HEPATITIS B VIRUS & HEPATITIS C VIRUS

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 Hepatitis B virus (HBV), a member of the Hepadnaviridae family, is characterized by 42-nm spherical virions with a circular genome of double-stranded DNA (3.2 kbp). One strand of the DNA is incomplete and variable in length. The virus particle, (virion) consists of an outer lipid envelope and an icosahedral nucleocapsid core composed of protein. The nucleocapsid encloses the viral DNA and a DNA polymerase that has reverse transcriptase activity. The outer envelope contains embedded proteins which are involved in viral binding of, and entry into, susceptible cells

In addition to causing hepatitis, hepatitis B virus is a risk factor in the development of liver cancer in humans. Epidemiologic and laboratory studies have proved persistent infection with hepatitis B virus to be an important cause of chronic liver disease and the development of hepatocellular carcinoma. Hepatitis B virus infections occurring in adults are usually resolved, but primary infections in neonates and young children tend to become chronic in up to 90% of cases. It is these persistent hepatitis B virus infections established early in life that carry the highest risk of hepatocellular carcinoma later in life.

The mechanism of oncogenesis remains obscure. Persistent viral infection leads to necrosis, inflammation, and liver regeneration which over time result in cirrhosis; hepatocellular carcinoma usually arises out of this background. The hepatitis B virus transactivator protein, X protein, is a potential viral oncoprotein. A dietary carcinogen, aflatoxin, may be a cofactor for hepatocellular carcinoma, especially in Africa and China.

The advent of an effective hepatitis B vaccine for the prevention of primary infection raises the possibility of prevention of hepatocellular carcinoma, particularly in areas of the world where infection with hepatitis B virus is hyperendemic (eg, Africa, China, Southeast Asia). Because of the long latent period before cancer development, however, the effects of vaccination will not be apparent for at least 20 years.

Hepatitis C virus (HCV) is an enveloped RNA virus, which causes most non‑B viral hepatitis that is transmitted parenterally (i.e., by injection, transfusion, or other contact with body fluids). It is a member of the Flaviviridae family of viruses and has a particle size of about 50 nm in diameter (Figure 4). The positive-sense RNA genome codes for production of a polyprotein; enzymes produced by the virus and the host cell then cleave the polyprotein into the smaller structural and nonstructural proteins that make up the mature virus particle. The structural proteins, which are incorporated into the viral envelope, consist of the core (nucleocapsid) protein and two glycoproteins (E1 and E2).

Replication of HCV often results in random mutations that are not corrected by the RNA polymerase because it lacks a proofreading function. As a result, the genomes of HCV strains show extensive variability. However, some regions of the genome are more variable than others, and classification of HCV genotypes is based on differences in the less variable regions of the genome.

It appears that the majority of infections become persistent, even in adults.

Chronic infection with hepatitis C virus is also considered to be a causative factor in hepatocellular carcinoma. Most probably, hepatitis C virus acts indirectly in the development of hepatocellular carcinoma.

There are currently over 250 million people worldwide persistently infected with hepatitis B virus and over 170 million chronic carriers of hepatitis C virus—a large pool of individuals at risk of developing liver cancer.

Hepatocellular carcinoma (HCC). Mechanism of transformation. With over 600 000 new cases per year, hepatocellular carcinoma is the 5th most common cancer and the 3rd cause of cancer mortality worldwide. Over 80% of the cases occur in non-Western countries, in particular in South-Eastern Asia. The main risk factors are chronic infections by Hepatitis B or C viruses.

The role of HBV in tumour formation appears to be complex and may involve both direct and indirect mechanisms.

The mechanisms by which HBV contributes to liver cancer are multiple, complex, and far from being fully understood. In brief, three main effects can be distinguished. First, chronic infection induces inflammation and deregulation of the physiological balance between liver cell proliferation, differentiation and apoptosis. This disrupted state often leads to cirrhosis, a precursor of HCC and may favour the accumulation of genetic alterations in infected hepatocytes. Second, early in the carcinogenic process, HBV DNA becomes integrated in the host cell genome, potentially acting as an insertional mutagen to deregulate adjacent oncogenes or tumor suppressors. Third, HBV expresses proteins such as HBxAg that interacts with a variety of cell components, affecting many aspects of transcription, proliferation, or survival and sensitize liver cells to carcinogenic factors. HBxAg is a trans-activating protein that may promote tumor formation by altering the patterns of host gene expression. HBxAg may do this by activating signal transduction pathways and by binding to transcription factors that influence host gene expression. Among these changes, HBxAg upregulates the expression of cellular proteins that promote cell growth and survival and suppress expression or functionally inactivates negative growth regulatory proteins.

The contribution of each of the above mechanisms depends on the host immune response, the synergic effects of environmental factors, and the molecular characteristics of the strain of HBV involved. Eight major HBV genotypes have been identified (genotypes A to H), characterizing groups of viruses that show less than 8% sequence divergence between them. These genotypes differ by their geographic and ethnic distribution and their pathogenicity. In South-Eastern Asia, the predominant genotypes are B and C, in contrast with, for example, genotype A in Northwest Europe and North America, genotype D in Southern Europe and the Middle East, and genotype E in West Africa. Disease severity has also been shown to be associated with mutation in the Basal Core Promoter (BCP) region of the viral genome, resulting in a double base substitution (G1762A/A1764T).

Hepatocarcinogenesis is accompanied by genetic and epigenetic alterations at multiple loci, the most frequent of which are inactivating mutations in TP53 (encoding the p53 protein, in 20 to 80% of the cases depending upon geographic and exposure contexts) and activating mutations in the N-terminus of CTNNB1 (encoding the transcription factor β-catenin, in 10 to 30% of the cases).

Recent genetic strongly support the notion that chronic HBV infection might trigger specific oncogenic pathways, thus playing a role beyond stimulation of host immune responses and chronic necro-inflammatory liver disease.

As HCV is an RNA virus with little potential for integration of its genetic material into the host genome, the mechanisms underlying HCV promotion of cancer are likely to differ from other models of viral carcinogenesis. In patients persistently infected with HCV, chronic inflammation resulting from immune responses against infected hepatocytes is associated with progressive fibrosis and cirrhosis. Cirrhosis is an important risk factor for HCC independent of HCV infection, and a majority of HCV-associated HCC arises in the setting of cirrhosis. However, a significant minority arises in the absence of cirrhosis, indicating that cirrhosis is not a prerequisite for cancer. Other lines of evidence suggest that direct, virus-specific mechanisms may be involved. In vitro studies have revealed multiple interactions of HCV-encoded proteins with cell cycle regulators and tumor suppressor proteins p53, raising the possibility that HCV can disrupt control of cellular proliferation, or impair the cell's response to DNA damage. A combination of virus-specific, host genetic, environmental and immune-related factors are likely to determine the progression to HCC in patients who are chronically infected with HCV.