Issue: 2004 > October > original article

A pilot study exploring the role of glucocorticoid receptor variants in primary biliary cirrhosis and primary sclerosing cholangitis

P.C.J. ter Borg, A. Hagendorf, H.R. van Buuren, J.W. Koper, S.W.J. Lamberts


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 α). Recently a causative role for a splicing variant of the glucocorticoid receptor (hGR β) 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 β mRNA was significantly increased (p=0.02) and hGR α 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 α 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.