Accuracy of the 10 μg desmopressin test for differential diagnosis of Cushing syndrome: a systematic review and meta-analysis

Abstract

We evaluated the accuracy of the 10 μg desmopressin test in differentiating Cushing disease (CD) from non-neoplastic hypercortisolism (NNH) and ectopic ACTH syndrome (EAS). A systematic review of studies on diagnostic test accuracy in patients with CD, NNH, or EAS subjected to the desmopressin test obtained from LILACS, PubMed, EMBASE, and CENTRAL databases was performed. Two reviewers independently selected the studies, assessed the risk of bias, and extracted the data. Hierarchical and bivariate models on Stata software were used for meta-analytical summaries. The certainty of evidence was measured using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation Working Group) approach. In total, 14 studies were included: 3 studies on differentiated CD versus NNH and 11 studies on differentiated CD versus EAS. Considering ΔACTH in 8 studies involving 429 patients, the pooled sensitivity for distinguishing CD from EAS was 0.85 (95% confidence interval [CI]: 0.80-0.89, I2 = 17.6%) and specificity was 0.64 (95% CI: 0.49-0.76, I2 = 9.46%). Regarding Δcortisol in 6 studies involving 233 participants, the sensitivity for distinguishing CD from EAS was 0.81 (95% CI: 0.74-0.87, I2 = 7.98%) and specificity was 0.80 (95% CI: 0.61-0.91, I2 = 12.89%). The sensitivity and specificity of the combination of ΔACTH > 35% and Δcortisol > 20% in 5 studies involving 511 participants were 0.88 (95% CI: 0.79-0.93, I2 = 35%) and 0.74 (95% CI: 0.55-0.87, I2 = 27%), respectively. The pooled sensitivity for distinguishing CD from NNH in 3 studies involving 170 participants was 0.88 (95% CI: 0.79-0.93) and the specificity was 0.94 (95% CI: 0.86-0.97). Based on the desmopressin test for differentiating CD from EAS, considering ΔACTH, Δcortisol, or both percent increments, 15%, 19%, or 20% of patients with CD, respectively, would be incorrectly classified as having EAS. For CD versus NNH, 11% of patients with CD would be falsely diagnosed as having NNH, whereas 7% of patients with NNH would be falsely diagnosed as having CD. However, in all hierarchical plots, the prediction intervals were considerably wider than the confidence intervals. This indicates low confidence in the estimated accuracy, and the true accuracy is likely to be different.

Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=85634, identifier CRD42018085634; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=68317, identifier CRD42017068317.

Keywords: Cushing disease; Cushing syndrome; desmopressin test; non-neoplastic hypercortisolism; pseudo-Cushing syndrome; systematic review.

Figure 1

Flowchart of the identification of eligible studies.

Figure 2

Risk of bias and applicability concerns: authors’ judgment on each domain for all included studies. (A) Desmopressin test to distinguish Cushing disease from non-neoplastic hypercortisolism. (B) Desmopressin test to distinguish Cushing disease from ectopic ACTH syndrome.

Figure 3

(A) Forest plot depicting the sensitivity and specificity considering ACTH percent increment after 10 µg desmopressin test to distinguish Cushing disease from ectopic ACTH syndrome. The figure indicates the estimated sensitivity and specificity of the study (black circle) and its 95% confidence interval (black horizontal line). (B) Summary ROC plots from Stata after fitting the hierarchical model to ACTH percent increment. The circles represent the estimates of individual primary studies, and square indicates the summary points of sensitivity and specificity. HSROC curve is plotted as a curvilinear line passing through summary point. The 95% confidence interval and 95% prediction interval are also provided. HSROC, hierarchical summary receiver operating characteristic.

Figure 4

(A) Forest plot depicting the sensitivity and specificity considering the cortisol percent increment after the 10 µg desmopressin test to distinguish Cushing disease from ectopic ACTH syndrome. Estimated study sensitivity and specificity (black circle); 95% confidence interval (black horizontal line). (B) Summary ROC plots from Stata after fitting the hierarchical model to cortisol percent increment. Circles represent the estimates of individual primary studies, and squares indicate the summary points of sensitivity and specificity. HSROC curve is plotted as a curvilinear line passing through the summary point. The 95% confidence interval and 95% prediction interval are also provided. HSROC, hierarchical summary receiver operating characteristic.

Figure 5

(A) Forest plot depicting the sensitivity and specificity considering the ACTH and cortisol percent increments after the 10 µg desmopressin test to distinguish Cushing disease from ectopic ACTH syndrome. Estimated study sensitivity and specificity (black circle); 95% confidence interval (black horizontal line). (B) Summary ROC plots from Stata after fitting the hierarchical model to ACTH and cortisol percent increment. Circles represent the estimates of individual primary studies, and squares indicate the summary points of sensitivity and specificity. HSROC curve is plotted as a curvilinear line passing through the summary point. The 95% confidence interval and 95% prediction interval are also provided. HSROC, hierarchical summary receiver operating characteristic.

Figure 6

(A) Forest plot depicting the sensitivity and specificity considering the ACTH percent increment after the 10 µg desmopressin test to distinguish Cushing disease from non-neoplastic hypercortisolism. Estimated study sensitivity and specificity (black circle); 95% confidence interval (black horizontal line). (B) Summary ROC plots from Stata after fitting the hierarchical model to ACTH percent increment. Circles represent the estimates of individual primary studies, and squares indicate the summary points of sensitivity and specificity. HSROC curve is plotted as a curvilinear line passing through the summary point. The 95% confidence interval and 95% prediction interval are also provided. HSROC, hierarchical summary receiver operating characteristic.