Oncotarget

Research Papers:

Resistance of ground glass hepatocytes to oral antivirals in chronic hepatitis B patients and implication for the development of hepatocellular carcinoma

Hung-Wen Tsai, Yih-Jyh Lin, Han-Chieh Wu, Ting-Tsung Chang, I-Chin Wu, Pin-Nan Cheng, Chia-Jui Yen, Shih-Huang Chan, Wenya Huang and Ih-Jen Su _

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Oncotarget. 2016; 7:27724-27734. https://doi.org/10.18632/oncotarget.8388

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Abstract

Hung-Wen Tsai1,2,3, Yih-Jyh Lin4, Han-Chieh Wu5, Ting-Tsung Chang3,6, I-Chin Wu6, Pin-Nan Cheng6, Chia-Jui Yen6, Shih-Huang Chan7, Wenya Huang3,8, Ih-Jen Su3,5,9

1Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan

2Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan

3Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan

4Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan

5National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan

6Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan

7Department of Statistics, National Cheng Kung University, Tainan, Taiwan

8Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan

9Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan

Correspondence to:

Ih-Jen Su, e-mail: [email protected]

Keywords: ground glass hepatocytes, pre-S mutation, hepatitis B virus, anti-viral therapy, hepatocellular carcinoma

Received: September 21, 2015     Accepted: March 08, 2016     Published: March 26, 2016

ABSTRACT

Ground glass hepatocytes (GGHs) have been shown to predict the development of hepatocellular carcinoma (HCC). Type I GGH and type II GGH harbor hepatitis B virus (HBV) pre-S1 and pre-S2 deletion mutants, respectively. Whether anti-HBV therapy can inhibit the expression of GGHs and potentially reduce HCC development is explored in this study. Two sets of liver specimens were included: the first contained 31 paired biopsy specimens obtained from chronic HBV patients receiving oral nucleos(t)ide analogue (NA) treatment; the second contained 186 resected liver tissues obtained from HBV-related HCC patients receiving surgery: 82 received NA before surgery and 104 did not. Compared with the baseline biopsy specimens, type I (P=0.527) and type II GGH (P=0.077) were not significantly decreased after 48 weeks of NA treatment in the first set of patients. In the second set, despite suppression of viral load (P<0.001) and periportal necrosis (P=0.006) in treated patients, GGH (P=0.594), cccDNA (P=0.172) and serum pre-S mutants (p=0.401) were not significantly suppressed. A significant decrease of type I (P=0.049) and type II GGH (P=0.029) could only be observed in patients after long duration of treatment (median duration: 4.3 years). In the treated patients, the persisted type II GGH remained an independent variable associated with decreased local recurrence-free survival of HCC (P=0.019) as in non-treated patients (P=0.001). In conclusion, the persistence of GGHs could explain the residual risk of HCC development under anti-HBV treatment. Therefore, intrahepatic GGHs and pre-S mutant are potential additional targets for HCC prevention in patients already receiving anti-HBV treatment.


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