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Proinflammatory cytokines remain elevated despite long-term remission in Cushing's disease: a prospective study
Nirali Shah1, Henry H Ruiz1, Usman Zafar1
1Division of Endocrinology, Metabolism and Diabetes, The Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Insights
Patients with Cushing's disease (CD) show persistent inflammation even after remission, potentially explaining higher cardiovascular risk. This chronic low-grade inflammation may persist despite improved metabolic markers.
Area of Science:
- Endocrinology
- Cardiovascular Medicine
- Immunology
Background:
- Cushing's disease (CD) involves chronic excess glucocorticoids, leading to obesity and insulin resistance.
- CD is linked to increased systemic inflammation and elevated cardiovascular mortality, even post-remission.
- The persistence of low-grade inflammation after CD remission is not well understood.
Purpose of the Study:
- Assess circulating proinflammatory cytokines in active CD patients versus controls.
- Track plasma cytokine levels in CD patients before and after surgical remission.
- Correlate plasma cytokine concentrations with adipose tissue distribution and ectopic fat.
Main Methods:
- Quantified plasma cytokines (IL-6, IL-1β, TNF-α, IL-8, IL-17, IL-10) using multiplex assays.
- Measured total and regional fat mass via whole-body MRI.
- Prospectively analyzed 31 CD patients and 18 controls, with follow-up post-remission.
Main Results:
- Elevated IL-6 and IL-1β in active CD patients compared to controls.
- These cytokines remained elevated post-remission despite reduced BMI, HOMA-IR, and ectopic fat.
- Significant decreases in BMI, HOMA-IR, visceral, hepatic, and intermuscular fat were observed post-surgery.
Conclusions:
- Cushing's disease patients may experience chronic low-grade inflammation post-remission.
- This persistent inflammation could be a factor in elevated cardiovascular mortality.
- Improvements in metabolic markers do not fully resolve the inflammatory state in CD.
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.
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