The Nature of Piecemeal Necrosis in Chronic Active Hepatitis

Kerr, Judith; Searle, Jeffrey; Halliday, W. J.; Cooksley, W. G. E.; Halliday, June W.; Holder, Laura; Burnett, W.; Powell, Lawrie W.

doi:10.1016/s0140-6736(79)92178-0

Cited by 113 publications

(43 citation statements)

References 17 publications

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“…[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.…”

Section: H Epatitis C Virus (Hcv) Is Estimated To Infect Upmentioning

confidence: 99%

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

226

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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Section: H Epatitis C Virus (Hcv) Is Estimated To Infect Upmentioning

confidence: 99%

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

226

238

View full text Add to dashboard Cite

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“…At the same time, co-infection increases the persistence of HCV infection and, subsequently, the risk of developing liver disease 30 . As several studies have suggested, liver damage is related mainly to immune mediated mechanisms, with the stimulation of cytotoxic T cell (CTL) response against hepatocytes infected with HCV 9,10,20,32 . This response would lead to hepatocyte lysis and consequent increased release of liver transaminases in plasma.…”

mentioning

confidence: 99%

Influence of human t-cell lymphotropic virus type 1 (HTLV-1) Infection on laboratory parameters of patients with chronic hepatitis C virus

Cardoso¹,

Souza

Fonseca³

et al. 2009

Rev. Inst. Med. trop. S. Paulo

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SUMMARYHepatitis C virus (HCV) and human T-cell lymphotropic virus type 1 (HTLV-1) share routes of transmission and some individuals have dual infection. Although some studies point to a worse prognosis of hepatitis C virus in patients co-infected with HTLV-1, the interaction between these two infections is poorly understood. This study evaluated the influence of HTLV-1 infection on laboratory parameters in chronic HCV patients. Twelve HTLV-1/HCV-coinfected patients were compared to 23 patients infected only with HCV, in regard to demographic data, risk factors for viral acquisition, HCV genotype, presence of cirrhosis, T CD4 + and CD8 + cell counts and liver function tests. There was no difference in regard to age, gender, alcohol consumption, smoking habits, HCV genotype or presence of cirrhosis between the groups. Intravenous drug use was the most common risk factor among individuals co-infected with HTLV-1. These patients showed higher TCD8 + counts (p = 0.0159) and significantly lower median values of AST and ALT (p = 0.0437 and 0.0159, respectively). In conclusion, we have shown that HCV/HTLV-1 co-infected patients differs in laboratorial parameters involving both liver and immunological patterns. The meaning of these interactions in the natural history of these infections is a matter that deserves further studies.

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“…6 Three pathomorphologic features are suggestive of increased apoptosis in the liver of patients with chronic hepatitis C including (1) presence of shrinkage and fragmentation of nucleus/cytoplasm in areas of piecemeal necrosis, (2) presence of acidophilic bodies, and (3) focal cell drop out in the liver lobule. 7,8 Increased expression of Fas, one of the most important members of the tumor necrosis factor family receptors able to transduce the apoptotic signal to programmed cell death, has been described in chronic hepatitis C. Hepatic up-regulation of Fas was found to correlate with more severe inflammation 9 and with ongoing HCV infection. 10 Parallel activation of T lymphocytes expressing Fas ligand was detected in liver infiltrating mononuclear cells, allowing transduction of the apoptotic death signal to Fas-bearing hepatocytes 3 and to proinflammatory activated cells that continuously migrate from extrahepatic sites.…”

mentioning

confidence: 99%

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

et al. 2000

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In hepatitis C virus (HCV) infection, mechanisms responsible for liver cell damage are still poorly understood and both necrosis and apoptosis may be operative. By using terminal deoxynucleotydil transferase-mediated d-UTPbiotin nick-end labeling (TUNEL) we have evaluated and quantified apoptosis in liver biopsy specimens from 61 patients with chronic hepatitis C. All patients had detectable apoptotic cells in the liver. Presence of increased apoptotic activity was confirmed in selected cases by electron microscopy and by DNA gel electrophoresis. The amount of liver cell apoptosis expressed as apoptotic index, ranged between 0.01% to 0.54% and showed a positive correlation with histological activity grading (P F .0005) and with the amount of infiltrating CD8-positive cells (P ‫؍‬ Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma 1 worldwide. The infection has a high propensity to chronicity and the majority of HCV carriers have histological evidence of liver inflammation and chronic damage, although with a very wide spectrum of severity and progression rate. 2 The mechanisms leading to liver cell injury, inflammation, and fibrosis in chronic hepatitis C, are not fully understood. Both immunemediated reactions and more direct cytopathic effects of HCV and of its proteins may be involved. Evidence has been provided that apoptosis of liver cells may play a significant role in the pathogenesis of hepatitis C. [3][4][5] Apoptosis is an active, genetically programmed phenomenon of cell death characterized by a unique sequence of events, with morphological features distinct from necrosis. 6 Three pathomorphologic features are suggestive of increased apoptosis in the liver of patients with chronic hepatitis C including (1) presence of shrinkage and fragmentation of nucleus/cytoplasm in areas of piecemeal necrosis, (2) presence of acidophilic bodies, and (3) focal cell drop out in the liver lobule. 7,8 Increased expression of Fas, one of the most important members of the tumor necrosis factor family receptors able to transduce the apoptotic signal to programmed cell death, has been described in chronic hepatitis C. Hepatic up-regulation of Fas was found to correlate with more severe inflammation 9 and with ongoing HCV infection. 10 Parallel activation of T lymphocytes expressing Fas ligand was detected in liver infiltrating mononuclear cells, allowing transduction of the apoptotic death signal to Fas-bearing hepatocytes 3 and to proinflammatory activated cells that continuously migrate from extrahepatic sites. 11 In addition, both structural and nonstructural HCV proteins have been shown to interact with apoptosis mediators and possibly modulate the active cascade of events leading to programmed cell death. The core protein has shown both proapoptotic or antiapoptotic activities, depending of the experimental conditions and type of cell used, 12-14 whereas both the NS3 15 and the NS5A 16 proteins were shown to have antiapoptotic effects. In this study we have quant...

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The Nature of Piecemeal Necrosis in Chronic Active Hepatitis

Cited by 113 publications

References 17 publications

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

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

Influence of human t-cell lymphotropic virus type 1 (HTLV-1) Infection on laboratory parameters of patients with chronic hepatitis C virus

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

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