Hepatitis viruses under immunosuppressive agents

Clinical and experimental studies have shown that T cell-mediated immune mechanisms are involved in the pathogenesis of hepatitis B virus (HBV) and hepatitis C virus infection. Immunosuppressants may impair T cell function and thereby reduce immune-mediated hepatocytolysis and virus clearance. In addition, corticosteroid may activate the glucocorticoid responsive element in the HBV genome to enhance HBV replication and gene expression. These combined effects result in an increase of viraemia in association with a decrease of serum aminotransferase and hepatic necroinflammation. In acute infection, use of immunosuppressants will increase the incidence of chronic evolution. In chronic infection, withdrawal of immunosuppressants will be followed by a clinical flare due to a rebound of immune attack to hepatocytes with increased viral load. This may lead to a subsequent decrease of the viraemia. Therefore, short-term use of immunosuppressant before antiviral therapy may be beneficial in the treatment of chronic viral hepatitis. However, the clinical rebound may be extremely severe and lead to hepatitis failure; thus, the patients should be monitored closely upon tapering and after the withdrawal of immunosuppressants. Long-term use of immunosuppressants in patients with hepatitis virus infection is usually deleterious, particularly in patients after organ transplantation. These findings suggest that clinicians should be cautious in the use of immunosuppressants in patients with hepatitis virus infection.     

Hepatitis viruses and chronic liver disease

We have investigated several groups of Thai patients diagnosed with chronic liver disease including chronic hepatitis, cirrhosis and hepatocellular carcinoma, as well as cholangiocarcinoma, for the prevalence of infection with either one of the hepatitis viruses B, C, G and the novel hepatitis virus TT (TTV). The 168 patients tested comprised 120 men and 48 women with their median age ranging from 42.3 to 62.3 years. Screening for antibodies to HBV and HCV was performed by a commercially available serological test kit, for the presence of HBV and TTV DNA by PCR, and of HCV and HGV RNA by RT-PCR, respectively. There was a clear two-fold higher prevalence of HBV (49%) over HCV (27%) infection and a four-fold higher frequency compared to HGV (13%) and TTV (11%) infection, respectively, in those individuals with chronic hepatitis, cirrhosis, and hepatocellular carcinoma, whereas all but one patient with cholangiocarcinoma the etiology of which has been ascribed to parasitic infestation, were free of all viral markers. In Thailand chronic HBV, and to a lesser extent, chronic HCV infection represent the two most common causes of hepatitis potentially proceeding to chronic liver disease, whereas the clinical significance pertinent to HGV and TTV remains to be elucidated.     

Hepatitis viruses: A Pandora's box?

Abstract The term hepatitis virus is reserved for those viruses that are predominantly hepatotropic, although several new agents have been assigned to this category in the absence of hepatotropism and clinical disease. The hepatitis viruses can be broadly divided into those transmitted via the fecal‐oral route, and those by blood, blood products and body fluids. Hepatitis A (picornaviridae), hepatitis B (hepadnaviridae) and hepatitis C (flaviviridae) represent the major public health problems. The epidemiology of hepatitis A virus (HAV) and hepatitis B virus (HBV) is changing in response to vaccination. In the case of HAV, older age groups are now deemed at risk, particularly of fulminant hepatitis if exposed over the age of 50. Chronic hepatitis B in some regions is now predominantly of the so‐called precore mutant type where high levels of HBV replication persist in the presence of anti‐hepatitis B virus (HBe) antibodies. The HBV vaccination is among the most cost‐effective health care measures. The epidemiological significance of mutations found increasingly in the HBV S gene isolated from vaccinated children is unclear. Evidence that hepatitis G and TT virus are significant causes of hepatitis is lacking. Of interest, however, is the finding that the related GBV‐B agent of monkeys may be a model for developing new antiviral agents against HCV. Animal models of hepatitis infections are providing new insights into the pathogenesis of hepatitis in humans. Indeed it is possible that hepatitis E is primarily an agent of pigs and other domesticated livestock. Intriguingly, the new TT virus shares many properties with the circoviruses, significant pathogens of chickens and pigs. The challenge in the next decade will be to assess the significance of these new agents in terms of public health and resources. Value judgements will have to be made in assessing the risks associated with blood containing trace amounts of these adventitious agents. © 2002 Blackwell Publishing Asia Pty Ltd     

Hepatitis caused by herpes viruses: A review

Herpes virus hepatitis varies in presentation, ranging from asymptomatic to acute liver failure, in both immunocompetent and immunocompromised individuals. Hepatitis caused by the Herpesviridae family is uncommon and usually results in mild disease. It is also often self‐limiting, although in certain populations especially immunosuppressed patients, it can cause severe infections, leading to acute to fulminant hepatic failure. In addition, some isolated cases of fulminant disease in immunocompetent individuals have been reported. As the presentation is frequently non‐specific, it is important to maintain a high level of suspicion for these viral etiologies and start empiric therapy with antiviral agents as soon as possible. Liver transplantation is the last resort. Mortality remains high in fulminant hepatic failure caused by Herpesviridae without liver transplantation. Here we review the literatures on hepatitis caused by three members of the Herpesviridae family, cytomegalovirus, Epstein–Barr virus and herpes simplex virus to discuss the epidemiology, diagnostic methods, clinical features and current management, and also to determine which aspects need to be investigated in further detail. Herpesviridae‐mediated acute liver failure is rare but is associated with a poor prognosis, even after early treatment.     

Hepatitis viruses: live and let die.

Viral hepatitis is a diffuse inflammatory reaction of the liver caused by hepatotropic viruses. Among the hepatitis viruses, only hepatitis B virus and hepatitis C virus are able to persist in the host and cause chronic hepatitis. In the course of persistent infection, inflammation forms the pathogenetic basis of chronic hepatitis that can lead to nodular fibrosis, which can progress to cirrhosis and, eventually, hepatocellular carcinoma (HCC). Of the different antiviral defense systems employed by the host, apoptosis significantly contributes to the prevention of viral replication, dissemination, and persistence. Pathomorphologic studies have shown acidophilic bodies and hepatocyte dropout, features that are compatible with apoptosis. The number of hepatocytes showing features of apoptosis in patients with chronic hepatitis B and C was found to be higher than in healthy subjects, indicating that apoptosis is involved in the pathogenesis of these diseases. There are various data suggesting that hepatitis B and C viral proteins may modulate apoptosis. Vice versa, mechanisms of apoptosis inhibition might represent central survival strategies employed by the virus which, in the end, may contribute to HCC development. While the expression and retention of viral proteins in hepatocytes may influence the severity and progression of liver disease, the mechanisms of liver injury in viral hepatitis are defined to be due not only to the direct cytopathic effects of viruses, but also to the host immune response to viral proteins expressed by infected hepatocytes. However, the exact role of these observations in relation to pathogenesis remains to be established. The mechanism and systems are complex. This report aims to provide an overview and intends to cite only a small number of pertinent references.     

Hepatitis viruses and the safety of blood donations

Since the beginning of blood transfusions concomitant transmission of viral hepatitis has been a frequent and serious side-effect. A first measure to reduce the frequency of transmission was the screening of blood donors for elevated levels of liver enzymes in the blood, which was introduced in Germany in the 1960s, but not in most other countries. After the discovery of hepatitis B virus (HBV), donors in all countries have been screened since the 1970s for its surface antigen (HBsAg). When it was realized that there was at least one other type of virus that was even more frequently transmitted, screening for liver enzymes and HBV antibodies (anti-HBc) was introduced as a surrogate marker in most, but not all, countries in the 1980s. Furthermore, donors at risk for parenterally transmitted viruses were excluded. The discovery of the hepatitis C virus (HCV) genome and the development of sensitive anti-HCV assays has meant that reliable detection of persistently infected HCV carriers has been possible since 1991. Recently infected donors, however, are infectious for several weeks or months before anti-HCV is detectable. Therefore, starting in April 1999 all donations in Germany have to be tested, by nucleic acid amplification tests, for the presence of HCV RNA, although preliminary experience shows that such recent HCV infections are very rare. Newly detected viruses, named GBV-C or HGV and TTV, have been detected in patients with non-A-E post-transfusion hepatitis, but their association with the disease seems to be coincidental. These viruses cause persistent viraemia and are quite prevalent world-wide, but do not cause any known disease. At present, transfusion-transmitted hepatitis has been virtually eliminated, and any improvement in safety will be very small and will require huge costs.     

Hepatitis B and delta viruses in fulminant hepatitis

From June 1985 to 1989, we studied 39 cases with fulminant viral hepatitis. These included 32 cases due to hepatitis B, of whom 27 died. Twenty of the 32 cases were positive for delta antibody, and all of them died. Four cases who died were negative for IgM anti-HAV, HBsAg and IgM anti-HBc and were classified as NANB. Thus, a total of 31 patients died. Hepatitis B and delta virus infection were the major risk factors for fulminant hepatitis and eventual death.     

Hepatitis viruses in southern Taiwan--mass survey of 2985 inhabitants

A survey of 2985 apparently healthy Taiwanese in southern Taiwan revealed a high prevalence (18.2%) of hepatitis B surface antigen (HBsAg). It was significantly higher in males (22.3%) than in females (13.6%), but no correlation with family origin, socioeconomic status or residence was established. About one-third of the breeding female HBsAg carriers were HBeAg-positive, and these may be an important source in the spread of HBV. Subtyping of HBsAg in 63 subjects showed adw to be dominant in this area, and 8 subjects with suspicious results had overlapping heterotypic HBV's (7 adwr and 1 adyw) in addition to 2 subjects in which coexistence of HBsAg and anti-HBs was recognized. The association between HBsAg positivity and serum transaminase elevation was significant, especially in the older groups who had a higher abnormal rate. Hepatitis A virus infection was serious too, with nearly 100% of people above 20 years of age being anti-HA antibody positive.     

Hepatitis viruses as aetiological agents of hepatocellular carcinoma.

Hepatitis viruses, particularly HBV and HCV, are major causes of hepatocellular carcinoma worldwide, due to the induction of chronic liver disease and of cirrhotic transformation of the liver. Cirrhosis certainly represents the most important link between chronic viral hepatitis and HCC. Under these circumstances, risk of HCC development in chronic HBV and HCV infection is strictly dependent on the propensity to cirrhotic transformation. Intervention of other, more direct, molecular events induced by the virus itself are suspected, particularly for HBV which is able to integrate into the host genome, but not yet incontrovertibly proved.     

Hepatitis viruses: changing patterns of human disease.

Viral hepatitis is a disease of antiquity, but evidence for more than one etiologic agent has been recognized only since the 1940s, when two viruses (hepatitis A virus and hepatitis B virus) were thought to account for all disease. In the past 20 years, three additional hepatitis agents (hepatitis C virus, hepatitis D virus, and hepatitis E virus) have been discovered, and there is evidence for at least one additional virus. Each of the five recognized hepatitis viruses belongs to a different virus family, and each has a unique epidemiology. The medical impact of these viruses on society has been strongly influenced by changes in human ecology. This has resulted in some cases in diminished disease and in others in increases in the incidence of disease.     

Hepatitis B and C viruses and primary liver cancer

The data presented indicate that viral agents (namely, HBV and HCV) are major environmental aetiological factors for human primary liver cancer. It is important to elucidate the molecular mechanisms further because HCC is one of the few examples of virus-related human cancers. In addition, the available evidence points to the possibility of at least partial prevention of the tumour by large-scale vaccination.     

Hepatitis B and C viruses are not risks for pancreatic adenocarcinoma

AIM:To investigate whether hepatitis B virus(HBV)and hepatitis C virus(HCV)increase risk of pancreatic ductal adenocarcinoma(PDAC).METHODS:We recruited 585 patients with cytological and/or pathologically confirmed PDAC in National Taiwan University Hospital from September 2000 to September 2013,and 1716 age-,sex-,and race-matched controls who received a screening program in a community located in Northern Taiwan.Blood samples were tested for the presence of HCV antibodies(anti-HCV),HBV surface antigen(HBsAg),antibodies against HBsAg(anti-HBs),and hepatitis B core antigen(anti-HBc)in all cases and controls.The odds ratio(OR)of PDAC was estimated by logistic regression analysis with adjustment diabetes mellitus(DM)and smoking.RESULTS:HBsAg was positive in 73 cases(12.5%)and 213 controls(12.4%).Anti-HCV was positive in22 cases(3.8%)and 45 controls(2.6%).Anti-HBs was positive in 338 cases(57.8%)and 1047 controls(61.0%).The estimated ORs of PDAC in multivariate analysis were as follows:DM,2.08(95%CI:1.56-2.76,P<0.001),smoking,1.36(95%CI:1.02-1.80,P=0.035),HBsAg+/anti-HBc+/anti-HBs-,0.89(95%CI:0.89-1.68,P=0.219),HBsAg-/anti-HBc+/anti-HBs+,1.03(95%CI:0.84-1.25,P=0.802).CONCLUSION:HBV and HCV infection are not associated with risk of PDCA after adjustment for age,sex,DM and smoking,which were independent risk factors of PDAC.