Citations

Abstract Objective Adrenal adenomas are commonly encountered in clinical practice. To date, population-based data on their impact on cognition, mental health, and sleep are lacking. We aimed to study possible associations between adrenal adenomas and dementia, psychiatric or sleep disorders. Design Population-based cohort study, Olmsted County, MN, 1995-2017. Methods Patients with adrenal adenoma and absent overt hormone excess were age- and sex-matched 1:1 to a referent person without adrenal adenoma. Outcomes were baseline and incident diagnoses of dementia, psychiatric or sleep disorders, assessed using ICD codes. Results Of 1004 patients with adrenal adenomas, 582 (58%) were women, and median age at diagnosis was 63 years. At baseline, and after adjusting for age, sex, education, BMI, and tobacco use, patients with adenoma had higher odds of depression (adjusted odds ratio, aOR: 1.3, 95% CI, 1.1-1.6), anxiety (aOR: 1.4, 95% CI, 1.1-1.8), and substance abuse (aOR: 2.4, 95% CI, 1.7-3.4) compared to referents. During a median follow-up of 6.8 years, and after adjusting for age, sex, socioeconomic status, BMI, tobacco, and substance abuse, patients demonstrated a higher risk of psychiatric and sleep disorders [adjusted hazard ratio (95% CI)]: depression [1.7 (1.3-2.2)], anxiety [1.4, CI (1.1-1.7)], insomnia [1.4 (1.0-1.9)], sleep-related breathing disorders [1.5 (1.1-1.9)], hypersomnias [2.1 (1.0-4.2)], parasomnias [2.1 (1.0-4.2)], and sleep-related movement disorders [1.5 (1.0-2.1)], but not dementia. Conclusions Patients with adenomas demonstrate a higher incidence of psychiatric and sleep disorders, possibly due to the underlying subtle increase in cortisol secretion.

Abstract Objective To assess (1) comorbidities associated with and (2) treatment strategies for patients with adrenal incidentalomas and mild autonomous cortisol secretion (MACS; > 1.8 µg/dL (>50 nmol/L) cortisol level cut-off following the 1 mg dexamethasone suppression test). Design Systematic review and meta-analysis. Methods Seven databases were searched up to July 14, 2022. Eligible studies were (randomized) trials, cohort studies, and cross-sectional studies assessing comorbidities potentially attributable to cortisol excess or mortality in patients with adrenal incidentaloma with or without MACS or the effects of conservative or surgical management of MACS. Random-effects meta-analysis was performed to estimate pooled proportions (with 95% CIs). Results In 30 cross-sectional and 16 cohort studies (n = 17 156 patients in total), patients with MACS had a higher prevalence of diabetes (relative risk [RR] 1.44 [1.23-1.69]), hypertension (RR = 1.24 [1.16-1.32]), and dyslipidemia (RR = 1.23 [1.13-1.34]). All-cause mortality (adjusted for confounders) in patients with MACS, assessed in 4 studies (n = 5921), was increased (hazard ratio [HR] = 1.54 [1.27-1.81]). Nine observational studies (n = 856) and 2 randomized trials (n = 107) suggest an improvement in glucometabolic control (RR = 7.99 [2.95-21.90]), hypertension (RR = 8.75 [3.99-19.18]), and dyslipidemia (RR = 3.24 [1.19-8.82]) following adrenalectomy. Conclusions The present systematic review and meta-analysis highlight the relevance of MACS, since both cardiometabolic morbidities and mortality appeared to have increased in patients with MACS compared to patients with non-functioning incidentalomas. However, due to heterogeneous definitions, various outcomes, selective reporting, and missing data, the reported pooled estimates need to be interpreted with caution. The small number of patients in randomized trials prevents any strong conclusion on the causality between MACS and these comorbidities.

Abstract Objective Frailty, characterized by multi-system decline, increases vulnerability to adverse health outcomes and can be measured using Frailty Index (FI). We aimed to assess the prevalence of frailty in patients with adrenal disorders (based on hormonal sub-type) and examine association between FI and performance-based measures of physical function. Design Multi-centre, cross-sectional study (March 2019-August 2022). Methods Adult patients with adrenal disorders (non-functioning adrenal adenomas [NFA], mild autonomous cortisol secretion [MACS], Cushing syndrome [CS], primary aldosteronism [PA]) and referent subjects without adrenal disorders completed a questionnaire encompassing 47 health variables (comorbidities, symptoms, daily living activities). FI was calculated as the average score of all variables and frailty defined as FI ≥ 0.25. Physical function was assessed with hand grip, timed up-and-go test, chair rising test, 6-minute walk test, and gait speed. Results Compared to referent subjects (n = 89), patients with adrenal disorders (n = 520) showed increased age, sex, and body mass index-adjusted prevalence of frailty (CS [odds ratio—OR 19.2, 95% confidence interval—CI 6.7-70], MACS [OR 12.5, 95% CI 4.8-42.9], PA [OR 8.4, 95% CI 2.9-30.4], NFA [OR 4.5, 95% CI 1.7-15.9]). Prevalence of frailty was similar to referent subjects when post-dexamethasone cortisol was <28 nmol/L and was higher when post-dexamethasone cortisol was 28-50 nmol/L (OR 4.6, 95% CI 1.7-16.5). FI correlated with all measures of physical function (P < .001). Conclusions Whilst frailty prevalence was highest in patients with adrenocortical hormone excess, even patients with NFA demonstrated an increased prevalence compared to the referent population. Future longitudinal studies are needed to evaluate the impact of various management strategies on frailty.

Abstract Primary aldosteronism (PA) is the most common cause of secondary hypertension and is associated with increased morbidity and mortality when compared with blood pressure–matched cases of primary hypertension. Current limitations in patient care stem from delayed recognition of the condition, limited access to key diagnostic procedures, and lack of a definitive therapy option for nonsurgical candidates. However, several recent advances have the potential to address these barriers to optimal care. From a diagnostic perspective, machine-learning algorithms have shown promise in the prediction of PA subtypes, while the development of noninvasive alternatives to adrenal vein sampling (including molecular positron emission tomography imaging) has made accurate localization of functioning adrenal nodules possible. In parallel, more selective approaches to targeting the causative aldosterone-producing adrenal adenoma/nodule (APA/APN) have emerged with the advent of partial adrenalectomy or precision ablation. Additionally, the development of novel pharmacological agents may help to mitigate off-target effects of aldosterone and improve clinical efficacy and outcomes. Here, we consider how each of these innovations might change our approach to the patient with PA, to allow more tailored investigation and treatment plans, with corresponding improvement in clinical outcomes and resource utilization, for this highly prevalent disorder.

Abstract Sparse data are available on the etiology, morphology, clinical presentation, and outcomes of adrenal calcification. In this single-center retrospective study of 540 consecutive patients (median age 65 years, 45% women) with adrenal calcification on computed tomography (December 2017 to January 2021), most were discovered incidentally (472, 87%). The commonest etiology was idiopathic (389, 72%), followed by the adrenal tumor (113, 21%), hemorrhage (29, 5%), and infiltrative disease (7, 1%). Calcified adrenal tumors were predominantly benign (92, 81%) and primarily adenomas (63, 69%), whereas the most common calcified adrenal malignancy (16, 18%) was metastasis (12, 67%). Calcification (unilateral 94%, bilateral 6%) morphology varied from punctate (313, 58%) to coarse (165, 30%), linear/curvilinear (46, 9%), and rim-like (16, 3%). In summary, adrenal calcifications are usually incidentally discovered unilateral, punctate, or coarse lesions of unclear etiology. Most calcified adrenal tumors are benign and <20% malignant or pheochromocytomas.

Abstract Objective Glucocorticoid withdrawal syndrome (GWS) is a scarcely studied phenomenon that complicates the recovery following surgical remission of hypercortisolism. We aimed to characterize the presence and trajectory of glucocorticoid withdrawal symptoms in the postoperative period and to determine presurgical predictors of GWS severity. Design Longitudinal observational study. Methods Glucocorticoid withdrawal symptoms were prospectively evaluated weekly for the first 12 weeks following surgical remission of hypercortisolism. Quality of life (CushingQoL and Short-Form-36) and muscle function (hand grip strength and sit-to-stand test) were assessed at the baseline and at 12 weeks after surgery. Results Prevalent symptoms were myalgias and arthralgias (50%), fatigue (45%), weakness (34%), sleep disturbance (29%), and mood changes (19%). Most symptoms persisted, while myalgias, arthralgias, and weakness worsened during weeks 5-12 postoperatively. At 12 weeks after surgery, normative hand grip strength was weaker than at baseline (mean Z-score delta −0.37, P = .009), while normative sit-to-stand test performance improved (mean Z-score delta 0.50, P = .013). Short-Form-36 Physical Component Summary score worsened (mean delta −2.6, P = .015), but CushingQoL score improved (mean delta 7.8, P < .001) at 12 weeks compared to baseline. Cushing syndrome (CS) clinical severity was predictive of postoperative GWS symptomology. Conclusion Glucocorticoid withdrawal symptoms are prevalent and persistent following surgical remission of hypercortisolism with baseline CS clinical severity predictive of postoperative GWS symptom burden. Differential changes observed in muscle function and quality of life in the early postoperative period may reflect the competing influences of GWS and recovery from hypercortisolism.

MRI–Negative Cushing disease is a very difficult disease to treat medically and surgically. In the past, after negative gland exploration, hemihypophysectomy was commonly performed on the localizing side of inferior petrosal sampling. However, this generally resulted in 50% remission/cure rates. Therefore, other techniques have arisen based on the percent chance of microadenoma tumor being present in the gland. Subtotal gland resection is a technique aimed at removing 75% of the gland that results in a similar chance of remission and a 10% chance of pituitary dysfunction. In this video, the authors demonstrate this important technique for MRI–Negative Cushing disease. The video can be found here: https://thejns.org/doi/abs/10.3171/2023.4.FOCVID2320

Abstract Objective Prospective data on determinants of muscle strength impairment and quality of life in patients with various subtypes and severity of endogenous hypercortisolism are lacking. Design Single-center cross-sectional study, 2019 to 2022. Methods Patients with Cushing syndrome (CS) and mild autonomous cortisol secretion (MACS) were assessed with clinical and biochemical severity scores, muscle function (nondominant hand grip strength and sit-to-stand test), and quality of life (Short Form-36 [SF36] and CushingQoL). Referent subjects were recruited from the local population undergoing abdominal imaging for reasons other than suspected adrenal disorder. Results Of 164 patients, 81 (49%) had MACS, 14 (9%) had adrenal CS, 60 (37%) had pituitary CS, and 9 (5%) had ectopic CS. Median age was 53 years (interquartile range: 42-63 years), and 126 (77%) were women. The SF36 mental component score was similarly low in patients with MACS vs CS, but physical component score was lower in CS when compared to MACS (mean of 34.0 vs 40.5, P = .001). Compared to MACS, patients with CS had lower scores on the standardized CushingQoL (mean of 47.1 vs 34.2, P < .001). Compared to referent subjects, patients with MACS demonstrated reduced muscle strength, similar to patients with CS (mean sit to stand Z-score of −0.47 vs −0.54, P = .822). Clinical severity (r = −0.22, P = .004) but not biochemical severity was associated with sit-to-stand test performance. Conclusions Both patients with overt CS and MACS demonstrate reduced muscle strength and low quality of life. The clinical severity score utilized is associated with both physical and psychosocial components of CushingQoL and with the physical component of SF36.

Abstract Adrenal incidentalomas are adrenal masses detected on imaging performed for reasons other than suspected adrenal disease. In most cases, adrenal incidentalomas are nonfunctioning adrenocortical adenomas but may also require therapeutic intervention including that for adrenocortical carcinoma, pheochromocytoma, hormone-producing adenoma, or metastases. Here, we provide a revision of the first international, interdisciplinary guidelines on incidentalomas. We followed the Grading of Recommendations Assessment, Development and Evaluation system and updated systematic reviews on 4 predefined clinical questions crucial for the management of incidentalomas: (1) How to assess risk of malignancy?; (2) How to define and manage mild autonomous cortisol secretion?; (3) Who should have surgical treatment and how should it be performed?; and (4) What follow-up is indicated if the adrenal incidentaloma is not surgically removed? Selected Recommendations: (1) Each adrenal mass requires dedicated adrenal imaging. Recent advances now allow discrimination between risk categories: Homogeneous lesions with Hounsfield unit (HU) ≤ 10 on unenhanced CT are benign and do not require any additional imaging independent of size. All other patients should be discussed in a multidisciplinary expert meeting, but only lesions >4 cm that are inhomogeneous or have HU >20 have sufficiently high risk of malignancy that surgery will be the usual management of choice. (2) Every patient needs a thorough clinical and endocrine work-up to exclude hormone excess including the measurement of plasma or urinary metanephrines and a 1-mg overnight dexamethasone suppression test (applying a cutoff value of serum cortisol ≤50 nmol/L [≤1.8 µg/dL]). Recent studies have provided evidence that most patients without clinical signs of overt Cushing's syndrome but serum cortisol levels post dexamethasone >50 nmol/L (>1.8 µg/dL) harbor increased risk of morbidity and mortality. For this condition, we propose the term “mild autonomous cortisol secretion” (MACS). (3) All patients with MACS should be screened for potential cortisol-related comorbidities that are potentially attributably to cortisol (eg, hypertension and type 2 diabetes mellitus), to ensure these are appropriately treated. (4) In patients with MACS who also have relevant comorbidities surgical treatment should be considered in an individualized approach. (5) The appropriateness of surgical intervention should be guided by the likelihood of malignancy, the presence and degree of hormone excess, age, general health, and patient preference. We provide guidance on which surgical approach should be considered for adrenal masses with radiological findings suspicious of malignancy. (6) Surgery is not usually indicated in patients with an asymptomatic, nonfunctioning unilateral adrenal mass and obvious benign features on imaging studies. Furthermore, we offer recommendations for the follow-up of nonoperated patients, management of patients with bilateral incidentalomas, for patients with extra-adrenal malignancy and adrenal masses, and for young and elderly patients with adrenal incidentalomas. Finally, we suggest 10 important research questions for the future.