Predictors of mortality and long-term outcomes in treated Cushing's disease: a study of 346 patients

Abstract

Context: Active Cushing's disease (CD) confers a 4-fold increase in mortality and is associated with significant morbidities. Although excess mortality risk may persist even after CD treatment, predictors of risk in treated CD are not well understood.

Objective: To identify predictors of mortality, cardiovascular (CV) disease, and recurrence after long-term follow-up among patients with treated CD.

Design, setting, and patients: A retrospective chart review was conducted to evaluate patients with CD who underwent transsphenoidal adenectomy with a single surgeon.

Outcome measures: Patients were categorized based on disease response after initial treatment. Cox proportional hazard models identified predictors of mortality, recurrence, and CV outcomes in the overall cohort and each subgroup.

Results: Three hundred forty-six subjects were included. Mean age was 39.9 years, and mean duration of follow-up was 6.3 years (range, 1 mo to 30 y). Duration of exposure to excess glucocorticoids, estimated by duration of symptoms before diagnosis until remission was achieved by any means, was 40.0 months. Multivariate analyses demonstrated that duration of glucocorticoid exposure elevated the risk of death (P = .038), as did older age at diagnosis (P = 0.0001) and preoperative ACTH concentration (P = .007). Among patients who achieved remission, depression increased the hazard of death (P < .01). Male sex, age at diagnosis, diabetes, and depression elevated the risk of CV disease (P < .05).

Conclusion: Long-term follow-up of a large cohort of treated patients with CD identified several novel predictors of mortality. These data illustrate the importance of early recognition and treatment of CD. Long-term follow-up, with management of persistent comorbidities, is needed even after successful treatment of CD.

Figure 1.

Study design and classification of patients based on treatment outcomes. A total of 367 patients with CD were screened from retrospective chart review of patients seen and operated on by a single surgeon. After excluding 21 patients from statistical analysis based on ectopic CS, silent ACTH tumors, and lack of definitive CD diagnosis because of inconclusive biochemical testing, 346 subjects were included in the statistical analysis. After surgery, patients were classified into 1 of 3 outcomes: immediate remission vs late remission (based on the need for subsequent postoperative therapy that resulted in endocrine cure of CD) vs persistent disease. Sufficient postoperative laboratory and clinical follow-up were not available for 89 patients in the cohort, and subsequently remission status could not be confirmed for these patients. At the time of most recent biochemical follow-up, patients were classified as overall remission (including immediate and late) vs persistent disease.

Figure 2.

Kaplan-Meier survival curves. Top, Mortality and length of GC exposure in the total cohort. (Because there are no known clinically relevant cutoffs for risk associated with GC exposure, exposure length was arbitrarily divided into tertiles for Kaplan-Meier curve.) Bottom, Mortality and depression in subjects who achieved immediate remission.