Liver cell apoptosis in chronic hepatitis C correlates with histological but not biochemical activity or serum HCV-RNA levels

Calabrese, Fiorella; Pontisso, Patrizia; Pettenazzo, Elena; Benvegnù, Luisa; Vario, Alessandro; Chemello, Liliana; Alberti, Alfredo; Valente, Marialuisa

doi:10.1053/he.2000.7123

Cited by 136 publications

(121 citation statements)

References 38 publications

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“…In both diseases apoptosis has been recognized as an important feature of liver injury. 37,[52][53][54][55] The present data and a recent study of steatohepatitis patients 56 indicate that the increased TRAIL sensitivity in diseased liver is mediated by the elevated expression of TRAIL receptors. Apoptosis sensitivity might be further enhanced by altered expression profiles of Bcl-2 proteins or other cytotoxic events that might render diseased liver generally more susceptible to injury, regardless of the presence of death ligands.…”

Section: Discussionsupporting

confidence: 62%

Increased hepatotoxicity of tumor necrosis factor-related apoptosis-inducing ligand in diseased human liver

Fischer²,

et al. 2007

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Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in tumor cells but not in most normal cells and has therefore been proposed as a promising antitumor agent. Recent experiments suggested that isolated primary human hepatocytes but not monkey liver cells are susceptible to certain TRAIL agonists, raising concerns about the use of TRAIL in cancer treatment. Whether TRAIL indeed exerts hepatotoxicity in vivo and how this is influenced by chemotherapeutic drugs or liver disease are completely unknown. Employing different forms of recombinant TRAIL, we found that the cytokine can induce proapoptotic caspase activity in isolated human hepatocytes. However in marked contrast, these different TRAIL preparations induced little or no cytotoxicity when incubated with tissue explants of fresh healthy liver, an experimental model that may more faithfully mimic the in vivo situation. In healthy liver, TRAIL induced apoptosis only when combined with histone deacetylase inhibitors. Strikingly, however, TRAIL alone triggered massive apoptosis accompanied by caspase activation in tissue explants from patients with liver steatosis or hepatitis C viral infection. This enhanced sensitivity of diseased liver was associated with an increased expression of TRAIL receptors and up-regulation of proapoptotic Bcl-2 proteins. Conclusion: These results suggest that clinical trials should be performed with great caution when TRAIL is combined with chemotherapy or administered to patients with inflammatory liver diseases.

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Section: Discussionsupporting

confidence: 62%

Increased hepatotoxicity of tumor necrosis factor-related apoptosis-inducing ligand in diseased human liver

Fischer²,

et al. 2007

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“…5 and 6). These results were consistent with a clinical observation, in which up to 0.54% hepatocytes in chronic hepatitis C liver biopsies were found to be TUNEL-positive (Calabrese et al, 2000). Furthermore, the cell deaths observed in these animals were not readily detectable by the routine serum ALT test, a finding reminiscent of that seen in a subset of patients who have active HCV disease, as assessed by HCV RNA levels and liver histopathology, but who also exhibit persistently normal serum ALT values (Calabrese et al, 2000;Rodrigues et al, 2000;Shiffman et al, 2006).…”

Section: Discussionsupporting

confidence: 92%

“…In HCV infection, hepatocyte apoptosis is emerging as an important feature of liver injury (Bantel and SchulzeOsthoff, 2003;Calabrese et al, 2000;Patel et al, 1998;Rodrigues et al, 2000;Walsh et al, 2004). The ensuing responses of cell repair, regeneration and fibrosis may be triggered by this process (Canbay et al, 2004;Takehara et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Cre-estrogen receptor-mediated hepatitis C virus structural protein expression in mice

Tumurbaatar

Sun

Chan

et al. 2007

Journal of Virological Methods

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Hepatocyte apoptosis is an important feature of liver injury in hepatitis C virus (HCV) infection. However, the mechanism of apoptosis and consequences on disease progression in vivo have not been investigated fully in part due to the lack of adequate small animal models. In this study, transgenic (tg) mice were produced that express conditionally HCV structural proteins (core, E1, E2 and p7) in the liver following Cre-mediated DNA recombination. Using a novel Cre-estrogen receptor fusion protein (Cre-ER) induction strategy, tamoxifen was injected intraperitoneally (i.p.), which induced Cre nuclear translocation, transgene recombination and HCV protein expression in the liver. Hepatic expression of HCV core and envelope proteins resulted in increased hepatocyte apoptosis, detected by the TUNEL assay, between 7 and 33 days after induction. These results were confirmed by the presence of increased levels of apoptosis-associated cytokeratin 18 (CK18) in the sera of the same animals. The presence of cleaved caspase-3 and elevated levels of CHOP/GADD153 in the liver suggests an endoplasmic reticulum (ER) stress-associated apoptosis mechanism. This study suggests an in vivo correlation between HCV structural protein expression, ER stress and hepatocyte apoptosis, implicating a potentially important mechanism of HCV pathogenesis.

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“…Furthermore, surrogate markers such as the serum levels of aminotransferases did not significantly correlate with either the histological degree of liver injury or with the immunohistological detection of caspase activation. 26,37,43 As demonstrated by regression analysis, and unlike caspase activation measured in liver biopsies, serological detection of CK-18 fragments generally correlated with both ALT and AST levels. However, a strict correlation is mainly observed for higher CK-18 fragment levels (Ͼ500 U/L), whereas this could not be observed for lower CK-18 fragment levels.…”

Section: Discussionmentioning

confidence: 90%

“…37 We recently demonstrated that caspase activation in HCV-infected liver is not correlated to serum HCV RNA concentration. 25 In accordance with our previous observation, serum caspase activity did not correlate with the viral load in HCV-infected patients (data not shown).…”

Section: Resultsmentioning

confidence: 98%

Detection of apoptotic caspase activation in sera from patients with chronic HCV infection is associated with fibrotic liver injury

Bantel¹,

Lügering²,

Heidemann³

et al. 2004

Hepatology

229

238

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Chronic hepatitis C virus (HCV) infection is characterized by inflammatory liver damageand is associated with a high risk of development of cirrhosis and hepatocellular carcinoma. Although histological examination of liver biopsies is currently the gold standard for the detection of early liver damage, there is a strong need for better noninvasive methods. We recently demonstrated that the proapoptotic activation of caspases is considerably enhanced in histological sections from HCV-infected liver tissue, suggesting an important role of apoptosis in liver damage. Here, we investigated whether caspase activation is detectable also in sera from patients with chronic HCV infection. Using a novel enzyme-linked immunosorbent assay that selectively recognizes a proteolytic neoepitope of the caspase substrate cytokeratin-18, we demonstrate that caspase activity is markedly increased in the sera of HCV patients. Interestingly, while 27% of patients with chronic HCV infection showed normal aminotransferase levels despite inflammatory and fibrotic liver damage, more than 50% of those patients exhibited already elevated serum caspase activity. Moreover, 30% of patients with normal aminotransferase but elevated caspase activity revealed higher stages of fibrosis. In conclusion, compared with conventional surrogate markers such as aminotransferases, detection of caspase activity in serum might be a more sensitive method of detecting early liver injury. Thus, measurement of caspase activity might provide a novel diagnostic tool, especially for patients with normal aminotransferases but otherwise undiagnosed histologically active hepatitis and progressive fibrosis. H epatitis C virus (HCV) is estimated to infect upto 200 million people worldwide-more than 3% of the world population. 1 HCV infection is characterized by inflammatory liver damage and a long viral persistence associated with a high risk of developing cirrhosis and hepatocellular carcinoma. There is increasing evidence suggesting that liver cell damage in chronic HCV infection is mediated by the induction of apoptosis. [2][3][4][5][6] The importance of apoptosis in HCV infection has originally been proposed in view of patho-morphological features, including cell shrinkage and fragmentation of the nucleus-particularly in areas of piecemeal necrosis, the presence of acidophilic bodies, and focal cell dropouts in the liver lobule, which are characteristic features of individually infected hepatocytes. 7 The molecular mechanisms and signal transduction pathways that cause liver cell damage during HCV infection have not been clearly defined. Over the last few years there has been increasing evidence that death receptor/ligand systems, particularly CD95, play a crucial role in liver damage. Both CD95 and its ligand CD95L have been shown to be up-regulated in HCV infection. 8 -11 Various recent studies demonstrate that the key morphological alterations of apoptosis are mediated by a family of intracellular cysteine proteases, called caspases, that cleave several cellul...

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Liver cell apoptosis in chronic hepatitis C correlates with histological but not biochemical activity or serum HCV-RNA levels

Cited by 136 publications

References 38 publications

Increased hepatotoxicity of tumor necrosis factor-related apoptosis-inducing ligand in diseased human liver

Increased hepatotoxicity of tumor necrosis factor-related apoptosis-inducing ligand in diseased human liver

Cre-estrogen receptor-mediated hepatitis C virus structural protein expression in mice

Detection of apoptotic caspase activation in sera from patients with chronic HCV infection is associated with fibrotic liver injury

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