Decreasing fibrogenesis: an immunohistochemical study of paired liver biopsies following lamivudine therapy for chronic hepatitis B.
BACKGROUND
Activation of hepatic stellate cells is the earliest step in fibrogenesis. Alpha-smooth muscle actin (alpha-SMA), expressed by activated hepatic stellate cells, and C-terminal procollagen alpha1(III) propeptide (PIIICP) are early markers of fibrogenesis and should precede fibrosis.


OBJECTIVE
Determine if suppression of hepatitis B virus replication with lamivudine would decrease fibrogenesis as measured by immunohistochemical markers.


METHODS
Paired liver biopsies from patients with hepatitis B before and after therapy with lamivudine (n=47) or placebo (n=33) were studied. alpha-SMA and PIIICP were detected in paraffin-embedded tissue by immunohistochemistry and quantified in a blinded manner by video imaging analysis.


RESULTS
Liver biopsies from patients treated with lamivudine showed a significant decrease in alpha-SMA expression (1.06+/-0.23 vs. 0.58+/-0.11, pre vs. post, P<0.05). Placebo recipients had increased levels of alpha-SMA (0.82+/-0.14 vs. 1.32+/-0.21, P<0.05). PIIICP was similarly decreased after lamivudine. Among subjects whose Histologic Activity Index fibrosis score was unchanged or worsened, the mean change in alpha-SMA expression was significantly decreased in the lamivudine group compared with placebo.


CONCLUSIONS
Lamivudine decreased markers of hepatic stellate cell activation and collagen synthesis. Immunohistochemical techniques are sensitive for assessing fibrogenesis and will be useful in trials of antiviral and antifibrotic agents.
Kweon
Y O
YO
University of North Carolina, CB# 7080, Room 708, Burnett-Womack Building, Chapel Hill, NC 27599, USA.
Goodman
Z D
ZD
Dienstag
J L
JL
Schiff
E R
ER
Brown
N A
NA
Burchardt
E
E
Schoonhoven
R
R
Brenner
D A
DA
Fried
M W
MW
Burkhardt
E
E
D000199:Actins / Q000378:metabolism; D000328:Adult; D001706:Biopsy; D024061:Collagen Type III / Q000378:metabolism; D005260:Female; D019694:Hepatitis B, Chronic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007150:Immunohistochemistry; D019259:Lamivudine / Q000627:therapeutic use*; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D008297:Male; D008875:Middle Aged; D009130:Muscle, Smooth / Q000378:metabolism; D011347:Procollagen / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use*
D000199:Actins; D024061:Collagen Type III; D011347:Procollagen; D018894:Reverse Transcriptase Inhibitors; D019259:Lamivudine