Proliferative activity of hepatocytes in chronic viral hepatitis as revealed by immunohistochemistry for proliferating cell nuclear antigen

Nakamura, Toshitsugu; Hayama, Masayoshi; Sakai, Toshihiko; Hotchi, Masao; Tanaka, Eiji

doi:10.1016/0046-8177(93)90012-6

Cited by 32 publications

(26 citation statements)

References 20 publications

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“…of cell mitotic activity, we assessed the expression of PCNA, which is a well-established marker of cellular proliferative activity. 30,31 3 CAH patients (cases 7, 8, and 12) and in all cirrhotic patients, with the exception of case 21 (Fig. 3).…”

Section: Pcna Expression In Normal Controls and Hcv-re-mentioning

confidence: 87%

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Activation of fetal promoters of insulinlike growth factors II gene in hepatitis C virus-related chronic hepatitis, cirrhosis, and hepatocellular carcinoma

et al. 1996

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Hepatitis C virus (HCV) is a positive-stranded RNA expressed abundantly in most CAH and all cirrhotic pa-virus that plays a major role in the development of tients. Transcripts from fetal P4 promoter were detected chronic liver disease (CLD). 1,2 Acute posttransfusion at high levels in 3 of 9 CAH patients and in the majority hepatitis due to HCV is followed by chronic hepatitis of cirrhotic patients. Increased expression of fetal proin more than 50% of cases, 3,4 and 20% to 50% of these moter-derived transcripts was also found in the liver of patients eventually progress to cirrhosis. 3,5 Mounting HCC patients, although levels were lower than in cirrhoevidence suggests that HCV infection may play a role in the development of hepatocellular carcinoma (HCC) in cirrhotic patients. [5][6][7] Chronic injury of liver cells and Abbreviations: HCV, hepatitis C virus; CLD, chronic liver disease; HCC, the associated inflammatory and regenerative rehepatocellular carcinoma; IGF-II, insulinlike growth factor II; IGF-IR, insusponse that occurs in CLD are known to represent a linlike growth factor type I receptor; RT-PCR, reverse-transcription polymerase chain reaction; CAH, chronic active hepatitis; PCNA, proliferating cell preneoplastic process that may evolve toward malignuclear antigen; PCR, polymerase chain reaction; mRNA, messenger RNA; nancy. [8][9][10] However, the mechanisms responsible for the GAPDH, glyceraldehyde-3-phosphate dehydrogenase.development of HCC in HCV-related CLD are not well Insulinlike growth factor II (IGF-II) is a small pep-2 Cattedra di Gastroenterologia, Facoltà di Medicina e Chirurgia, Università di Napoli ''Federico II''; 3 Dipartimento di Internistica Clinica e Sperimentale, tide that is structurally related to proinsulin and disCattedra di Gastroenterologia; 4 Istituto di Medicina Generale e Metodologia plays multiform effects on cell growth and metaboClinica, Secondo Ateneo di Napoli, Napoli; and the 5 Dipartimento di Fisiopatolism. 11 IGF-II exerts its mitogenic activity through the logia,

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Section: Pcna Expression In Normal Controls and Hcv-re-mentioning

confidence: 87%

“…[15][16][17][18] Each sion of proliferating cell nuclear antigen (PCNA), which is a known marker of cell proliferation. 30,31 promoter is followed by one or more alternative untranslated exons, which are all spliced to the last three…”

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confidence: 99%

Activation of fetal promoters of insulinlike growth factors II gene in hepatitis C virus-related chronic hepatitis, cirrhosis, and hepatocellular carcinoma

et al. 1996

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“…34 The finding of PCNA-positive liver cells clustered near areas of spotty, confluent, or piecemeal necrosis in patients with acute and chronic viral hepatitis 35,36 provides further support to a possible correlation between increased liver cell proliferation rate and high hepatic inflammation scores in patients with chronic liver diseases. [37][38][39][40] Interestingly, HCV-infected livers show a significant correlation between the number of CD8-positive T cells in the lobule, which are pathogenetically involved in HCV-mediated liver cell necrosis, and the hepatocyte proliferation rate, measured by Ki67. 41 In our prospective study a PCNA-LI Ͼ2.0% was the strongest independent predictor of HCC development, followed by older age, alcohol abuse, and higher staging score of liver disease.…”

Section: Discussionmentioning

confidence: 99%

High rates of hepatocellular carcinoma in cirrhotic patients with high liver cell proliferative activity

et al. 2001

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The prevalence, risk factors, and clinical significance of high liver cell proliferative activity were investigated in 208 well-compensated cirrhotic patients (150 men; 50 years; 135 with chronic hepatitis C) who had been under prospective surveillance for hepatocellular carcinoma (HCC) with annual abdominal ultrasound (US) and serum ␣-fetoprotein (AFP) determination. Immunostaining for proliferating cell nuclear antigen (PCNA) was employed to assess liver cell proliferative activity in formalin-fixed, paraffin-embedded liver specimens. The percentage of reactive nuclei was calculated by a computer-assisted image analysis system. The overall PCNA labeling index (LI) ranged from 0.1% to 12.5% (mean, 2.1%), being significantly higher in the 50 patients who developed HCC during 88 ؎ 42 months of follow-up than in the 158 patients who remained cancer-free (3.6% ؎ 2.4% vs. 1.6% ؎ 1.5%; P < .0001). By receiver operating curve (ROC), a 2.0% cut-off value of PCNA-LI discriminated between patients at high and low risk for developing cancer. By multivariate analysis, high histologic grading scores and gender were associated to PCNA LI >2.0%. The yearly incidence of HCC was 5.2% for the 80 patients with PCNA-LI >2.0% compared with 1.1% for the 128 with low PCNA-LI (relative risk, 4.90; 95% CI, 2.63-9.55). By multivariate analysis, PCNA-LI >2.0% was the strongest independent predictor of cancer (hazard ratio, 5.49; 95% CI, 2.90-10.37). Overall, survival was significantly lower in patients with high liver cell proliferative activity rates than in those with low proliferative rates (10% vs. 75%; P < .0001). In conclusion, development of HCC in patients with compensated cirrhosis seems to be reliably predicted by liver cell proliferation status. (HEPATOLOGY 2001;34:523-528.)Cirrhosis is the dominant risk factor for hepatocellular carcinoma (HCC), worldwide. 1 Prospective surveillance programs based on repeat ultrasound (US) examinations of the liver have shown that HCC risk is particularly high in cirrhotic men older than age 50 who have either advanced liver disease or increased serum ␣-fetoprotein (AFP) levels. [2][3][4][5][6][7][8] To improve the effectiveness and cost-benefit ratio of HCC surveillance programs, close monitoring focused on patients with cirrhosis who have this particularly high risk for developing HCC has been considered. 9,10 However, the use of epidemiologic and clinical predictors for the selection of patients to be surveyed would result in an inappropriate loss of target population, because each of these predictors identifies nonoverlapping HCC risk groups. Conversely, assessment of liver cell proliferation, which is a critical step in cancer development, 11,12 might help to better estimate HCC risk at the individual level. Bromodeoxyuridine uptake assay, 13 silver staining of nucleolar organizer region proteins (AgNOR), 14,15 immunostaining of Ki67, 16 and proliferating cell nuclear antigen (PCNA) 17 have been employed for assessing liver cell proliferation in patients with chronic liver diseases, beca...

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“…6 Therefore the proliferative rate of regenerating hepatocytes may be an important pathogenetic and prognostic factor in chronic liver disease. 7 A number of markers have been used in the assessment of the proliferative status of cells, like bromodeoxyuridine, 8 Ki-67 9 and DNA polymerase alpha. 10 Techniques utilizing these markers are complex, however, and require fresh or snap frozen tissue, except for Ki-67, which can be used on paraffin sections.…”

mentioning

confidence: 99%

“…Proliferating cell nuclear antigen (PCNA), an accessory protein of DNA polymerase delta, is one of the best markers for evaluating cell proliferation in studies on retrospective material, since the antigen can be localized in routine formalin-fixed paraffin-embedded tissue. 7,[11][12][13][14] Limited reports are available on the proliferation kinetics of normal human livers, though in recent years several studies reported on hepatocytic proliferation rates in acute and chronic liver diseases. Normal hepatocytes are generally quiescent and divide very slowly.…”

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confidence: 99%

Hepatocytic Proliferation in Chronic Liver Disease: A Study of Liver Biopsies Using Immunohistochemical Localization of Proliferating Cell Nuclear Antigen

1997

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Proliferative activity of hepatocytes in chronic viral hepatitis as revealed by immunohistochemistry for proliferating cell nuclear antigen

Cited by 32 publications

References 20 publications

Activation of fetal promoters of insulinlike growth factors II gene in hepatitis C virus-related chronic hepatitis, cirrhosis, and hepatocellular carcinoma

Activation of fetal promoters of insulinlike growth factors II gene in hepatitis C virus-related chronic hepatitis, cirrhosis, and hepatocellular carcinoma

High rates of hepatocellular carcinoma in cirrhotic patients with high liver cell proliferative activity

Hepatocytic Proliferation in Chronic Liver Disease: A Study of Liver Biopsies Using Immunohistochemical Localization of Proliferating Cell Nuclear Antigen

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