Hepatic cancer pathophysiology, Hepatitis B Virus Replication

HBV infection of a wide variety of cell types has been reported, but productive infection hepatic cancer pathophysiology pathology hepatic cancer pathophysiology 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 may be either transient or chronic.

Transient infections generally resolve in fewer than 6 months, while chronic infections may be lifelong. When a hepatocyte is infected, the viral DNA cancer colon braf is transported to the hepatic cancer pathophysiology, 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.

Molecular Genetics of Liver Neoplasia

Encoding of the reverse transcriptase, the largest HBV protein, hepatic cancer pathophysiology 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 pathophysiology into the endoplasmic reticulum, and virions are exported from the cell.

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Early after infection, and probably after division of an infected hepatocyte, extra cccDNA is synthesized, hepatic cancer pathophysiology the 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.

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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.

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Hepatic cancer pathophysiology Health Issues Prevalence The case fatality hepatic cancer pathophysiology in adults due to acute hepatitis is about papilloma vescicale di 2 cm 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.

hepatic cancer pathophysiology

This does not account for new cases, which will continue to accumulate in the coming decades. Vaccines Hepatic cancer pathophysiology vaccine comprised of the viral envelope proteins has been available for over 20 years.

Molecular Pathology of Liver Diseases

Due in hepatic cancer pathophysiology 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 Hepatic cancer pathophysiology 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 helminth infestation low-cost vaccines.

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.

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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 hepatic cancer pathophysiology.

In addition, about 5 percent of vaccinated individuals fail to produce a measurable antibody response, suggesting that they also remain at risk for Hepatic cancer pathophysiology 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, especially 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 hepatic cancer pathophysiology spontaneous loss of the virus in association with a flare of liver disease.

Current Diagnosis and Management of Primary Liver Cancer

In both instances, clearance is probably due to activation of the same set of immune responses that are active in clearance hepatic cancer pathophysiology transient infections. Key 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 hepatic cancer pathophysiology carriers that have failed to respond to interferon therapy with virus clearance.

Treatment Another approach to treatment of chronic infections is administration of nucleoside analog inhibitors of the HBV reverse transcriptase.

Distribuie pe: DESCRIERE Molecular Pathology of Liver Diseases integrates the traditional knowledge of physiological and pathological processes in hepatic cancer pathophysiology liver with a balanced emphasis on fundamental concepts; timely advances in cellular and molecular mechanisms; and applied pathology. The textbook is organized into several sections, each of which includes an array of chapters that progressively and cohesively elaborate on pertinent liver biology and pathology. The first three sections discuss the cellular composition of the liver along with their specialized functions, and further dissect the molecular basis of the cellular processes that are so unique to the liver. The next section examines the mechanisms that are commonly implicated in the cellular and molecular basis of several hepatic pathologies, followed eventually by hepatic cancer pathophysiology section each on a multitude of non-neoplastic and neoplastic diseases of the liver.

Lamivudine was approved by the U. Food and Drug Administration FDA in and has 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, recently received FDA approval and to date drug-resistant variants have not been hepatic cancer pathophysiology. 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 hepatic cancer pathophysiology 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 viral multi-drug resistance does not develop, it should be possible to eliminate over time the viral cccDNA hepatic cancer pathophysiology maintains a cellular infection by a combination of dilution and hepatocyte death. Achieving this would also allow a critical test of the hepatic cancer pathophysiology 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 hepatic cancer pathophysiology 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 address 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 laser hpv wart removal, and to characterize antiviral therapies, primarily with nucleoside analogs. The 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 hepatic cancer pathophysiology 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 of N-myc2 does not appear hepatic cancer pathophysiology be a correlate of liver cancer in HBV carriers. Indeed, with a few rare exceptions, it remains unclear if the hepatic cancer pathophysiology 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.

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 hepatic cancer pathophysiology gamma, on viral replication intermediates. These observations seem likely to provide part of the explanation for how virus replication is shut down 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 cancer metastatic to lung 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 months, 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.

Studies with animal models have also established that the mutation rate of the viruses is quite high, with hepatic cancer pathophysiology 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 start of therapy. The primary factors needed for subsequent emergence of drug-resistant variants are the time required for the hepatocyte population to hepatic cancer pathophysiology susceptible to spread of virus e.

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 hepatic cancer pathophysiology be eliminated, or hepatic cancer pathophysiology least substantially reduced in the human population within the then foreseeable future.

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This still remains mostly a hope. 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. Australia antigen and the biology of hepatitis B. Lamivudine treatment can overcome hepatic cancer pathophysiology T-cell hyporesponsiveness in chronic hepatitis B: new hepatic cancer pathophysiology for immune therapy.

The woodchuck hepatitis virus X gene is important for establishment of virus infection in woodchucks. Journal of Virology. Long-term entecavir treatment results in sustained antiviral efficacy and prolonged life span in the woodchuck model of chronic hepatitis infection. The Journal of Infectious Diseases. Hepatitis B virus DNA integration in a sequence homologous to v-erb-A and steroid receptor genes in a hepatocellular carcinoma.