Irregular regeneration of hepatocytes and risk of hepatocellular carcinoma in chronic hepatitis and cirrhosis with hepatitis-C-virus infection

Shibata, Minoru; Morizane, Toshio; Uchida, Tatsuo; Yamagami, Tomoyuki; Onozuka, Yasushi; Nakano, Masayuki; Mitamura, Keiji; Ueno, Yoshio

doi:10.1016/s0140-6736(97)08002-1

Cited by 114 publications

(83 citation statements)

References 22 publications

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“…30 We did not assess our biopsies for the presence of severe irregular regeneration of hepatocytes, which is considered a powerful histologic predictor of HCC, at least in Japanese patients with chronic viral hepatitis and alcoholic liver disease. 32,33 By logistic regression analysis, we found a clear-cut association between high PCNA-LI, male sex, and high histologic activity in the liver. A correlation between male gender and increased liver cell proliferation status has been previously reported in both non-HCC and HCC patients.…”

Section: Discussionmentioning

confidence: 77%

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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Section: Discussionmentioning

confidence: 77%

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

et al. 2001

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“…Other factors are histologic staging 1 and irregular regeneration of hepatocytes. 12 It has been reported that elevated serum ALT is a risk factor for HCC in patients with cirrhosis. 21,22 Furthermore, IFN was reported to prevent the development of HCC even in the patients for whom the therapy was not effective.…”

Section: Discussionmentioning

confidence: 99%

Analysis of factors affecting the appearance of hepatocellular carcinoma in patients with chronic hepatitis C

Aizawa

Takagi

et al. 2000

Cancer

105

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“…The incidence of HCC has increased substantially in Japan during the past several decades 1,2 and also has increased slightly in the United Kingdom, France, 3,4 and the U.S. 5 These increases in the incidence of HCC have been attributed to the increased numbers of patients with hepatitis C virus (HCV)-associated liver cirrhosis. Several risk factors for the development of HCVassociated HCC have been reported, such as aging, gender, total alcohol intake, 6,7 cirrhosis, 8 irregular regeneration of hepatocytes, 9,10 and HCV genotype. 11,12 Recent studies have indicated that interferon (IFN) treatment can reduce the incidence of HCC.…”

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confidence: 99%

Hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C virus infection

Ohata¹,

Hamasaki²,

Toriyama³

et al. 2003

Cancer

292

220

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BACKGROUNDHepatic steatosis is one of the histopathologic features of chronic hepatitis C. It was reported recently that the expression of hepatitis C virus (HCV) core protein in transgenic mice induced hepatocellular carcinoma (HCC) in association with steatosis. The objective of this study was to determine the relation between hepatic steatosis and hepatocarcinogenesis in patients with chronic HCV infection.METHODSThe authors studied 161 patients with chronic HCV infection who were diagnosed at Nagasaki University Hospital, Nagasaki, Japan, between January 1980 and December 1999. Age, gender, body mass index (BMI), habitual drinking, diabetes mellitus, serum alanine aminotransferase (ALT) level, HCV serotype, serum level of HCV core protein, interferon (IFN) treatment, hepatic fibrosis inflammation, and hepatic steatosis were studied with regard to their significance in the development of HCC using univariate and multivariate analyses.RESULTSThe cumulative incidence rates of HCC were 24%, 51%, and 63% at 5 years, 10 years, and 15 years, respectively. Multivariate analysis identified hepatic steatosis, together with aging, cirrhosis, and no IFN treatment, as independent and significant risk factors for HCC (P = 0.0135, P = 0.0390, P = 0.0068, and P = 0.0142, respectively). In addition, hepatic steatosis was correlated with BMI, serum ALT levels, and triglyceride levels.CONCLUSIONSThe findings of the current study indicate that hepatic steatosis is a risk factor for HCC in patients with chronic HCV infection. Patients with chronic HCV and hepatic steatosis should be monitored carefully for HCC. Cancer 2003;97:3036–43. © 2003 American Cancer Society.DOI 10.1002/cncr.11427

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Irregular regeneration of hepatocytes and risk of hepatocellular carcinoma in chronic hepatitis and cirrhosis with hepatitis-C-virus infection

Cited by 114 publications

References 22 publications

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

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

Analysis of factors affecting the appearance of hepatocellular carcinoma in patients with chronic hepatitis C

Hepatic steatosis is a risk factor for hepatocellular carcinoma in patients with chronic hepatitis C virus infection

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