Does ursodeoxycholic acid mediate immunomodulatory and anti-inflammatory effects in patients with primary sclerosing cholangitis?
OBJECTIVE
Therapy with ursodeoxycholic acid (UDCA) has been reported to be associated with improvements in abnormal serum biochemical liver tests in patients with primary sclerosing cholangitis (PSC). To evaluate further the effects of UDCA on this disease, we evaluated immunological markers and indices of inflammation during a one-year, prospective, open-label trial of UDCA therapy in patients with PSC.


METHODS
Seventeen PSC patients were enrolled for one year of treatment with UDCA 12-15 mg/kg/day. Serum biochemical variables, immunological markers and indices of inflammation were compared before and at the end of therapy and 4 months after treatment had been withdrawn. Liver histology and immunohistochemistry for human leucocyte antigen (HLA) class I/II and intercellular adhesion molecule 1 (ICAM-1) expression were compared before and at the end of therapy.


RESULTS
UDCA treatment was associated with significant improvements in serum biochemical liver tests, immunoglobulin levels and blood coagulation factors. Tumour necrosis factor alpha (TNF-alpha) production after in vitro whole-blood phytohaemagglutinin (PHA) stimulation was increased, but unaltered by UDCA therapy. Baseline serum levels of interleukin-6 (IL-6) and soluble IL-2 receptor were normal, and serum IL-8 levels were increased, but none of these variables was significantly affected by UDCA therapy. Liver histological stage/grade and HLA class I/II and ICAM-1 expression on biliary epithelial cells and hepatocytes were not markedly altered by UDCA therapy.


CONCLUSIONS
UDCA therapy in PSC patients was associated with a decrease in cholestasis, but no consistent improvement in hepatic inflammation, fibrosis or histological stage of the disease. Immunomodulatory effects of UDCA in PSC do not appear to be HLA-restricted.
van Milligen de Wit
A W
AW
Department of Gastroenterology and Hepatology, Academic Medical Centre, Amsterdam, The Netherlands.
Kuiper
H
H
Camoglio
L
L
van Bracht
J
J
Jones
E A
EA
Tytgat
G N
GN
van Deventer
S J
SJ
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000328:Adult; D000893:Anti-Inflammatory Agents / Q000627:therapeutic use*; D015415:Biomarkers / Q000097:blood; D001779:Blood Coagulation Factors / Q000032:analysis; D002756:Cholagogues and Choleretics / Q000627:therapeutic use*; D015209:Cholangitis, Sclerosing / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D005260:Female; D005500:Follow-Up Studies; D005786:Gene Expression Regulation; D015395:Histocompatibility Antigens Class I / Q000097:blood / Q000235:genetics; D000949:Histocompatibility Antigens Class II / Q000097:blood / Q000235:genetics; D006801:Humans; D007136:Immunoglobulins / Q000097:blood; D007150:Immunohistochemistry; D018799:Intercellular Adhesion Molecule-1 / Q000097:blood / Q000235:genetics; D015850:Interleukin-6 / Q000097:blood; D016209:Interleukin-8 / Q000097:blood; D008099:Liver / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D015375:Receptors, Interleukin-2 / Q000097:blood; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use*
D000276:Adjuvants, Immunologic; D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D001779:Blood Coagulation Factors; D002756:Cholagogues and Choleretics; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; D007136:Immunoglobulins; D015850:Interleukin-6; D016209:Interleukin-8; D015375:Receptors, Interleukin-2; D014409:Tumor Necrosis Factor-alpha; D018799:Intercellular Adhesion Molecule-1; D014580:Ursodeoxycholic Acid