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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 (␥-H2AX [H2A histone family, member X]), telomere lengths, chromosomal instability (micronuclei index), and senescence-associated ␤-galactosidase (SA-␤-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, ␥-H2AX foci, and net cellular gain were significantly increased from normal hepatocytes, NLCH, LLCC, SLCC, to HCC. The SA-␤-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, ␥-H2AX labeling index, and micronuclei index; shorter telomere length; decreased SA-␤-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;50:752-762.) L iver cell change (dysplasia) is characterized by individually scattered or clusters of hepatocytes with atypia, measuring Ͻ1 mm in diameter which do not form circumscribed nodules (dysplastic nodules), and have been often found in chronic liver disease. 1,2 These lesions have been classified into two types: large liver cell change (LLCC) and small liver cell change (SLCC). SLCC, a lesion first proposed by Watanabe et al. in 1983, Abbreviations: CFI, centromere fluorescence intensity; DAPI, 4,6-diamidine-2-phenylindole; HBV, hepatitis B virus; HCC, hepatocellular From the

Objectives: Large liver cell dysplasia (LCD) is frequently associated with hepatitis B virus (HBV), but it remains uncertain whether it is reactive, senescent or preneoplastic. Methods: The HBX transgenic mice and normal control mice were sacrificed at 1, 3, 5, 7, 9, 11, 13 and 15 months after birth. Twenty-three cases of human B viral chronic hepatitis/cirrhosis with prominent LCD were selected. The immunohistochemical stain of proliferating cell nuclear antigen (PCNA), transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay and senescence-associated β-galactosidase (SA-β-Gal) were evaluated. Results: In HBX transgenic mice, LCD was developed since 3 months and formed small nodules of hepatocellular adenoma, which progressed to hepatocellular carcinoma. The hepatocytes with LCD in HBX transgenic mice showed significantly higher PCNA-labeling index (LI) and lower TUNEL-LI than normal hepatocytes of control mice (p < 0.05). In the majority of human B viral chronic hepatitis/cirrhosis, the hepatocytes with LCD revealed higher PCNA-LI and lower TUNEL-LI than those without, when compared in each case using the same tissue block. SA-β-Gal staining showed no difference between hepatocytes with and without LCD. Conclusion: It is suggested that LCD, related to HBV, might not be just an innocent bystander, but closely related to hepatocarcinogenesis.