Hepatitis C virus. A review.

Hepatitis C virus has been shown to be responsible for most cases of posttransfusion hepatitis, as well as for sporadic non-A, non-B viral hepatitis. Hepatitis C virus has also been implicated in the development of primary hepatocellular carcinoma, autoimmune hepatitis, and fulminant viral hepatitis. Although the role of the parenteral transmission of hepatitis C virus is well established, its route of transmission in cases of sporadic infection remains unclear. Sexual transmission is suspected but not confirmed. Recent work regarding treatment has shown interferon alfa to be effective, but the discontinuation of therapy is associated with a 50% relapse rate.     

Hepatitis B viral factors and clinical outcomes of chronic hepatitis B

Hepatitis B virus (HBV) infection is an important health problem and the major cause of chronic hepatitis, cirrhosis as well as hepatocellular carcinoma (HCC) worldwide. The natural history of chronic HBV infection can be divided into 4 dynamic phases in HBV carriers who acquire the virus early in life. In general, the frequency and severity of hepatitis flares in the immune clearance or reactivation phase predict disease progression in HBV carriers, and early HBeAg seroconversion typically confers a favorable outcome. In contrast, late or absent HBeAg seroconversion after multiple hepatitis flares accelerates the progression of chronic hepatitis to cirrhosis. Recently, several hepatitis B viral factors predictive of clinical outcomes have been identified. For example, serum HBV DNA level at enrollment is the best predictor of adverse outcomes (cirrhosis, HCC and death from liver disease) in adults with chronic HBV infection. In addition, HBV genotype C, basal core promoter (BCP) mutant and pre-S deletion mutant are associated with increased risk of HCC development. In conclusion, hepatitis B viral factors such as serum HBV DNA level, genotype and mutants have already been clarified to influence disease progression of chronic hepatitis B. Further studies are needed to investigate the pathogenic mechanism of each viral factor.     

Hepatitis A

Hepatitis A is a disease of worldwide distribution which occurs in endemic and epidemic form and is transmitted primarily by person-to-person contact through the fecal-oral route. Common source epidemics due to contamination of food are relatively common, and water-borne epidemics have been described less frequently. The presumed etiologic agent of hepatitis A has now been visualized by immune electron microscopic (IEM) techniques in early acute-illness-phase stools of humans with hepatitis A as well as in chimpanzees experimentally infected with material known to contain hepatitis A virus. In addition, several new serologic tests for the detection of antibody against hepatitis A virus have been described. These include complement fixation and immune adherence techniques. Current data suggest that hepatitis A is caused by a single viral agent lacking the morphologic heterogeneity of hepatitis B viral components and that there may be relative antigenic homogeneity between strains of virus recovered from various parts of the world. Serologic studies to date also indicate that hepatitis A virus is not a major contributing cause in post-transfusion hepatitis.     

Epidemiology of viral hepatitis in the Estonian SSR

The epidemiological peculiarities of viral hepatitis in the Estonial SSR as a whole, as well as in Tallinn and in the surrounding Harju region were studied. The study revealed that during the last 10 years the total decrease of morbidity in viral hepatitis was observed due to a decrease in infectious hepatitis, pronounced periodic and seasonal morbidity fluctuations being absent. A sharp decrease in infectious hepatitis morbidity had been achieved by carrying out planned gamma globulin prophylaxis among children. Viral hepatitis morbidity in the republic was determined by the adult population and manifested as sporadic cases of infectious and serum hepatitis. Infectious hepatitis was transmitted mainly through every day contacts, while the leading factor in the transmission of serum hepatitis consisted in various injections. The relatively high morbidity level of serum hepatitis was mainly determined by morbidity in large cities.     

Multiplication of hepatitis B virus in fulminant hepatitis B.

The presence in serum of hepatitis B e antigen (HBeAg) and hepatitis B virus DNA, which are each regarded as reflecting multiplication of hepatitis B virus, were looked for one to five days after the onset of hepatic encephalopathy in 64 patients with fulminant hepatitis B. HBeAg and hepatitis B virus DNA were found in the serum of only 24 (37%) and six (9%) patients, respectively. Hepatitis B virus DNA was absent from the serum in all 13 patients positive for anti-HBs. These findings indicate that replication of hepatitis B virus stopped after the onset of hepatic encephalopathy in most of the patients and support the view that an enhanced immune response stops the replication. Agents that inhibit viral multiplication would probably not have any effect at this stage of the disease.     

Vaccine- and hepatitis B immune globulin-induced escape mutations of hepatitis B virus surface antigen

Hepatitis B virus surface antigen (HBsAg) vaccination has been shown to be effective in preventing hepatitis B virus (HBV) infection. The protection is based on the induction of anti-HBs antibodies against a major cluster of antigenic epitopes of HBsAg, defined as the 'a' determinant region of small HBsAg. Prophylaxis of recurrent HBV infection in patients who have undergone liver transplantation for hepatitis B-related end-stage liver disease is achieved by the administration of hepatitis B immune globulins (HBIg) derived from HBsAg-vaccinated subjects. The anti-HBs-mediated immune pressure on HBV, however, seems to go along with the emergence and/or selection of immune escape HBV mutants that enable viral persistence in spite of adequate antibody titers. These HBsAg escape mutants harbor single or double point mutations that may significantly alter the immunological characteristics of HBsAg. Most escape mutations that influence HBsAg recognition by anti-HBs antibodies are located in the second 'a' determinant loop. Notably, HBsAg with an arginine replacement for glycine at amino acid 145 is considered the quintessential immune escape mutant because it has been isolated consistently in clinical samples of HBIg-treated individuals and vaccinated infants of chronically infected mothers. Direct binding studies with monoclonal antibodies demonstrated a more dramatic impact of this mutation on anti-HBs antibody recognition, compared with other point mutations in this antigenic domain. The clinical and epidemiological significance of these emerging HBsAg mutants will be a matter of research for years to come, especially as data available so far document that these mutants are viable and infectious strains. Strategies for vaccination programs and posttransplantation prophylaxis of recurrent hepatitis need to be developed that may prevent immune escape mutant HBV from spreading and to prevent these strains from becoming dominant during the next decennia.     

消化道传播病毒性肝炎研究进展

病毒性肝炎是由多种不同肝炎病毒引起的,以肝脏损害为主要表现,具有广泛流行性和严重传染性的一类疾病,严重危害人类健康,是我国目前重大的公共卫生问题之一。迄今鉴定出的具有明确致病性的肝炎病毒主要是甲型肝炎病毒(HAV)、乙型肝炎病毒(HBV)、丙型肝炎病毒(HCV)、丁型肝炎病毒(HDV)和戊型肝炎病毒(HEV),分别引起甲、乙、丙、丁、戊型肝炎。病毒性肝炎按传播途径的不同可以分为两类,一类是经肠道外传播的病毒性肝炎,包括乙、丙、丁型肝炎;另一类是经肠道(即消化道)传播的肝炎病毒,包括甲肝和戊肝,其发病有季节性,可呈暴发流行。本文旨在对经消化道传播的病毒型肝炎(甲肝、戊肝)的病原学、流行病学特征及其影响因素、控制和预防作一综述,以期对其流行和科学防控研究提供参考。     

Immunopathogenesis of hepatitis C virus infection

Hepatitis C virus, a recently identified member of the family Flaviviridae, is an important cause of chronic viral hepatitis and cirrhosis. There are similarities in the nature of the immune response to this pathogen with immunity in other flavivirus and hepatotropic virus infections, such as hepatitis B. However, the high rate of viral persistence after primary hepatitis C infection, and the observation that neutralizing antibodies are not protective, would suggest that there are a number of important differences between hepatitis C, other flaviviruses, and hepatitis B. The phenomenon of quasispecies evolution and other viral factors have been proposed to contribute to immune evasion by hepatitis C virus. In the face of established persistent infection, virus-specific cytotoxic T lymphocytes may exert some control over viral replication. However, these same effectors may also be responsible for the progressive liver damage characteristic of chronic hepatitis C infection. The nature of protective immunity, including the role of innate immune responses early after hepatitis C exposure, remains to be defined.     

Viral Hepatitis: Problems of Incidence and Control in Military Personnel

(A) Hepatitis B virus (HBV) is now the major cause of infectious viral hepatitis in U.S. military personnel and probably also in the civilian population over 15 years of age. (B) The incidence of icteric, viral hepatitis is much higher in U.S. military personnel than in comparable age groups in the civilian population. The 17-to 20-year-old enlisted men show the highest rates. (C) In parts of the world (e.g., U.S.A., Germany) where most of the inapparent infection is caused by the adw subtype of HBV, most of the acute clinical disease is caused by the ayw subtype. In the U.S.A. and Germany, 95% or more of HB_s Ag isolates from U.S. military personnel with acute hepatitis is ayw. (D) It may be many years before one can expect to have sufficient data for a decision as to the possible availability of an effective HBV vaccine. Accordingly, a decision is urgently needed regarding either the immediate use of the best practically available hepatitis immune gamma globulin, that can be prepared by modern techniques, for the prevention of hepatitis in U.S. military personnel or postponement of such use until an adequate and properly controlled trial can be carried out in active duty military personnel in an area of high incidence.     

Determination of antibody to hepatitis B core antigen by means of immune adherence hemagglutination.

A simple and rapid method utilizing immune adherence hemagglutination has been developed for the detection of antibodies to hepatitis B core antigen (anti-HBc). Hepatitis B core antigen (HBcAG) was prepared from Dane particles that had been isolated from plasma of asymptomatic antigen carriers. The method was specific and about 10 times more sensitive than the conventional complement-fixation method. A total of 215 serum samples obtained from healthy blood donors were surveyed for HBsAG and anti-HEc, as well as for hepatitis B surface antigen (HBsAg) and antibody to HBsAG (anti-HBs). Anti-HBc was found in 36 serum samples, at a prevalence rate higher than that of anti-HBs (31/215)...     

The characteristics of an outbreak of non-A, non-B hepatitis with a fecal-oral mechanism of the transmission of the causative agent in Osh Province, the Kirghiz SSR

The results of epidemiological, clinical and laboratory studies revealed that the sharp rise of morbidity in viral hepatitides in Osh Province, the Kirghiz SSR in autumn 1987 was caused by hepatitis non A, non B virus with fecal-oral transmission. At this period the results of the enzyme immunoassay showed the absence of the markers of hepatitides A, B and Delta in 72.2% of viral hepatitis patients. Hepatitis non A, non B occurred only in 2.4% of viral hepatitis patients of preschool age (of these, 83.3% had hepatitis A) and was diagnosed in autumn 1987 in 50% of the patients aged 7-14 years and in 97.4% of the patients aged 15-29 years (in the latter age group 95-98% of the patients had IgG to hepatitis A virus in their blood). The appearance of the outbreak of the above-mentioned infection in Kirghizia is linked with the water route of the transmission of the infective agent. The epidemiological and clinical signs, characteristic of fecal-oral hepatitis non A, non B in Kirghizia, were not different from those registered earlier in other republics of the Central Asia and could be used for the identification of this infection.     

Specific immune adherence assay for human hepatitis A antibody application to diagnostic and epidemiologic investigations.

A specific immune adherence (IA) test for hepatitis A antibody in human serum was described employing liver extract of marmosets infected with CR326 strain human hepatitis A virus. Persons with hepatitis A, but not hepatitis B, developed hepatitis A IA antibody soon after onset of the acute illness and this persisted thereafter. There was very close agreement in the tests for human hepatitis A immune adherence, complement fixing (CF) and neutralizing antibodies. IA antibodies appeared to develop somewhat later than CF or neutralizing antibody. A limited epidemiologic study of a family outbreak of hepatitis A and B in Costa Rica showed simultaneous occurrence of the two diseases and was supportive of the concept that susceptible persons in a country with high hepatitis A prevalence generally acquire their infections at an early age and are immune thereafter. Most persons of high socioeconomic level in an area of low hepatitis A incidence may proceed to adulthood without experience with hepatitis A. Person of low socioeconomic level, however, such as commercial blood bank donors and prisoners, show high incidence of hepatitis A antibody. Hepatitis IA and CF antibodies persisted in human subjects for at least 7 hr after hepatitis A virus infection. Captive chimpanzees and grivet and rhesus monkeys, not given hepatitis A virus, showed evidence of previous experience with human hepatitis A or an antigenically related virus based on tests for hepatitis A antibody. Other subhuman primates, rodents, and swine, not given hepatitis A virus, were without hepatitis A antibody. The IA test provides an excellent tool for diagnostic and epidemiologic investigations of hepatitis A and should be of considerable value to detect hepatitis A virus in attempts to propagate the virus in cell culture. There was considerable difference in hepatitis A IA antibody content of different lots of commercial human immune globulin, though the majority titered 1:4000 or 1:8000.     

Nucleic acid-amplification testing for hepatitis B in cornea donors

Careful donor selection and implementation of tests of appropriate sensitivity and specificity are of paramount importance for minimizing the risk of transmitting infectious diseases from donors to corneal allograft recipients. Reported cases of viral transmission with corneal grafts are very unusual. Nevertheless potential virus transmission through the engraftment cannot be ruled out. According to European Guideline 2006/17/EC, screening for antibodies for Hepatitis B core antigen (anti HBc) is mandatory, and when this test is positive, some criteria must be established before using corneas. Despite the continuous progress in screening tests, donors carrying an occult hepatitis B infection (OBI) can cause transplant-transmitted hepatitis B. To date, Nucleic Acid Testing (NAT) is not an obligatory assay in corneal tissue setting neither in our country nor in the rest of European countries. Herein, we report three cornea donors that were rejected with the diagnosis of OBI through the testing of sensitive NAT and the serological profile of Hepatitis B virus. The aim of this report is to emphasize the need to include NAT in new reviews of EU Tissues and Cells Directives in order to increase level of security in tissue donation as well as not to reject a high number of donors with isolated profile of anti HBc in geographical areas with high prevalence of Hepatitis B, that could be rejected without a true criterion of Hepatitis B infection.     

TLR3 plays significant roles against hepatitis B virus

Hepatitis B virus (HBV) as the main prevalent infectious agent, play important roles in inducing severe liver diseases. Previous studies demonstrated that during prolonged forms of hepatitis B infection including chronic, asymptomatic and occult forms, patients are unable to eradicate HBV from hepatocytes completely. The main mechanisms responsible for development of the forms of hepatitis B are yet to be identified. Investigators suggested that the various genetic and immunological parameters of the patients may are responsible for resulting in the prolonged infection forms. It has been evidenced that TLRs play key roles in inducing appropriate immune responses, against viral infections. Therefore, these molecules can be considered as crucial sensors for HBV detection to induce immune responses against this virus. It has also been documented that the TLR3 detects intracellular viral dsRNA and subsequently activates NF-κB via the TRIF pathway. Therefore, impaired TLR3 expression may result in inappropriate immune responses against HBV which is reported in prolonged forms of hepatitis B. This review collected the recent information regarding the important roles of TLR3 in immune responses against HBV and also the status of TLR3 expression and its genetic variations in prolonged forms of HBV infections.     

Feedback Circuits in Hepatitis B Virus Infection

A simplified model using kinetic logic is proposed to approach the problem after Hepatitis B viral (HBV) infection. It accounts for several stable regimes or attractors corresponding to the essential dynamic behaviour of the replication of the Hepatitis B virus. Infection with the virus can result in viral clearance, fulminant hepatic failure and death, or chronic transmissible infection, that is multistationarity corresponding to the existence of the positive feedback circuit in our modelling. Another implication of this model is the existence of oscillations or homeostatic mechanisms, sometimes observed in the viral cycle, consistent with the existence of the negative feedback circuit. Thus, this report shows how a simple model of kinetic logic may be used to account for the variety of manifestations of HBV infection. This model implies the presence of the Hepatitis B e antigen, whose conservation suggests that it plays an important role in the life cycle of hepadnaviruses. Its function in the viral cycle is still unknown, but our model suggests that this antigen could explain the passage from one state of the viral infection (acute or latent) to another, as well as the oscillatory behavior which may account for the intermittent symptoms of hepatitis observed in some patients. Furthermore, this model shows a virgin state. This state is also reached after recovery. The model proposed demonstrates that starting from a viral acute infection, the host's immune response, depending on the immunological status of the patient, can lead to viral clearance, or to periodic spontaneous reactivation.     

Detection of hepatitis B virus in bone allografts from donors with occult hepatitis B infection

The implementation of nucleic acid testing in donor screening has improved the safety of tissue allografts. Although infectious disease transmission can be considered a rare event, the detection of occult hepatitis B infection remains challenging. The studies concerning this risk are mainly based on testing blood specimens. This work shows the correlation between results of samples obtained from donor blood and the corresponding tissue washing solution. Hepatitis B virus deoxyribonucleic acid was detected both in bone allografts from donors with serological profiles associated to active hepatitis B infection and occult hepatitis B infection. These results suggest that hepatitis B virus seems to concentrate in bone marrow even when a low viral load is present in peripheral blood. Even detection at molecular level is not enough to avoid the risk of hepatitis B virus transmission and a multiparametrical evaluation is required in tissue donor screening. The role of clinicians in recognition and reporting of allograft-associated infections is a major concern for the acquisition of experience to be applied in risk control of disease transmission.     

Arthritis and Hepatitis

The evidence relating four clinically distinct rheumatologic syndromes to infection by the hepatitis B virus is reviewed. Acute hepatitis B is not infrequently heralded by a prodromal rash and rheumatoidlike polyarthritis. Chronic active hepatitis B more rarely is associated with transient arthritis or arthralgias. Polyarteritis nodosa may be a manifestation of hepatitis B infection in as many as 40 percent of cases, and recently the syndrome of “essential” mixed cryoglobulinemia has also been linked to infection with this virus. The finding of immune complexes of varying composition, sometimes with the viral antigen or its antibody (or both) contained in both the serum and synovial fluid suggests that these four syndromes are clinical manifestations of immune complex disease resulting from hepatitis B infection.