CLINICAL STUDY Mortality in Cushing’s syndrome: data from 386 patients from a single tertiary referral center Maria Yaneva, Krassimir Kalinov 1 and Sabina Zacharieva Clinical Centre of Endocrinology, USHATE ‘Acad. Ivan Penchev’, Medical University, 2, Zdrave Street, Sofia 1431, Bulgaria and 1 New Bulgarian University, res. quarter Ovcha Kupel, 21, Montevideo Street, Sofia 1618, Bulgaria (Correspondence should be addressed to S Zacharieva; Email: zacharieva@uheg.medicalnet-bg.org) Abstract Objective: Data on the incidence, mortality, and causes of death in patients with Cushing’s syndrome (CS) are scarce, due to the rarity of CS. The aim of the study was to analyze mortality in a large cohort of patients of all etiologies and to determine the cause of death. Design: This was a retrospective study of patients with CS, treated over a period of 45 years in the main tertiary referral center in Bulgaria. Methods: Three hundred and eighty-six patients with CS of all etiologies were included. The main outcome measures were the standardized mortality ratio (SMR) and the cause of death. Results: Mean (GS.D.) age at diagnosis was 38G13 years; 84% of patients were women; mean follow-up was 85 months (range: 0–494 months). The SMR in the CS cohort was 4.05 (95% CI 2.50–5.80) (P!0.0001). The following subgroups did not have a significantly increased SMR: patients with Cushing’s disease SMR – 1.88 (95% CI 0.69–4.08), adrenal adenomas 1.67 (95% CI 0.20–6.02), and ACTH-independent bilateral adrenal hyperplasia 1.14 (95% CI 0.21–6.34). Patients with adrenal carcinomas, ectopic CS, and those with CS of undetermined etiology had significantly increased SMR: 48.00 (95% CI 30.75–71.42), 13.33 (95% CI 0.00–24.59), and 4.00 (95% CI 0.48–14.45) respectively (P!0.0001). The significant predictors for mortality were active disease at death, age, male sex, etiology of the disease, and the overall duration of active disease. The major causes of death were vascular events (40%) – cardiovascular 29%, and cerebrovascular 11% – followed by infections (12%). Conclusions: Patients with CS have increased mortality due to vascular events and infections. European Journal of Endocrinology 169 621–627 Introduction Cushing’s syndrome (CS) is a rare condition that has a significant long-term impact on patients’ physical and mental welfare. Recent studies on the epidemio- logy of the disease have demonstrated its low incidence (1.4–2.7/million per year) (1, 2, 3, 4, 5) and a mean standardized mortality ratio (SMR), calculated on the basis of a meta-analysis, of 1.84 for patients with Cushing’s disease (CD) and 1.90 for patients with adrenal adenomas (AA) (6). One study reported SMR data in patients with ectopic adrenocorticotrophic hormone (ACTH)-secretion and ACTH-independent adrenal hyperplasia (4); SMR data in patients with cortisol-secreting adrenal carcinomas have not been reported. Almost all mortality studies in CS have small patient numbers (49–289), which is attributable to the rarity of CS. Moreover, most studies focused only on CD. The aim of this study was to analyze mortality in CS patients in a large cohort of CS patients with different etiologies. To our knowledge, this study includes the largest number of patients treated in a single tertiary center for a significant period of time (45 years). We performed a detailed analysis of the causes of death in our cohort of patients. Subjects and methods Patients A total of 386 patients with proven CS, treated over a period of 45 years, were included. All patients were treated in the Clinical Center of Endocrinology at the Medical University of Sofia, Bulgaria, between 1965 and 2010. All data were obtained from the patients’ medical records. As it was a retrospective audit study, no approval by the local ethics committee was required. The diagnosis of CS was based on the guidelines for diagnosis of the disease that were in force at that time. This varied depending on the time of diagnosis (elevated 17-OH and ketosteroids/elevated urinary free cortisol (UFC); lack of suppression after 2/1 mg dexamethasone (DXM); and disrupted diurnal serum/salivary cortisol cycle). The differential diagnosis was confirmed on the basis of the basal and dynamic tests available at the European Journal of Endocrinology (2013) 169 621–627 ISSN 0804-4643 q 2013 European Society of Endocrinology DOI: 10.1530/EJE-13-0320 Online version via www.eje-online.org