Tumor necrosis factor-alpha and transforming growth factor-beta reflect severity of liver damage in primary biliary cirrhosis.
OBJECTIVE
The pathogenesis of primary biliary cirrhosis (PBC) is unknown. The role of cytokines such as tumor necrosis factor-alpha (TNF-alpha) and transforming growth factor-beta (TGF-beta), and the effect of ursodeoxycholic acid (UDCA) in modifying the cytokine environment in patients with PBC has remained largely unstudied. Our aims were to determine: (i) the relationship between serum levels of TNF-alpha and TGF-beta and the severity of PBC; and (ii) the effects of UDCA therapy on TNF-alpha and TGF-beta levels in patients with PBC.


METHODS
We studied 90 patients who had been treated with UDCA (53 patients) or placebo (37 patients) for 2 years as part of a randomized, double-blind, controlled trial. Patients were divided into histological stage I/II or stage III/IV disease. Serum TNF-alpha and TGF-beta levels were quantified by enzyme-linked immunoabsorbent assay.


RESULTS
Baseline levels of TNF-alpha were significantly greater in patients with stage III/IV compared to stage I/II disease. After 2 years of treatment with UDCA, patients showed a significantly greater decrease in TNF-alpha levels and progression risk score compared to placebo-treated patients. TNF-alpha and TGF-beta levels were significantly reduced compared to baseline levels in the UDCA-treated group after 2 years, while there was no significant change in the levels of placebo-treated patients.


CONCLUSIONS
Serum TNF-alpha and TGF-beta levels may reflect severity of disease in patients with PBC. The beneficial effects of UDCA therapy may be explained by lowering serum levels of these two cytokines.
Neuman
Manuela
M
Division of Clinical Pharmacology, Sunnybrook and Women's Health Sciences Center, University of Toronto, Toronto, Ontario, Canada. manuela@sten.sunnybrook.utoronto.ca
Angulo
Paul
P
Malkiewicz
Izabella
I
Jorgensen
Roberta
R
Shear
Neil
N
Dickson
E Rolland
ER
Haber
Julia
J
Katz
Gady
G
Lindor
Keith
K
D000328:Adult; D015415:Biomarkers / Q000097:blood; D001706:Biopsy; D002756:Cholagogues and Choleretics / Q000627:therapeutic use*; D015209:Cholangitis, Sclerosing / Q000097:blood / Q000473:pathology; D004311:Double-Blind Method; D005260:Female; D006526:Hepatitis C / Q000097:blood / Q000473:pathology; D006801:Humans; D008099:Liver / Q000473:pathology*; D008105:Liver Cirrhosis, Biliary / Q000097:blood / Q000188:drug therapy / Q000473:pathology*; D008108:Liver Diseases, Alcoholic / Q000097:blood / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016212:Transforming Growth Factor beta / Q000097:blood*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis*; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use*
D015415:Biomarkers; D002756:Cholagogues and Choleretics; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; D014580:Ursodeoxycholic Acid