Distinct plasma protein profiles after long-term remission of Cushing's disease

OBJECTIVE: Cortisol excess in Cushing's disease (CD) induces widespread plasma protein alterations, affecting various pathways including coagulation and lipid metabolism. The extent to which these abnormalities normalize during long-term remission remains unclear. DESIGN: Cohort study investigating plasma protein profiles in CD patients before, and during long-term remission. METHODS: EDTA plasma samples of 26 CD patients were collected during active disease and during long-term remission (median 4.4 years, interquartile range 3.3-5.1). Plasma protein profiles were generated using quantitative protein mass spectrometry for 159 proteins, including 21 coagulation-related proteins, 18 complement proteins, 15 transport proteins, and 14 apolipoproteins. Protein levels before and after remission were compared with 80 controls (false discovery rate-adjusted t-test) with similar age and sex distribution. RESULTS: During active CD, 78 out of 159 proteins differed from controls, including 11 coagulation proteins, 10 transport proteins, and 3 apolipoproteins. Gelsolin and extracellular matrix protein-1 were most significantly changed. Following remission, 69 proteins changed significantly relative to active disease, but normalization was incomplete. Of the 78 proteins initially altered, 56 were similar to controls upon remission. After remission, 31 proteins remained different from controls, including coagulation proteins factor IX and factor XIII A chain, apolipoprotein A-II, several complement factors and extracellular matrix protein-1. CONCLUSION: Active CD is associated with profound alterations in plasma protein profiles across various functional domains. Long-term remission is accompanied by substantial, but incomplete normalization of plasma proteins. Sustained plasma protein abnormalities may contribute to persistent morbidities and ongoing adverse health risks after remission of CD.