Granulocyte-colony stimulating factor induces proliferation of hepatic progenitors in alcoholic steatohepatitis: a randomized trial.
Liver failure is the major cause of death in alcoholic steatohepatitis (ASH). In experimental hepatitis, granulocyte-colony stimulating factor (G-CSF) mobilizes hematopoietic stem cells, induces liver regeneration, and improves survival. We studied the short-term effects of G-CSF on CD34+ stem cell mobilization, liver cell proliferation, and liver function in patients with ASH. Twenty-four patients (mean age 54 years) with alcoholic cirrhosis [Child-Turcotte-Pugh score 10 (7-12)] and concomitant biopsy-proven ASH [Maddrey score 36 (21-60)] were randomized to standard care associated with 5 days of G-CSF (10 microg/kg/day, group A, n = 13) or standard care alone (group B, n = 11). Serial measurement of CD34+ cells, liver tests, cytokines [hepatocyte growth factor (HGF); tumor necrosis factor alpha; tumor necrosis factor-R1; interleukin-6; alfa-fetoprotein], and (13)C-aminopyrine breath tests were performed. Proliferating hepatic progenitor cells [HPC; double immunostaining (Ki67/cytokeratin 7)], histology, and neutrophils were assessed on baseline and day 7 biopsies. Abstinent alcoholic patients with cirrhosis served as controls for immunohistochemistry. G-CSF was well tolerated. At day 7, both CD34+ cells (+747% versus -6%, P < 0.003), and HGF (+212% versus -7%, P < 0.03) increased in group A but not in group B. Cytokines and aminopyrine breath test changes were similar between groups. On repeat biopsy, a >50% increase in proliferating HPC was more frequent in group A than in group B (11 versus 2, P < 0.003). Changes in Ki67+/cytokeratin 7+ cells correlated with changes in CD34+ cells (r = 0.65, P < 0.03). Neutrophils and histological changes were similar in both groups.


CONCLUSIONS
G-CSF mobilizes CD34+ cells, increases HGF, and induces HPC to proliferate within 7 days of administration. Larger trials would be required to determine whether these changes translate into improved liver function.
Department of Gastroenterology and Hepatology, University Hospital, Geneva, Switzerland. laurent.spahr@hcuge.ch
Laurent
L
Spahr
Jean-François
JF
Lambert
Laura
L
Rubbia-Brandt
Yves
Y
Chalandon
Jean-Louis
JL
Frossard
Emiliano
E
Giostra
Antoine
A
Hadengue
D000328:Adult; D000368:Aged; D018952:Antigens, CD34 / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects*; D016207:Cytokines / Q000097:blood; D005235:Fatty Liver, Alcoholic / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D005260:Female; D000069585:Filgrastim; D005500:Follow-Up Studies; D016179:Granulocyte Colony-Stimulating Factor / Q000009:adverse effects / Q000627:therapeutic use*; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D007158:Immunologic Techniques; D053552:Keratin-7 / Q000378:metabolism; D019394:Ki-67 Antigen / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009504:Neutrophils / Q000473:pathology; D011994:Recombinant Proteins; D013194:Staining and Labeling; D013234:Stem Cells / Q000473:pathology*
D018952:Antigens, CD34; D016207:Cytokines; D053552:Keratin-7; D019394:Ki-67 Antigen; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D017228:Hepatocyte Growth Factor; D000069585:Filgrastim