Background: There is currently no readily measurable biomarker of glucocorticoid activity in clinical use. We have investigated a ratio between Thrombospondin-1 (TSP1), a matricellular protein and Osteocalcin (OCN), a non-collagenous protein secreted by osteoblasts, known to be up-regulated and down-regulated by glucocorticoids, respectively. The aim was to determine if the TSP1:OCN ratio was useful for the diagnosis of Cushing’s syndrome (CS) and/or as a tool for therapeutic drug monitoring in patients on exogenous glucocorticoids.
Material and Methods: Patients with CS (n=19), asthma or giant cell arteritis on chronic prednisolone treatment (PRED, n=13), primary or secondary adrenal insufficiency (AI, n=16) and healthy controls (HC, n=20) were included in this prospective observational study. We measured plasma TSP1 and serum total OCN (by ELISA) across the day at 8am, 12pm and 4pm in patients with CS, in patients with AI taking their usual substitution therapy, in HC before and after a single 4 mg dexamethasone dose and in patients on PRED measured pre-dose at 8am and 4-hours post-dose at 12pm.
Results: Circulating concentrations of TSP1 in CS were higher (P<0.0001) and OCN were lower (P<0.001) compared to HC. A TSP1:OCN ratio of >73 diagnosed CS with a sensitivity of 95% and a specificity of 100%. The TSP1:OCN ratio in HC increased significantly after 4 mg dexamethasone at all time points (P<0.001) and increased during the day in AI patients after taking their hydrocortisone replacement therapy (P<0.001). Patients on PRED had a higher TSP1:OCN ratio as compared to HC at both 8am and 12pm (P=0.002 and P=0.003), but no significant change was found from pre- to post-dose.
Conclusion: The TSP1:OCN ratio in plasma/serum is a sensitive marker of total body glucocorticoid activity. It is high in patients on PRED and in CS, allowing the identification of patients with CS with high sensitivity and specificity.