Association between fulminant hepatic failure and a strain of GBV virus C

doi:10.1016/S0140-6736(96)04413-3

The Lancet

Volume 348, Issue 9042, 14 December 1996, Pages 1626-1629

https://doi.org/10.1016/S0140-6736(96)04413-3 Get rights and content

Summary

Background

The GB virus C (GBV-C) and the hepatitis G virus (HGV) have been detected in patients with acute indeterminant hepatitis and post-transfusion hepatitis. However, the role of the new hepatitis viruses in the aetiology of fulminant hepatitis is little understood. We investigated the presence of GBV-C/HGV in patients with fulminant hepatic failure.

Methods

Serum samples from 22 German patients with fulminant hepatic failure and 106 symptom-free blood donors (controls) were studied for presence of GBV-C RNA by seminested reverse transcriptase PCR. Primer sequences were derived from the published gene sequences of the conserved NS3 region of the GBV-C prototype and the published isolates. Nucleotide and aminoacid sequences of GBV-C-positive isolates, the control RNA, and the published HGV and GBV-C prototype sequences were compared by multiple sequence alignment. We also compared the GBV-C sequences of virus-positive patients who had fulminant hepatic failure with those of 19 patients with chronic hepatitis from our centre. In addition, we searched databases and published papers for further GBV-C helicase sequences in patients with non-fulminant hepatitis.

Findings

GBV-C RNA was detected in 11 (50%) of the 22 patients with fulminant hepatic failure and in five (4·7%) of 106 control-group blood donors. Among the patients with fulminant hepatic failure, six of seven with fulminant hepatitis B and five of ten with fulminant non-A-E hepatitis were positive for GBV-C RNA. Analysis of nucleic acid sequences showed six mutations at defined positions in all 11 patients with fulminant hepatic failure who were positive for GBV-C. None of these mutations were found in the five GBV-C-positive control-group blood donors. Of the six nucleotide changes, four caused no aminoacid changes, whereas two mutations at position 100 (G to T) and 102 (T to C) led to an alanine to serine change in the predicted translation product. However, comparison with GBV-C sequences of patients with non-fulminant hepatitis showed that this aminoacid mutation was not specific for fulminant hepatic failure. The sequence-motif containing the six nucleotide mutations detected in all patients with fulminant hepatic failure was found in only two of 19 German patients with chronic hepatitis from our centre, and in only one of 88 GBV-C sequences from non-fulminant patients reported by others.

Interpretation

The frequency of GBV-C RNA is higher in fulminant hepatic failure than in any other group of patients with hepatitis, particularly in patients with fulminant hepatitis B or fulminant non-A-E hepatitis. A specific strain of GBV-C may occur in serum of German patients with fulminant hepatic failure.

Introduction

Simons and colleagues¹ have identified two flavivirus-like genomes, GB-A and GB-B, in tamarins after infection with the GB hepatitis agent. The role of GB-A and GB-B in the pathogenesis of viral hepatitis in humans is not clear. However, a third GB virus, GBV-C, was identified in African patients with acute hepatitis of unknown aetiology.² In addition, Linnen and colleagues³ identified the hepatitis G virus (HGV) in plasma samples from two patients with indeterminate post-transfusion hepatitis. GBV-C and HGV are flavi-like hepatitis viruses with 85–5% nucleotide homology and 100% aminoacid identity in the presumed NS3-helicase region, which suggests that they may be two isolates of the same virus.³ The reported frequency of GBV-C and HGV RNA in volunteer blood donors is 1·3–1·7%,3, 4, 5 which is twice as high as that reported for hepatitis C.⁶ Yoshiba et al⁷ have reported the possible involvement of GBV-C in the aetiology of fulminant hepatic failure; three of six patients with fulminant hepatitis were found to be positive for GBV-C RNA.⁷ By contrast, Sallie and colleagues⁸ found no GBV-C in 20 liver specimens from patients with fulminant hepatic failure. Such conflicting data mean that the role of the new hepatitis viruses in patients with fulminant hepatic failure is little understood. In this study, we used seminested PCR to detect the presence of GBV-C in patients with fulminant hepatic failure and blood donors without clinical or biochemical signs of hepatitis (controls). In our analysis of nucleotide and aminoacid sequences, we also compared the GBV-C sequences of patients who had fulminant hepatic failure with those of patients with chronic hepatitis and patients with non-fulminant hepatitis.

Section snippets

Methods

Between 1992 and 1995, 22 patients with well-documented fulminant hepatic failure were treated at our university hospital. 14 of these patients had undergone liver transplantation according to O'Grady and colleagues' criteria.⁹ We recorded clinical data for all patients and obtained serum samples in accordance with the guidelines of our local ethics committee. Blood specimens were taken on admission and serum was stored at −70°C. We randomly selected 106 healthy blood donors without clinical or

Results

GBV-C RNA was found in 11 (50%) of the 22 patients with fulminant hepatic failure and in five (4–7%) of the 106 control-group blood donors. The underlying causes of fulminant hepatic failure in the 22 patients are given in table 1. 20 patients were German, and two were immigrants who had lived in Germany for several years. The ages of the 11 GBV-C-positive patients and the 11 GBV-C-negative patients did not differ significantly (median age 33·4 [IQR 19·1–47·7] vs 27·5 [16·1–38·9] years). The

Discussion

We found GBV-C RNA in five (4·7%) of 106 control-group blood donors; this rate is between the reported prevalence of GBV-C in volunteer and commercial blood donors in the USA (1·3–1·7% and 12·9%, respectively).3, 4, 5 Risk factors for disease transmission are more common among commercial blood donors than among volunteer donors. Thus, in our study the rate of GBV-C might have been slightly higher than expected because the control-group blood donors received an expense allowance.

Previous studies

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Detection of the GBV-C hepatitis virus genome in serum from patients with fulminant hepatitis of unknown aetiology
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GB virus infection: a silent anti-HIV panacea within?
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The GB virus (GBV)/hepatitis G virus is a member of the Flaviviridae family and belongs to the hepatitis group of viruses transmitted parenterally, common among intravenous drug users. The strong association between GBV and HIV infection suggests that the two viruses may share similar epidemiological and transmission features. GBV infection is widely believed to prolong HIV disease progression as well as decreasing the HIV viral load and increasing the CD4⁺ T-cell level. GBV-driven anti-E2 antibodies have been shown to inhibit HIV replication in vitro. Preliminary studies also suggest that GBV infection of peripheral blood mononuclear cells leads to increased production of β-chemokines, which may explain the in vitro inhibitory effects and warrants further studies. With sufficient knowledge of resistance patterns studied in tropical south India, researchers are now keen to study the competitive interactions between GBV-induced chemokines and HIV ligands to bind CCR5.
Detection of hepatitis G virus envelope protein E2 antibody in blood donors
2008, International Journal of Infectious Diseases
Citation Excerpt :
Most HGV infections appear to be asymptomatic. The clinical significance of this agent is still uncertain; several studies have failed to demonstrate serious liver disease in patients with HGV viremia,2 although the possibility of it having a role in fulminant hepatitis4,5 and aplastic anemia has been debated.6 In the absence of any reliable serological assay for the diagnosis of infection, HGV RNA detection by reverse transcriptase polymerase chain reaction (RT-PCR) remains the only available method indicating an ongoing HGV infection.7
The frequency of hepatitis G virus exposure in blood donors varies between 2.5% in Japan to 24.2% in Poland. Therefore there is a geographic difference in distribution of hepatitis G virus (HGV) in the world. We aimed to determine the frequency of HGV exposure in Iranian blood donors.
Blood samples from 478 Iranian volunteer blood donors were tested. Positive anti-E2 samples were tested for HGV RNA by reverse transcriptase polymerase chain reaction (RT PCR) using primers derived from the NS5A region of the viral genome.
Of the 478 donors enrolled in our study, five (1%) were positive for anti-E2. Only one donor out of a total of three HBsAg-positive donors was co-infected with HGV, but we did not find HGV and HCV co-infection in our subjects. HGV RNA was not observed in the five anti-E2-positive subjects. We did not find HGV viremia and antibody at the same time.
A low frequency of HGV exposure in blood donors was found in this study. We did not observe co-infection of HGV with HCV in our subjects, supporting the theory that although the parenteral route is the most effective means of transmission, other routes such as sexual contact and intra-familial contact may also play a role in HGV transmission.
Is GB virus C alias "hepatitis" G virus involved in human pathology?
2003, Transfusion Clinique et Biologique
Le GBV-C ou virus « dit » de l’hépatite G, découvert en 1995, a été proposé comme candidat responsable d’hépatites non A-E. Il s’agit d’un virus très répandu, dont la prévalence chez les donneurs de sang dans les pays développés se situe entre 1 à 5 %. Sept années d’études ont permis d’exclure son rôle direct en tant qu’agent étiologique significatif d’hépatites. Son site de réplication in vivo n’est pas définitivement identifié et aucune corrélation directe entre l’infection virale seule et l’induction de maladies hépatiques ou extra-hépatiques n’a pu être mise en évidence. Cependant, lors de co-infections avec d’autres virus, un rôle modulateur de l’infection GBV-C, susceptible d’aggraver les lésions hépatiques, ou au contraire, de ralentir la progression de l’infection VIH-1 vers le sida, semble se confirmer. À ce jour, aucun pays n’a pris la décision de mettre en œuvre un dépistage de l’infection à virus GBV-C chez les donneurs de sang. Des études complémentaires restent indispensables avant de pouvoir définitivement affirmer l’absence d’influence de l’infection à GBV-C sur la santé humaine dans le contexte d’autres infections virales.
Cette revue fait état de l’ensemble des données de la littérature sur une implication éventuelle du GBV-C dans des pathologies associées ou non à d’autres infections.
GB virus-C alias “hepatitis” virus G was discovered in 1995 as a putative causative virus of non A-E hepatitis. It is a very common virus found in 1 to 5% of eligible blood donors in developed countries. Numerous studies over seven years led to the exclusion of its role as a significant etiological agent of hepatitis. Its in vivo replication site is still unknown. Its direct involvement in the induction of significant hepatic or extra-hepatic diseases could not be demonstrated. However, coinfections with other viruses may contribute to changes in the evolution of both liver disease (negatively) and HIV/AIDS (favourably). Today, no country has decided to screen GBV-C in blood donors. However, more studies are necessary before the absence of influence of GBV-C infection on human health in the context of other viral infections could be confirmed definitely. This article is a review of the literature on a possible involvement of GBV-C in pathologies whether associated or not to other infections.
Prevalence of GB virus C/hepatitis G virus in Hungary
2002, FEMS Immunology and Medical Microbiology
In 1995 a new flavivirus, GB virus C/hepatitis G virus (GBV-C/HGV), was discovered. The aim of this study was to determine the prevalence of the virus in healthy persons and hepatitis patients in Hungary. The sera of 408 healthy persons older than 60 years were tested for the presence of GBV-C/HGV antibodies, and 113 were positive (28%). Eight of the 71 healthy persons younger than 60 years and twenty of the 51 sera (39%) taken from patients suffering from hepatitis of unknown origin proved to be positive for GBV-C/HGV antibodies. Ten of the 124 sera (8%) of healthy persons and 36 of the 247 sera (14.6%) of hepatitis patients proved to be positive for GBV-C/HGV RNA. Eleven PCR products were sequenced, and the sequences were found to be different from each other and from the previously published ones. However, three sequences taken from the same patient at different times were identical. These results show that GBV-C/HGV is present in Hungary and cannot be considered rare.
Fulminant hepatic failure in a pediatric patient with active GB virus C (GBV-C)/hepatitis G virus (HGV) infection
2002, Hepatology Research
We describe a rare case of a pediatric patient with active GB virus C (GBV-C)/hepatitis G virus (HGV) infection who died of fulminant hepatic failure within less than a month after the onset of jaundice. The child tested negative for all other known hepatitis viruses and had no history of blood transfusions. This observation suggests that although GBV-C/HGV is usually not pathogenic to the liver, it may be associated with certain idiopathic forms of fulminant hepatitis. Whether this association is etiological or circumstantial remains to be seen.

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Early ReportAssociation between fulminant hepatic failure and a strain of GBV virus C

Summary

Background

Methods

Findings

Interpretation

Introduction

Section snippets

Methods

Results

Discussion

J Hepatol

Lancet

Lancet

Gastroenterology

Gastroenterology

Gastroenterology

J Biol Chem

FEBS Lett

Identification of two flavivirus-like genomes in the GB hepatitis agent

Proc Natl Acad Sci USA

Isolation of novel virus-like sequences associated with human hepatitis

Nat Med

Early Report
Association between fulminant hepatic failure and a strain of GBV virus C