The differential diagnosis and treatment of Cushing's syndrome

National Institute Of Diabetes And Digestive And Kidney Diseases

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Abstract

Early prediction of hypothalamic-pituitary-adrenal (HPA) axis function following transsphenoidal surgery (TSS) can improve patient safety and reduce costs. In a retrospective analysis of129 patients, we measured ACTH and cortisol at extubation following transsphenoidal exploration to predict remission from Cushing's disease (CD) and HPA axis preservation following non-CD surgery. We then obtained serial 6-hourly measurements in CD patients. ACTH and cortisol increased sharply in all patients at extubation. CD patients (n = 101) had lower ACTH values than non-CD patients (110.1 vs 293.1 pg/mL; P < 0.01). In non-CD patients, lower plasma ACTH at extubation predicted the need for eventual corticosteroid replacement (105.8 vs 449.1 pg/mL, P < 0.01). In CD patients, the peak post-extubation cortisol at 6 hours was a robust predictor for nonremission (60.7 vs 219.2 g/dL, P = 0.03). However, normalized early postoperative value (NEPV; the post-extubation values minus the peak preoperative CRH or desmopressin test values) of cortisol reliably distinguished nonremission earlier, at the time of extubation (-6.1 vs 5.9, P = 0.01), and later. Thus, ACTH can predict the need for eventual steroid replacement in non-Cushing's patients. In patients with CD, the NEPV cortisol at extubation robustly predicted nonremission. In general, single adrenocorticotropic hormone (ACTH) measurements have limited ability to distinguish patients with Cushing's disease (CD) from those in remission or with other conditions. In a retrospective analysis of 253 patients, we evaluated changes in ACTH levels before and after transsphenoidal surgery (TSS) to identify trends that could confirm remission from CD. The 223 patients with remission had higher ACTH variability at AM (p=0.02) and PM (p < 0.001) time points compared to non-remission. The non-remission group had a significantly narrower diurnal range compared to remission group (p = < 0.0001). A decrease in plasma ACTH of 50% from mean pre-operative levels predicted CD remission after TSS, especially when using PM values. This suggest that ACTH variability is suppressed in CD, and remission from CD is associated with the restoration of this variability. Furthermore, a decrease in plasma ACTH by 50% or more may serve as a predictor of remission post-TSS. Determining the etiology of ACTH-dependent Cushing's syndrome (CS) is often difficult. The gold standard test, inferior petrosal sinus sampling (IPSS), is expensive and not widely available. In a retrospective study of 328 patients with Cushing's disease (CD) and 78 with ectopic ACTH secretion (EAS), we evaluated the performance of the CRH stimulation test (CRH-ST) and the 8 mg high dose dexamethasone suppression test (HDDST) in distinguishing CD from EAS. The CRH-ST performed better than the HDDST (DA 91%, 95%CI: 87% - 94% vs 75%, 95%CI: 69% - 79%). Optimal response criteria were a 40% increase of ACTH and/or cortisol during the CRH test and a 69% suppression of cortisol during the HDDST. A 40% cortisol increase during the CRH test was the most specific measure, PPV 99%. 74% of subjects had concordant positive CRH test and HDDST results, yielding Se 93%, Sp 98%, DA 95% and PPV 99%, with a pretest likelihood of 85%. A proposed algorithm diagnosed 64% of patients with CD with near perfect accuracy (99%), obviating the need for IPSS. These data confirm that CRH is a valuable tool to correctly diagnose the etiology of ACTH-dependent CS. Its current world-wide unavailability impedes optimal management of these patients.