title: Resistance of ground glass hepatocytes to oral antivirals in chronic hepatitis B patients and implication for the development of hepatocellular carcinoma.
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.
authors.affiliation: Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Institute of Clinical Medicine, College of Medicine, National Cheng Kung University, Tainan, Taiwan.|Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Hung-Wen
authors.initials: HW
authors.lastname: Tsai
authors.affiliation: Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Yih-Jyh
authors.initials: YJ
authors.lastname: Lin
authors.affiliation: National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan.
authors.forename: Han-Chieh
authors.initials: HC
authors.lastname: Wu
authors.affiliation: Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan.|Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Ting-Tsung
authors.initials: TT
authors.lastname: Chang
authors.affiliation: Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: I-Chin
authors.initials: IC
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Pin-Nan
authors.initials: PN
authors.lastname: Cheng
authors.affiliation: Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Chia-Jui
authors.initials: CJ
authors.lastname: Yen
authors.affiliation: Department of Statistics, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Shih-Huang
authors.initials: SH
authors.lastname: Chan
authors.affiliation: Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan.|Department of Medical Laboratory Science and Biotechnology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
authors.forename: Wenya
authors.initials: W
authors.lastname: Huang
authors.affiliation: Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan.|National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan.|Department of Biotechnology, Southern Taiwan University of Science and Technology, Tainan, Taiwan.
authors.forename: Ih-Jen
authors.initials: IJ
authors.lastname: Su
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence / Q000235:genetics; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use; D001706:Biopsy; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000473:pathology / Q000601:surgery / Q000821:virology*; D004270:DNA, Circular / Q000378:metabolism; D024882:Drug Resistance, Viral; D005234:Fatty Liver / Q000473:pathology; D005260:Female; D006147:Guanine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D006514:Hepatitis B Surface Antigens / Q000235:genetics; D006515:Hepatitis B virus / Q000302:isolation & purification / Q000502:physiology*; D019694:Hepatitis B, Chronic / Q000097:blood / Q000150:complications / Q000188:drug therapy*; D022781:Hepatocytes / Q000473:pathology* / Q000821:virology; D006801:Humans; D019259:Lamivudine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D008099:Liver / Q000166:cytology / Q000473:pathology*; D008113:Liver Neoplasms / Q000097:blood / Q000473:pathology / Q000601:surgery / Q000821:virology*; D008297:Male; D008875:Middle Aged; D009336:Necrosis; D063065:Organophosphonates / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D011498:Protein Precursors / Q000235:genetics; D017384:Sequence Deletion; D019562:Viral Load / Q000187:drug effects; D055815:Young Adult
chemical_list: D000998:Antiviral Agents; D004270:DNA, Circular; D006514:Hepatitis B Surface Antigens; D063065:Organophosphonates; D011498:Protein Precursors; C050806:presurface protein 1, hepatitis B surface antigen; C050807:presurface protein 2, hepatitis B surface antigen; D019259:Lamivudine; C413685:entecavir; D006147:Guanine; C053001:adefovir; D000225:Adenine
keywords: anti-viral therapy; ground glass hepatocytes; hepatitis B virus; hepatocellular carcinoma; pre-S mutation