Approach to the Patient: Diagnosis of Cushing Syndrome

Abstract

Cushing syndrome results from supraphysiological exposure to glucocorticoids and is associated with significant morbidity and mortality. The pathogenesis includes administration of corticosteroids (exogenous Cushing syndrome) or autonomous cortisol overproduction, whether or not ACTH-dependent (endogenous Cushing syndrome). An early diagnosis of Cushing syndrome is warranted; however, in clinical practice, it is very challenging partly because of resemblance with other common conditions (ie, pseudo-Cushing syndrome). Initial workup should start with excluding local and systemic corticosteroid use. First-line screening tests including the 1-mg dexamethasone suppression test, 24-hour urinary free cortisol excretion, and late-night salivary cortisol measurement should be performed to screen for endogenous Cushing syndrome. Scalp-hair cortisol/cortisone analysis helps in the assessment of long-term glucocorticoid exposure as well as in detection of transient periods of hypercortisolism as observed in cyclical Cushing syndrome. Interpretation of results can be difficult because of individual patient characteristics and hence requires awareness of test limitations. Once endogenous Cushing syndrome is established, measurement of plasma ACTH concentrations differentiates between ACTH-dependent (80%-85%) or ACTH-independent (15%-20%) causes. Further assessment with different imaging modalities and dynamic biochemical testing including bilateral inferior petrosal sinus sampling helps further pinpoint the cause of Cushing's syndrome. In this issue of "Approach to the patient," the diagnostic workup of Cushing syndrome is discussed with answering the questions when to screen, how to screen, and how to differentiate the different causes. In this respect, the latest developments in biochemical and imaging techniques are discussed as well.

Keywords: Cushing’s syndrome; cortisol; diagnosis; glucocorticoids.

Figure 1.

Clinical features and comorbidities associated with Cushing syndrome. Based on Agrawal et al (1), Sharma et al (5), and Pivonello et al (27).

Figure 2.

Diagnostic workup of Cushing syndrome. Flowchart is based on Lacroix et al (3). The likelihood ratios (LRs) for the first-line screening tests and scalp hair analysis concern pooled data from (47) and findings from (48), respectively. LRs take sensitivity and specificity into account and determine the posttest probability given a certain pretest probability (higher LR⁺ = increasing probability of disease with positive test result; lower LR^- = decreasing probability of disease with negative test result). Abbreviations: CBG, cortisol-binding globulin; LR-, negative likelihood ratio; LR+, positive likelihood ratio.

Figure 3.

Sources of ectopic ACTH secretion. Based on Lacroix et al (2).

Figure 4.

(Patho)physiologic changes of hypothalamus-pituitary-adrenal axis during pregnancy. Based on Brue et al (90). Abbreviation: CRH, corticotropin-releasing hormone.