Histological Damage in Chronic Hepatitis C Is Not Related to the Extent of Infection in the Liver

Rodríguez‐Iñigo, Elena; Bartolomé, Javier; Lucas, Susana de; Manzarbeitia, Félix; Pardo, Margarita; Arocena, C; Gosálvez, Jaime; Oliva, H; Carréño, Vicente

doi:10.1016/s0002-9440(10)65445-4

Cited by 53 publications

(34 citation statements)

References 24 publications

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“…Finally, no differences in either liver enzyme levels or liver damage were found between patients with and those without detectable levels of HCV RNA in serum, indicating that, as occurs in patients with classical chronic HCV infection (16,17), liver damage in occult HCV infection does not depend on HCV RNA serum levels.…”

Section: Discussionmentioning

confidence: 79%

“…Genomic HCV RNA was detected as described previously (7,9,16), with a cRNA probe labeled with digoxigenin 11-UTP obtained by in vitro transcription of pC5ЈNCR, which contains the complete 5Ј noncoding region of the HCV genome. The percentage of infected cells was determined by visual inspection, and at least 2,000 cells from each liver section were counted.…”

Section: Patientsmentioning

confidence: 99%

See 1 more Smart Citation

Ultracentrifugation of Serum Samples Allows Detection of Hepatitis C Virus RNA in Patients with Occult Hepatitis C

Bartolomé

López‐Alcorocho

Castillo

et al. 2007

J Virol

105

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Occult hepatitis C virus (HCV) infection of patients with abnormal liver function tests of unknown originwho are anti-HCV and serum HCV RNA negative but who have HCV RNA in the liver has been described. As HCV replicates in the liver cells of these patients, it could be that the amount of circulating viral particles is under the detection limit of the most sensitive techniques. To prove this hypothesis, serum samples from 106 patients with occult HCV infection were analyzed. Two milliliters of serum was ultracentrifuged over a 10% sucrose cushion for 17 h at 100,000 ؋ g av , where av means average, and HCV RNA detection was performed by strand-specific real-time PCR. Out of the 106 patients, 62 (58.5%) had detectable serum HCV RNA levels after ultracentrifugation, with a median load of 70.5 copies/ml (range, 18 to 192). Iodixanol density gradient studies revealed that HCV RNA was positive at densities of 1.03 to 1.04 and from 1.08 to 1.19 g/ml, which were very similar to those found in the sera of patients with classical chronic HCV infection. The viral genome of hepatitis C virus (HCV) is a 9.6-kb linear single-stranded RNA molecule of positive polarity that replicates via an HCV RNA strand of negative polarity (18).Chronic HCV infection is a progressive disease that may lead to liver cirrhosis and hepatocellular carcinoma (6, 21). The hallmark of chronic hepatitis C is the presence of anti-HCV and HCV RNA in serum for more than 6 months after acute infection. Recently, a new form of chronic HCV infection called "occult HCV infection," characterized by the presence of genomic HCV RNA in liver in the absence of anti-HCV and serum HCV RNA, in patients with abnormal liver function tests of unknown etiology was described (3). In 84% of patients with occult HCV infection, the negative-polarity (antigenomic) HCV RNA strand was also detected in liver, indicating that the virus was replicating. Furthermore, 70% of these patients had HCV RNA in peripheral blood mononuclear cells (PBMCs) (3), and viral replication in these cells was also reported (4).Since HCV replicates in the livers of patients with occult HCV infection, the reason why HCV RNA is not detected in serum is unknown. One possible explanation is that the number of circulating viral particles is too low to be detected even using the most sensitive reverse transcription (RT)-PCR techniques.In the present study, by using ultracentrifugation and a sensitive real-time PCR technique, we have demonstrated that sera from patients with occult HCV infection contain low amounts of viral particles and that the physical characteristics of these virions are similar to those found in patients with classical chronic HCV infection. MATERIALS AND METHODS Patients.One hundred six patients (74 males) with occult HCV infection were analyzed in this study. Patients had abnormal liver function tests, were anti-HCV negative (INNOTEST HCV Ab IV; Innogenetics, Ghent, Belgium), and did not have serum HCV RNA levels tested by real-time RT-PCR (see below). Other causes of liver disease...

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Section: Discussionmentioning

confidence: 79%

Section: Patientsmentioning

confidence: 99%

Ultracentrifugation of Serum Samples Allows Detection of Hepatitis C Virus RNA in Patients with Occult Hepatitis C

Bartolomé

López‐Alcorocho

Castillo

et al. 2007

J Virol

105

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“…39 Kinetic analysis of viral turnover in patients indicated that HCV infection is a highly dynamic process with a short half-life of viral particles and HCV-infected cells. 40 It has been calculated that the daily turnover of HCV-infected cells may be as high as 13% to 25%.…”

Section: Discussionmentioning

confidence: 99%

Caspase activation correlates with the degree of inflammatory liver injury in chronic hepatitis C virus infection

et al. 2001

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Hepatitis C virus (HCV) infection is a major cause of liver disease characterized by inflammation, cell damage, and fibrotic reactions of hepatocytes. Apoptosis has been implicated in the pathogenesis, although it is unclear whether proteases of the caspase family as the central executioners of apoptosis are involved and how caspase activation contributes to liver injury. In the present study, we measured the activation of effector caspases in liver biopsy specimens of patients with chronic HCV infection. The activation of caspase-3, caspase-7, and cleavage of poly(ADP-ribose)polymerase (PARP), a specific caspase substrate, were measured by immunohistochemistry and Western blot analysis by using antibodies that selectively detect the active truncated, but not the inactive precursor forms of the caspases and PARP. We found that caspase activation was considerably elevated in liver lobules of HCV patients in comparison to normal controls. Interestingly, the immunoreactive cells did yet not reveal an overt apoptotic morphology. The extent of caspase activation correlated significantly with the disease grade, i.e., necroinflammatory activity. In contrast, no correlation was observed with other surrogate markers such as serum transaminases and viral load. In biopsy specimens with low activity ( Hepatitis C virus (HCV) infection is one of the major causes of liver disease with an increased risk of cirrhosis and hepatocellular carcinoma. The infection has a high propensity to chronicity, and the majority of HCV carriers have histologic evidence for liver inflammation, cell damage, and fibrotic reactions of hepatocytes. The mechanisms responsible for HCVmediated liver cell damage are poorly understood, and both immune-mediated reactions and direct cytopathic effects of HCV may be involved in its pathogenesis. It has been suggested that apoptosis plays an important role in HCV-associated liver injury, 1-4 although it is unclear which cellular and molecular mechanisms participate in the process.One of the best-defined apoptotic pathways is mediated by the death receptor CD95, a member of the tumor necrosis factor superfamily that is constitutively expressed on hepatocytes. 5 Experiments in mice have shown that agonistic CD95 antibodies cause massive liver cell lysis, resulting in increased serum levels of transaminases and death from fulminant hepatic failure. 6 In patients with chronic HCV infection, expression of CD95 is increased and associated with disease activity and the severity of liver inflammation. 7,8 When HCV-specific T cells migrate towards hepatocytes and recognize viral antigens through the T-cell receptor, they become activated and inducibly express the ligand CD95L that can transduce the apoptotic death signal to CD95-bearing hepatocytes. 2 In addition to CD95L and other cytokines, both structural and nonstructural HCV proteins have been shown to modulate the sensitivity of hepatocytes for cell death. [9][10][11][12][13] Cells undergoing apoptosis show a sequence of morphologic features including membrane...

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“…De Moliner et al reported an association between the levels of viremia and the amount of virus in the liver but no relationship between viral load and ALT level, genotype, or histological diagnosis (2). Likewise, Rodriguez et al demonstrated a significant association between the proportion of infected hepatocytes and viral load but no relationship with the histological activity index (18). Fanning et al, however, noted a weak association (r s ϭ 0.26) between viral load and degree of inflammation but no relationship between viral load and degree of fibrosis or ALT level (4).…”

Section: Discussionmentioning

confidence: 99%

“…The majority of studies have not been able to find any relationship between HCV RNA concentrations and liver fibrosis (2,4,18). However, in a multivariate logistic analysis, Iijima et al noted a significant association between deterioration of the histological stage and amount of HCV viremia though the odds ratio was extremely low (8).…”

mentioning

confidence: 99%

Comparison of Serum Hepatitis C Virus RNA and Core Antigen Concentrations and Determination of Whether Levels Are Associated with Liver Histology or Affected by Specimen Storage Time

Lagging

Garcia²,

Westin

et al. 2002

J Clin Microbiol

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An enzyme immunoassay has recently been developed for the hepatitis C virus (HCV) core antigen. To evaluate the possible association between core antigen and HCV RNA levels with regards to the change in liver histology over time as well as study the effect of duration of storage on viral load results, sequential sera were analyzed from 45 patients with chronic HCV infection who had undergone two or more liver biopsies. A relatively strong association was found between the core antigen and HCV RNA concentrations (r s ‫؍‬ 0.8), with a core antigen level of 1 pg/ml corresponding to approximately 1,000 IU/ml. All 42 sera with detectable HCV RNA at the time of the second biopsy had core antigen concentrations above 1 pg/ml, and the three sera without detectable HCV RNA had concentrations below 1 pg/ml. No association was found between HCV RNA or core antigen levels and the stage of fibrosis in biopsy samples, progression of fibrosis, necro-inflammatory grade, steatosis, genotype, alanine aminotransferase level, or alcohol consumption. A significant association was demonstrated between the storage time of the samples and both the HCV RNA and core antigen concentrations. The median log HCV RNA concentrations (international units/milliliter) were 3.92 for the sera obtained at the time of the first biopsy (median storage time, 13.0 years) and 4.41 for the sera obtained at the time of the second biopsy (median storage time, 6.6 years) compared to 5.96, the median for 102 different routine clinical patient samples.

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Histological Damage in Chronic Hepatitis C Is Not Related to the Extent of Infection in the Liver

Cited by 53 publications

References 24 publications

Ultracentrifugation of Serum Samples Allows Detection of Hepatitis C Virus RNA in Patients with Occult Hepatitis C

Ultracentrifugation of Serum Samples Allows Detection of Hepatitis C Virus RNA in Patients with Occult Hepatitis C

Caspase activation correlates with the degree of inflammatory liver injury in chronic hepatitis C virus infection

Comparison of Serum Hepatitis C Virus RNA and Core Antigen Concentrations and Determination of Whether Levels Are Associated with Liver Histology or Affected by Specimen Storage Time

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