A pilot study exploring the role of glucocorticoid receptor variants in primary biliary cirrhosis and primary sclerosing cholangitis
BACKGROUND: In primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) significant therapeutic effects of glucocorticoids have not been documented. The most important clinical problem in patients with these diseases is fatigue, which is occasionally invalidating. Abnormalities in the hypothalamo-pituitary-adrenal axis have been suggested as a cause of fatigue. Most effects of glucocorticoids are mediated by the glucocorticoid receptor (hGR alpha). Recently a causative role for a splicing variant of the glucocorticoid receptor (hGR beta) has been proposed in glucocorticoid resistance in asthma and ulcerative colitis, whereas another splicing variant (hGR P) might be associated with glucocorticoid-resistant haematological malignancies. The aims of the present pilot study were to assess abnormalities in glucocorticoid receptor expression and to relate these abnormalities to the development of fatigue and to disease activity and severity in autoimmune cholestatic liver disease. METHODS: Five fatigued and five nonfatigued patients with PBC or PSC were included, and the results were compared with healthy controls. RESULTS: The expression of hGR P was not different from controls, but hGR beta mRNA was significantly increased (p=0.02) and hGR alpha mRNA decreased (p=0.015). There were no significant differences between fatigued and nonfatigued patients. A significant negative correlation between the serum activity of alkaline phosphatase and hGR alpha and hGR P mRNA was found. CONCLUSION: Although there was no relation with fatigue, abnormalities in hGR expression appear to occur in patients with these diseases, and may play a role in its pathophysiology and the poor response to glucocorticoid treatment.
|Keywords||Adult, Aged, Case-Control Studies, Cholangitis, Sclerosing/genetics/*metabolism/physiopathology, Fatigue/etiology, Female, Humans, Leukocytes, Mononuclear, Liver Cirrhosis, Biliary/genetics/*metabolism/physiopathology, Male, Middle aged, Pilot Projects, RNA, Messenger/*metabolism, Receptors, Glucocorticoid/genetics/*metabolism|
Hagendorf, A., van Buuren, H.R., Koper, J.W., Lamberts, S.W.J., & ter Borg, P.C.J.. (2004). A pilot study exploring the role of glucocorticoid receptor variants in primary biliary cirrhosis and primary sclerosing cholangitis. Netherlands Journal of Medicine. Retrieved from http://hdl.handle.net/1765/10371