alcoholic cirrhosis in the Department of Veterans Affairs Medical Center's Patient Treatment File. RESULTS: A total of 1605 patients were diagnosed with primary liver cancer between 1993 and 1998. The overall age-adjusted proportional hospitalization rate for primary liver cancer increased from 36.4 per 100,000 (95% confidence interval [CI], 34.0-38.9) between 1993 and 1995 to 47.5 per 100,000 (95% CI, 44.6-50.1) between 1996 and 1998. There was a 3-fold increase in the age-adjusted rates for primary liver cancer associated with hepatitis C virus, from 2.3 per 100,000 (95% CI, 1. 8-3.0) between 1993 and 1995 to 7.0 per 100,000 (95% CI, 5.9-8.1) between 1996 and 1998. Concomitant with this rise, the age-specific rates for primary liver cancer associated with hepatitis C also shifted toward younger patients. During the same periods, the age-adjusted rates for primary liver cancer associated with either hepatitis B virus (2.2 vs 3.1 per 100,000) or alcoholic cirrhosis (8. 4 vs 9.1 per 100,000) remained stable. The rates for primary liver cancer without risk factors also remained without a statistically significant change, from 17.5 (95% CI, 15.8-19.1) between 1993 and 1995 to 19.0 per 100,000 (95% CI, 17.3-20.7) between 1996 and 1998. CONCLUSIONS: Hepatitis C virus infection accounts for most of the increase in the number of cases of primary liver cancer among US veterans. The rates of primary liver cancer associated with alcoholic cirrhosis and hepatitis B virus infection have remained stable. Arch Intern Med. 2000;160:3227-3230.     

Viral hepatitis

Developments over the last four years in our understanding of viral hepatitis are analyzed. The molecular structure of hepatitis A has been established, and vaccines for prevention are under development. The recognition of the replicative and integrated stages of hepatitis B infection has allowed more rational approaches to therapy. Vaccines are of proven value. Delta virus infection has assumed an important role world wide as a cause of serious and fulminant liver disease in hepatitis B carriers. The agents for non-A, non-B virus hepatitis have eluded identification. These are important causes of chronic liver disease particularly in recipients of blood transfusion.     

Hepatitis B and C virus infection and liver dysfunction in patients receiving chemotherapy]

BACKGROUND/AIMS: Liver dysfunction and reactivation of hepatitis virus are well-described complications in cancer patients who receive cytotoxic chemotherapy and may result in varying degrees of liver damage. However, there has been just few reports on such complications and on the preemptive use of lamivudine in Korea. The aims of this study were to determine the prevalence of hepatitis B and C virus infection and the incidence of liver dysfunction in patients with malignancies who receive chemotherapy, to determine the reactivation rate of hepatitis B virus (HBV) in those patients, to evaluate the effect of preemptive use of lamivudine in patients with HBV infection. METHODS: Among 1,477 patients who received chemotherapy due to various malignancies from January 2000 to June 2005, 668 patients with incomplete viral studies or hepatitis related malignancy were excluded. A retrospective study was conducted by reviewing the medical records of remaining 809 patients. RESULTS: The overall prevalence rate of hepatitis B or C virus in patients receiving chemotherapy was 6.55% (53/809). The incidences of liver dysfunction was not significantly different between hepatitis virus positive group and negative group. Reactivation rate of hepatitis B or C virus after chemotherapy was 15% (6/40). In all patients who received lamivudine therapy, aspartate aminotransferase and alanine aminotransferase level were normalized and HBV DNA negativity achieved. CONCLUSIONS: The existence of hepatitis virus in patients receiving chemotherapy did not significantly influence the development of severe liver dysfunction, owing probably to the lamivudine therapy. Further prospective studies are required to ascertain the reactivation of hepatitis virus in patients receiving chemotherapy and the need for prophylactic lamivudine therapy in HBV positive patients.     

Primary liver cancer is of multifactorial origin: Importance of hepatitis B virus infection and dietary aflatoxin

Primary liver cancer has a variable incidence worldwide, occurring most frequently in South-East Asia and China, which indicates that environmental factors are important in its aetiology. Although hepatitis B virus and chemical agents are the major risk factors for primary liver cancer, current evidence strongly suggests that it is of multifactorial origin. Aflatoxins are thought to be important because they are common food contaminants and are potent liver carcinogens in a wide variety of animal species. Evidence for the possible interactions between aflatoxin and hepatitis B infection, and their effects on the prevalence of primary liver cancer, is obtained from animal data and epidemiological studies. The risk of developing primary liver cancer following exposure to hepatitis B infection and aflatoxin is shown to be increased and the possible molecular mechanisms involved are discussed.