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Large liver cell change in hepatitis B virus–related liver cirrhosis†
Article first published online: 11 MAY 2009
Copyright © 2009 American Association for the Study of Liver Diseases
Volume 50, Issue 3, pages 752–762, September 2009
How to Cite
Kim, H., Oh, B.-K., Roncalli, M., Park, C., Yoon, S.-M., Yoo, J. E. and Park, Y. N. (2009), Large liver cell change in hepatitis B virus–related liver cirrhosis. Hepatology, 50: 752–762. doi: 10.1002/hep.23072
Potential conflict of interest: Nothing to report.
- Issue published online: 27 AUG 2009
- Article first published online: 11 MAY 2009
- Accepted manuscript online: 11 MAY 2009 12:00AM EST
- Manuscript Accepted: 6 MAY 2009
- Manuscript Received: 7 JAN 2009
- Korea Science and Engineering Foundation (KOSEF) grant funded by the Korea government (Ministry of Science and Technology). Grant Number: R13-2002-054-03004-0
- SNUBH Research Fund. Grant Number: 11-2008-019
Large liver cell change (LLCC) refers to microscopic lesions often found in various chronic liver diseases; however, its nature is still controversial. Thirty-four formalin-fixed and 19 fresh frozen hepatitis B virus (HBV)-related cirrhosis samples were examined for the presence of LLCC, small liver cell change (SLCC), and hepatocellular carcinoma (HCC). The cell cycle checkpoint status (p21, p27, p16, Tp53), cell dynamics (proliferating cell nuclear antigen, Ki-67, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick-end labeling, M30), DNA damage (γ-H2AX [H2A histone family, member X]), telomere lengths, chromosomal instability (micronuclei index), and senescence-associated β-galactosidase (SA-β-Gal) activity were evaluated using an in situ approach and compared to those in normal liver (n = 5) and liver with chronic cholestasis (34 cases of hepatolithiasis and three cases of primary biliary cirrhosis). In HBV-related cirrhosis, the p21, p27, and p16 cell cycle checkpoint markers were activated in normal-looking cirrhotic hepatocytes (NLCH), but diminished gradually from LLCC, SLCC, to HCC, with an increase in Tp53 expression. There was a general decrease in telomere length from NLCH, LLCC, SLCC, to HCC. Micronuclei, γ-H2AX foci, and net cellular gain were significantly increased from normal hepatocytes, NLCH, LLCC, SLCC, to HCC. The SA-β-Gal activity was weaker in LLCC compared to NLCH and absent in SLCC and HCC. In contrast, cholestatic LLCC showed retained expression of cell cycle checkpoint markers and decreased net cellular gain compared to adjacent normal-looking hepatocytes. HBV-related LLCC showed significantly higher Tp53 labeling index, γ-H2AX labeling index, and micronuclei index; shorter telomere length; decreased SA-β-Gal activity; and increased net cellular gain compared to cholestatic LLCC. Conclusion: The nature of LLCC is rather heterogeneous depending on the biological setting. The characteristics of HBV-related LLCC are more consistent with dysplastic rather than merely reactive hepatocytes, whereas cholestatic LLCC more likely represents reactive change with more stringent cell cycle checkpoint control. (HEPATOLOGY 2009.)