Diagnosis Of Cushing's Syndrome Research Articles

The Utility of Preoperative ACTH/Cortisol Ratio for the Diagnosis and Prognosis of Cushing's Disease.

Purpose:Cushing's syndrome (CS) is a rare disease having diagnostic difficulties. Many diagnostic tests have been defined but none of these are diagnostic alone. Determination of the cause is another problem which sometimes requires more sophisticated and invasive procedures. Therefore, we aimed to evaluate the utility of pretreatment plasma adrenocorticotropic hormone (ACTH)/cortisol ratios in patients with confirmed endogenous CS for the diagnosis and differential diagnosis of CS.Materials and Methods:This retrospective evaluation included 145 patients with the diagnosis of CS, 119 patients with Cushing's disease (CD), and 26 patients with ACTH-independent CS (AICS), in a university hospital. Furthermore, 114 individuals in whom CS diagnosis was excluded with at least one negative screening test were enrolled to the study as control group. The clinical, laboratory, imaging, postsurgical pathologic records and also clinical follow-up data of all patients were evaluated.Results:The median basal ACTH/cortisol ratio of the patients with CD was significantly higher than AICS and controls. A cutoff ACTH/cortisol ratio >2.5 was found to be diagnostic for CD with 82% specificity and 63% sensitivity. Among CD group, patients with recurrent disease had higher preoperative ACTH levels and ACTH/cortisol ratio than patients with sustained remission. Furthermore, these patients had more invasive, atypical, and larger tumors.Conclusion:An ACTH/cortisol ratio >2.5 would be beneficial to diagnose CD together with other diagnostic tests. It is a simple test with no additional cost. Higher ratios might be related with larger, invasive, and atypical adenoma and also might be helpful to predict recurrence.

TSH ratio as a novel diagnostic method for Cushing's syndrome.

Circadian variations impact thyrotropin (TSH) secretion; in Cushing's syndrome (CS) patients, the nocturnal serum TSH surge is abolished. The aim of this prospective study is to examine whether serum TSH surge may be a useful diagnostic method for CS. This prospective study recruited 136 inpatients for differential diagnosis of CS or subclinical CS (SCS), and 21 inpatients with depression at Osaka University Hospital. Serum TSH surge was assessed by the midnight-to-morning serum TSH ratio (2300-2400 h to 0800-0900 h). The diagnostic accuracy (sensitivity and specificity) between TSH ratio and ordinary screening tests [low-dose dexamethasone suppression test (LDDST), late-night serum cortisol and urine free cortisol (UFC)] were compared. Twenty-two patients were diagnosed as CS (12 overt CS and 10 SCS) and the remaining 120 patients were excluded for CS. The diagnostic accuracy of TSH ratio (cutoff value 1.0) yielded sensitivity 90.9% [95% confidence interval (CI) 70.8-98.9], specificity 95.0% (95% CI 89.4-98.1), and a high positive and low negative likelihood ratio [18.2 (95% CI 8.2-40.1) and 0.096 (95% CI 0.026-0.359), respectively]. The specificity of TSH ratio was significantly higher than LDDST and midnight serum cortisol test. The sensitivity of TSH ratio was significantly higher than UFC. TSH ratio showed more than 1.0 in all patients with depression and CYP3A4 inducer users. TSH ratio is a novel supportive diagnostic method with higher specificity than the current diagnostic methods for CS.

Equine hyperadrenocorticism: A report of 4 natural cases

Hyperadrenocorticism, the most common equine endocrinopathy, is the result of hyperplasia or a functional adenoma of the pars intermedia (intermediate lobe) of the pituitary gland. The study population included a 20-year old Irish hunting gelding (case 1), a 13-year old English Thoroughbred stud horse (case 2), an 18-year old intact male donkey (case 3) and a 22-year old mare belonging to a mixed breed (case 4). From a historical and clinical standpoint, the most common clinical signs were hypertrichosis (4/4), progressive loss of body weight (3/4), polyuria-polydipsia (3/4), laminitis (3/4), depression-lethargy (2/4), sway-back (lordosis) (2/4), pot-belly (2/4), bulging of the supraorbital region due to the excessive deposition of adipose tissue (2/4), hyperhidrosis (2/4) and delayed wound healing (2/4). The results of the routine laboratory testing showed lymphopenia (4/4), anemia (2/4), mature neutrophilia (1/4), monocytosis (1/4), hypertriglyceridemia (4/4), increased ALP activity (3/4), hypocalcemia (3/4) and hypoalbuminemia (2/4). Also, case 2 developed type III diabetes mellitus as a consequence of the disease. The diagnosis of hyperadrenocorticism, that was initially based on the classical clinical signs, noticed in all 4 animals, was further confirmed in 3 of them (cases 1, 3, 4) with the overnight dexamethasone suppression test. Oral bromocryptine (dopamine agonist), that was subsequently prescribed in two horses (cases 1, 4) resulted in a remarkable clinical improvement, first noticed in both animals approximately two months after the beginning of the treatment.

Incidence and risk factors for hypoadrenocorticism in dogs treated with trilostane

The aim of this study was to describe the incidence and permanence of hypoadrenocorticism associated with trilostane treatment and to assess potential risk factors for hypoadrenocorticism. A retrospective cohort study was conducted using case records for 156 dogs treated with trilostane after a diagnosis of hyperadrenocorticism. Occurrences of hypoadrenocorticism were categorised as either transient or permanent. After initiation of treatment with trilostane, the estimated cumulative incidence of hypoadrenocorticism was 15% by 2 years and 26% by 4.3 years, respectively. Occurrences of hypoadrenocorticism were transient in 14/19 (74%) affected study dogs. The risk of hypoadrenocorticism was not significantly associated with trilostane dose rate and other potential risk factors assessed were not significantly associated with subhazard of hypoadrenocorticism, but effect estimates for most were imprecise. In conclusion, approximately 15% of dogs being treated with trilostane developed hypoadrenocorticism within the first 2 years of treatment and about one quarter became affected by 4 years. However, first occurrences of hypoadrenocorticism were mostly transient. Over the range of dose rates studied, each 1mg/kg/day increase in trilostane dose rate resulted in, at most, only a small increase in the risk of developing hypoadrenocorticism.

Paraneoplastic Cushing Syndrome: A Sign of Occult Malignancy

SESSION TITLE: Metastatic and Other Primary Lung Tumors SESSION TYPE: Affiliate Case Report Poster PRESENTED ON: Tuesday, October 31, 2017 at 01:30 PM - 02:30 PM INTRODUCTION: Cushing Syndrome (CS) results from prolonged hypercortisolism. While often caused by iatrogenic administration of exogenous steroids or Cushing Disease, CS is also rarely caused by secretion of ACTH from ectopic sources, such as malignancies. Though rare - with ectopic ACTH secretion (EAS) accounting for only >15% of endogenous CS cases - diagnosis of CS can lead to earlier discovery of occult malignancy and increase potential for successful treatment. Clinicians therefore need a high degree of suspicion when faced with such presentations. CASE PRESENTATION: 57-yo man with CKD, CAD, HTN, DM and a long smoking history was admitted with respiratory failure due to CAP with dyspnea, weight gain, abdominal distention, and extremity weakness x 1 month. Physical exam showed reduced breath sounds over his right lower lung fields and abdominal obesity, but no Cushingoid appearance. He had marked refractory HTN. Labs showed profound hypokalemia with metabolic alkalosis, hypoxemia, hypercapnia and leukocytosis. CXR showed a right pleural effusion and basilar infiltrate. Elevated serum cortisol and ACTH levels helped diagnose CS. Abdominal CT showed no adrenal mass. Lab tests ruled out pheochromocytoma. A negative dexamethasone suppression test led to suspicion for EAS. CT Chest showed a mass with RML bronchial obstruction, mediastinal LAD and bilateral noncalcified lung nodules concerning for metastatic disease. While pleural fluid analysis showed a transudative effusion and microbiology was negative, cytology showed atypical cells suspicious for malignancy. Biopsy of the RML mass allowed for a unifying diagnosis of small cell carcinoma (SCLC) as the cause of the paraneoplastic CS. Chemotherapy was promptly started. DISCUSSION: Current standard practice for CS diagnostic work-up includes 8 mg dexamethasone suppression and CRH stimulation tests, inferior petrosal sinus sampling (IPPS), and imaging including CT, MRI, octreotide scans and venous sampling. In cases of EAS, the majority did not respond to CRH stimulation or dexamethasone suppression. IPPS was found most likely to identify the disease. Hypercortisol control treatments range from medications such as ketoconazole, metyrapone, or etomidate to surgical bilateral adrenalectomy. The highest rate of cure, up to 65%, came with the surgical removal of the ectopic ACTH-secreting neoplasm though recurrence was a possible complication. While cure in nonsurgical candidates is relatively rare, survival was common except in those cases of paraneoplastic CS caused by aggressive diseases. CONCLUSIONS: Though rare and difficult to recognize, Paraneoplastic CS may be the first sign of malignancy. While the source of EAS may be benign, it can be seen with SCLC, gastrinoma, medullary thyroid cancer and other such aggressive malignancies. Early identification may be lifesaving. Reference #1: Bertherat J. Cushing syndrome due to ectopic ACTH secretion. Orpha Net. 2012; ORPHA:99889 DISCLOSURE: The following authors have nothing to disclose: Vandana Pai, Kim Phung Nguyen, Jennifer Treece, Badar Siddiqui, Lisa McKinney-Smith No Product/Research Disclosure Information

Simultaneous assay of cortisol and dexamethasone improved diagnostic accuracy of the dexamethasone suppression test.

The overnight dexamethasone (DXM) suppression test (DST) has high sensitivity, but moderate specificity, for diagnosing hypercortisolism. We have evaluated if simultaneous measurement of S-DXM may correct for variable DXM bioavailability and increase the diagnostic performance of DST, and if saliva (sa) is a feasible adjunct or alternative to serum. Prospective study of DST was carried out in patients with suspected Cushing's syndrome (CS) (n = 49), incidentaloma (n = 152) and healthy controls (n = 101). Cortisol, cortisone and DXM were assayed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Three hundred and two subjects underwent DST; S-cortisol was ≥50 nmol/L in 83 patients, of whom 11 had CS and 27 had autonomous cortisol secretion. The lower 2.5 percentile of S-DXM in subjects with negative DST (n = 208) was 3.3 nmol/L, which was selected as the DXM cut-off level. Nine patients had the combination of low S-DXM and positive DST. Of these, three had been misdiagnosed as having autonomous cortisol secretion. DST results were highly reproducible and confirmed in a replication cohort (n = 58). Patients with overt CS had significantly elevated post-DST sa-cortisol and sa-cortisone levels compared with controls; 23 of 25 with autonomous cortisol secretion had elevated sa-cortisone and 14 had elevated sa-cortisol. Simultaneous measurement of serum DXM and cortisol reduced false-positive DSTs by 20% and improved the specificity. S-DXM >3.3 nmol/L is sufficient for the suppression of cortisol <50 nmol/L. Measurement of glucocorticoids in saliva is a non-invasive and easy procedure and post-DST sa-cortisone was found particularly useful in the diagnosis of CS.

Metabolomic Biomarkers in Urine of Cushing's Syndrome Patients.

Cushing’s syndrome (CS) is a disease which results from excessive levels of cortisol in the human body. The disorder is associated with various signs and symptoms which are also common for the general population not suffering from compound hypersecretion. Thus, more sensitive and selective methods are required for the diagnosis of CS. This follow-up study was conducted to determine which steroid metabolites could serve as potential indicators of CS and possible subclinical hypercortisolism in patients diagnosed with so called non-functioning adrenal incidentalomas (AIs). Urine samples from negative controls (n = 37), patients with CS characterized by hypercortisolism and excluding iatrogenic CS (n = 16), and patients with non-functioning AIs with possible subclinical Cushing’s syndrome (n = 25) were analyzed using gas chromatography-mass spectrometry (GC/MS) and gas chromatograph equipped with flame ionization detector (GC/FID). Statistical and multivariate methods were applied to investigate the profile differences between examined individuals. The analyses revealed hormonal differences between patients with CS and the rest of examined individuals. The concentrations of selected metabolites of cortisol, androgens, and pregnenetriol were elevated whereas the levels of tetrahydrocortisone were decreased for CS when opposed to the rest of the study population. Moreover, after analysis of potential confounding factors, it was also possible to distinguish six steroid hormones which discriminated CS patients from other study subjects. The obtained discriminant functions enabled classification of CS patients and AI group characterized by mild hypersecretion of cortisol metabolites. It can be concluded that steroid hormones selected by applying urinary profiling may serve the role of potential biomarkers of CS and can aid in its early diagnosis.

Incidence of Cushing’s syndrome in patients with significant hypercortisoluria

To investigate the incidence of Cushing's syndrome (CS) in patients with significant hypercortisoluria and the performance of urinary free cortisol (UFC) screening. Retrospective file review. The computerized database of a publicly funded health maintenance organization (HMO) in Israel was searched for all patients who underwent 24-h UFC testing in 2005-2014 with a result of more than twice the upper limit of normal (ULN). The patients' medical files were reviewed for a subsequent diagnosis of CS by an expert endocrinologist. Findings were evaluated for patterns in CS diagnosis and UFC testing over time. Of 41 183 individuals tested, 510 (1.2%) had UFC >2× ULN (214 >3× ULN). Eighty-five (16.7%) individuals were diagnosed with CS (63 female and mean age 47.2 ± 15.1 years), mainly Cushing's disease (55.3%) or adrenal Cushing's syndrome (37.6%). The number of UFC tests increased steadily, from 1804 in 2005 to 6464 in 2014; yet, the resultant detection rate of CS remained generally stable. The calculated incidence of CS in the general HMO-insured population based only on the patients identified in the present cohort was 4.5 new cases/million/year (median 4.9/million/year, range 1.7-5.9/million/year), which was also relatively stable. The most common reason for referral for UFC screening was obesity. Of the 148 patients before bariatric surgery with UFC >2× ULN, 2 were diagnosed with CS. The incidence of CS is higher than previously suggested. The consistently increasing number of UFC tests being performed has not been accompanied by a similar increase in CS detection rate. The expected yield of routine UFC testing before bariatric surgery is low.

Cushing's syndrome and pregnancy outcomes: a systematic review of published cases.

Pregnancy in Cushing's syndrome (CS) is extremely rare due to the influence of hypercortisolism on the reproductive axis. Purpose of this study is to investigate whether the etiology of CS in pregnancy determines a different impact on the fetal/newborn and maternal outcomes. We performed a systematic review of cases published in the literature from January 1952 to April 2015 including the words "Cushing AND pregnancy". We included 168 manuscripts containing 220 patients and 263 pregnancies with active CS during pregnancy and with a history of CS but treated and cured hypercortisolism at the time of gestation. Adrenal adenoma was the main cause of active CS during pregnancy (44.1 %). Women with active CS had more gestational diabetes mellitus (36.9 vs. 2.3 %, p = 0.003), gestational hypertension (40.5 vs. 2.3 %, p < 0.001) and preeclampsia (26.3 vs. 2.3 %, p = 0.001) than those with cured disease. The proportion of fetal loss in active CS was higher than in cured CS (23.6 vs. 8.5 %, p = 0.021), as well as global fetal morbidity (33.3 vs. 4.9 %, p < 0.001). The predictors of fetal loss in active CS were etiology of hypercortisolism [Odds Ratio -OR-for pregnancy-induced CS 4.7 (95 % Confidence Interval-CI 1.16-18.96), p = 0.03], publication period [OR for "1975-1994" 0.10 (95 % CI 0.03-0.40), p = 0.001] and treatment during gestation (p = 0.037, [OR medical treatment 0.25 (95 % CI 0.06-1.02), p = 0.052], [OR surgical treatment 0.34 (95 % CI 0.11-1.06), p = 0.063]). The period of diagnosis of CS (before, during or after pregnancy) was the only predictor of overall fetal morbimortality [OR for diagnosis during pregnancy 4.66 (95 % CI 1.37-15.83), p = 0.014]. Patients with active CS, especially in pregnancy-induced CS, experienced more problems in pregnancy and had the worst fetal prognosis in comparison to other causes. Diagnosis of CS during pregnancy was also associated with worse overall fetal morbimortality. Both medical treatment and surgery during pregnancy appeared to be protective in avoiding fetal loss.

Carbon dioxide combining power/potassium ratio in etiological diagnosis of Cushing's syndrome

Objective To evaluate carbon dioxide combining power/potassium ratio (CO2CP/K)in etiological diagnosis of Cushing's syndrome. Methods The clinical data 489 patients with pathohistologically confirmed Cushing's syndrome treated in PLA General Hospital between 1993 and 2015 were retrospectively reviewed. Among 489 patients, there were 246 cases of adrenocorticotropic hormone(ACTH) nondependent Cushing's syndrome and 243 cases of ACTH dependent Cushing's syndrome, including 214 cases of Cushing's disease (CD) and 29 cases of ectopic ACTH syndrome (EAS). Receiver operating characteristic(ROC) curve was used to evaluate efficacy of CO2CP/K for etiological diagnosis and the cut-off value and corresponding sensitivity and specificity were analyzed. Results Blood potassium levels were lower in ACTH nondependent group than those in ACTH dependent group[(3.46±0.77) vs.(3.69±0.57)mmol/L, t=3.433, P=0.001]. Bicarbonate, base excess and CO2CP/K (10.0±5.5 vs. 7.6±2.1) were higher in ACTH nondependent group than those in ACTH dependent group (t=-3.612, P=0.000). There was no significant difference in serum sodium, carbon dioxide binding force and pH value between two groups (P>0.05). Blood potassium [(2.47±0.63) vs.(3.62±0.67)mmol/L] and chlorine levels were lower in EAS group than those in CD group. Bicarbonate, base excess and CO2CP/K (15.6±8.0 vs. 7.8±2.4) were higher in EAS group than those in CD group (t=- 10.145, P=0.000). There was no significant difference in serum sodium, carbon dioxide binding force and PH value between two groups (P>0.05). Taking 8.95 as cut-off value the sensitivity and specificity of CO2CP/K in diagnosis of ACTH dependent Cushing's syndrome were 0.34 and 0.85, while taking 9.09 as cut-off value the sensitivity and specificity of CO2CP/K in diagnosis of EAS were 0.89 and 0.78, respectively. Conclusions The value of CO2CP/K is limited in distinguishing between ACTH dependent and non-ACTH independent Cushing, s syndrome. It may distinguish CD from EAS to some extent, indicating that it might be used as the screening method for etiological diagnosis. Key words: Cushing's syndrome; Hypokalemia; Etiology; Diagnosis; Adrenal gland neoplasms

A Probabilistic Model for Cushing's Syndrome Screening in At-Risk Populations: A Prospective Multicenter Study.

Cushing's syndrome (CS) is challenging to diagnose. Increased prevalence of CS in specific patient populations has been reported, but routine screening for CS remains questionable. To decrease the diagnostic delay and improve disease outcomes, simple new screening methods for CS in at-risk populations are needed. To develop and validate a simple scoring system to predict CS based on clinical signs and an easy-to-use biochemical test. Observational, prospective, multicenter. Referral hospital. A cohort of 353 patients attending endocrinology units for outpatient visits. All patients were evaluated with late-night salivary cortisol (LNSC) and a low-dose dexamethasone suppression test for CS. Diagnosis or exclusion of CS. Twenty-six cases of CS were diagnosed in the cohort. A risk scoring system was developed by logistic regression analysis, and cutoff values were derived from a receiver operating characteristic curve. This risk score included clinical signs and symptoms (muscular atrophy, osteoporosis, and dorsocervical fat pad) and LNSC levels. The estimated area under the receiver operating characteristic curve was 0.93, with a sensitivity of 96.2% and specificity of 82.9%. We developed a risk score to predict CS in an at-risk population. This score may help to identify at-risk patients in non-endocrinological settings such as primary care, but external validation is warranted.

Comparison of efficacy between the serum cortisol and 24 hour urine free cortisol in combined dexamethasone suppression test in the diagnosis of Cushing syndrome

To compare the sensitivity and specificity between the 24 hour urine free cortisol (24 h UFC) and serum cortisol in dexamethasone suppression test (DST) in the diagnosis of Cushing syndrome (CS). Combined low dose DST (LDDST) and high dose DST (HDDST) were carried out in 67 cases of CS with surgically confirmed cases in recent 3 years(from January 2011 to November 2015). The serum cortisol and 24 h UFC were collected simultaneously for each subject and the sensitivity and specificity of serum cortisol and 24 h UFC were compared. There were Cushing disease (CD) group (n=53), ectopic adrenocorticotropic hormone (ACTH) syndrome group (n=7) and ACTH-independent Cushing syndrome group (n=7) according to the etiology of hypercorticordism.There were no significant differences among 3 groups in gender and age.The sensitivity of serum cortisol of different cut off points(50, 110, 140 nmol/L and 50% of control)after LDDST was 97.01%, 86.57%, 83.58% and 70.15% respectively.Meanwhile, the sensitivity of cutoff point of 24 h UFC <32 nmol in combined LDDST was 92.54% in the diagnosis of Cushing syndrome.There was no significant differences in two groups between serum cortisol <110 nmol/L and 24 h UFC <32 nmol.However, the sensitivity of serum cortisol <50 nmol/L was significantly higher than 24 h UFC<32 nmol (P<0.05). Furthermore, in combined HDDST, if the suppression rate was ≥50%, the sensitivity of serum cortisol and 24 h UFC in differentiating the etiology of Cushing disease was 60.38% and 90.57%, and the specificity was 91.43% and 96.00% respectively.There were significant differences between serum cortisol and 24 h UFC in both of sensitivity and specificity (both P<0.05). In addition, if the suppression rate of 24 h UFC in HDDST was adjusted to 60.85% according to receiver operating characteristic (ROC) curve, it could have the best levels of sensitivity (92.6%) with the specificity of 85.7%. If the suppression rate of serum cortisol was adjusted to 61.53% in HDDST according to ROC curve, it could have the best sensitivity (64.8%) with the specificity of 78.6% accordingly. In combined LDDST, the serum cortisol <50 nmol/L had a higher sensitivity than the 24 h UFC<32 nmol when they were used as the criteria in determining the diagnosis of CS.In HDDST, the sensitivity and specificity of suppression rate of 24 h UFC ≥50% were better than serum cortisol to differentiate the etiology of CS.

Six controversial issues on subclinical Cushing's syndrome.

Subclinical Cushing's syndrome is a condition of hypercortisolism in the absence of signs specific of overt cortisol excess, and it is associated with an increased risk of diabetes, hypertension, fragility fractures, cardiovascular events and mortality. The subclinical Cushing's syndrome is not rare, being estimated to be between 0.2-2 % in the adult population. Despite the huge number of studies that have been published in the recent years, several issues remain controversial for the subclinical Cushing's syndrome screening, diagnosis and treatment. The Altogether to Beat Cushing's syndrome Group was founded in 2012 for bringing together the leading Italian experts in the hypercortisolism-related diseases. This document represents the Altogether to Beat Cushing's syndrome viewpoint regarding the following controversial issues on Subclinical Cushing's syndrome (SCS): (1) Who has to be screened for subclinical Cushing's syndrome? (2) How to screen the populations at risk? (3) How to diagnose subclinical Cushing's syndrome in patients with an adrenal incidentaloma? (4) Which consequence of subclinical Cushing's syndrome has to be searched for? (5) How to address the therapy of choice in AI patients with subclinical Cushing's syndrome? (6) How to follow-up adrenal incidentaloma patients with subclinical Cushing's syndrome surgically or conservatively treated? Notwithstanding the fact that most studies that faced these points may have several biases (e.g., retrospective design, small sample size, different criteria for the subclinical Cushing's syndrome diagnosis), we believe that the literature evidence is sufficient to affirm that the subclinical Cushing's syndrome condition is not harmless and that the currently available diagnostic tools are reliable for identifying the majority of individuals with subclinical Cushing's syndrome.

Investigation for Paediatric Cushing's Syndrome Using Twenty-Four-Hour Urinary Free Cortisol Determination

Objective: Paediatric Cushing's syndrome (CS) remains a challenge to diagnose and exclude. We assessed the accuracy of 24-hour urinary free cortisol (UFC) determination in children referred for suspected CS. Design: We conducted a retrospective study of paediatric patients referred to our centre with suspected CS between 1982 and 2014. Patients: Of 66 subjects (mean age 12.9 years; range 4.4-16.9), there were 47 cases of CS (29 males), which included Cushing's disease (CD; 39 patients, 25 males), primary pigmented nodular adrenocortical disease (8 patients, 4 males) and 19 ‘controls' (6 males) in whom the diagnosis of CS was excluded. Measurements: The subjects had between one and five 24-hour UFC collections analysed by radioimmunoassay, chemiluminescent immunoassay or liquid chromatography-mass spectrometry. The data were normalised, corrected for body surface area (m²) and assessed using receiver operating characteristic analysis and an independent two-tailed t test. Results: The diagnostic accuracy of 24-hour UFC for CS was excellent (area under the curve 0.98, 95% CI 0.946-1.00, sensitivity 89%, specificity 100%). Conclusions: Twenty-four-hour UFC is a reliable and practical investigation with high diagnostic accuracy for paediatric CS. However, further investigations may be required if the UFC is normal but there is a high diagnostic suspicion of CS.

Second-line tests in the differential diagnosis of ACTH-dependent Cushing's syndrome.

Diagnosing Cushing's syndrome (CS) can be a challenge, especially in ACTH-dependent CS, when it comes to detecting the origin of ACTH secretion. Retrospective data were collected on 170 patients with ACTH-dependent CS (149 CD, 21 EAS) referring to two endocrinology units, focusing on three non-invasive tests: dexamethasone 8mg overnight challenge (HDDST); corticotrophin-releasing hormone (CRH) assay and the desmopressin (DDAVP) test. Patients with EAS were slightly older and had higher ACTH, serum and urinary cortisol levels than patients with CD (p<0.01). CD patients had a stronger ACTH and cortisol response after CRH injection (p<0.0001), and a more pronounced reduction in cortisol levels after HDDST (p<0.0001). A threshold percentage ACTH increase after CRH stimulation of 72.4% was able to identify CD with a sensitivity (SE) of 76% (95% CI 68-83) and a specificity (SP) of 100% (95% CI 83-100). As for HDDST, a cortisol suppression >52.7% below the basal level suggested a pituitary origin with a SE of 88% (95% CI 81-93) and a SP of 90% (95% CI 68-99). There were no cases of EAS with positive responses to both these tests. Increases in ACTH and cortisol levels after the DDAVP test were also higher in CD than in EAS (p<0.01), though the SE and SP were lower. Patients with CD showed a stronger response to HDDST and CRH, and the adopted cut-offs showed a good SE and SP in discriminating them from patients with EAS. Concordant tests indicated CD when positive, whereas no response to either test was highly suggestive of EAS. The DDAVP test was of limited utility in the diagnostic phase. In conclusion, the choice of tests may play an important part in the differential diagnosis of ACTH-dependent CS.

Use of 3-Dimensional Volumetric Modeling of Adrenal Gland Size in Patients with Primary Pigmented Nodular Adrenocortical Disease.

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare type of bilateral adrenal hyperplasia leading to hypercortisolemia. Adrenal nodularity is often appreciable with computed tomography (CT); however, accurate radiologic characterization of adrenal size in PPNAD has not been studied well. We used 3-dimensional (3D) volumetric analysis to characterize and compare adrenal size in PPNAD patients, with and without Cushing's syndrome (CS). Patients diagnosed with PPNAD and their family members with known mutations in PRKAR1A were screened. CT scans were used to create 3D models of each adrenal. Criteria for biochemical diagnosis of CS included loss of diurnal variation and/or elevated midnight cortisol levels, and paradoxical increase in urinary free cortisol and/or urinary 17-hydroxysteroids after dexamethasone administration. Forty-five patients with PPNAD (24 females, 27.8±17.6 years) and 8 controls (19±3 years) were evaluated. 3D volumetric modeling of adrenal glands was performed in all. Thirty-eight patients out of 45 (84.4%) had CS. Their mean adrenal volume was 8.1 cc±4.1, 7.2 cc±4.5 (p=0.643) for non-CS, and 8.0cc±1.6 for controls. Mean values were corrected for body surface area; 4.7 cc/kg/m(2)±2.2 for CS, and 3.9 cc/kg/m(2)±1.3 for non-CS (p=0.189). Adrenal volume and midnight cortisol in both groups was positively correlated, r=0.35, p=0.03. We conclude that adrenal volume measured by 3D CT in patients with PPNAD and CS was similar to those without CS, confirming empirical CT imaging-based observations. However, the association between adrenal volume and midnight cortisol levels may be used as a marker of who among patients with PPNAD may develop CS, something that routine CT cannot do.

Nonsuppressible Oral Dexamethasone Suppression Tests but Not Cushing Syndrome.

In spite of the presence of definitive diagnostic criteria to diagnose Cushing syndrome diagnosis may become challenging. We report a young female with mild clinical features of Cushing syndrome, who had nonsuppressible oral dexamethasone suppression tests; also she had a suspicious pituitary lesion. She underwent pituitary surgery and a pituitary microadenoma (non-ACTH staining) was removed. Now she had come to us with similar complaints to those before. Again she had nonsuppressible oral dexamethasone suppression tests. As the diurnal variation of serum and salivary cortisol was maintained and urinary free cortisol was normal, further evaluation with IV dexamethasone suppression test was performed which clearly ruled out Cushing syndrome. The patient was not on any medicines known to alter dexamethasone metabolism. Fat malabsorption was also ruled out using appropriate tests. The reason for this discrepancy is thought to be altered (increased) metabolism of dexamethasone in this patient as it is widely variable in the general population.

Clinical manifestations and qualitative diagnosis of Cushing's syndrome in adolescence

Objective To analyze the clinical features and qualitative diagnosis methods of Cushing's syndrome (CS) in adolescence. Methods The clinical features and laboratory findings of 50 adolescent patients with CS admitted to the Department of Endocrinology, Peking Union Medical College Hospital from January 1990 to March 2012 were analyzed retrospectively. Results The age of medical treatment was 14±4 years. Male︰female=1.00︰1.17. Thirty-six adolescent patients (72%) had CS, and it was the most common cause. The proportions of the typical clinical manifestations, supraclavicular fat pads, moon face, centripetal obesity, and buffalo hump of the adolescent patients were more than 90%. The height of 63% adolescent patients with CS was below the third percentile, but the body mass of 42% adolescent patients was higher than the 75th percentile. Hypertension, osteoporosis, glucose metabolism disorder, and hyperlipidemia were also more common. If the 1.8 μg/dl cut-off point was used, the diagnostic sensitivity of midnight serum cortisol was the highest (100%); followed by the classic low-dose dexamethasone suppression test, 24 h urine free cortisol and overnight low-dose dexamethasone suppression test, their sensitivities were 95%, 88%, and 70%, respectively. Conclusions The most common cause is CS in adolescent patients with CS. The clinical manifestations are more typical, including dumpy figure, etc. When the midnight serum cortisol cut-off point is 18.8 μg/dl, its diagnostic sensitivity is the highest. Key words: Cushing's syndrome; Adolescent; Qualitative diagnosis; Sensitivity and specificity

Salivary cortisol and cortisone by LC–MS/MS: validation, reference intervals and diagnostic accuracy in Cushing's syndrome

BackgroundThe Endocrine Society recommends late-night salivary cortisol (LNS-F) as a first-line screening test for Cushing's syndrome (CS). In the parotid gland, 11β-hydroxysteroid dehydrogenase type 2 inactivates cortisol (F) to cortisone (E), a known source of interference in the more frequently used immunoassays. A highly specific method is mandatory in determining salivary F and E: it is widely accepted that liquid chromatography–tandem mass spectrometry (LC–MS/MS) is the best available technique for this purpose. MethodsA LC–MS/MS method with SPE of saliva samples was developed and validated. Appropriate awakening and bedtime reference ranges were established. The diagnostic performance for F, E and the ratio at bedtime was evaluated in 25 cases of CS. ResultsThe method was linear, with up to 55.4nmol/L and 51.0nmol/L, LLOQ of 0.51nmol/L and 0.55nmol/L, for F and E, respectively. Within-run and between-run imprecisions were <10% for both analytes. No ion suppression was observed. A cut-off of 2.4nmol/L for LNS-F yielded a sensitivity of 100% and a specificity of 98% in the diagnosis of CS. ConclusionsThe analytical performance of this method justifies its introduction into clinical practice, thus allowing clinicians the opportunity to further investigate CS and other endocrine diseases.

Screening Tests for Cushing's Syndrome: Urinary Free Cortisol Role Measured by LC-MS/MS.

As initial screening for Cushing's syndrome (CS), The Endocrine Society guidelines recommend one of the following: the 1-mg dexamethasone suppression test (DST) or late-night salivary cortisol (LNSC) or urinary free cortisol (UFC) measurement. We examined the diagnostic performance of the above-mentioned tests in a series of patients. We retrospectively analyzed 137 patients with clinical conditions suggestive of hypercortisolism: 38 with confirmed CS diagnosis and 99 without (termed non-CS). UFC was measured by liquid chromatography tandem-mass spectrometry, whereas LNSC by the radioimmunometric method and serum cortisol were measured by a chemiluminescence immunoassay. Comparing CS vs non-CS, a cutoff of 138 nmol/L after 1-mg DST revealed the best specificity (SP; 97%), whereas the 50-nmol/L cutoff confirmed the best sensitivity (SE; 100%); the SE and SP for LNSC greater than 14.46 nmol/L were, respectively, 84% and 89%, whereas the SE and SP for UFC greater than 170 nmol per 24 hours, they were 97% and 91%. Overall, UFC revealed both a combined higher positive and a lower negative likelihood ratio among first-line tests (respectively 10.7 and 0.03). Computing a receiver-operating curve -contrast analysis to compare the power of each single test with that of the others, alone or combined (DST+LNSC, DST+UFC, and LNSC+UFC) or with that of all the tests together (DST+LNSC+UFC), the UFC assay was at least as good as all the other possible combinations. Measuring UFC by liquid chromatography tandem-mass spectrometry achieves the best accuracy in diagnosing CS among patients presenting with suspected hypercortisolism.