HBV infection of a wide variety of cell types has been reported, but productive infection and pathology appear to be limited to the liver. Among the many cell types found in the liver, HBV infects the hepatocyte, the major parenchymal cell. Following infection, virus is shed from hepatocytes into the bloodstream, so that every hepatocyte may become infected. During the peak of an infection, titers of virus in the blood may reach per cubic centimeter. Infection of hepatocytes is not typically cytopathic, and the liver pathology results from the immune response to the infected cells.
Depending on the strength of the immune response, infections hepatic cancer percentage be hepatic cancer percentage transient or chronic.
Transient infections generally resolve hepatic cancer percentage fewer than 6 months, while chronic infections may be lifelong. When a hepatocyte is infected, the viral DNA genome is transported to the nucleus, where it is converted from a relaxed circular DNA to a covalently closed circular form cccDNAwhich serves as the template for viral mRNA synthesis.
Though the coding capacity of HBV is limited, it is still capable of encoding three envelope proteins, a nucleocapsid protein, a transcriptional transactivator, and a reverse transcriptase RT. Encoding of the reverse transcriptase, the largest HBV protein, requires almost the entire viral genome. To facilitate this, the reverse transcriptase is encoded in different translational reading frames than the other viral gene products, so that overlapping reading frames can be utilized.
Following completion of reverse transcription, the RT then synthesizes most, but not all of the second DNA strand, to recreate the partially double stranded virion DNA. Prior to completion of the second strand, nucleocapsids are packaged into viral envelopes by hepatic cancer percentage into the endoplasmic reticulum, and virions are exported from the cell.
Early after infection, and probably after division of an infected hepatic cancer percentage, extra cccDNA is synthesized, maintaining cancer cerebral radiacion copy number at 5 to 50 per cell.
Transmission Transmission is parenteral, requiring exposure to the blood or blood-contaminated materials of infected individuals. The most common mode of exposure leading to chronic infection occurs at birth when the mother is chronically infected, or during the first year of life. During this period, the risk of an infection becoming chronic is at least 90 percent. In contrast, the risk of chronic infection in adults is greater than 10 percent.
According to the CDC, the most common exposure risks in adults in the United States are sexual activity 50 percent of cases and intravenous drug abuse 15 percent of cases.
Public Health Issues Prevalence The case fatality rate in adults due to acute hepatitis is about 1 percent. According to WHO, there are now million chronically infected individuals worldwide.
Of these, 60 million are expected to die prematurely of liver cancer or cirrhosis, at a rate of approximately 1 million per year 5, per year in the United States. This does not account for new cases, which will continue to accumulate in the coming hepatic cancer percentage.
Vaccines A vaccine comprised of the viral envelope proteins has been available for over 20 years. Due in part to high cost, universal vaccination was not initially feasible in many parts of the world, but lower cost vaccines have subsequently come into use. Universal vaccination of school children is now in effect in the United States. In some parts of the world, especially in Africa and regions of Asia, chronic infection rates exceed 5—10 percent of the population, but vaccination has not yet been economically feasible in all of these areas, even with low-cost vaccines.
Hepatitis B Virus Replication
Although attempts are under way to address this problem Kane,for various reasons of cost and delivery, HBV is likely to remain a major public health problem. On top of this problem there is evidence for vaccine escape mutants He et al. Though these do not yet seem to be a major public health problem, they remain a concern even for the large pool of individuals that have already received the current vaccine.
In addition, about 5 percent of vaccinated individuals fail to produce a measurable antibody response, suggesting that they also remain at risk for HBV infection. Current Research A major goal of current research has thus been the development of therapies to cure chronically infected individuals. A problem in achieving this is that hepatocytes comprise a self-renewing population with a low turnover rate, and this population often appears to be percent infected.
This same barrier is confronted and overcome during immune clearance of transient infections, though it remains controversial how the virus is actually destroyed Guidotti et al.
However, in chronic carriers, the immune system is usually unable to mount such a response, human papilloma virus terapija in those infected as children. Some hope for better immunotherapies has however been sustained by the fact that interferon alpha administration induces virus loss in about 20—30 percent of carriers Hoofnagle and Lau,typically those with adult-acquired infections.
In addition, some carriers experience spontaneous loss of the virus in association with a flare of liver disease. In both instances, clearance is probably due to hepatic cancer percentage of the same set of immune responses that are active in clearance of transient infections. Hepatic cancer percentage issues now are how this clearance is carried out, whether it requires destruction of all of the infected hepatocytes, if the immune system has the capacity to cure an infected hepatocyte, and if it can be induced in carriers that have failed to respond to interferon therapy with virus clearance.
Treatment Another approach to hepatic cancer percentage of chronic infections is administration of nucleoside analog inhibitors of the HBV reverse transcriptase. Lamivudine was approved by the U. Food and Drug Administration FDA in and hepatic cancer percentage been shown in clinical trials to have a treatment success rate similar to interferon alpha Perrillo, A significant problem with lamivudine is the emergence of drug-resistant variants of HBV as therapy continues past a year.
Another nucleoside, adefovir dipivoxil, hepatic cancer percentage received FDA approval and to date drug-resistant variants have not been reported.
Moreover, this drug retains activity against lamivudine-resistant HBV Delaney et al. However, at doses higher than used for HBV carriers, nephrotoxicity has been observed Tanji et al.
It may be that nephrotoxicity will become a problem in HBV therapy due to a cumulative effect if carriers require treatment indefinitely. A number of other nucleoside analogs are now in Phase II trials. If these compounds are not toxic during long-term administration, and if hepatic cancer percentage multi-drug resistance does not hepatic cancer percentage, it should be possible to eliminate over time the viral cccDNA that maintains a cellular infection by a combination of dilution and hepatocyte death.
CHRONIC HEPATITIS B VIRUS INFECTIONS - The Infectious Etiology of Chronic Diseases - NCBI Bookshelf
Achieving this would also allow a critical test of the hypothesis that curing a chronic infection would significantly reduce the risk of death due to cirrhosis, which seems likely, and due to liver cancer, which is difficult to predict, because liver cancer may occur in a liver that appears relatively healthy histologically.
Research Models HBV research generally reflects public health concerns. How can chronic infections be cured? Will eliminating the virus reduce the risk of liver cancer and premature death from liver disease? What is the mechanism of carcinogenesis? It is speculated that immune-mediated chronic injury, insertional mutagenesis, and viral proteins all may play a role. These questions have been investigated using clinical samples and a number of model systems. Woodchucks are naturally infected with woodchuck hepatitis virus WHV Summers et al.
HBV transgenic mice have been powerful tools for studying certain aspects of the antiviral immune response Guidotti and Chisari,even though these mice do not support a complete HBV infection cycle Tang and McLachlan, On occasion, chimpanzees, which are susceptible to HBV, have been used to hepatic cancer percentage research issues Guidotti et al.
Among the model systems, the duck has been heavily used to understand the virus life cycle at the molecular level, to study the biology of infection, and to characterize antiviral therapies, primarily with nucleoside analogs. Hepatic cancer percentage wood-chuck model has been less used to study molecular biology issues, but has been employed extensively in the development of antiviral therapies and in characterization of the link between chronic infection and liver cancer. An unresolved issue arose in the latter studies.
It was found that liver cancer in woodchucks is almost always associated with transcriptional activation of N-myc2 expression in the liver by insertion of viral enhancer sequences Fourel et al. Contrary to expectation, insertional activation hepatic cancer percentage N-myc2 does not appear to be a correlate of liver cancer in HBV carriers.
Indeed, with a few rare exceptions, it remains unclear hepatic cancer percentage the frequent sporadic integration of viral DNA that characterizes an infection has a role in most liver cancers that occur in individuals chronically infected with HBV Dejean et al.
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The HBV transgenic mouse, in contrast to the natural infection models, has been most heavily used to demonstrate the effects of immune cytokines, such as interferons alpha and gamma, on viral replication intermediates. These observations seem likely to provide part of the explanation for how virus replication is shut hepatic cancer percentage during the clearance of transient HBV infections.
Though the relationship to natural infections is still unclear, a number of studies have shown that mice carrying the HBV transcriptional activator, X, as a transgene, are at increased risk of developing liver cancer Kim et al. These data suggest that X is in fact a viral oncogene, but clinical evidence to support this conclusion is still lacking, and it is difficult to address this issue in the woodchuck model, because X is needed to establish a productive infection Chen et al.
In addition to characterizing infections and therapies, the animal models have also provided, along with clinical studies, a better understanding of the difficulties of treating chronic infections with nucleoside analogs.
From such studies, it has been determined that cccDNA can persist in the liver for hepatic cancer percentage, and probably years, even when virus DNA synthesis is effectively inhibited Colonno et al.
Persistence of cccDNA may be attributable to two factors: 1 an inherent stability within non-dividing hepatocytes, and 2 the relatively low turnover perhaps a few percent per day of hepatocytes in most carriers.
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Studies with animal hepatic cancer percentage have also established that the mutation rate of the viruses is quite high, with a single-base mutation prevalence of about Pult et al. Thus, drug-resistant variants, especially those requiring only one or two base changes, are likely to be present at the hepatic cancer percentage of therapy.
The primary factors needed for subsequent emergence of drug-resistant variants are the time required for the hepatocyte population to become susceptible to spread of virus hepatic cancer percentage.
In practice, emergence of mutants can take from months to several years, the variation probably reflecting additional factors, including the effect of nucleoside therapy on the antiviral immune response of the host Boni et al.
Outlook Discovery of an effective HBV vaccine in the s Blumberg, led to the hope that HBV would be eliminated, or at least substantially reduced in the human population within the then foreseeable future. This still remains mostly a hope.
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Two objectives still need to be fulfilled, universal vaccination Kane,and development of an effective therapy for chronic infection. Even though not everyone will be protected using the current vaccine, most would be, and the carrier incidence should decline substantially, first among the young.
The goal of complete elimination seems unlikely without major advances in the treatment and elimination of chronic infections, particularly treatments that are rapid acting and cost-effective.
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Impactul diabetului de tip 2 asupra prognosticului pacienților cu carcinom hepatocelular
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Impactul diabetului de tip 2 asupra prognosticului pacienților cu carcinom hepatocelular
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