title: Effect of antiviral therapy on the immunohistochemical expression of bcl-xL and bax protein in patients with HBeAg-negative chronic hepatitis B.
abstract: The effect of antiviral treatment on apoptosis in chronic hepatitis B (CHB) has not been clarified. We evaluated the hepatic immunohistochemical expression of the pro-apoptotic bax and the antiapoptotic bcl-xL protein in HBeAg-negative CHB patients before and after treatment. In our study we included 72 paired biopsies from 36 HBeAg-negative CHB patients: 29 treated (interferon-alfa: 17, adefovir: 12) and 7 untreated. Changes in expression of apoptotic proteins (D-bax, D-bcl-xL), necroinflammation and fibrosis (D-grade/D-stage) (Ishak classification) were evaluated. We found that Bax-positive compared to bax-negative biopsies had worse necroinflammation (8.2 vs. 6.7, P = 0.05) and fibrosis score (3.9 vs. 3, P = 0.036). bcl-xL-positive compared to bcl-xL-negative biopsies had lower intralobular inflammation (1.6 vs. 2.2, P = 0.03). Decreased compared to stable/increased D-bax was associated with greater improvement in necroinflammation only in treated patients (D-grade: -4.6 vs. -1.6, P = 0.05) and greater fibrosis improvement in interferon treated patients (D-stage: -0.4 vs. 0.55, P = 0.05). Increased compared to stable/decreased total apoptotic trend [D-apoptosis: (D-bax)-(D-bcl-xL)], was associated with worsening fibrosis, particularly in adefovir treated patients (D-stage: 2.3 vs. 0, P = 0.004). In the 11 patients without significant changes from 1st to 2nd biopsy, increased apoptosis was more frequent in treated than untreated cases (P = 0.046). In multivariate analysis, bax change was independently associated with change of grade (P = 0.038) and antiviral therapy (P = 0.015). In conclusions, in HBeAg-negative CHB, histological improvement after treatment is associated with decreased hepatocyte apoptosis. In patients without substantial histological changes, treatment seems to increase the apoptosis of hepatocytes, thus having a possible protective effect on hepatocarcinogenesis.
authors.affiliation: 2nd Department of Internal Medicine, Hippokration General Hospital, National University of Athens School of Medicine, Athens, Greece. cholongitas@yahoo.gr
authors.forename: Evangelos
authors.initials: E
authors.lastname: Cholongitas
authors.forename: George V
authors.initials: GV
authors.lastname: Papatheodoridis
authors.forename: Emanuel K
authors.initials: EK
authors.lastname: Manesis
authors.forename: Kaliopi
authors.initials: K
authors.lastname: Petraki
authors.forename: Dina
authors.initials: D
authors.lastname: Tiniakos
authors.forename: Stephanos J
authors.initials: SJ
authors.lastname: Hadziyannis
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000328:Adult; D000998:Antiviral Agents / Q000008:administration & dosage*; D017209:Apoptosis / Q000187:drug effects*; D001706:Biopsy; D005260:Female; D005355:Fibrosis / Q000209:etiology / Q000473:pathology; D006513:Hepatitis B e Antigens / Q000032:analysis; D006515:Hepatitis B virus / Q000254:growth & development; D019694:Hepatitis B, Chronic / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000209:etiology / Q000473:pathology; D016898:Interferon-alpha / Q000008:administration & dosage; D008099:Liver / Q000187:drug effects* / Q000473:pathology / Q000821:virology; D008297:Male; D008875:Middle Aged; D063065:Organophosphonates / Q000008:administration & dosage; D012189:Retrospective Studies; D012720:Severity of Illness Index; D051028:bcl-2-Associated X Protein / Q000032:analysis / Q000096:biosynthesis*; D051020:bcl-X Protein / Q000032:analysis / Q000096:biosynthesis*
chemical_list: D000998:Antiviral Agents; D006513:Hepatitis B e Antigens; D016898:Interferon-alpha; D063065:Organophosphonates; D051028:bcl-2-Associated X Protein; D051020:bcl-X Protein; C053001:adefovir; D000225:Adenine