Distribution of hepatitis C virus RNA in the liver and its relation to histopathological changes

Abstract

To investigate a cellular mode of HCV‐infection in the liver and its pathological implications in relation to histopathological changes or clinical data, we studied the distribution of HCV‐RNA in the livers of 21 patients with HCV‐related chronic liver disease (chronic active hepatitis, 14 cases; cirrhosis, 7 cases) using the in situ hybridization technique. In situ hybridization was performed on 4% paraformaldehyde‐fixed frozen sections with digoxigenin‐labeled DNA probe deduced from the core region of HC–J4. In situ hybridization showed positive signals in the liver specimens of 20/21 cases. The signals were localized in the cytoplasm of hepatocytes. The distribution pattern of positive cells was individually different, whereas the pattern was identical in the right and left lobes. There were no correlations of the HCV‐positive cell number with serum aminotransferase levels at biopsy or with genotypes of HCV. The positive hepatocytes were occasionally associated with infiltrating mononuclear cells, and they were sparsely distributed in the area of piecemeal necrosis. These findings suggest that factors such as host immunoreaction to the virus may be more important than its direct cytopathy in the pathogenesis of chronic hepatitis C virus infection.

Immunohistochemical detection of C-100 hepatitis C virus antigen in formaldehyde-fixed paraffin-embedded liver tissue. Correlation with serum, tissue and in situ RT-PCR results

“…In a previous paper, (Biagini et al, 2001), we emphasize the lack of clear correlation between HCV RNA molecular detection methods in biologic samples of patients with chronic hepatitis C, thus confirming the literature data (Akyol et al, 1992;Bresters et al, 1994;Negro and Hadengue, 1997;Scheuer et al, 1997;Dries et al, 1999;Chang et al, 2000). Moreover, our findings based on in situ RT-PCR approach revealed a nuclear detection of HCV RNA as previously described by several authors (Haruna et al, 1993;Nouri-Aria et al, 1993;Cho et al, 1996;Walker et al, 1998), but in discrepancy with others studies showing a cytoplas- mic localization (Tanaka et al, 1993;Tang et al, 1995;Kojima et al, 1996;Lau et al, 1996;Sansonno et al, 1996;Sansonno et al, 1997;Bettinger et al, 1999;Ohishi et al, 1999;Chang et al, 2000;Rodriguez-Inigo et al, 2000).…”

“…everal studies based on the detection of hepatitis C virus (HCV) RNA or virus-related proteins in formaldehyde-fixed paraffin-embedded liver biopsies have been already reported. These studies used reverse transcriptase-polymerase chain reaction (RT-PCR) performed on extracted RNA (Guerrero et al, 1997;Svoboda-Newman et al, 1997;Dries et al, 1999;Soguero et al, 2000), in situ hybridization (Haruna et al, 1993;Nouri-Aria et al, 1993;Tang et al, 1995;Cho et al, 1996;Felgar et al, 1996;Kojima et al, 1996;Sansonno et al, 1996;Sansonno et al, 1997;Ohishi et al, 1999;Chang et al, 2000;Rodriguez-Inigo et al, 2000), in situ RT-PCR (Lidonnici et al, 1995;Nuovo, 1998;Walker et al, 1998;Biagini et al, 2001) and immunohistochemistry (IMH) (Gonzalez-Peralta et al, 1994;Komminoth et al, 1994;Chamlian et al, 1996;Vartanian et al, 1996;Kawamura et al, 1997;Moriya et al, 1997;Muramarsu et al, 1997;Brody et al, 1998;Yasui et al, 1998;Errington et al, 1999;Gomez et al, 1999;Kim et al, 1999;Nakopoulo et al, 1999;Nayak and Sathar, 1999;Wölk et al, 2000). Analysis of the corresponding data concerning the intracellular localization of HCV RNA and proteins revealed controversial results.…”

“…Most studies located HCV constituents in cytoplasm of hepatocytes (Gonzalez-Peralta et al, 1994;Komminoth et al, 1994;Tang et al, 1995;Sansonno et al, 1996;Vartanian et al, 1996;Sansonno et al, 1997;Bettinger et al, 1999;Nakopoulo et al, 1999;Ohishi et al, 1999;Chang et al, 2000;Rodriguez-Inigo et al, 2000;Wölk et al, 2000) whereas some other works described a cytoplasmic and/or nuclear localization (Haruna et al, 1993;Nouri-Aria et al, 1993;Lidonnici et al, 1995;Chamlian et al, 1996;Cho et al, 1996;Felgar et al, 1996;Kawamura et al, 1997;Morimoto et al, 1997;Moriya et al, 1997;Brody et al, 1998;Walker et al, 1998;Errington et al, 1999;Kim et al, 1999;Nayak and Sathar, 1999). Furthermore, no significant correlation between diagnosis, in situ detection of viral RNA and immunohistochemical results has been frequently described (Kojima et al, 1996;Vartanian et al, 1996;Negro and Hadengue, 1997;Scheuer et al, 1997;Dries et al, 1999;Gomez et al, 1999;Biagini et al, 2001). In addition, conflicting results on the correlation between serum and hepatic HCV RNA detected in tissue extracts or in situ RT-PCR and IMH have been underlined (Gonzalez-Peralta et al, 1994;Lidonnici et al, 1995;Gomez et al, 1999).…”

Hepatitis C virus genotype 4 with normal transaminases: histological changes, schistosomiasis and response to treatment

“…Some authors attributed this to the ultimate increase in ALT during the natural course of the disease [14]. While others suggested that ALT levels are released by direct virus-related cytopathic activity and/or by an immune-mediated process that is less activated in patients with PNALT [15]. Less likely, the clinical outcome of HCV infection can be influenced by the HCV genotype and/or to a lower degree of viral replication [16].…”