Diagnosis Of Cushing's Syndrome Research Articles

Can we predict the risk of venous thromboembolism in patients with Cushing's syndrome: a nationwide cohort analysis.

Patients with Cushing's syndrome (CS) have an increased venous thromboembolism (VTE) risk with most studies focusing on the perioperative period. The purpose of this study was to assess the 5-year VTE risk and identify predictors of VTE at CS diagnosis. A comparative nationwide retrospective cohort study of 609 patients (mean age 48.1 ± 17.2years, 65.0% women) with CS, and 3018 age-, sex-, body mass index-, and socioeconomic status-individually matched controls. Ectopic CS and adrenal cancer were excluded. The time-to-event of pulmonary embolism (PE) or deep vein thrombosis (DVT) within 5years of CS diagnosis was examined. VTE risk was calculated with death as competing event. VTE occurred in 16 cases (2.6%), compared to 17 (0.56%) controls (hazard ratio [HR] 4.71, 95% CI, 2.38-9.33). The 5-year HRs for PE and DVT were 7.47 (95% CI, 2.66-20.98) and 3.32 (95% CI, 1.36-8.12), respectively. After excluding patients and controls with current or prior malignancy the risk for VTE was 7.57 (95% CI, 2.98-19.20). Patients with CS ≥ 60years at diagnosis (HR, 3.49; 95% CI, 1.30-9.35), with hypertension (HR, 5.53; 95% CI, 1.26-24.27), ischemic heart disease (HR, 3.60; 95% CI, 1.25-10.36), kidney disease (HR, 4.85; 95% CI, 1.39-16.90), or VTE event prior to CS diagnosis (HR, 33.65; 95% CI, 10.07-112.42) had an increased risk of VTE within five years. In this large cohort of patients with CS, the 5-year VTE risk was 5 times higher compared with matched controls. Key baseline predictors included age ≥ 60, hypertension, heart/kidney disease, and prior VTE.

Multiple Osteoporotic Fractures in Cushing Syndrome: A Case Report and a Review of the Literature

Background: Osteoporotic fractures are a common clinical sign of Cushing syndrome (CS). However, Cushing diagnosis can occur years after this clinical manifestation. Methods: Herein, we present the case of a 45-year-old woman who was referred to our department for further diagnosis and treatment. Results: The patient was already under treatment for arterial hypertension and osteoporosis and was recently diagnosed with dyslipidemia and type 2 diabetes. She reported several previous fractures starting already 8 years before presentation. An adrenal CS was diagnosed, and the patient was treated with laparoscopic adrenalectomy, with a subsequent complete remission of her hypercortisolism. This case report presenting a particularly long time gap between initial osteoporosis signs and the final diagnosis underlines the need for an investigation into secondary osteoporosis in low-energy fractures also in the peripheral skeleton. In this context, we performed a literature review, including case reports with fragility fractures that were attributed to endogenous CS. Conclusions: In summary, a delayed diagnosis of CS in patients with a previous accumulation of such fractures is a worrisome observation and should be considered in everyday clinical practice in order to improve the timely diagnosis and treatment of CS.

Who and how to screen for endogenous hypercortisolism in patients with mood disorders.

A strict association exists between mood disorders and endogenous hypercortisolism, namely Cushing's syndrome (CS). Indeed, CS is characterized by a wide range of mood disorders, such as major depression, generalized anxiety, panic disorders, bipolar disorders up to psychosis, with major depression being the most frequent, with a prevalence of 50-80%, and potentially representing the clinical onset of disease. Despite this observation, the exact prevalence of hypercortisolism in patients with mood disorders is unknown and who/how to screen for endogenous hypercortisolism among patients with mood disorders is still unclear. In this context, an accurate anamnestic and clinical examination are crucial in order to identify those patients who may benefit from CS screening. In particular, the presence of specific signs and symptoms of CS, comorbidities typically associated with CS, and lack of improvement of depressive symptoms with standard treatments can further guide the decision to screen for CS. Anyhow, it is noteworthy that mood disorders represent a cause of functional activation of hypothalamic-pituitary-adrenal (HPA) axis, a condition formerly known as non-neoplastic hypercortisolism (NNH). The differential diagnosis between CS and NNH is challenging. Beyond anamnestic and clinical features, various tests, including measurement of daily urinary cortisol and late-night salivary cortisol, together with low dose-dexamethasone suppression test, are used for initial screening. However, considering their low accuracy, a definitive diagnosis may require a longitudinal follow-up along with second-line dynamic tests like combined dexamethasone-CRH test and desmopressin test. In conclusion, available data suggest the need for a comprehensive assessment and follow-up of individuals with mood disorders to detect possible underlying CS, considering the pitfalls in diagnosis and the overlap of symptoms with other conditions like NNH. Specialized centers with expertise in CS diagnosis and differential testing are recommended for accurate evaluation and management of these patients.

7385 Prevalence of Central Hypothyroidism in Cushing Syndrome and Thyroid Function Tests After Cushing Treatment

Abstract Disclosure: T. Kunavisarut: None. A. Sriwijitkamol: None. Cushing syndrome can be associated with thyroid dysfunction. We investigated the association between Cushing syndrome and thyroid dysfunction. We conducted a retrospective study at Siriraj Hospital in Thailand and analyzed thyroid function tests in 80 Cushing's patients. The inclusion criteria were patients diagnosed with Cushing syndrome with thyroid function tests recorded at diagnosis of Cushing syndrome. Patients who had an abnormal thyroid function test at diagnosis of Cushing syndrome must have a thyroid function test after treatment of Cushing syndrome. Of the 80 patients, sixty-five patients (81.2%) had normal thyroid function at diagnosis, 12 patients (15%) had central hypothyroidism and three patients (3.8%) had subclinical hyperthyroidism.Interestingly, among 12 patients who had central hypothyroidism, eight patients (66.7%) were diagnosed with Cushing disease. Three patients (25%) were diagnosed with adrenal Cushing syndrome and one patient (8.3%) was diagnosed with ectopic Cushing syndrome. This finding suggested that central hypothyroidism may not be exclusively due to the mass effect of the pituitary tumor on the normal pituitary because adrenal Cushing syndrome and ectopic Cushing syndrome can also cause central hypothyroidism. Among 12 patients with central hypothyroidism at diagnosis of Cushing syndrome, nine patients (75%) normalized their thyroid function after remission of Cushing syndrome without Levothyroxine replacement. Moreover, patients with central hypothyroidism had significantly higher median 24-hour urine-free cortisol levels than euthyroid patients (1030.5 ug/day vs. 404.5 ug/day, p=0.017), indicating a potential correlation between cortisol excess and low FT4 levels. These findings suggest that hypercortisolism in Cushing syndrome can suppress the hypothalamic-pituitary-thyroid axis, but this suppression is often reversible with successful Cushing's treatment. This study highlights the importance of central hypothyroidism, which can occur in all types of Cushing syndrome. If the patients did not have hypothyroid symptoms, Levothyroxine replacement may not be necessary. For patients who already received Levothyroxine and had normal thyroid function tests, Levothyroxine can be carefully tapered and potentially discontinued because successful Cushing syndrome treatment can ultimately normalize thyroid function tests. Presentation: 6/1/2024

7010 The Incidence Of Cushing Syndrome In Wisconsin Is More Common Than Population-Based Studies From Europe

Abstract Disclosure: T. Matoska: None. T.B. Carroll: Consulting Fee; Self; Corcept Therapeutics. Research Investigator; Self; Corcept Therapeutics. T.S. Wang: None. S. Dream: None. N. Zwagerman: None. J.W. Findling: Advisory Board Member; Self; Corcept Therapeutics, Recordati, Diurnal. Introduction: Endogenous neoplastic hypercortisolism [Cushing syndrome (CS)] is considered to be a rare disorder. Population-based studies from Europe estimate the incidence of CS to range from 1.8-3.2 cases/million patient-years, and there is limited data reporting the incidence of CS in the United States. All previous studies have shown that pituitary ACTH secreting tumors [Cushing disease (CD)] are the most common cause of CS. Based on our clinical experience, we speculated that the incidence of CS was more common than reported and that adrenal CS (ACS) was more common than CD. This study reports the incidence and etiology of CS from a single tertiary care center in Wisconsin (WI). Methods: Institutional clinic records between May 1, 2017, and December 31, 2022, were queried to identify WI residents treated for CS. Only patients diagnosed and treated at our institution during the study period were included. The diagnosis of CS was established with standard guideline-supported biochemical testing and appropriate imaging. Patients diagnosed with exogenous CS and those who did not undergo therapy for CS were excluded. Results: The query identified 185 patients who were diagnosed and treated for CS. These patients resided in 27 of the 72 WI counties representing a population of 4.5 million of the total WI population of 5.9 million. This suggests that, at a minimum, the incidence of CS in WI is 7.2 cases/million patient-years. Moreover, data from the WI Hospital Association show our institution treated <50% of all patients with CS discharged from WI hospitals from 2019-2023. Mean age at diagnosis was 52.4 years (SD 14.7) and 135 (73%) were female. Of the total cohort, 111 (60%) had ACS, 68 (36.8%) had CD, and 6 (3.2%) had ectopic ACTH syndrome (EAS). Patients with ACS had significantly lower LNSC, DST cortisol, and UFC when compared to those with CD and EAS. ACS had mean (SD) LNSC, DST cortisol, and UFC of 0.236 µg/dL (0.367), 6.5 µg/dL (8.7), and 64.2 µg/24h (92.8), respectively. CD had mean (SD) LNSC, DST cortisol, and UFC of 0.425 µg/dL (0.403), 11.7 µg/dL (7.5), and 151.1 µg/24h (287.4), respectively. EAS had mean (SD) LNSC, DST cortisol, and UFC of 3.189 µg/dL (0.931), 42.5 µg/dL (40.5), and 1514.2 µg/24h (1278.9), respectively. Overt physical features of CS were documented in the medical record of 117 (63.2%) patients at diagnosis ((ACS: 49 (44%); CD: 62 (91%); EAS: 6 (100%)). Conclusion: This study suggests that ACS is more common than CD as a cause of CS, and patients with ACS more frequently presented without physical features of hypercortisolism, probably due to the milder degree of cortisol excess. The incidence of CS in WI is at least 7.2 cases/million patient-years. As our institution cares for <50% of patients with CS in WI, the true incidence is likely far greater and may approach 14-15 cases/million patient-years. Presentation: 6/1/2024

9388 Unusual Case Of Ectopic Adrenocorticotropic Hormone Syndrome Secondary To Non-small Cell Lung Cancer

Abstract Disclosure: A. TakallooBakhtiari: None. G.L. Nunlee-Bland: None. V. Ganta: None. A. Zenebe: None. H. Abdalla: None. A. Elobeid: None. W.A. Odonkor: None. Introduction: Ectopic adrenocorticotropic hormone syndrome (EAS) is a rare condition due to adrenocorticotropic hormone (ACTH) release from non-pituitary tumors. It increases the mortality of affected patients thus finding and removal of the ACTH-producing source allows for curing or reduction of symptoms and serum cortisol levels. The most common cause of EAS is lung cancer. Cushing syndrome (CS) due to EAS is an uncommon paraneoplastic phenomenon in non-small cell lung cancer. Clinical case: The patient is an 80-year-old man with a past medical history of hypertension, dementia, stroke, schizophrenia, and recently diagnosed lung adenocarcinoma. He presented with a few weeks history of dysuria and generalized fatigue. There was no family history for any endocrine disorders. He has a 40 pack-year history of tobacco use. He denied alcohol or illicit drug use. Upon initial evaluation, VS: BP 155/95 mmHg, HR 82 beats/min, Ht 77 inches, Wt 125 lb with a BMI 14.7 Kg/m2. He had no typical symptoms of CS. A physical exam showed a cachectic man with no other remarkable findings. Laboratory tests on admission showed severe hypokalemia of 1.8 mEq/L (3.5-5 mEq/L) with hypochloremic metabolic alkalosis. (bicarbonate 45 mEq/L (22-28 mEq/L) and chloride 79 mEq/L (96-106 mEq/L)). Patient was normoglycemic with HbA1c of 5.0%. Random morning cortisol was 55 μg/dL (13-24 μg/dL). Supine renin and aldosterone levels were 0.45 ng/ml/h (0.25-5.8 ng/ml/h) and 1.0 ng/dL (3-16 ng/dL), respectively, excluding hyperaldosteronism. Beside urinary tract infection, other biochemical workup revealed elevated 24-h urinary free cortisol level 5233 mcg/24h (4.0-50.0 mcg/24h) with creatinine 0.7 g/24h (0.5-2.15 g/24h). Failure to suppress cortisol with low dose dexamethasone suppression test (LDDST) was evident: morning cortisol >60.0 g/dL , with concurrent serum dexamethasone 299 ng/dL (180-550 ng/dL). Plasma ACTH level was elevated 327 pg/ml (6-50 pg/ml), favoring ACTH-dependent CS. A magnetic resonance imaging (MRI) of the sella and computed tomography (CT) of the abdomen did not show pituitary or adrenal masses. Therefore, a diagnosis of ectopic CS due to lung cancer was established. Pathology of the lung mass showed tumor cells were negative for synaptophysin, chromogranin, and CD52. The immunohistochemically findings support primary adenocarcinoma of the lung. Patient refused surgical or medical treatment and was discharged to a hospice facility. Conclusion: The clinical presentation of EAS ranges from the abrupt onset of the signs and symptoms of severe hypercortisolism, including hypertension, hypokalaemia, metabolic alkalosis as in our patient to the gradual and slow onset of the classical signs and symptoms of CS. Though EAS with adenocarcinoma of the lung is rare, it is important to consider it within the differential diagnosis of any adenocarcinoma of the lung presenting with the relevant symptoms. Presentation: 6/3/2024

8130 A Case of Cushing’s Disease Presenting with Posterior Reversible Encephalopathy Syndrome

Abstract Disclosure: A.H. Chincholi: None. M.D. Goldberg: None. Introduction: Posterior reversible encephalopathy syndrome (PRES) is characterized by headaches, altered mental status, vision changes, and seizures, along with characteristic imaging findings of bilateral white matteredema in the posterior cerebral hemispheres. The syndrome often occurs in the context of severe hypertension, and has previously been reported in 6 patients with Cushing’s syndrome (CS) - 4 with ectopic sources of ACTH, 1 with micronodular adrenal hyperplasia and 1 pediatric case with Cushing’s disease. Clinical Case: An 18-year-old-man was admitted to our hospital after experiencing a second seizure at home. His presentation was significant for lethargy, hypertension, facial plethora, acne, proximal muscle weakness,central obesity, extensive purple striae, hyperglycemia, and hypokalemia. Two months prior, a diagnosis of ACTH-dependent CS had been made at an outside facility when he presented with a hypertensive emergency and new-onset diabetes. One month prior, he had been hospitalized with pneumonia complicated by acute kidney injury requiring temporary hemodialysis, and his first seizure. Brain MRI had shown extensive T2/FLAIR hyperintensities in the temporal lobes and cerebellum,consistent with PRES. On this admission, morning serum cortisol was 56.1 mcg/dL, and then 57.9 mcg/dL following 10 mg dexamethasone at night; ACTH was 120 pg/mL, and 24-hour UFC was 2,204 mcg. Ketoconazole and spironolactone were added, with no appreciable improvement in his cortisol levels but normalization of blood pressure. He required up to 150 units of insulin per day to manage his hyperglycemia. PituitaryMRI revealed a 0.6 cm adenoma, along with the T2/FLAIR hyperintensities. Chest CT showed no masses. A 10 mcg IV desmopressin stimulation test resulted in a 248% increase in ACTH and 32% increase in cortisol, and a second MRI with a 3T scanner measured the pituitary adenoma to be 1.0 cm. It was concluded that he had Cushing’s disease, and he underwent transsphenoidal resection of the pituitary adenoma. The surgery was curative, as reflected by postoperative central adrenal insufficiency. The patient was discharged on postoperative day 3 with oral hydrocortisone. Two weeks later, he was euglycemic off insulin and his blood pressure had normalized off spironolactone. Three months later, his muscle weakness and his headaches had completely resolved. Brain MRI showed complete resection of the pituitary adenoma and resolution of the white matter changes. Conclusion: To our knowledge, this is the first report of PRES associated with CS due to an ACTH-secreting pituitary adenoma in an adult. We suspect that this patient’s marked secondary hypertension triggered the reversible encephalopathy. Providers should be aware of this potential complication of hypercortisolism. This case also highlights the utility of desmopressin stimulation test in defining the cause of ACTH-dependent CS. Presentation: 6/3/2024

6640 Utility of bilateral inferior petrosal sinus sampling for diagnosis and management of Cushing's disease in children ; a case report

Abstract Disclosure: V. leal: None. L. Socha: None. S.S. Awadalla: None. The causes of adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS) are Cushing's disease (CD) and ectopic ACTH syndrome (EAS). The differential diagnosis of CS and the localization of lesions in CD and EAS are often challenging. The utility of bilateral inferior petrosal sinus sampling (BIPSS), an important test in adults, is less defined in children.A 16-year-old girl was referred for evaluation and treatment of Cushing syndrome she experienced weight gain, secondary amenorrhea, and back pain. 24-hour urinary free cortisol and low-dose dexamethasone suppression tests suggested Cushing syndrome. Adrenocorticotropic hormone (ACTH) level and high-dose dexamethasone suppression test confirmed Cushing disease. Pituitary magnetic resonance reported a microadenoma. To rule ectopic ACTH syndrome, and localize the pituitary tumor, bilateral inferior petrosal sinus sampling (BIPSS) was performed with desmopressin to stimulate ACTH. Finally, the patient was diagnosed with Cushing disease due to right ACTH-secreting pituitary microadenoma and underwent endoscopic endo-nasal transsphenoidal surgery.In conclusion , BIPSS can be a valuable tool not only for discriminating between pituitary origin and ectopic ACTH-secreting Cushing syndrome, but also for providing precise localization of pituitary adenomas, thereby facilitating appropriate treatment. Presentation: 6/1/2024

Cushing syndrome in paediatric population: who and how to screen.

Cushing's syndrome (CS) is characterised by signs and symptoms resulting from excessive and prolonged exposure to exogenous glucocorticoids or endogenous hypercortisolism. In childhood, exogenous CS represents the main cause of CS due to the widespread therapeutic use of glucocorticoids, while endogenous CS is very rare and accounts for about 10% of CS cases. According to the origin of the hypercortisolism, the ACTH-dependent form due to pituitary ACTH-secreting tumours is the most common form of endogenous CS in paediatric age (about 75-80% of cases), following by adrenal causes (about 15-20% of cases) including adenoma, carcinoma (which has a peak of incidence in the first decade), bilateral adrenal hyperplasia or Carney complex, with a different distribution by age. Ectopic ACTH-secreting CS, genetic forms of pituitary adenomas are more uncommon. The insidious onset of hypercortisolism and the absence of salient early signs make the diagnosis of endogenous CS difficult. Facial changes, weight gain with simultaneous growth failure, prepubertal virilisation, or hypogonadism in adolescence represent some of the key features of CS. The diagnostic workup is essentially aimed at confirming hypercortisolism through screening tests whose diagnostic accuracy is not 100% and therefore the combination of more than two tests is mandatory to confirm the diagnosis of CS.

Endogenous Cushing's syndrome and cancer risk.

Cancer incidence in patients with endogenous Cushing's syndrome (CS) has never been established. Here, we aimed to assess the cancer risk in patients with CS as compared with individually matched controls. A nationwide retrospective matched cohort study of patients with endogenous CS diagnosed between 2000 and 2023 using the database of Clalit Health Services in Israel. Patients with adrenal carcinoma or ectopic CS were excluded. Patients with CS were matched in a 1:5 ratio, with controls individually matched for age, sex, socioeconomic status, and body mass index. The primary outcome was defined as the first diagnosis of any malignancy following a CS diagnosis. Risk of malignancy was calculated using the Cox proportional hazard model, with death as a competing event. A total of 609 patients with CS and 3018 controls were included [mean age at diagnosis, 48.0 ± 17.2 years; 2371 (65.4%) women]. The median follow-up was 14.7 years (IQR, 9.9-20.2 years). Patients with CS had an increased cancer risk, with a hazard ratio (HR) of 1.78 (95% CI 1.44-2.20) compared with their matched controls. The risk of malignancy was elevated in patients with Cushing's disease (251 cases and 1246 controls; HR 1.65, 95% CI 1.15-2.36) and in patients with adrenal CS (200 cases and 991 controls; HR 2.36, 95% CI 1.70-3.29). The increased cancer risk in patients with CS persists after exclusion of thyroid malignancies. Endogenous CS is associated with increased malignancy risk. These findings underscore the need for further research to establish recommendations for cancer screening in this population.

Clinical and biochemical data for the diagnosis of endogenous hypercortisolism: the "Cushingomic" approach.

The clinical presentation of Cushing's syndrome (CS) overlaps with common conditions. Recommended screening tests are serum cortisol after 1-mg overnight dexamethasone suppression test (DST), urinary free cortisol (UFC), and late-night salivary cortisol (LNSC). We analyzed the diagnostic accuracy of screening tests in 615 patients without CS (263 suspected CS, 319 adrenal and 33 pituitary incidentaloma) and 40 with CS. Principal component analysis, K-means clustering, and neural network were used to compute an integrated analysis among tests, comorbidities, and signs/symptoms of hypercortisolism. The diagnostic accuracy of screening tests for CS was high, DST and UFC were slightly superior to LNSC. The threshold of DST should be adapted to the population considered, especially in adrenal incidentaloma with mild autonomous cortisol secretion: the cutoff to differentiate CS should be increased to 196 nmol/L. Diabetes, hypertension, and obesity were more common in patients without CS: the direction of their vectors was not aligned and their correlation with screening tests was poor. Clustering allowed us to differentiate those patients without CS in cluster one (aged osteoporotic patients with impaired screening tests), cluster two (hypertensive and metabolic phenotype), and cluster three (young subjects with a low likelihood of overt CS). A neural network model that combined screening tests and clinical presentation was able to predict the CS diagnosis in the validation cohort with 99% precision and 86% accuracy. Despite the high diagnostic accuracy of screening tests to detect CS, cortisol-related comorbidities or adrenal incidentaloma should be considered when interpreting a positive test.

Circulating miR-28-5p is overexpressed in patients with sarcopenia despite long-term remission of Cushing's syndrome: a pilot study.

Patients with Cushing's syndrome (CS) in remission show sustained fatigue, myopathy, and an increased prevalence of sarcopenia. The mechanisms that determine these persistent muscle problems are not well known. We aimed to identify circulating microRNAs (miRNAs) with differential expression that could be potential biomarkers for the diagnosis and/or prognosis in CS. Thirty-six women in sustained remission for 13 ± 7 years (mean ± SD) from CS, with a median age (IQ range) of 51 (45.2-60) years and mean ± SD BMI of 27 ± 4 Kg/m2, and 36 matched healthy controls were investigated. In 7 patients sarcopenia was present according to the European Working Group on Sarcopenia in Older People (EWGSOP) criteria. Small RNA libraries were generated and indexed using a modified Illumina TruSeq small RNA-sequencing protocol. MiRNAs were identified in plasma using bioinformatic analysis, and validation was carried out using RT-qPCR. For the validation, Taqman probes were performed on QuantStudio 5 equipment (Applied Biosystems). In a first discovery group using RNA-sequencing, plasma samples of 18 CS patients and 18 healthy subjects were investigated; circulating miR-28-5p, miR-495-3p and miR-654-5p were upregulated in CS patients as compared with controls (p<0.05). In a validation study of the 3 upregulated miRNAs in 36 patients and 26 controls, no differences were observed by RT-qPCR; however, the expression of circulating miR-28-5p was upregulated in CS patients with sarcopenia as compared with those without (AUC for fold-change in the ROC analysis, 0.798; p=0.0156). The optimized cut-off value for miR-28-5p to identify CS patients with sarcopenia was 3.80, which yielded a sensitivity of 86% and a specificity of 69%. MiR-28-5p, a muscle-specific microRNA involved in myotube proliferation and differentiation in vivo, may serve as an independent non-invasive biomarker for identifying CS patients at high-risk of sarcopenia despite biochemical remission.

Cushing's Syndrome is Associated with a Higher Risk of Cancer - A Nationwide Cohort Study.

Patients with Cushing's syndrome (CS) have higher risk of obesity and diabetes, which are important risk factors of cancers. However, if patients with CS have a higher incidence of cancer remains unknown. To investigate if endogenous CS is associated with increased cancer incidence. A nationwide cohort study. Analysis of the data retrieved from Taiwan's National Health Insurance program in 2006-2017. Between 2006-2017, 1278 patients with newly diagnosed endogenous CS were identified. Among them, 1246 patients without a history of malignancy were enrolled in this study. Endogenous CS. The age- and sex-standardized incidence rate of all-cause cancer and age-sex-calendar year standardized incidence ratio (SIR) of cancer in association with endogenous CS. The age- and sex-standardized incidences of CS decreased from 4.84 to 3.77 per million person-years between 2006-2017. The age at diagnosis of CS was 45.3 ± 14.8 years, and 80.0% of the patients were female. Cushing's disease and adrenal CS accounted for 35.4% and 64.6% of patients with CS, respectively. The incidence rate of cancer in patients with CS was 7.77 (95% Confidence Interval [CI] = 5.84-10.14) per 1000 person-years, with an SIR of 2.08 (95% CI = 1.54-2.75). The three most common cancer types were liver (27.7%), kidney (16.7%), and lung (13.0%). Patients with endogenous CS have a higher incidence of cancer.

Subtyping of Cushing's Syndrome: A Step Ahead.

Cushing's Syndrome (CS) is a rare disease due to chronic endogenous cortisol secretion. In recent years, new developments have broadened the spectrum of differential diagnosis, traditionally categorized as adrenocorticotropic hormone (ACTH)-dependent and ACTH-independent forms. Moreover, increased awareness of the detrimental effects of cortisol on cardiometabolic health and the risk of cardiovascular events lead to increased diagnosis of mild forms, especially in the context of adrenal incidentalomas.This review provides an up-to-date narrative of the most recent literature regarding the challenges of CS diagnosis. After the description of the diagnostic tools available, the functional non-neoplastic hypercortisolism (formerly known as pseudo-Cushing state) is characterized, followed by the subtyping of the different conditions of hypercortisolism, including the differential diagnosis of ACTH-dependent forms and the management of adrenal hypercortisolism, with peculiar attention to the new genetic classification of adrenal CS, mild autonomous cortisol secretion, and bilateral adrenal adenomas.

Steroid Profiling in the Differential Diagnosis of Cushing's Syndrome and Diagnosis of MACS

Abstract Background Cushing's Syndrome (CS) is the consequence of the exposure of tissues to extremely high levels of glucocorticoids. Early diagnosis and treatment are the mainstay of optimizing patient outcomes and improving their quality of life. In the recent years steroid profiling by LC-MS sheds more light on the diagnosis of CS. Materials and methods This was a retrospective cross-sectional study. Objective To investigate serum steroid precursor differences between different etiological forms of CS and to suggest a steroid panel for the diagnosis of MACS in patients with adrenal incidentalomas. Results Our studied patients with CD had significantly lower levels of 11-deoxycorticosterone (p = 0.047) and 17 OH progesterone (p = 0.024) compared to those with adrenal forms of CS. In out cohort of patients with adrenal incidentalomas, those with MACS had significantly lower levels of androgens (DHEA, p = 0.001) and cortisone (p = 0.015) and higher levels of 11-deoxycortisol (p = 0.039) compared to the patients with non-secreting adenomas (NSA). Conclusion Introducing LC-MS based steroid profiling would be very helpful in the diagnostic process of patients with CS.

Frequency of low-dose dexamethasone suppression test (LDDST) response patterns and their correlation with clinicopathologic signs in dogs suspected of having Cushing's syndrome: A retrospective study

A retrospective cross-sectional study was conducted to assess the frequency of low-dose dexamethasone suppression test (LDDST) patterns in canine patients that had clinicopathologic signs consistent with Cushing's syndrome (CS). Medical records for patients of interest (N = 128) were reviewed between January 2014 and December 2020 to analyse and classify LDDST results based upon the following patterns: lack of suppression, partial suppression, complete suppression, escape, or inverse. Complete suppression, lack of suppression, partial suppression, escape, and inverse patterns were identified in 39.1%, 31.2%, 14.1%, 10.1% and 5.5% of cases respectively. LDDST results were also evaluated with respect to clinical signs, serum alkaline phosphatase (ALP) activity, urine specific gravity (USG) and adrenal ultrasonographic findings. There was no association between LDDST patterns and clinical signs (p = 0.11), increased ALP (p = 0.32), USG (p = 0.33) or adrenal ultrasonographic findings (p = 0.19). In all dogs that demonstrated complete suppression or an inverse pattern, CS was excluded by the attending clinician. The diagnosis of CS was also excluded without further exploration in 23.1%, 7.5% and 5.6% of dogs that demonstrated an escape pattern, lack of suppression and partial suppression pattern, respectively. These results suggest that the clinical significance of LDDST patterns, particularly escape and inverse patterns, are misunderstood by some clinicians, leading them to prematurely exclude the diagnosis of CS.

Impact of etiology, sex, diabetes mellitus and remission status on erythrocytic profile in patients with cushing's syndrome: a large population database study.

The study aimed to characterize the erythrocytic profile in patients with cushing's syndrome (CS) versus controls from the normal population according to etiology, sex, presence of diabetes mellitus (DM) and hypercortisolemia remission status. This retrospective cohort analysis compared erythrocytic parameters between patients with CS of pituitary (CD) and adrenal (aCS) etiology and age, sex, body mass index (BMI) and socioeconomic status-matched controls in a 1:5 ratio. Laboratory values at baseline were calculated as mean values during the year preceding CS diagnosis, and over one year thereafter. The cohort included 397 CS patients (68.26% female; mean age 51.11 ± 16.85years) and 1970 controls. Patients with CS had significantly higher baseline median levels of hemoglobin (Hgb) (13.70g/dL vs. 13.12g/dL [p < 0.0001]) and hematocrit (Hct) (41.64% vs. 39.80% [p < 0.0001]) compared to controls. These differences were observed for both CD and aCS and for both sexes. Patients who attained remission had Hgb and Hct levels comparable to controls (13.20g/dL and 40.08% in patients with CD and aCS vs. 13.20g/dL and 39.98% in controls). Meanwhile, those with persistent/recurrent disease maintained elevated levels. Patients with comorbid DM had similar Hgb but higher Hct (p = 0.0419), while patients without DM showed elevated erythrocytic values compared to controls (p < 0.0001). Our data illustrates that erythrocytic parameters are directly influenced by glucocorticoid excess as Hgb and Hct are higher in patients with CS, and normalize after remission. We have identified the influence of DM on erythrocytic parameters in patients with CS for the first time.

Venous thromboembolism in Cushing syndrome: results from an EuRRECa and Endo-ERN survey.

Patients with Cushing syndrome (CS) are at increased risk of venous thromboembolism (VTE). The aim was to evaluate the current management of new cases of CS with a focus on VTE and thromboprophylaxis. A survey was conducted within those that report in the electronic reporting tool (e-REC) of the European Registries for Rare Endocrine Conditions (EuRRECa) and the involved main thematic groups (MTG's) of the European Reference Networks for Rare Endocrine Disorders (Endo-ERN) on new patients with CS from January 2021 to July 2022. Of 222 patients (mean age 44 years, 165 females), 141 patients had Cushing disease (64%), 69 adrenal CS (31%), and 12 patients with ectopic CS (5.4%). The mean follow-up period post-CS diagnosis was 15 months (range 3-30). Cortisol-lowering medications were initiated in 38% of patients. One hundred fifty-four patients (69%) received thromboprophylaxis (including patients on chronic anticoagulant treatment), of which low-molecular-weight heparins were used in 96% of cases. VTE was reported in six patients (2.7%), of which one was fatal: two long before CS diagnosis, two between diagnosis and surgery, and two postoperatively. Three patients were using thromboprophylaxis at time of the VTE diagnosis. The incidence rate of VTE in patients after Cushing syndrome diagnosis in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Thirty percent of patients with CS did not receive preoperative thromboprophylaxis during their active disease stage, and half of the VTE cases even occurred during this stage despite thromboprophylaxis. Prospective trials to establish the optimal thromboprophylaxis strategy in CS patients are highly needed. The incidence rate of venous thromboembolism in our study cohort was 14.6 (95% CI 5.5; 38.6) per 1000 person-years. Notably, this survey showed that there is great heterogeneity regarding time of initiation and duration of thromboprophylaxis in expert centers throughout Europe.

Development of diagnostic algorithm for Cushing’s syndrome: a tertiary centre experience

PurposeNo consensus exists as the gold standard for Cushing’s Syndrome (CS) screening. This study aimed to evaluate the diagnostic accuracy and utility of late-night salivary cortisol (LNSC) and cortisone (LNSE), overnight dexamethasone suppression test (ODST), and urinary free cortisol (UFC) in developing a screening algorithm for CS.MethodsA retrospective, single-centre analysis on 93 adult patients referred to the Oxford Centre for Diabetes, Endocrinology, and Metabolism for CS evaluation (2017–2022). Data were analysed using binomial logistic regression and area under the receiver-operating curve (AUROC).ResultsFifty-three patients were diagnosed with CS. LNSC (sensitivity 87.5%, specificity 64.9%, AUC 0.76), LNSE (sensitivity 72.4%, specificity 85.7%, AUC 0.79), and ODST (sensitivity 94.7%, specificity 52.1%; AUC 0.74) demonstrated comparable effectiveness for CS diagnosis. Their combined application increased diagnostic accuracy (AUC 0.91). UFC was not statistically significant. Pre-test clinical symptom inclusion improved screening test performance (AUC LNSC: 0.83; LNSE: 0.84; ODST: 0.82). For CD diagnosis, LNSE + LNSC (AUC 0.95) outperformed ODST. Combining these with ACTH levels < 12.6 pmol/L perfectly distinguished MACS (AUC 1.00). ODST (AUC 0.76) exhibited superior performance (sensitivity 100.0%, specificity 52.2%) in MACS detection.ConclusionsLNSC, LNSE, and ODST are robust tools for CS screening, with their combined use offering the highest diagnostic precision. LNSE, especially when used with LNSC, is highly effective for CD diagnosis, exceeding ODST accuracy. ODST is preferable for MACS identification. Integrating ACTH levels markedly improves differentiation between CD and MACS. Conversely, UFC shows limited diagnostic utility.

Machine Learning May Be An Alternative To BIPSS In The Differential Diagnosis Of ACTH-Dependent Cushing's Syndrome.

This study aimed to develop machine learning (ML) algorithms for the differential diagnosis of adrenocorticotropic hormone (ACTH)-dependent Cushing's syndrome (CS) based on biochemical and radiological features. Logistic regression algorithms were used for ML, and the area under the receiver operating characteristics curve (AUROC) was used to measure performance. We used Shapley Contributed Comments (SHAP) values, which help explain the results of the ML models to identify the meaning of each feature and facilitate interpretation. A total of 106 patients, 80 with Cushing's disease (CD) and 26 with ectopic ACTH syndrome (EAS), were enrolled in the study. The ML task was created to classify patients with ACTH-dependent CS into CD and EAS. The average AUROC value obtained in the cross-validation of the logistic regression model created for the classification task was 0.850. The diagnostic accuracy of the algorithm was 86%. The SHAP values indicated that the most important determinants for the model were the 2-day 2-mg dexamethasone suppression test, the > 50% suppression in the 8-mg high-dose dexamethasone test, late-night salivary cortisol, and the diameter of the pituitary adenoma. We have also made our algorithm available to all clinicians via a user-friendly interface. ML algorithms have the potential to serve as an alternative decision support tool to invasive procedures in the differential diagnosis of ACTH-dependent CS.