Approach to the Patient: Diagnosis of Cushing Syndrome

Abstract

Cushing’s syndrome results from supraphysiological exposure to glucocorticoids and is associated with significant morbidity and mortality. The pathogenesis includes administration of corticosteroids (exogenous Cushing’s syndrome) or autonomous cortisol overproduction, whether or not adrenocorticotropin hormone (ACTH) dependent (endogenous Cushing’s syndrome). An early diagnosis of Cushing’s syndrome is warranted, however, in clinical practice very challenging partly due to resemblance with other common conditions (i.e. pseudo-Cushing’s 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’s 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’s syndrome. Interpretation of results can be difficult due to individual patient characteristics and hence requires awareness of test limitations. Once endogenous Cushing’s 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’s syndrome is discussed with answering the questions when to screen, how to screen and how to differentiate the different causes. In this respect, latest developments in biochemical and imaging techniques are discussed as well.

Pitfalls in the Diagnosis and Management of Hypercortisolism (Cushing Syndrome) in Humans; A Review of the Laboratory Medicine Perspective

“…This specimen type is yet to be widely used in clinical practice due to a range of issues, including lack of standardised collection and storage procedures, reference materials and reference intervals, and uncertainty regarding interferents and physiology [ 92 ]. Hair cortisone may improve diagnostic efficiency; however, hair cortisol and cortisone may miss cases in mild Cushing syndrome phenotypes [ 93 , 94 ].…”

“…Therefore, a raised androstenedione is not specific to either organ, but an elevated DHEAS may decrease the chance of an ovarian source [ 13 ]. DHEAS will be raised when hypercortisolism is ACTH-dependent [ 13 , 93 ].…”

The promising role of risk scoring system for Cushing syndrome: Time to reconsider current screening recommendations

“…To complicate matters, patients may present with few clinical or nonspecific features (1,5). Therefore, it is very challenging to diagnose CS in the early stages or in cyclic CS (6)(7)(8).…”

Screening for Cushing’s syndrome: The ‘CS-Screening’ Shiny app

“…Cushing's syndrome (CS) results from supraphysiological exposure to glucocorticoids, due to administration of corticosteroids (exogenous CS) or autonomous cortisol overproduction, whether or not ACTH-dependent (endogenous CS). 1 As CS is associated with significant morbidity and mortality, an early diagnosis of CS is warranted though it is very challenging partly because of similarity with other common conditions (i.e. pseudo-CS).…”

“…2 Users are reminded that synthetic glucocorticoids have the potential to cause similar symptoms as seen in endogenous CS; of note, glucocorticoid use is reportedly the most prevalent cause of CS. 1 If exogenous glucocorticoid use is excluded, then the recommended initial tests for suspected CS include UFC, LNSC or, if the first two are not suitable, the ONDST. 2 If the LNSC test is performed, the app reminds users of the need for two LNSC tests to account for withinindividual variability.…”