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ternyata tak ku duga, di sini mulai cerita KRONOLOGIS KARYA » HEPATITIS B ± Resensi - Technologi © MIS. Posted : 2012-03-02 : 04:12:08 (4438 hari -04:11:27 lalu) HITS : 1767  ()  RESENSI : Hepatitis B virus was originally recognized as the agent responsible for “serum hepatitis”, the most common form of parenterally transmitted viral hepatitis, and an important cause of acute and chronic infection of the liver. The incubation period of hepatitis B is variable with a range of 1 to 6 months.
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Hepatitis B virus was originally recognized as the agent responsible for “serum hepatitis”, the most common form of parenterally transmitted viral hepatitis, and an important cause of acute and chronic infection of the liver. The incubation period of hepatitis B is variable with a range of 1 to 6 months. The clinical features of acute infection resemble those of the other viral hepatitides. Acute hepatitis B is frequently anicteric and asymptomatic, although a severe illness with jaundice can occur and occasionally acute liver failure may develop.Distinctive properties The virus persists in 5 to 10% of immunocompetent adults, and in as many as 90% of infants infected perinatally. Persistent carriage of hepatitis B, defined by the presence of hepatitis B surface antigen (HBsAg) in the serum for more than six months, have been estimated to affect about 350 million people worldwide. The pathology is mediated by the responses of the cellular immune response of the host to the infected hepatocytes. Long term continuing virus replication may lead to progression to cirrhosis and hepatocellular carcinoma. In the first phase of chronicity, virus replication continues in the liver, and replicative intermediates of the viral genome may be detected in DNA extracted from liver biopsies. Markers of virus replication in serum include HBV DNA, the S1 proteins (HBsAg) and a soluble antigen, hepatitis B e antigen (HBeAg) which is secreted by infected hepatocytes. In those infected at a very young age, this phase may persist for life but, more usually, virus levels decline over time. Eventually, in most individuals, there is immune clearance of infected hepatocytes associated with seroconversion from HBeAg to anti-HBe. During the period of replication, the viral genome may integrate into the chromosomal DNA of some hepatocytes and these cells may persist and expand clonally. Rarely does seroconversion to anti-HBs follow clearance of virus replication but, more frequently, HBsAg persists during a second phase of chronicity as a result of the expression of integrated viral DNA. Structure of the Virus The hepatitis B virion is a 42-nm particle comprising an electron-dense core (nucleocapsid) 27 nm in diameter surrounded by an outer envelope of the surface protein (HBsAg) embedded in membranous lipid derived from the host cell (Figura 3). The surface antigen is produced in excess by the infected hepatocytes and is secreted in the form of 22-nm particles and tubular structures of the same diameter (initially referred to as Australia antigen).  Figure 3.-- Electron micrograph of serum containing hepatitis B virus after negative staining.Electron micrograph of serum containing hepatitis B virus after negative staining. The three morphologic forms are shown intermingled in this photograph: small pleomorphic spherical particles (more...) The 22 nm particles are composed of the major surface protein in both non-glycosylated (p 24) and glycosylated (gp 27) form in approximately equimolar amounts, together with a minority component of the so-called middle proteins (gp 33 and gp 36) which contain the pre-S2 domain, a glycosylated 55 amino acid N-terminal extension. The surface of the virion has a similar composition but also contains the large surface proteins (p 39 and gp 42), which include both the pre-S1 and pre-S2 regions. These large surface proteins are not found in the 22 nm spherical particles (but may be present in the tubular forms in highly viremic individuals) and their detection in serum correlates with viremia. The domain which binds to the specific HBV receptor on the hepatocyte is believed to reside within the pre-S1 region. The nucleocapsid of the virion consists of the viral genome surrounded by the core antigen (HBcAg). The genome, which is approximately 3.2 kilobases in length, has an unusual structure and is composed of two linear strands of DNA held in a circular configuration by base-pairing at the 5′ ends. One of the strands is incomplete and the 3′ end is associated with a DNA polymerase molecule which is able to complete that strand when supplied with deoxynucleoside triphosphates. Organization of the HBV Genome The genomes of more than a dozen isolates of hepatitis B virus have been cloned and the complete nucleotide sequences determined. Analysis of the coding potential of the genome reveals four open reading frames (ORFs) which are conserved between all of these isolates. The first ORF encodes the various forms of the surface protein and contains three in-frame methionine codons which are used for initiation of translation. A second promoter is located upstream of the pre-S1 initiation codon. This directs the synthesis of a 2.4 kb mRNA which is co-terminal with the other surface messages and is translated to yield the large (pre-S1) surface proteins. The core open reading frame also has two in-phase initiation codons. The “precore” region is highly conserved, has the properties of a signal sequence and is responsible for the secretion of HBeAg. The third ORF, which is the largest and overlaps the other three, encodes the viral polymerase. This protein appears to be another translation product of the 3.5 kb RNA, and is synthesized apparently following internal initiation of the ribosome. The amino terminal domain is believed to be the protein primer for minus strand synthesis. There is then a spacer region followed by the (RNA and DNA-dependent) DNA polymerase. The fourth ORF was designated “x” because the function of its small gene product was not known. However, “x” has now been demonstrated to be a transcriptional transactivator (Fig.70-4).  Figure 4.-- Structure and genomic organization of hepatitis B virus.Structure and genomic organization of hepatitis B virus. Host Defenses Antibody and cell-mediated immune responses to various types of antigens are induced during the infection. However, these do not always seem to be protective and, in some instances, may cause autoimmune phenomena that contribute to disease pathogenesis. The immune response to infection with hepatitis B virus is directed toward at least three antigens: hepatitis B surface antigen, the core antigen, and the e antigen. The view that hepatitis B exerts its damaging effect on hepatocytes by direct cytopathic changes is inconsistent with the persistence of large quantities of surface antigen in liver cells of many apparently healthy persons who are carriers. Additional evidence suggests that the pathogenesis of liver damage in the course of hepatitis B infection is related to the immune response by the host. The surface antigen appears in the sera of most patients during the incubation period, 2–8 weeks before biochemical evidence of liver damage or onset of jaundice. The antigen persists during the acute illness and usually clears from the circulation during convalescence. Next to appear in the circulation is the virus-associated DNA polymerase activity, which correlates in time with damage to liver cells as indicated by elevated serum transaminases. The polymerase activity persists for days or weeks in acute cases and for months or years in some persistent carriers. Antibody to the core antigen is found in the serum 2–10 weeks after the surface antigen appears, and it is frequently detectable for many years after recovery. The titer of core antibody appears to correlate with the amount and duration of virus replication. Finally, antibody to the surface antigen component appears. During the incubation period and during the acute phase of the illness, surface antigen-antibody complexes may be found in the sera of some patients. Immune complexes have been found by electron microscopy in the sera of all patients with fulminant hepatitis, but are seen only infrequently in nonfulminant infection. Immune complexes also are important in the pathogenesis of other disease syndromes characterized by severe damage of blood vessels (for example, polyarteritis nodosa, some forms of chronic glomerulo-nephritits, and infantile papular acrodermatitis). Immune complexes have been identified in variable proportions of patients with virtually all the recognized chronic sequelae of acute hepatitis. Deposits of such immune complexes have also been demonstrated in the cytoplasm and plasma membrane of hepatocytes and on or in the nuclei; why only a small proportion of patients with circulating complexes develop vasculitis or polyarteritis is, however, not clear. Perhaps complexes are critical pathogenic factors only if they are of a particular size and of a certain antigen-to-antibody ratio. Cellular immune responses are known to be particularly important in determining the clinical features and course of viral infections. The occurrence of cell-mediated immunity to hepatitis B antigens has been demonstrated in most patients during the acute phase of hepatitis B and in a significant proportion of patients with surface-antigen-positive chronic active hepatitis, but not in asymptomatic persistent hepatitis B carriers. These observations suggest that cell-mediated immunity may be important in terminating the infection and, under certain circumstances, in promoting immune-mediated liver damage and in the genesis of autoimmunity. Also, evidence suggests that progressive liver damage may result from an autoimmune reaction directed against hepatocyte membrane antigens, initiated in many cases by infection with hepatitis B virus. Although exogenous interferon may be effective in treating some patients with chronic hepatitis, as yet endogenous interferon production has not been detected during the natural infection. More studies to define the role of interferon are needed. Epidemiology Although various body fluids (blood, saliva, menstrual and vaginal discharges, serous exudates, seminal fluid, and breast milk) have been implicated in the spread of infection, infectivity appears to be especially related to blood. The epidemiologic propensities of this infection are, therefore, wide. They include infection by inadequately sterilized syringes and instruments, transmission by unscreened blood transfusion and blood products, by close contact, and by sexual contact. Antenatal (rarely) and perinatal (frequently) transmission of hepatitis B infection from mother to child may take place; in some parts of the world (Southeast Asia and Japan) Table 70-1, perinatal transmission is very common.  Table 70-1.-- Prevalence of Hepatitis B in Various Areas.Prevalence of Hepatitis B in Various Areas. Diagnosis Direct demonstration of virus in serum samples is feasible by visualizing the virus particles by electron microscopy, by detecting virus-associated DNA polymerase, and by assay of viral DNA. All of these direct techniques are impractical under general diagnostic laboratory conditions, and specific diagnoses must therefore rely on serologic tests (Table 70-2).  Table 70-2.-- Interpretation of Results of Serologic Tests for Hepatitis B.Interpretation of Results of Serologic Tests for Hepatitis B. Hepatitis B surface antigen first appears during the late stages of the incubation period and is easily detectable by radioimmunoassay or enzyme immunoassay. The antigen persists during the acute phase of the disease and sharply decreases when antibody to the surface antigen becomes detectable. Antibody of the IgM class to the core antigen is found in the serum after the onset of the clinical symptoms and slowly declines after recovery. Its persistence at high titer suggests continuation of the infection. Core antibody of the IgG class persists for many years and provides evidence of past infection. Protection of hepatitis B The discovery of variation in the epitopes presented on the surface of the virions and subviral particles identified several subtypes of HBV which differ in their geographical distribution. All isolates of the virus share a common epitope, a, which is a domain of the major surface protein which is believed to protrude as a double loop from the surface of the particle. Two other pairs of mutually exclusive antigenic determinants, d or y and w or r, are also present on the major surface protein. These variations have been correlated with single nucleotide changes in the surface ORF which lead to variation in single amino acids in the protein. Four principal subtypes of HBV are recognized: adw, adr, ayw and ayr. Subtype adw predominates in northern Europe, the Americas and Australasia and also is found in Africa and Asia. Subtype ayw is found in the Mediterranean region, eastern Europe, northern and western Africa, the near East and the Indian subcontinent. In the Far East, adr predominates. But the rarer ayr occasionally may be found in Japan and Papua New Guinea. The major response of recipients of hepatitis B vaccine is to the common a epitope with consequent protection against all subtypes of the virus. First generation vaccines were prepared from 22 nm HBsAg particles purified from plasma donations from chronic carriers. These preparations are safe and immunogenic but have been superseded in some countries by recombinant vaccines produced by the expression of HBsAg in yeast cells. The expression plasmid contains only the 3′ portion of the HBV surface ORF and only the major surface protein, without pre-S epitopes, is produced. Vaccines containing pre-S2 and pre-S1, as well as the major surface proteins expressed by recombinant DNA technology, are undergoing clinical trials. In many areas of the world with a high prevalence of HBsAg carriage, such as China and Southeast Asia, the predominant route of transmission is perinatal. Although HBV does not usually cross the placenta, the infants of viremic mothers have a very high risk of infection at the time of birth. Administration of a course of vaccine with the first dose immediately after birth is effective in preventing transmission from an HBeAg-positive mother in approximately 70% of cases, and this protective efficacy rate may be increased to greater than 90% if the vaccine is accompanied by the simultaneous administration of hepatitis B immune globulin (HBIG). Immunization against hepatitis B is now recognized as a high priority in preventive medicine in all countries and strategies for immunization are being revised and universal vaccination of infants and adolescents is under examination as a possible strategy to control the transmission of this infection. About 30 countries including the United States now offer hepatitis B vaccine to all children. However, immunization against hepatitis B is at present recommended in a number of countries with a low prevalence of hepatitis B only to groups which are at an increased risk of acquiring this infection. These groups include individuals requiring repeated transfusions of blood or blood products, prolonged in-patient treatment, patients who require frequent tissue penetration or need repeated access to the circulation, patients with natural or acquired immune deficiency and patients with malignant diseases. Viral hepatitis is an occupational hazard among health care personnel and the staff of institutions for the mentally retarded, and those in some semi-closed institutions. High rates of infection with hepatitis B occur in intravenous drug abusers, sexually active male homosexuals and prostitutes. Individuals working in high endemic areas are, however, at an increased risk of infections and should be immunized. Young infants, children and susceptible persons (including travellers) living in certain tropical and sub-tropical areas where present socio-economic conditions are poor and the prevalence of hepatitis B is high, should also be immunized. Hepatitis B Antibody Escape Mutants Production of antibodies to the group antigenic determinant a mediates cross-protection against all sub-types, as has been demonstrated by challenge with a second subtype of the virus following recovery from an initial experimental infection. The epitope a is located in the region of amino acids 124–148 of the major surface protein, and appears to have a double-loop conformation. A monoclonal antibody which recognizes a region within this a epitope is capable of neutralizing the infectivity of hepatitis B virus for chimpanzees, and competitive inhibition assays using the same monoclonal antibody demonstrate that equivalent antibodies are present in the sera of subjects immunized with either plasma-derived or recombinant hepatitis B vaccine. During a study of the immunogenicity and efficacy of hepatitis B vaccines in Italy, a number of individuals who had apparently mounted a successful immune response and become anti-surface antibody (anti-HBs)-positive, later became infected with HBV. These cases were characterized by the co-existence of non-complexed anti-HBs and HBsAg, and in 32 of 44 vaccinated subjects there were other markers of hepatitis B infection. Furthermore, analysis of the antigen using monoclonal antibodies suggested that the a epitope was either absent or masked by antibody. Subsequent sequence analysis of the virus from one of these cases revealed a mutation in the nucleotide sequence encoding the a epitope, the consequence of which was a substitution of arginine for glycine at amino acid position 145. There is now considerable evidence for a wide geographical distribution of the point mutation in hepatitis B virus from guanosine to adenosine at position 587, resulting in an amino acid substitution at position 145 from glycine to arginine in the highly antigenic group determinant a of the surface antigen. This stable mutation has been found in viral isolates from children several years later and it has been described in Italy, Singapore, Japan, and Brunei, and from liver transplant recipients with hepatitis B in the US, Germany, and the UK who had been treated with specific hepatitis B immunoglobulin or humanized hepatitis B monoclonal antibody. The region in which this mutation occurs is an important virus epitope to which vaccine-induced neutralizing antibody binds, as discussed above, and the mutant virus is not neutralized by antibody to this specificity. It can replicate as a competent virus, implying that the amino acid substitution does not alter the attachment of the virus to the liver cell. Variants of HBV with altered antigenicity of the envelope protein show that HBV is not as antigenically singular as previously believed and that humoral escape mutation can occur in vivo. There are two causes for concern: failure to detect HBsAg may lead to transmission through donated blood or organs, and HBV may infect individuals who are anti-HBs positive after immunization. Variation in the second loop of the a determinant seems especially important. Mutants, variants, altered genotypes, and unusual strains are now being sought in many laboratories. HBV Precore mutants The nucleotide sequence of the genome of a strain of HBV cloned from the serum of a naturally infected chimpanzee has been reported. A surprising feature was a point mutation in the penultimate codon of the precore region which changed the tryptophan codon (TGG) to an amber termination codon (TAG). The nucleotide sequence of the HBV precore region from a number of anti-HBe-positive Greek patients was investigated by direct sequencing PCR-amplified HBV DNA from serum. An identical mutation of the penultimate codon of the precore region to a termination codon was found in seven of eight anti-HBe positive patients who were positive for HBV DNA in serum by hybridization. In most cases there was an additional mutation in the proceeding codon. Similar variants were found by amplification of HBV DNA from serum of anti-HBe positive patients in Italy and Greece. These variants are not confined to the Mediterranean region. The same nonsense mutation (without a second mutation in the adjacent codon) has been observed in patients from Japan and elsewhere, along with rarer examples of defective precore regions caused by frameshifts or loss of the initiation codon for the precore region. In many cases, precore variants have been described in patients with severe chronic liver disease and who may have failed to respond to therapy with interferon. This observation raises the question of whether they are more pathogenic than the wild-type virus. HBV and Hepatocellular Carcinoma When tests for HBsAg became widely available, regions of the world where the chronic carrier state is common were found to be coincident with those where there is a high prevalence of primary liver cancer. Furthermore, in these areas, patients with tumor almost invariably are seropositive for HBsAg. A prospective study in Taiwan revealed that 184 cases of hepatocellular carcinoma occurred in 3,454 carriers of HBsAg at the start of the study, but only 10 such tumors arose in the 19,253 control males who were HBsAg negative. Southern hybridization of tumor DNA yields evidence of chromosomal integration of viral sequences in at least 80% of HCCs from HBsAg carriers. There is no similarity in the pattern of integration between different tumors, and variation is seen both in the integration site(s) and in the number of copies or partial copies of the viral genome. Sequence analysis of the integrants reveals direct repeats in the viral genome often lie close to the virus/cell junctions, suggesting that sequences around the ends of the viral genome may be involved in recombination with host DNA. Integration seems to involve microdeletion of host sequences and rearrangements and deletions of part of the viral genome also may occur. When an intact surface gene is present, the tumor cells may produce and secrete HBsAg in the form of 22 nm particles. Production of HBcAg by tumors is rare, however, and the core ORF is often incomplete and modifications such as methylation may also modulate its expression. Cytotoxic T cells targeted against core gene products on the hepatocyte surface seem to be the major mechanism of clearance of infected cells from the liver, and cells with integrated viral DNA which are capable of expressing these proteins also may be lysed. Thus, there may be immune selection of cells with integrated viral DNA which are incapable of expressing HBcAg. The mechanisms of oncogenesis by HBV remain obscure. HBV may act non-specifically by stimulating active regeneration and cirrhosis which may be associated with long-term chronicity. However, HBV-associated tumors occasionally arise in the absence of cirrhosis, and such hypotheses do not explain the frequent finding of integrated viral DNA in tumors. In rare instances, the viral genome has been found to be integrated into cellular genes such as cyclin A and a retinoic acid receptor. Translocations and other chromosomal rearrangements also have been observed. Although insertional mutagenesis of HBV remains an attractive hypothesis to explain its oncogenicity, there is insufficient supportive evidence. Like many other cancers, development of hepatocellular carcinoma is likely to be a multifactorial process. The clonal expansion of cells with integrated viral DNA seems to be an early stage in this process and such clones may accumulate in the liver throughout the period of active virus replication. In areas where the prevalence of primary liver cancer is high, virus infection usually occurs at an early age and virus replication may be prolonged, although the peak incidence of tumor is many years after the initial infection.   Jawa, 2012-03-02 : 04:12:08 Salam Hormat MIS Mutiara Sukma MIS Mutiara Sukma mulai gabung sejak tepatnya Minggu, 2011-04-24 21:23:51. MIS Mutiara Sukma dilahirkan di Bandung mempunyai motto Jadikan diri sebagai haadiah bagi kebaikan untuk sesama. 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