Mild autonomous cortisol secretion: pathophysiology, comorbidities and management approaches.

The majority of incidentally discovered adrenal tumours are benign adrenocortical adenomas and the prevalence of adrenocortical adenomas is around 1-7% on cross-sectional abdominal imaging. These can be non-functioning adrenal tumours or they can be associated with autonomous cortisol secretion on a spectrum that ranges from rare clinically overt adrenal Cushing syndrome to the much more prevalent mild autonomous cortisol secretion (MACS) without signs of Cushing syndrome. MACS is diagnosed (based on an abnormal overnight dexamethasone suppression test) in 20-50% of patients with adrenal adenomas. MACS is associated with cardiovascular morbidity, frailty, fragility fractures, decreased quality of life and increased mortality. Management of MACS should be individualized based on patient characteristics and includes adrenalectomy or conservative follow-up with treatment of associated comorbidities. Identifying patients with MACS who are most likely to benefit from adrenalectomy is challenging, as adrenalectomy results in improvement of cardiovascular morbidity in some, but not all, patients with MACS. Of note, diagnosis and management of patients with bilateral MACS is especially challenging. Current gaps in MACS clinical practice include a lack of specific biomarkers diagnostic of MACS-related health outcomes and a paucity of clinical trials demonstrating the efficacy of adrenalectomy on comorbidities associated with MACS. In addition, little evidence exists to demonstrate the efficacy and safety of long-term medical therapy in patients with MACS.

High prevalence of venous thrombotic events in Cushing's syndrome: data from ERCUSYN and details in relation to surgery.

OBJECTIVE: The aim of this study was to evaluate the prevalence of venous thromboembolism (VTE) in patients included in the European Registry on Cushing's syndrome (ERCUSYN), compare their clinical characteristics with those who did not develop VTE and identify risk factors for VTE. DESIGN: A retrospective observational cohort study. METHODS: Data extraction from the registry was taken on February, 7, 2022. At the time there were 2174 patients diagnosed with Cushing's syndrome (CS) and 95 VTEs were reported in the database. RESULTS: Of 95 VTE events 70 (74%) were in pituitary-dependent CS patients, 12 (12.5%) in adrenal-dependant CS, 10 (10.5%) in ectopic CS, and 3 (3%) in CS due to other causes. Sex, 24-hour urinary free cortisol (UFC) value at diagnosis, as well as the number of operations remained statistically significant predictors of VTE. Of patients who were treated with at least one surgery, 12 (13%) VTE occurred before and 80 (87%) after the surgery. Nearly half of these VTEs occurred within six months since the operation (36; 45%). Over half of the centers that reported VTE did not routinely anticoagulate CS patients. Anticoagulation schemes varied widely. CONCLUSION: Patients with CS have an elevated risk of developing VTE for an extended period of time. From ERCUSYN cohort patients have higher risk for VTE if they need multiple surgeries to treat CS, are males and have high UFC values at the diagnosis of CS. Since there is no agreement on thromboprohpylaxis, a protocol for VTE prevention that is widely adopted appears to be necessary for patients with CS.

Cushing's Syndrome Is Associated With Early Medical- and Surgical-Related Complications Following Total Joint Arthroplasty: A National Database Study.

BACKGROUND: Cushing's syndrome (CS) is a disorder characterized by exposure to supraphysiologic levels of glucocorticoids. The purpose of this study was to evaluate the association between CS and postoperative complication rates following total joint arthroplasty (TJA). METHODS: Patients diagnosed with CS undergoing TJA for degenerative etiologies were identified from a large national database and matched 1:5 to a control cohort using propensity scoring. Propensity score matching resulted in 1,059 total hip arthroplasty (THA) patients with CS matched to 5,295 control THA patients and 1,561 total knee arthroplasty (TKA) patients with CS matched to 7,805 control TKA patients. Rates of medical complications occurring within 90 days of TJA and surgical-related complications occurring within 1 year of TJA were compared using odds ratios (ORs). RESULTS: The THA patients with CS had higher incidences of pulmonary embolism (OR 2.21, P = .0026), urinary tract infection (UTI) (OR 1.29, P = .0417), pneumonia (OR 1.58, P = .0071), sepsis (OR 1.89, P = .0134), periprosthetic joint infection (OR 1.45, P = .0109), and all-cause revision surgery (OR 1.54, P = .0036). The TKA patients with CS had significantly higher incidences of UTI (OR 1.34, P = .0044), pneumonia (OR 1.62, P = .0042), and dislocation (OR 2.43, P = .0049) and a lower incidence of manipulation under anesthesia (MUA) (OR 0.63, P = .0027). CONCLUSION: CS is associated with early medical- and surgical-related complications following TJA and a reduced incidence of MUA following TKA.

Possible, probable, and certain hypercortisolism: A continuum in the risk of comorbidity.

Hypercortisolism may be considered as a continuum in terms of both hormonal and cardiometabolic abnormalities. It ranges from cases with "normal" hormonal profile and low to intermediate risk of comorbidity to florid cases with clear clinical and hormonal evidence of glucocorticoid excess and clearly increased cardiometabolic risk. Even in patients with nonfunctioning adrenal incidentaloma (NFAI), defined as adrenal incidentaloma with normal results on the currently available hormonal test for evaluation of hypercortisolism, cardiometabolic and mortality risk is higher than in the general population without adrenal lesions. Mild hypercortisolism or autonomous cortisol secretion (ACS) is a term used for patients with adrenal incidentaloma and pathological dexamethasone suppression test (DST) results, but without specific clinical signs of hypercortisolism. It is widely known that this condition is linked to higher prevalence of several cardiometabolic comorbidities, including diabetes, hypertension, osteoporosis and metabolic syndrome, than in patients with NFAI or without adrenal tumor. In case of overt Cushing's syndrome, cardiovascular risk is extremely high, and standard mortality ratio is high, cardiovascular disease being the leading cause of death. The present review summarizes the current evidence for a detrimental cardiometabolic profile in patients with possible (NFAI), probable (ACS) and certain hypercortisolism (overt Cushing's syndrome).

Prevalence of Functioning Adrenal Incidentalomas: A Systematic Review and Meta-analysis.

CONTEXT: Adrenal hyperfunction is associated with an increased risk of cardiometabolic complications in subjects with adrenal incidentaloma (AI). Reliable prevalence estimates of functioning AIs are important to direct resources allocations. OBJECTIVE: To assess the prevalence of autonomous/possible autonomous cortisol secretion (ACS), primary aldosteronism (PA), pheochromocytoma (PHEO), and Cushing syndrome (CS) in patients with AI. METHODS: We performed a comprehensive search of multiple databases (PubMed, Ovid MEDLINE, Web of Science) for potentially relevant studies without language restriction, up to February 2022. Of the 1661 publications evaluated at title and abstract levels, 161 were examined as full text and 36 were included. Study level clinical data were extracted by 3 independent reviewers. RESULTS: The overall prevalence of functioning AIs was 27.5% (95% CI 23.0, 32.5). ACS/possible ACS, with a prevalence of 11.7% (95% CI 8.6, 15.7), was the most frequent hormonal alteration, while PA occurred in 4.4% of the patients (95% CI 3.1, 6.2). Subgroup analysis showed that PA was more prevalent in patients from Asia than in patients from Europe/America; in contrast, ACS/possible ACS had a lower prevalence in Asian countries. At meta-regression analysis, the prevalence of ACS/possible ACS was influenced by the proportion of female patients, while the prevalence of PA was positively associated with the proportion of patients with hypertension and the publication year. Finally, PHEO and CS prevalence were 3.8% (95% CI 2.8, 5.0) and 3.1% (95% CI 2.3, 4.3) respectively. CONCLUSION: This meta-analysis provides extensive data on the prevalence of functioning AIs and the factors affecting heterogeneity in prevalence estimates.

Pneumocystis pneumonia in patients with Cushing's syndrome: A French multicenter retrospective study.

OBJECTIVE: Pneumocystis pneumonia (PcP) is an opportunistic infection occurring in immunocompromised patients. Cushing's syndrome (CS) impairs the immune system, and several authors have reported PcP in patients with CS. The present study aimed to characterize PcP occurring in a CS context and its management in French tertiary centers, in order to highlight the similarities in clinical presentation and treatment according to whether prophylaxis is implemented or not. METHODS: This was a multicenter retrospective study conducted in several French University Hospitals and Cancer Centers. Patients with PcP and confirmed CS regardless of etiology were included. We excluded patients with other known causes of acquired immunodeficiency with increased risk of PcP. RESULTS: Twenty-five patients were included. CS etiology was neoplastic in 84.0% of cases. CS clinical presentation associated predominant catabolic signs (76.0%), hypokalemia (91.7%) and lymphopenia (89.5%). CS was intense in most patients, with mean plasma cortisol levels at diagnosis of 2.424±1.102nmol/L and urinary free cortisol>10× the upper limit of normal in 85.0%. In all patients, PcP onset followed introduction of cortisol blockers, at a median 5.5 days. Patients were treated with 1 to 3 cortisol blockers, mainly metyrapone (88%), which significatively lowered plasma cortisol levels to 667±541nmol/L at the onset of PcP (P<0.001). PcP occurred in 7 patients despite prophylaxis. Finally, 60.0% patients were admitted to intensive care, and 20.0% died of PcP. CONCLUSION: High mortality in patients with PcP implies that clinicians should be better informed about this rare infectious complication. Prophylaxis remains controversial, requiring comparative studies.

Susceptibility and characteristics of infections in patients with glucocorticoid excess or insufficiency: the ICARO tool.

Objective: Registry data show that Cushing's syndrome (CS) and adrenal insufficiency (AI) increase mortality rates associated with infectious diseases. Little information is available on susceptibility to milder forms of infections, especially those not requiring hospitalization. This study aimed to investigate infectious diseases in patients with glucocorticoid disorders through the development of a specific tool. Methods: We developed and administered the InfeCtions in pAtients with endocRinOpathies (ICARO) questionnaire, addressing infectious events over a 12-month observation period, to 1017 outpatients referred to 4 University Hospitals. The ICARO questionnaire showed good test-retest reliability. The odds of infection (OR (95% CI)) were estimated after adjustment for confounders and collated into the ICARO score, reflecting the frequency and duration of infections. Results: In total, 780 patients met the inclusion criteria: 43 with CS, 32 with adrenal incidentaloma and mild autonomous cortisol secretion (MACS), and 135 with AI, plus 570 controls. Compared to controls, CS was associated with higher odds of urinary tract infections (UTIs) (5.1 (2.3-9.9)), mycoses (4.4 (2.1-8.8)), and flu (2.9 (1.4-5.8)). Patients with adrenal incidentaloma and MACS also showed an increased risk of UTIs (3.7 (1.7-8.0)) and flu (3.2 (1.5-6.9)). Post-dexamethasone cortisol levels correlated with the ICARO score in patients with CS. AI was associated with higher odds of UTIs (2.5 (1.6-3.9)), mycoses (2.3 (1.4-3.8)), and gastrointestinal infections (2.2 (1.5-3.3)), independently of any glucocorticoid replacement dose. Conclusions: The ICARO tool revealed a high prevalence of self-reported infections in patients with glucocorticoid disorders. ICARO is the first of its kind questionnaire, which could be a valuable tool for monitoring infections in various clinical settings.

Epidemiology and blood parameter changes in Cushing's syndrome - a population-based study.

PURPOSE: To provide complete epidemiological data on Cushing's syndrome (CS) with analysis and differentiation of biochemical parameters, including blood count indices and serum inflammation-based scores. METHODS: Clinical records of 35 patients diagnosed with CS between 2008 and 2020 at Malta's only central National Health Service hospital were retrospectively analyzed. Detailed clinical and biochemical data were obtained for each patient. Correlation and receiver operator characteristics (ROC) curve analyses were used to establish a threshold value for different variables to predict malignant CS. RESULTS: Standardized incidence rate (SIR) (/million/year) of CS was 4.5, and SIR of Cushing's disease (CD) was 2.3, 0.5 for ectopic CS, 1.5 for cortisol secreting adrenal adenoma, and 0.3 cases for cortisol-producing ACC. Malignant cause of CS had statistically significantly higher cortisol levels and size of tumor and lower potassium at diagnosis (P < 0.001). Additionally, malignant causes had a higher neutrophil-to-lymphocyte ratio (NLR) (P = 0.001) and systemic immune inflammation index (P = 0.005) and a lower lymphocyte-to-monocyte ratio (P < 0.001). Using ROC curve analysis to predict malignant cause of CS, a potassium level of < 3.05 was 75% sensitive and 100% specific (ROC-AUC 0.907, P = 0.001), a post-ODST cortisol level of > 841 nmol/L was 100% sensitive and 91% specific (ROC-AUC 0.981, P < 0.001), while a NLR ratio > 3.9 was 100% sensitive and 57.7% specific (ROC-AUC 0.885, P = 0.001). CONCLUSION: Biochemical and blood count indices and serum inflammatory-based scores differ remarkably between benign and malignant causes of endogenous CS. Such indices can help predict the severity of disease and prognosis.

Prevalence and phenotype of primary bilateral macronodular adrenal hyperplasia with autonomous cortisol secretion: a study of 98 patients.

AIM: This study evaluated prevalence of primary bilateral macronodular adrenal hyperplasia (PBMAH). It also analyzed the differential phenotype of patients with PBMAH compared to other bilateral adrenal lesions that do not meet the definition of PBMAH. METHODS: We reviewed the medical records of 732 patients diagnosed with an adrenal incidentaloma at our center. Ninety-eight patients with subclinical hypercortisolism were included in the analysis. We defined PBMAH as the presence of plasma cortisol > 1.8 µg/dL after an over-night 1-mg dexamethasone test, bilateral adrenal hyperplasia, and bilateral adrenal nodules > 1 cm. RESULTS: A total of 31 patients had PBMAH. Patients with PBMAH showed greater prevalence of autonomous cortisol secretion (plasma cortisol > 5.0 µg/dL after an overnight 1-mg dexamethasone test) than patients without PBMAH (OR 4.1, 95%CI 1.38-12.09, p = 0.010). Tumor size and total adenomatous mass were significantly greater in patients with PBMAH compared to patients without PBMAH (30.2 ±â€¯12.16 vs. 24.3 ±â€¯8.47 mm, p = 0.010 and 53.9 ±â€¯20.8 vs. 43.3 ±â€¯14.62 mm, p = 0.023), respectively. A greater proportion of patients with PBMAH had diabetes compared to patients without PBMAH (45.2% vs. 25.4%, p = 0.05). CONCLUSION: PBMAH is present in one-third of patients with adrenal incidentaloma and subclinical hypercortisolism. Patients with PBMAH showed greater autonomous cortisol secretion, bigger tumor size, and higher rates of diabetes than those without PBMAH.

The Socioeconomic Consequences of Cushing's Syndrome: A Nationwide Cohort Study.

CONTEXT: The long-term somatic and psychiatric consequences of Cushing's syndrome are well-described, but the socioeconomic consequences are largely unknown. OBJECTIVE: We studied employment status, educational level, risk of depression, and other socioeconomic outcomes of Cushing's syndrome in the years before diagnosis and after surgery. DESIGN: Nationwide register-based cohort study. METHODS: We used a validated algorithm to identify 424 patients operated for adrenal (n = 199) or pituitary Cushing's syndrome (n = 225) in Denmark from January 1, 1986 to December 31, 2017. We obtained socioeconomic registry data from 10 years before diagnosis (year -10) to 10 years after surgery (year +10) and included a sex- and age-matched reference population. We identified prognostic factors for returning to work using modified Poisson regression. RESULTS: Compared to the reference population, the patients' employment was permanently reduced from year -6 [relative risk (RR) 0.92, 95% CI 0.84-0.99] to year +10 (RR 0.66, 95% CI 0.57-0.76). Sick leave (RR 2.15, 95% CI 1.40-3.32) and disability pension (RR 2.60, 95% CI 2.06-3.27) were still elevated in year +10. Annual income, education, parenthood, relationship status, and risk of depression were also negatively impacted, but parenthood and relationship status normalized after surgery. Among patients, negative predictors of full-time employment after surgery included female sex, low education, comorbidity, and depression. CONCLUSION: Cushing's syndrome negatively affects a wide spectrum of socioeconomic variables many years before diagnosis of which only some normalize after treatment. The data underpin the importance of early diagnosis and continuous follow-up of Cushing's syndrome and, not least, the pervasive health threats of glucocorticoid excess.

Indication to dynamic and invasive testing in Cushing's disease according to different neuroradiological findings.

PURPOSE: Dynamic testing represents the mainstay in the differential diagnosis of ACTH-dependent Cushing's syndrome. However, in case of undetectable or detectable lesion < 6 mm on MRI, bilateral inferior petrosal sinus sampling (BIPSS) is suggested by current guidelines. Aim of this study was to analyze the performance of CRH, desmopressin and high-dose dexamethasone suppression test (HDDST) in the differential diagnosis of ACTH-dependent Cushing's syndrome as well as the impact of invasive and noninvasive tests on surgical outcome in patients affected by Cushing's disease (CD). METHODS: Retrospective analysis on 148 patients with CD and 26 patients with ectopic ACTH syndrome. RESULTS: Among CD patients, negative MRI/lesion < 6 mm was detected in 97 patients (Group A); 29 had a 6-10 mm lesion (Group B) and 22 a macroadenoma (Group C). A positive response to CRH test, HDSST and desmopressin test was recorded in 89.4%, 91·4% and 70.1% of cases, respectively. Concordant positive response to both CRH/HDDST and CRH/desmopressin tests showed a positive predictive value of 100% for the diagnosis of CD. Among Group A patients with concordant CRH test and HDDST, no difference in surgical outcome was found between patients who performed BIPSS and those who did not (66.6% vs 70.4%, p = 0.78). CONCLUSIONS: CRH, desmopressin test and HDDST have high accuracy in the differential diagnosis of ACTH-dependent CS. In patients with microadenoma < 6 mm or non-visible lesion, a concordant positive response to noninvasive tests seems sufficient to diagnose CD, irrespective of MRI finding. In these patients, BIPSS should be reserved to discordant tests.

Adrenalectomy in ectopic Cushing's syndrome: A retrospective cohort study from a tertiary care centre.

Neuroendocrine neoplasms (NENs) causing ectopic Cushing's syndrome (ECS) are rare and challenging to treat. In this retrospective cohort study, we aimed to evaluate different approaches for bilateral adrenalectomy (BA) as a treatment option in ECS. Fifty-three patients with ECS caused by a NEN (35 females/18 men; mean ± SD age: 53 ± 15 years) were identified from medical records. Epidemiological and clinical parameters, survival, indications for surgery and timing, as well as duration of surgery, complications and surgical techniques, were collected and further analysed. The primary tumour location was thorax (n = 30), pancreas (n = 14) or unknown (n = 9). BA was performed in 37 patients. Median time from diagnosis of ECS to BA was 2 months (range 1-10 months). Thirty-two patients received different steroidogenesis inhibitors before BA to control hypercortisolaemia. ECS resolved completely after surgery in 33 patients and severe peri- or postoperative complications were detected in 12 patients. There were fewer severe complications in the endoscopic group compared to open surgery (p = .030). Posterior retroperitoneoscopic BA performed simultaneously by a two surgeon approach had the shortest operating time (p = .001). Despite the frequent use of adrenolytic treatment, BA was necessary in a majority of patients to gain control over ECS. Complication rate was high, probably as a result of the combination of metastatic disease and metabolic disorders caused by high cortisol levels. The two surgeon approach BA may be considered as the method of choice in ECS compared to other BA approaches as a result of fewer complications and a shorter operating time.

Impact of Adrenalectomy on Morbidity in Patients with Non-Functioning Adrenal Cortical Tumours, Mild Hypercortisolism and Cushing's Syndrome as Assessed by National and Quality Registries.

BACKGROUND: The impact of adrenalectomy on morbidity in patients with mild hypercortisolism and non-functioning adrenocortical adenoma is unclear. The present study evaluated morbidity before and after adrenalectomy in patients with benign adrenocortical tumour with Cushing´s syndrome (CS), autonomous cortisol secretion (ACS) and non-functioning adrenocortical adenoma as assessed by national and quality registries. METHODS: Patients registered in the Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal Surgery (SQRTPA) 2009-2017 with CS, ACS or non-functioning adrenocortical adenoma, were included in this retrospective study and analysed with age- and sex-matched controls, 1:3. Morbidity associated with CS was assessed pre- and postoperatively by analysing data from the Swedish National Patient Register and the Swedish Prescribed Drug Register. RESULTS: Some 271 patients were included, CS (127), ACS (45) and non-functioning adrenocortical adenoma (99), with 813 matched controls. The frequency of hypertension was almost 50% in all tumour groups. Antihypertensive medication preoperatively was more frequent in all tumour groups compared with controls. No preoperative differences in medication were detected between patients with CS and ACS. A decrease in the use of hypertensive drugs was noticed annually for all patient groups after adrenalectomy. CONCLUSIONS: Hypertension is common in patients with benign adrenocortical tumours regardless of cortisol hypersecretion. The use of antihypertensive drugs in patients with CS, ACS and non-functioning adrenocortical adenoma was reduced after adrenalectomy. These findings highlight the need for a randomized controlled trial to investigate the impact of adrenalectomy on morbidity in patients with mild hypercortisolism.

Hypercoagulability in Cushing's syndrome: From arterial to venous disease.

Cushing's syndrome (CS) is associated with multisystemic complications; the hematological system is not spared. Alteration in hemostatic parameters and in vivo endothelial dysfunction lead to increased thrombotic events. Arterial and venous thrombotic events carry significant morbidity and mortality. Death from cardiovascular and pulmonary embolism account for more than 50% of mortality. Surgery is a critical period; close to 50% of events occur in the 1-2 months after intervention. The evaluation and risk stratification of patients with CS is key to prevent events, balancing the risk-benefit of anticoagulation in this population. This current review will focus on up-to-date data on epidemiology, pathophysiology and management of hypercoagulability in CS.

Epidemiology and mortality of Cushing's syndrome.

Endogenous Cushing's syndrome (CS) is a rare endocrine disorder characterised by excess cortisol secretion due to either ACTH-dependent conditions [commonly an ACTH-producing pituitary adenoma (Cushing's disease)] or ACTH-independent causes (with most common aetiology being a benign adrenal adenoma). Overall, the annual incidence of CS ranges between 1.8 and 3.2 cases per million population. Mortality in active CS is elevated compared to the general population, and a number of studies support the view that survival is also compromised even after apparent successful treatment. The main cause of death is cardiovascular disease highlighting the negative impact of cortisol excess on cardiovascular risk factors. Early diagnosis and prompt treatment of the cortisol excess, as well as vigilant monitoring and stringent control of cardiovascular risk factors are key elements for the long-term prognosis of these patients.

Updates in adrenal steroidogenesis inhibitors for Cushing's syndrome - A practical guide.

Medical therapy is essential in the management of patients with Cushing's syndrome (CS) when curative surgery has failed, surgery is not feasible, when awaiting radiation effect, and in recurrent cases of CS. Steroidogenesis inhibitors have a rapid onset of action and are effective in reducing hypercortisolism, however, adverse effects, including adrenal insufficiency require very close patient monitoring. Osilodrostat is the only steroidogenesis inhibitor to have been assessed in prospective randomized controlled trials and approved for Cushing's disease (CD) by the US Food and Drug Administration and for CS by the European Medical Agency (EMA). Osilodrostat has been shown to be highly effective at maintaining normal urinary free cortisol in patients with CD. Drugs such as metyrapone, ketoconazole (both EMA approved), and etomidate lack prospective evaluation(s). There is, however, considerable clinical experience and retrospective data that show a very wide efficacy range in treating patients with CS. In the absence of head-to-head comparative clinical trials, therapy choice is determined by the specific clinical setting, risk of adverse events, cost, availability, and other factors. In this review practical points to help clinicians who are managing patients with CS being treated with steroidogenesis inhibitors are presented.

Maximum adenoma diameter, regardless of uni- or bilaterality, is a risk factor for autonomous cortisol secretion in adrenal incidentalomas.

PURPOSE: To evaluate differences between patients with unilateral and bilateral adrenal incidentalomas (AIs) in the prevalence of autonomous cortisol secretion (ACS) and related comorbidities. METHODS: In this multicentre retrospective study, AIs ≥ 1 cm without overt hormonal excess were included in the study. ACS was defined by a post-dexamethasone suppression test (DST) serum cortisol ≥ 5.0 µg/dl, in the absence of signs of hypercortisolism. For the association of ACS with the prevalence of comorbidities, post-DST serum cortisol was also analysed as a continuous variable. RESULTS: Inclusion criteria were met by 823 patients, 66.3% had unilateral and 33.7% bilateral AIs. ACS was demonstrated in 5.7% of patients. No differences in the prevalence of ACS and related comorbidities were found between bilateral and unilateral AIs (P > 0.05). However, we found that tumour size was a good predictor of ACS (OR = 1.1 for each mm, P < 0.001), and the cut-off of 25 mm presented a good diagnostic accuracy to predict ACS (sensitivity of 69.4%, specificity of 74.1%). During a median follow-up time of 31.2 (IQR = 14.4-56.5) months, the risk of developing dyslipidaemia was increased in bilateral compared with unilateral AIs (HR = 1.8, 95% CI = 1.1-3.0 but, this association depended on the tumour size observed at the end of follow-up (HR adjusted by last visit-tumour size = 0.9, 95% CI = 0.1-16.2). CONCLUSIONS: Tumour size, not bilaterality, is associated with a higher prevalence of ACS. During follow-up, neither tumour size nor bilaterality were associated with the development of new comorbidities, yet a larger tumour size after follow-up explained the association of bilateral AIs with the risk of dyslipidaemia.

Revisiting Cushing Syndrome, Milder Forms Are Now a Common Occurrence: A Single-Center Cohort of 76 Subjects.

OBJECTIVE: Guidelines recommend initiating testing for Cushing syndrome (CS) based on strong clinical suspicion. Our recent experience suggests the absence of classical stigmata in the majority of patients with CS. We aimed to confirm this premise by revisiting the clinical features of this syndrome in a modern series of patients from a single center. METHODS: Computerized records of subjects with CS diagnosed at Tel Aviv Sourasky Medical Center between 2000 and 2018 were reviewed. A Cushing inventory score, including all clinical components of the syndrome, was computed for each subject. Data were compared between the subtypes and evaluated in light of those in the literature. RESULTS: Of the 76 subjects with CS (60 women/16 men), 49 (64.5%) had Cushing disease; 16 (21.1%), adrenal adenoma; 7 (9.2%), adrenocortical carcinoma; and 4 (5.3%), ectopic adrenocorticotropic hormone secretion. In only 15 of 74 cases (20.3%), clinical suspicion of CS led to testing. Catabolic signs of CS were present in less than 30% of cases. The most common symptom was weight gain (52/67, 77.6%), and the most common comorbidity was hypertension (47/76, 61.8%). There were no differences in the Cushing inventory score between the subtypes. Signs, symptoms, and comorbidities were all significantly less common than in the classical syndrome. CONCLUSIONS: Modern-day CS presents with subtler features than in the past. Initiating a testing cascade solely based on a strong clinical suspicion may lead to underdiagnosis of milder cases. A concerted effort to devise cost-efficient testing for CS in the current era is needed.

Imaging cerebral microbleeds in Cushing's disease evaluated by quantitative susceptibility mapping: an observational cross-sectional study.

DESIGN: Cushing's disease (CD) is a rare clinical syndrome characterized by chronic exposure to hypercortisolism due to an adrenocorticotropic hormone-secreting pituitary adenoma. The adverse effects of chronic exposure to hypercortisolism on the human brain remain unclear. The purpose of this study was to assess the prevalence of cerebral microbleeds (CMBs) in CD patients and their associations with clinical characteristics. METHODS: In this study, 48 active CD patients, 39 remitted CD patients, and 52 healthy control (HC) subjects underwent MRI. CD patients also underwent neuropsychological testing and clinical examinations. The number, locations, and volumes of CMBs were assessed on quantitative susceptibility mapping (QSM) images and with the Microbleed Anatomical Rating Scale. The correlation between CMBs and clinical characteristics was explored. RESULTS: The prevalence of CMBs among active and remitted CD patients was higher than that among HCs (16.3%, 20.5%, and 3.3%, respectively). Moreover, the age of CD patients with CMBs were much younger than HCs with CMBs. Furthermore, the increased number of CMBs in active CD patients was associated with increased cerebrospinal fluid (CSF) volumes in remitted CD patients. CONCLUSIONS: Chronic exposure to hypercortisolism may be relevant to CMBs and significantly correlated with altered brain volumes in CD.

Thromboembolic disease in hypercortisolism.

PURPOSE OF REVIEW: Endogenous Cushing's syndrome (CS) is associated with increased patient morbidity (hypertension, diabetes mellitus, dyslipidemia, visceral obesity, osteoporosis, cognitive alterations, and impaired quality of life). Both arterial and venous thromboembolic events (TE) due to alterations in the hemostatic system and prothrombotic state are widely reported in patients with CS, more so postoperatively. Increased mortality, if not appropriately treated, is largely due to cardiovascular events and infections. RECENT FINDINGS: Patients with CS have markedly increased risk of thromboembolic episodes compared to the general population. The prothrombotic state is mediated by increased levels of procoagulant factors, but also by an impaired fibrinolytic capacity. All contribute to TE, atherosclerosis, and subsequent cardiovascular morbidity and mortality. Some abnormalities progressively improve after CS remission, but do not fully normalize for at least 1 year or more. SUMMARY: Due to the additional thrombotic risk of surgery or any invasive procedure, anticoagulation prophylaxis should be at least considered in patients with CS and balanced with individual bleeding risk. However, a clear protocol of thromboprophylaxis is lacking and increased awareness regarding risks per se is needed. Large prospective trials will clarify, which patients with CS are at the highest risk and the optimal prevention protocol to minimize risks and maximize efficacy.