Mortality in Cushing's syndrome: A systematic review and meta-analysis

Abstract

Context

Data on mortality associated with Cushing's disease (CD) and Cushing's syndrome (CS) are scarce.

Objective

To perform a systematic review and meta-analysis of mortality studies in patients with CD and CS secondary to a benign adrenal adenoma.

Data sources

A search was performed in seven electronic databases. Sixty-six articles were retrieved for analysis and 7 included in the final study. The main outcome measure was standardized mortality ratio (SMR).

Study eligibility criteria, participants, and interventions

Studies reporting SMR for patients diagnosed with CD and/or CS. Outcomes were stratified by subtype of Cushing's syndrome.

Study appraisal and synthesis methods

Studies were appraised by two authors and were synthesized using a weighted estimate based on the standard error of the SMR.

Results

The weighted mean of SMR for patients with CD was 1.84 (95% confidence interval (CI): 1.28–2.65). CD patients with persistent disease after initial surgery had a SMR of 3.73 (95% CI: 2.31–6.01), whereas mortality of CD patients with initial remission did not differ significantly from the general population (SMR: 1.23 (95% CI: 0.51–2.97)). SMR for patients with a benign adrenal adenoma was 1.90 (95% CI: 0.93–3.91). Age, sex and observation time did not significantly impact mortality.

Conclusions

CD as opposed to CS due to a benign adrenal adenoma is associated with an excess mortality, which is attributed to patients in whom initial surgical cure is not obtained. This underlines the importance of a rigorous and early follow-up of newly operated patients with CD.

Introduction

Cortisol hypersecretion in patients with Cushing's syndrome and Cushing's disease is associated with excess morbidity related to central obesity, insulin resistance, diabetes mellitus, hypertension, hyperlipidemia, and osteoporosis [1], [2]. This also translates into an increased cardiovascular risk profile, which may prevail after biochemical disease remission [3], [4]. Moreo!ver, mental disturbances have been documented in these patients ranging from anxiety to major depression [5]. The immune-suppressive effect of cortisol is also associated with an increased susceptibility to infections [6].

First line treatment for Cushing's disease is surgical removal of the pituitary adenoma, which provides initial cure in 65–95% of patients, but the risk of recurrence is relatively high, i.e. 10–20%, and continues for many years not only in primary care centers but also in specialized centers [7]. Even higher cure rates, i.e. close to 100%, are obtained after surgical removal of benign adrenal adenomas [8], whereas the outcome in patients with adrenal carcinomas and ectopic ACTH-secreting tumors is poor [9]. It is generally assumed that mortality is increased in Cushing's syndrome [9], but the data are conflicting and based on relatively small numbers (N = 49) [10] or selected study populations from tertiary care centers [11]. Since Cushing's syndrome is a rare but debilitating disease it is of particular importance to evaluate available data regarding the outcome of treatment.

We therefore conducted a systematic review and performed a meta-analysis of the quantitative data from published studies on mortality in patients with Cushing's syndrome restricted to Cushing's disease and patients with benign adrenal adenomas. The main outcome measure was the weighted mean standardized mortality ratio, and our analysis also elucidated the clinical significance of achieving immediate cure after initial pituitary surgery in Cushing's disease.