Clinicopathological study on TTV infection in hepatitis of unknown etiology

Abstract

To investigate the state of infection, replication site, pathogenicity and clinical significance of transfusion transmitted virus (TTV) in patients with hepatitis, especially in patients of unknown etiology. METHODS:Liver tissues taken from 136 cases of non-A non-G hepatitis were tested for TT virus antigen and nucleic acid by in situ hybridization (ISH) and nested-polymerase chain reaction (PCR). Among them, TT virus genome and its complemental strand were also detected in 24 cases of autopsy liver and extrahepatic tissues with ISH. Meanwhile, TTV DNA was detected in the sera of 187 hepatitis patients by nested-PCR. The pathological and clinical data of the cases infected with TTV only were analyzed. RESULTS:In liver, the total positive rate of TTV DNA was 32.4% and the positive signals were located in the nuclei of hepatocytes. In serus, TTV DNA was detected in 21.4% cases of hepatitis A-G, 34.4% of non-A non-G hepatitis and 15% of healthy donors. The correspondence rate of TTV DNA detection between liver tissue with ISH and sera with PCR was 63.2% and 89.3% in the same liver tissues by ISH and by PCR, respectively. Using double-strand probes and single-strand probes designed to detect TTV genome, the correspondence rate of TTV DNA detected in liver and extrahepatic tissues was 85.7%. Using singlestrand probes, TTV genome could be detected in liver and extrahepatic tissues by PCR, but its complemental strands (replication strands) could be observed only in livers. The liver function of most cases infected with TTV alone was abnormal and the liver tissues had different pathological damage such as ballooning, acidophilia degeneration, formation of apoptosis bodies and focus of necrosis, but the inflammation in the lobule and portal area was mild. CONCLUSION:The positive rate of TTV DNA among cases of hepatitis was higher than that of donors, especially in patients with non-A non-G hepatitis, but most of them were coinfected with other hepatitis viruses. TTV can infect not only hepatocytes, but also extrahepatic tissues. However, the chief replication place may be liver. The infection of TTV may have some pathogenicity. Although the pathogenicity is comparatively weak, it can still damage the liver tissues.The lesions in acute hepatitis (AH) and chronic hepatitis (CH) are mild, but in severe hepatitis (SH) , it can be very serious and cause liver function failure, therefore, we should pay more attention to TTV when studying the possible pathogens of so-called "liver hepatitis of unknown etiology".

Torque Teno Virus (SANBAN Isolate) ORF2 Protein Suppresses NF-κB Pathways via Interaction with IκB Kinases

“…Since the first isolation of TTV, most studies have shown that it might be relevant to liver disorders and liver damage and have a possible association with fulminant hepatitis, cryptogenic liver disease, non-A-G hepatitis, posttransfusion hepatitis, liver cirrhosis, and hepatocellular carcinoma (11,22,37,41,57,65). At the same time, epidemiological associations of TTV with B-cell lymphoma, Hodgkin's disease, aplastic anemia, idiopathic pulmonary fibrosis, acute respiratory disease, and autoimmune rheumatic disorders have also been described (6,16,29,30,32,52).…”

Replication of TT virus in hepatocyte and leucocyte cell lines

“…Moreover, the liver cell infection is productive, finally resulting in degeneration of infected cells. These findings seem to suggest that the biochemical liver function abnormalities seen in some of the viraemic subjects [Lou et al, 1999;Dai et al, 2001;Hu et al, 2002;Desai et al, 2005] may be a direct result of cellular changes due to viral infection. They also imply that the virus (at least the genotype 1a), has the potential to cause direct cell damage in the liver in case of unrestricted viral replication.…”

“…Also, it may be possible that release of virus in small doses in the extracellular matrix might result in sensitization of the host's immune response to the virus and may be responsible for the chronicity of the infection. Earlier, it has been indicated that TTV may act as a promoter of chronicity and deterioration of acute hepatitis and can affect liver cirrhosis and HCC in cases where the fibrosis is deeply advanced not as a genomic factor but through irregular regeneration [Sioda et al, 2001;Hu et al, 2002]. Altogether the TTV infection of the Chang liver cell line seems to be a valid model to study TTV infection of the liver.…”

“…Current data suggest that though TTV may account for only a small proportion of cryptogenic, non-A-E hepatitis, a pathogenic role in some cases cannot be excluded [Dai et al, 2001;Comar et al, 2002;Hu et al, 2002]. Considering that the virus shows a significant prevalence in the general population [Abe et al, 1999;Desai et al, 1999;Dai et al, 2001], a pathogenic role in only a few cases alludes to a role of host, viral, and environmental factors in determining the clinical course of the infection [Tuveri et al, 2000].…”

Development of an Immunoassay for Detection of Torque Teno Virus (TTV) Antibodies Using the N22 Expression Product from TTV Genotype 2

“…The virus has been detected in nearly all tissues of the body [22]. Several studies point towards its association with liver and renal diseases [23][24][25]. It has also been detected in various types of carcinoma including leukemia and colorectal cancer.…”