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Meta-Analysis
. 2022 Jul 14;107(8):2377-2388.
doi: 10.1210/clinem/dgac265.

The Effect of Endogenous Cushing Syndrome on All-cause and Cause-specific Mortality

Padiporn Limumpornpetch  1   2 , Ann W Morgan  1   3   4 , Ana Tiganescu  1 , Paul D Baxter  1 , Victoria Nyawira Nyaga  5 , Mar Pujades-Rodriguez  1 , Paul M Stewart  1   3
Affiliations
Meta-Analysis

The Effect of Endogenous Cushing Syndrome on All-cause and Cause-specific Mortality

Padiporn Limumpornpetch et al. J Clin Endocrinol Metab. .

Abstract

Objective: We aimed to perform a systematic review and meta-analysis of all-cause and cause-specific mortality of patients with benign endogenous Cushing syndrome (CS).

Methods: The protocol was registered in PROSPERO (CRD42017067530). PubMed, EMBASE, CINHAL, Web of Science, and Cochrane Central searches were undertaken from inception to January 2021. Outcomes were the standardized mortality ratio (SMR), proportion, and cause of deaths. The I2 test, subgroup analysis, and meta-regression were used to assess heterogeneity across studies.

Results: SMR was reported in 14 articles including 3691 patients (13 Cushing disease [CD] and 7 adrenal CS [ACS] cohorts). Overall SMR was 3.0 (95% CI, 2.3-3.9; I2 = 80.5%) for all CS, 2.8 (95% CI, 2.1-3.7; I2 = 81.2%) for CD and 3.3 (95% CI, 0.5-6.6; I2 = 77.9%) for ACS. Proportion of deaths, reported in 87 articles including 19 181 CS patients (53 CD, 24 ACS, and 20 combined CS cohorts), was 0.05 (95% CI, 0.03-0.06) for all CS subtypes with meta-regression analysis revealing no differences between CS subtypes (P = .052). The proportion of deaths was 0.1 (10%) in articles published before 2000 and 0.03 (3%) in 2000 until the last search for CS (P < .001), CD (P < .001), and ACS (P = .01). The causes of death were atherosclerotic diseases and thromboembolism (43.4%), infection (12.7%), malignancy (10.6%), active disease (3.5%), adrenal insufficiency (3.0%), and suicide (2.2%). Despite improved outcomes in recent years, increased mortality from CS persists. The causes of death highlight the need to prevent and manage comorbidities in addition to treating hypercortisolism.

Keywords: Cushing syndrome; causes of death; meta-analysis; meta-regression analysis; mortality.

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Figures

Figure 1.
Figure 1.
PRISMA flow diagram detailing articles and cohorts included for systematic review and meta-analysis. CS, Cushing syndrome; PRISMA, Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols; SMR, standardized mortality ratio.
Figure 2.
Figure 2.
Forest plot presenting standardized mortality ratio (SMR) all-cause mortality of all types of Cushing syndrome. ACS, adrenal Cushing syndrome; BAH, bilateral adrenal hyperplasia; CD, Cushing disease.
Figure 3.
Figure 3.
Forest plot of standardized mortality ratio stratified by subgroups of Cushing syndrome (CS) and factors contributing to mortality. The heterogeneity between subgroups analyzed by metan package being taken only from the inverse-variance fixed-effect model. AA, adrenal adenoma; ACS, adrenal Cushing syndrome; BAH, bilateral adrenal hyperplasia; CD, Cushing disease; NA, not applicable.
Figure 4.
Figure 4.
Estimates of the proportion of deaths in subtypes of Cushing syndrome (CS), stratified by published year (before 2000 vs after 2000). NA, not applicable. *, random-effects logistic regression fitted with period of study; ** fixed-effects logistic regression fitted with period of study.
Figure 5.
Figure 5.
Causes of death from all Cushing syndrome (CS) cohorts (n = 64).
See this image and copyright information in PMC

Comment in

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