Proinflammatory cytokines remain elevated despite long-term remission in Cushing's disease: a prospective study

Context: Inflammation contributes to the development of metabolic and cardiovascular disease. Cushing's disease (CD), a state of chronic glucocorticoid (GC) excess characterized by visceral obesity and insulin resistance, may be associated with increased systemic inflammation. Cardiovascular mortality in CD remains elevated even after successful remission. It is unclear whether a chronic low-grade inflammatory state persists even after remission of CD, which may account for the increased CVD mortality. Purpose: (1) To assess circulating proinflammatory cytokines in patients with active CD and BMI-matched controls; (2) to prospectively follow plasma cytokine concentrations in patients with CD before and after surgical remission; and (3) to assess whether plasma cytokine concentrations correlate with adipose tissue distribution and ectopic lipid content in liver and muscle. Methods: Plasma cytokines from prospectively enrolled patients with CD (N = 31) were quantified during active disease (v1) vs controls (N = 18) and 19·5 ± 12·9 months after surgical remission (v2). Fasting plasma IL-6, IL-1β, TNF-α, IL-8, IL-17 and IL-10 were quantified using a multiplex assay. Total and regional fat masses were measured by whole-body MRI. Results: Circulating IL-6 and IL-1β were elevated in patients with active CD vs controls (P < 0·05) and remained elevated in CD after surgical remission, despite decreases in BMI (P < 0·001), HOMA-IR (P < 0·001), and visceral, hepatic and intermuscular fat (P < 0·001, <0·001 and 0·03, respectively). Conclusions: Despite long-term remission and improvements in fat distribution and insulin sensitivity, patients with CD may suffer from a state of chronic low-grade inflammation, which could contribute to increased cardiovascular mortality.