Discriminative capacity of volumetry by CT scan to identify autonomous cortisol secretion in incidental adrenal adenomas

Context Incidentally discovered adrenal adenomas are common. Assessment for possible autonomous cortisol excess (ACS) is warranted for all adrenal adenomas given the association with increased cardiometabolic disease. Objective To evaluate the discriminatory capacity of three-dimensional volumetry on computed tomography (CT) to identify ACS. Design, Setting, Patients Two radiologists, blinded to hormonal levels, prospectively analyzed CT images on 149 adult patients with unilateral, incidentally-discovered, adrenal adenomas. Main Outcome Measures Diameter and volumetry of the adenoma, volumetry of the contralateral adrenal gland, and the adenoma volume-to-contralateral gland volume (AV/CV) ratio were measured. ACS was defined as cortisol≥1.8 mcg/dL after 1mg dexamethasone suppression test (DST) and a morning ACTH ≤15 pg/mL. Results We observed that ACS was diagnosed in 35 (23.4%) patients. Cortisol post-DST was positively correlated with adenoma diameter and volume, and inversely correlated with contralateral adrenal gland volume. Cortisol post-DST was positively correlated with the AV/CV ratio (r=0.46, p<0.001) and ACTH was inversely correlated (r=-0.28, p<0.001). The AV/CV ratio displayed the highest Odds Ratio (1.40 CI 95% 1.18-1.65) and area under curve (0.91 CI 95% 0.86-0.96) for predicting ACS. An AV/CV ratio ≥1 (48% of the cohort) had a sensitivity of 97% and a specificity of 70% to identify ACS. Conclusions CT volumetry of adrenal adenomas and contralateral adrenal glands has a high discriminatory capacity to identify ACS. The combination of this simple and low-cost radiological phenotyping can supplement biochemical testing to substantially improve the identification of ACS.

Enhanced performance of a modified diagnostic test of primary aldosteronism in patients with adrenal adenomas

Objective: Primary aldosteronism (PA) is the commonest cause of endocrine hypertension ranging from 4.6%-16.6% according to the diagnostic tests employed. The aim of this study was to compare the traditional saline infusion test (SIT) with the modified post-dexamethasone SIT (DSIT) by applying both tests on the same subjects. Methods: We studied 68 patients (72% hypertensives) with single adrenal adenoma and 55 normotensive controls, with normal adrenal imaging. Serum cortisol, aldosterone and plasma renin concentration (PRC) were measured and the aldosterone-to-renin ratio (ARR) was calculated. Using the mean+2SD values from the controls, we defined the upper normal limits (UNL) for cortisol, aldosterone and PRC for both the SIT and DSIT. Results: In the controls, the post-DSIT aldosterone levels and the ARR were approximately 2-fold and 3-fold lower respectively than the corresponding post-SIT values (all p=0.001) leading to lower cut-offs of aldosterone suppression. Applying these cut-offs to patients with adrenal adenomas, the prevalence of PA was 13.2% following the SIT and 29.4% following the DSIT, respectively. In addition, 54.5% of patients with PA had concomitant autonomous cortisol secretion. Targeted treatment of PA resulted in resolution of hypertension and restoration of normal secretory aldosterone dynamics. Conclusions: The DSIT improves the diagnostic accuracy of PA, allowing for the detection of milder forms of PA in patients with adrenal adenomas. This is of particular importance as such patients may be at an increased risk for developing cardiovascular and renal morbidity that could be enhanced in the presence of concomitant autonomous cortisol secretion.

Predictors of Tumour Growth and Autonomous Cortisol Secretion Development during Follow-Up in Non-Functioning Adrenal Incidentalomas

Purpose: To assess the risk of developing autonomous cortisol secretion (ACS) and tumour growth in non-functioning adrenal incidentalomas (NFAIs). Methods: Multicentre retrospective observational study of patients with NFAIs. ACS was defined as serum cortisol >1.8 µg/dL after 1 mg-dexamethasone suppression test (DST) without specific data on Cushing’s syndrome. Tumour growth was defined as an increase in maximum tumour diameter >20% from baseline; and of at least 5 mm. Results: Of 654 subjects with NFAIs included in the study, both tumour diameter and DST were re-evaluated during a follow-up longer than 12 months in 305 patients. After a median follow-up of 41.3 (IQR 24.7–63.1) months, 10.5% of NFAIs developed ACS. The risk for developing ACS was higher in patients with higher serum cortisol post-DST levels (HR 6.45 for each µg/dL, p = 0.001) at diagnosis. Significant tumour growth was observed in 5.2% of cases. The risk of tumour growth was higher in females (HR 10.7, p = 0.004). Conclusions: The frequency of re-evaluation with DST in NFAIs during the initial 5 years from diagnosis can probably be tailored to the serum cortisol post-DST level at presentation. Re-evaluation of NFAIs with imaging studies, on the other hand, seems unnecessary in most cases, particularly if the initial imaging demonstrates features specific to typical adenoma, given the low rate of significant tumour growth.

Assessment of Plasma-Free Cortisol Concentrations by LC-MS/MS in Patients with Autonomous Cortisol Secretion

Autonomous cortisol secretion (ACS) of an adrenal incidentaloma (AI) is associated with mild cortisol excess that could result in poor metabolic and cardiovascular outcomes. The biological activity of glucocorticoids depends on the unbound, free fraction. We aimed to evaluate plasma free cortisol (FC) concentrations in patients with ACS in this cross-sectional study. One hundred and ten AI patients in 3 groups; non-functioning (NFA, n=33), possible ACS (n=65), ACS (n=12) were enrolled. Following measurements were conducted: Clinical data and total serum cortisol (TC), plasma corticotrophin (ACTH), serum dehydroepiandrosterone sulfate (DHEA-S), cortisol after 1 mg dexamethasone by both immunoassay and LC-MS/MS (DexF), serum corticosteroid binding globulin (CBG), plasma dexamethasone concentration [DEX] and plasma FC by LC-MS/MS. Patients with ACS featured an unfavorable metabolic profile. Plasma [DEX] and serum CBG levels were similar between groups. Plasma FC was significantly higher in ACS when compared to NFA and possible ACS groups p<0.05 and p<0.01, respectively. In multiple regression analysis DexF (beta=0.402, p<0.001) and CBG (beta=−0.257, p=0.03) remained as the independent predictors of plasma FC while age, sex, BMI, smoking habit, and existing cardiovascular disease did not make a significant contribution to the regression model. In conclusion, the magnitude of cortisol excess in ACS could lead to increased plasma FC concentrations. Further studies in AI patients are needed to demonstrate whether any alterations of cortisol affinity for CBG exist and to establish whether plasma FC concentrations predict the unfavorable metabolic profile in ACS.

Aldosterone-producing nodules and CYP11B1 signaling correlate in primary aldosteronism

Autonomous cortisol secretion (ACS) could be found in some patients with unilateral primary aldosteronism (uPA). However, the histopathological patterns of uPA with concurrent ACS has not been well elucidated. The adrenal gland with the adenoma from 61 uPA patients who underwent unilateral adrenalectomy were assessed by immunohistochemistry. Bioinformatics analysis, including the Cancer Genome Atlas (TCGA) and Kyoto Encyclopedia of Genes and Genomes (KEGG), was applied. The prevalence of multiple aldosterone-producing nodules or micronodules (mAPN/mAPM) was 65.6% (40/61) among our uPA patients. Concurrent ACS was identified in 32% of this uPA cohort; they were associated with the interaction of larger tumor size (> 1.98 cm) and mAPN/mAPM (OR= 3.08, p= 0.004). Transcriptome analysis uncovered a dominant enrichment of HSD3B7 over-expression (p= 0.004) in the adenomas of the histopathologically classical adrenal uPA lesions with concomitant mAPN/mAPM, compared with those uPA adenomas without concurrent surrounding mAPN/mAPM. We identified a novel linkage of enhanced steroidogenic genes of HSD3B7 expression concurrent with downstream higher CYP11B1 expression; further relationship was confirmed by immunohistochemical staining and validated by TCGA bioinformatics. The presence of mAPN/mAPM in uPA patients had lower rate for biochemical success after adrenalectomy (p=0.047). In summary, two thirds of uPA patients had concomitant mAPN/mAPM; 1/3 of uPA patients had concurrent ACS. Steroidogenic HSD3B7/ CYP11B1 signaling was associated with uPA adenomas with surrounding mAPN/mAPM. Interaction of larger adenoma size with the presence of mAPN/mAPM was linked to co-existent ACS. Such uPA patients with concomitant mAPN/mAPM had lower rate of biochemical success.