The diagnostic challenge of occult glucocorticoid exposure causing Cushing's syndrome

Diagnostic challenges in cyclic Cushing's syndrome: a systematic review

Cognitive dysfunction severity evaluation in dogs with naturally-occurring Cushing´s syndrome: A matched case-control study

Cushing syndrome (CS) is the result of chronic exposure to glucocorticoid excess. CS in children is most often caused by the administration of exogenous steroids. Endogenous CS is rare in the paediatric population and is caused mainly by tumours of the pituitary and adrenal glands, with ectopic sources being extraordinarily rare before the age of 18 years. In addition, children and young adults with CS present with different epidemiology, management issues, prognosisand outcomes than older adult patients. This complex disorder needs early diagnosis and management to avoid the significant morbidity and even mortality that can result from chronic untreated CS. In this review, we present the complex case of a 7-year-old boy with CS that highlights the diagnostic and management challenges of paediatric CS patients, including the considerations for genetic predisposition and life-long consequences of CS in children and young adults. The diagnostic protocols for the evaluation of CS have been devised for adults and tested predominantly on adults. In this review, we discuss necessary modifications so that the testing can be adjusted for use in children. Additionally, pituitary adenomas in children are generally smaller and thus more difficult to recognize on pituitary imaging. The management of the case and its complexities underline the need for children with CS to be managed in a centre with experienced paediatric endocrinologists and skilled neurosurgeons both for their initial diagnosis and treatment as well as for their long-term follow-up and management.

Urine free cortisol in the diagnosis of Cushing's syndrome: is it worth doing and, if so, how?

Cushing's syndrome is a chronic disorder characterized by prolonged glucocorticoid exposure, leading to significant multisystem complications. Multiple epidemiological studies have demonstrated a substantially elevated risk of venous thromboembolism in patients with Cushing's syndrome, including deep vein thrombosis and pulmonary embolism, particularly during active disease, the perioperative period, but more importantly also after biochemical remission. Hypercortisolism promotes a hypercoagulable state through multiple mechanisms, including persistent endothelial dysfunction, increased procoagulant factors such as von Willebrand factor and factor VIII, impaired fibrinolysis, and venous stasis. Additionally, common comorbidities in Cushing's syndrome, such as obesity, hypertension, and diabetes, further amplify thrombotic risk. Given these findings, recent consensus recommends thromboprophylaxis for most patients with Cushing's syndrome, with anticoagulation therapy initiated at diagnosis, continued perioperatively, and extended post-remission when appropriate in patients both after surgery and also in patients on medical therapy. Low molecular weight heparin is the preferred anticoagulant, while direct oral anticoagulants require further investigation in patients with Cushing's syndrome. Despite these recommendations, clinical practice varies significantly across centers and countries, highlighting the need for standardized thromboprophylaxis protocols. Future research should focus on refining risk stratification models, optimizing prophylaxis duration, and evaluating the long-term thrombotic risk in Cushing's syndrome remission. Additionally, studies exploring the safety and efficacy of direct oral anticoagulants and personalized medicine approaches through biomarker-driven strategies may further improve patient outcomes. Addressing these gaps will enhance thromboembolism prevention strategies in Cushing's syndrome and ultimately may reduce morbidity and mortality in this high-risk population.

Paediatric Cushing's syndrome presents a diagnostic and therapeutic challenge. Most paediatric endocrinologists have limited experience in managing children or adolescents with Cushing's syndrome and thus benefit from close consultation with adult colleagues. A protocol for investigation of the child with suspected Cushing's syndrome is presented followed by principles of management. Cushing's syndrome is rare in childhood, but causes serious morbidity. Investigations have evolved and now include new genetic and imaging techniques as well as classical endocrine studies. In Cushing's disease trans-sphenoidal surgery has transformed management, although only a few surgeons have experience in children. Pituitary radiotherapy is effective second-line therapy. Early diagnosis and treatment of Cushing's syndrome is vital for long-term outcome. The overall prognosis for Cushing's syndrome is good but challenges remain to ensure normal postcure growth and body composition.

SummaryWe report a rare case of Cushing's syndrome in a pregnant woman carrying twins. Interestingly, the patient did exhibit many of the classic clinical features typically associated with hypercortisolism, including Cushingoid facies, violaceous striae, insulin-dependent diabetes, raised central adiposity, chronic hypertension and peripheral myopathy. Her case was less straightforward given her previous gastric sleeve bariatric surgery, which led to rapid weight loss prior to pregnancy. The occurrence of an atraumatic fracture of the femoral neck in a young woman with a medical history of type 2 diabetes mellitus, chronic hypertension and possible severe osteoporosis raised clinical suspicion of a unifying diagnosis, prompting further evaluation.Biochemical testing, including elevated cortisol and suppressed adrenocorticotropic hormone levels, alongside imaging studies, confirmed the diagnosis of adrenal Cushing's syndrome. This case prompted a deeper investigation into the physiological changes of the hypothalamic-pituitary-adrenal axis during normal pregnancy, as well as the unique challenges in diagnosing and managing Cushing's syndrome during pregnancy.This case highlights the need for a high index of suspicion and a multidisciplinary approach in diagnosing and managing complex presentations in pregnancy. Early recognition and treatment of Cushing's syndrome are critical to optimising maternal and fetal outcomes.Cushing's syndrome during pregnancy is a rare but serious hormonal syndrome characterised by elevated cortisol levels. This hypercortisolism may be a result of functional adrenal or pituitary tumours, or iatrogenic. Though uncommon, it poses a significant threat to both maternal and fetal health due to the high risk of complications. This case study aims to provide a current overview of the diagnosis and management of Cushing's syndrome in pregnancy, with an emphasis on minimising associated maternal and fetal morbidity. The case report highlights missed differential diagnoses of Cushing's syndrome in the pre-pregnancy period despite the presence of type 2 diabetes, hypertension and morbid obesity in a young patient. Bariatric surgery further complicated the differential diagnosis.

Background: Cushing's syndrome results from prolonged exposure to elevated glucocorticoids, leading to significant morbidity and mortality. Despite its historical identification over a century ago, challenges remain in diagnosing and treating this condition due to its non-specific symptoms and complex underlying mechanisms. Aim: This review aims to elucidate the pathophysiology, diagnostic approaches, and treatment options for Cushing's syndrome to enhance clinician understanding and improve patient outcomes. Methods: A comprehensive literature review was conducted, synthesizing data on the etiology, classification, and epidemiology of Cushing's syndrome. The review categorized Cushing's syndrome into ACTH-dependent and ACTH-independent forms, highlighting diagnostic challenges and therapeutic strategies, including surgical, medical, and radiation options. Results: The findings reveal that Cushing's syndrome predominantly arises from either endogenous factors (e.g., pituitary adenomas, ectopic ACTH production) or exogenous glucocorticoid use. ACTH-dependent Cushing's disease accounts for the majority of cases, particularly in women aged 25-40. The review also identifies key diagnostic tools, including biochemical tests and imaging studies, and discusses the importance of recognizing both overt and subtle clinical presentations. Conclusion: Cushing's syndrome remains a complex endocrine disorder requiring a multifaceted approach for accurate diagnosis and effective management.

Background/ObjectiveExogenous Cushing syndrome is usually diagnosed in the setting of known glucocorticoid exposure; however, occult glucocorticoid use is possible. We present 2 cases of patients who developed Cushing syndrome while taking Artri King (AK), an over-the-counter “herbal” supplement for joint pains reported to contain glucocorticoids. Case ReportPatient 1, a 49-year-old woman, reported rapid weight gain, large stretch marks, poor wound healing, and recent diagnoses of type 2 diabetes mellitus and hypertension over a course of 1 year. Her serum am cortisol level was <0.5 μg/dL (reference range, 4.0-22.0 μg/dL) and adrenocorticotropic hormone (ACTH) level was <5 pg/mL (reference range, 5-60 pg/mL). Synthetic glucocorticoid screening revealed a dexamethasone level of 210 ng/dL (reference value < 100 ng/dL) while she was taking AK; 5 days after stopping the supplement, the level was 24 ng/dL (reference value < 20 ng/dL). Patient 2, a 61-year-old woman, presented with weight gain, fatigue, swelling, and recent diagnoses of prediabetes and hypertension over a span of 6 months. Her serum am cortisol level was <1.0 μg/dL (reference range, 8.0-25.0 μg/dL) and ACTH level was <5 pg/mL (reference value < 46 pg/mL). She stopped AK, and 1 month later, her am cortisol level rose to 9.1 μg/dL (reference range, 8.0-25.0 μg/dL) and ACTH level rose to 68 pg/mL (reference value < 46 pg/mL). DiscussionSupplements containing hidden glucocorticoids and causing Cushing syndrome have been reported in rare cases and can pose a diagnostic challenge for providers. ConclusionExogenous glucocorticoid use because of unregulated herbal supplements should be considered when Cushing syndrome is suspected.

Cushing syndrome results from supraphysiological exposure to glucocorticoids and is associated with significant morbidity and mortality. The pathogenesis includes administration of corticosteroids (exogenous Cushing syndrome) or autonomous cortisol overproduction, whether or not ACTH-dependent (endogenous Cushing syndrome). An early diagnosis of Cushing syndrome is warranted; however, in clinical practice, it is very challenging partly because of resemblance with other common conditions (ie, pseudo-Cushing syndrome). Initial workup should start with excluding local and systemic corticosteroid use. First-line screening tests including the 1-mg dexamethasone suppression test, 24-hour urinary free cortisol excretion, and late-night salivary cortisol measurement should be performed to screen for endogenous Cushing syndrome. Scalp-hair cortisol/cortisone analysis helps in the assessment of long-term glucocorticoid exposure as well as in detection of transient periods of hypercortisolism as observed in cyclical Cushing syndrome. Interpretation of results can be difficult because of individual patient characteristics and hence requires awareness of test limitations. Once endogenous Cushing syndrome is established, measurement of plasma ACTH concentrations differentiates between ACTH-dependent (80%-85%) or ACTH-independent (15%-20%) causes. Further assessment with different imaging modalities and dynamic biochemical testing including bilateral inferior petrosal sinus sampling helps further pinpoint the cause of Cushing's syndrome. In this issue of "Approach to the patient," the diagnostic workup of Cushing syndrome is discussed with answering the questions when to screen, how to screen, and how to differentiate the different causes. In this respect, the latest developments in biochemical and imaging techniques are discussed as well.

Background: ACTH-independent causes of Cushing Syndrome (CS) have mostly benign etiologies. For the majority of these conditions, surgery is the recommended treatment and is nearly 100% curative. Current guidelines do not specify follow up imaging recommendations in patients with resected adenomas. We present a case of severe CS secondary to an adrenal adenoma that was completely resected, and presented later as a metastatic adrenocortical carcinoma (ACC). Clinical Case: A 34- year-old woman presented with worsening confusion, weight gain and new onset diabetes and hypertension. Her history was significant for a 7 cm left adrenal mass and ACTH- independent CS previously treated with left adrenalectomy 2 years prior to this presentation. She was following with an endocrinologist who weaned her hydrocortisone to 10-5 mg. She completed a successful pregnancy but had worsening depression. Her steroids were stopped on admission and evaluation showed hypokalemia [2.9 mmol/L (n 3.5-5.1)], hypercortisolemia [29.9 mcg/dL (n 6.7-22.6)], and ACTH <12 pg/mL (n<46). This was followed with 1 and 8 mg dexamethasone suppression tests that she failed with cortisol levels of 37.8 and 41.6 mcg/dL respectively, late-night salivary cortisol of 0.974 ug/dL (n <0.181), and extremely elevated 24-hr urinary cortisol of 3,700.2 ug/d (n<45). Of the steroid hormone precursors, 11 deoxycortisol was elevated at 725 ng/dL (n<32) and DHEA-S was 29mcg/dL (n 35-430). A CT scan revealed multiple liver lesions, and no residual nodularity in the left adrenalectomy bed. Liver lesions were PET-avid, and biopsy confirmed metastatic ACC. Due to the extensive hepatic involvement, she was not a candidate for local therapy. She was started on mitotane and metyrapone for CS. She was treated with doxorubicin, cisplatin and etoposide chemotherapy every 4 weeks. Due to insurance issues; metyrapone was replaced by mifepristone. Over 8 weeks, mitotane level became therapeutic at 20 mcg/mL, hepatic masses decreased in size, and she transitioned form CS to adrenal insufficiency (AI) with am cortisol of 3 mcg/dL with accompanying nausea and improved glycemic control without medication. Next generation sequencing studies of the liver biopsy specimen revealed a frameshift loss of function mutation in FH that encodes the protein fumarase (c.912_918del p.F305fs; variant allele fraction - 67.8%). Conclusion: Metastatic ACC presenting with life-threatening CS presents a diagnostic and management challenge. Combination therapy with mitotane and chemotherapy demonstrated benefit in our patient. The transition from severe CS to AI due to mitotane was challenging to monitor biochemically due to mifepristone use. Loss of function FH mutation is associated with cancer progression. Patients with resected large adrenal adenomas require close monitoring to identify malignant behavior.

Pitfalls in the diagnosis and differential diagnosis of <scp>C</scp>ushing's syndrome

Adults with Cushing syndrome frequently develop brain atrophy, memory impairment, and depression, with partial to complete resolution after cure. The effect of excess glucocorticoid exposure on the brain of children has not been systematically studied. Eleven children (six girls, five boys; ages, 8-16 yr) with endogenous Cushing syndrome seen at the National Institutes of Health Clinical Center from 1999-2000 and 10 healthy age- and sex-matched control subjects were studied. Cognitive and psychological evaluations and magnetic resonance imaging of the brain were done before and 1 yr after cure for patients with Cushing syndrome and once for controls. The estimated duration of Cushing syndrome was 4.4 +/- 1.2 yr. When compared with control subjects, children with Cushing syndrome had significantly smaller cerebral volumes (P < 0.001), larger ventricles (P = 0.02), and smaller amygdala (P = 0.004). At baseline, there were no significant differences in IQ between the two groups, and no psychopathology was identified. Despite reversal of cerebral atrophy 1 yr after surgical cure (total cerebral volume, 947 +/- 94 vs.1050 +/- 74 ml, P < 0.001; ventricular volume, 21.4 +/- 12.5 vs. 14.5 +/- 11.6 ml, P < 0.001), children with Cushing syndrome experienced a significant (P < 0.05) decline in Wechsler IQ scores (Full Scale, 112 +/- 19 vs. 98 +/- 14) and a decline in school performance, without any associated psychopathology. The effect of glucocorticoid excess on the brain of children appears to be different from adults. Despite rapid reversibility of cerebral atrophy, children experience a significant decline in cognitive function 1 yr after correction of hypercortisolism.

Endogenous Cushing’s syndrome (CS) poses considerable diagnostic challenges. Although late-night salivary cortisol (LNSC) is recommended as a first-line screening investigation, it remains the least widely used test in many countries. The combined measurement of LNSC and late-night salivary cortisone (LNS cortisone) has shown to further improve diagnostic accuracy. We present a retrospective study in a tertiary referral centre comparing LNSC, LNS cortisone, overnight dexamethasone suppression test, low-dose dexamethasone suppression test and 24-h urinary free cortisol results of patients investigated for CS. Patients were categorised into those who had CS (21 patients) and those who did not (33 patients). LNSC had a sensitivity of 95% and a specificity of 91%. LNS cortisone had a specificity of 100% and a sensitivity of 86%. With an optimal cut-off for LNS cortisone of >14.5 nmol/L the sensitivity was 95.2%, and the specificity was 100% with an area under the curve of 0.997, for diagnosing CS. Saliva collection is non-invasive and can be carried out at home. We therefore advocate simultaneous measurement of LNSC and LNS cortisone as the first-line screening test to evaluate patients with suspected CS.

Cushing's syndrome