Hepatic expression of cell proliferation markers and growth factors in giant cell hepatitis: implications for the pathogenetic mechanisms involved.
OBJECTIVE
The aim of this study is to determine whether amitotic division or nuclear proliferation is involved in the formation of giant cells (GCs) in giant cell hepatitis (GCH).


METHODS
Liver sections from 18 pediatric patients with idiopathic infantile GCH and 12 patients with postinfantile GCH were evaluated for the expression of proliferating cell nuclear antigen (PCNA) and human histone 3 (H3) mRNA, transforming growth factor-alpha (TGF-α), TGF-β1, hepatocyte growth factor (HGF), and epidermal growth factor receptor (EGFR).


RESULTS
Proliferation markers were detected in 1% to 80% in the nuclei of GC and non-GC hepatocytes in 10 of 18 (56%) infantile GCH biopsies and 11 of 12 (92%) postinfantile GCH biopsies, but not in normal liver. The expression of proliferation markers in GCs paralleled that in non-GC hepatocytes (P < 0.05 for both markers). TGF-α and EGFR were detected in both GCs (9/29 and 4/30 patients with infantile or postinfantile GCH, respectively) and non-GC hepatocytes (15/29 and 11/30 patients with infantile or postinfantile GCH, respectively). TGF-β1 and HGF were detected mainly in sinusoidal cells in 20 of 29 and 10 of 30 patients with infantile or postinfantile GCH, respectively; the expression of HGF was positively correlated with PCNA and H3 mRNA in non-GC hepatocytes and with H3 mRNA in GCs (P < 0.01).


CONCLUSIONS
Hepatic expressions of nuclear proliferation markers and growth factors were similar in infantile and postinfantile GCH, nuclear proliferation markers were detected in both GCs and non-GC hepatocytes in a high proportion of patients, and expression of HGF correlated positively with the proliferation markers. These data indicate that nuclear proliferation may contribute to the pathogenesis of GCs in at least a proportion of patients with GCH. A model for the pathogenesis of GCH is proposed.
Pediatric Hepatology and Liver Transplantation, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, University of Florida and Shands Children's Hospital, Gainesville, FL, USA. janewsfang@aol.com
Jane W S
JW
Fang
Regino P
RP
González-Peralta
Sonny K F
SK
Chong
Grace M
GM
Lau
Gillian M
GM
Lau
Johnson Y N
JY
Lau
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D049109:Cell Proliferation; D002648:Child; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D015726:Giant Cells / Q000378:metabolism* / Q000473:pathology; D006505:Hepatitis / Q000378:metabolism* / Q000473:pathology*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012698:Serologic Tests; D018709:Statistics, Nonparametric; D016211:Transforming Growth Factor alpha / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
D015415:Biomarkers; D006657:Histones; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D016211:Transforming Growth Factor alpha; D016212:Transforming Growth Factor beta; D017228:Hepatocyte Growth Factor; D066246:ErbB Receptors