Abstract
Cushing's disease recurrence following successful pituitary surgery is common and merits prompt and careful diagnosis, as untreated hypercortisolism leads to increased morbidity and mortality. However, an established recurrence definition has not been forthcoming. This poses a diagnostic challenge especially early in the course of returning hypercortisolemia and/or in the presence of non-neoplastic hypercortisolemia. A late-night salivary cortisol (LNSC) test is the first test to reveal abnormal results, however, has limitations related to assay performance as well as individual patient variability. Dexamethasone suppression tests and 24-h urinary free cortisol (UFC) results are next to reveal abnormal results. Other tests including, corticotropin-releasing hormone (CRH) stimulation test and combined CRH-dexamethasone test, as well as desmopressin stimulation test with/without dexamethasone are also used, although, none have proven to be the preeminent diagnostic test for recurrence determination. There is a possible role for these tests in predicting recurrence in patients who have experienced remission, though, this also remains challenging due to lack of established cutoff values. This article details and summarizes evidence about different diagnostic tests currently used to diagnose and predict Cushing's disease recurrence.
Highlights
Endogenous Cushing’s syndrome (CS) is caused in ∼80% of cases by an adrenocorticotropic hormone (ACTH)-producing pituitary adenoma (Cushing’s disease; CD), in other cases by a cortisol-producing adrenal source and in less frequent cases an ectopic ACTH-secreting neuroendocrine tumor [1,2,3,4].Hypercortisolemia is associated with changes in body composition and metabolic comorbidities such as dyslipidemia, insulin resistance, diabetes mellitus, hypercoagulability, and hypertension [1,2,3,4]
Hypercortisolemia, CD; Adiagnostic Challenge significantly increased after remission by standardized mortality ratios (SMR) of 2.5 compared to general population, mortality risk in the uncontrolled disease population is even higher (SMR 4.6) compared with patients in remission (SMR 1.8, 95% CI 0.95– 3.7) [3]
While disease remission is defined by a low serum cortisol (SC) in the immediate postoperative period [2, 12, 14] and in some studies normal urinary free cortisol (UFC) and normal late-night salivary cortisol (LNSC) [13, 15], there is no clear established definition of CD recurrence
Summary
Endogenous Cushing’s syndrome (CS) is caused in ∼80% of cases by an adrenocorticotropic hormone (ACTH)-producing pituitary adenoma (Cushing’s disease; CD), in other cases by a cortisol-producing adrenal source (adrenal adenoma, hyperplasia, or carcinoma) and in less frequent cases an ectopic ACTH-secreting neuroendocrine tumor [1,2,3,4]. Untreated CS, especially in severe cases, has a poor prognosis and high mortality, with patient survival rates of only 50% after 5 years [5] while treated disease has a much better prognosis [3]. Various studies on rates of CD remission using different criteria have been undertaken and a summary is shown in Supplemental Table 1. While disease remission is defined by a low serum cortisol (SC) in the immediate postoperative period [2, 12, 14] and in some studies normal UFC and normal LNSC [13, 15], there is no clear established definition of CD recurrence. Recurrence Recurrence Mean or median criteria (%) time to recurrence (range), months
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