Hypercortisolemia Recurrence in Cushing's Disease; a Diagnostic Challenge

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.

Keywords: Cushing; Cushing's disease; Cushing's syndrome; diagnostic testing; hypercortisolemia; recurrence; remission.

Figure 1

Chronological changes of recurrent hypercortisolemia in Cushing's disease. Overt hypercortisolemia is characterized by abnormal circadian rhythm which can be assessed by LNSC, impaired feedback shown by lack of suppression of ACTH/cortisol after dexamethasone, and increased levels of bioavailable cortisol measured by UFC. After TSS, patients with persistent disease will retain these abnormalities while they will resolve in the ones who experience remission, who will also have low post-TSS serum cortisol (remission) or normalized during the first ~25 days post-op (delayed remission). Residual neoplastic corticotrophs may be identified during remission or early recurrence by DDAVP/Dex-DDAVP and potentially by CRH/Dex-CRH. Abnormal circadian rhythm is the first abnormality that appears after recurrence, followed by impaired cortisol feedback, and finally by overt hypercortisolemia. DDAVP testing for hypercortisolemia is rarely performed in the United States. ACTH, adrenocorticotropic hormone; CRH, corticotropin releasing hormone stimulation test; DDAVP, desmopressin stimulation test; Dex-DDAVP, desmopressin stimulation test after low-dose dexamethasone suppression test; Dex-CRH, corticotropin releasing hormone stimulation test after low-dose dexamethasone suppression test; LNSC, late-night salivary cortisol; ODST, overnight dexamethasone suppression test; UFC, 24-h urinary free cortisol; TSS, transsphenoidal surgery.

Figure 2

Clinical suspicion of recurrent Cushing's Syndrome (2, 12, 78). DDAVP, desmopressin stimulation test; Dex-DDAVP, desmopressin stimulation test after low-dose dexamethasone suppression test; Dex-CRH, corticotropin releasing hormone stimulation test after low-dose dexamethasone suppression test; LNSC, Late-night salivary cortisol; ODST, overnight dexamethasone suppression test; UFC, 24-h urinary free cortisol.