The thrombotic risk in Cushing's syndrome-questions, answers, and the algorithm to consider in its assessment: part I-thrombotic risk not related to surgery.

Introduction: Recently, it has been reported that there is a great diversity in strategies used for thromboprophylaxis in patients with Cushing's syndrome (CS). An aim of this review was to discuss these practices in light of the existing data on the thrombotic risk in patients with CS and guidelines for medically ill patients. Methods: The four relevant topics and questions on thrombotic risk in CS were identified. The current guidelines on prevention and diagnosis of venous thromboembolism (VTE) were reviewed for the answers. An algorithm to consider in the assessment of the thrombotic risk in patients with CS was proposed. Results: To address both generic and CS-specific risk factors for VTE, the algorithm includes the stepwise approach consisting of Padua Score, urine free cortisol, and CS-VTE score, with no indication for routine thrombophilia testing in the prediction of an index VTE episode. Having confirmed VTE, selected patients require thrombophilia testing to aid the duration of anticoagulant treatment. The separate part of the algorithm is devoted to patients with ectopic adrenocorticotropic hormone syndrome in whom exclusion of VTE precedes introducing routine thromboprophylaxis to prevent VTE. The cancer-related VTE also prompts thromboprophylaxis, with the possible vessel invasion. The algorithm presents a unifactorial and multifactorial approach to exclude high-bleeding risks and safely introduce thromboprophylaxis with low-molecular-weight heparin. Summary: Our article is the first to present an algorithm to consider in the thrombotic risk assessment among patients with Cushing's syndrome as a starting point for a broader discussion in the environment. A plethora of factors affect the VTE risk in patients with CS, but no studies have conclusively evaluated the best thromboprophylaxis strategy so far. Future studies are needed to set standards of care.

Assessment of plasma dexamethasone levels after 1-mg dexamethasone suppression test in adults with obesity.

BACKGROUND: The 1-mg overnight dexamethasone suppression test is the most frequently used screening test for Cushing's syndrome. It has been proposed that people with obesity may have insufficient plasma dexamethasone levels for the test which may result in false positives. We sought to compare the plasma dexamethasone levels after 1-mg dexamethasone suppression test in healthy obese participants and in optimal-weight participants. METHODS: A total of 30 optimal-weight participants (BMI ≤ 25 kg/m2 ) and 62 obese participants (BMI > 25 kg/m2 ) were enroled in the study. Obese participants were further divided into class 1 (25-29.9 kg/m2 ) and class 2 (>30 kg/m2 ). After a standard overnight 1-mg dexamethasone suppression test, blood samples were obtained for serum cortisol and plasma dexamethasone levels. Plasma dexamethasone levels were quantified using liquid chromatography - mass spectrometry (LC-MS/MS). RESULTS: No significant difference in plasma dexamethasone levels were found between obese and optimal-weight participants (3.31 ± 1.35 vs. 2.82 ± 1.11 nmol/L, mean ± SD; p = .09 respectively). There were also no correlations found between sex, BMI, body surface area and plasma dexamethasone levels. There was also no significant difference in the proportion of participants who achieved a plasma dexamethasone level >3.3 nmol/L in comparison between obesity class 1, obesity class 2, and optimal-weight groups. CONCLUSION: Our results suggest that obesity does not affect plasma dexamethasone levels. However, dexamethasone measurement may still be helpful in patients who are being investigated for Cushing's syndrome and suspected to have a false-positive DST.

Toward Optimized and Cost-Efficient Protocols for Inferior Petrosal Sinus Sampling in the Diagnosis of Cushing Disease.

BACKGROUND AND OBJECTIVE: Conventional protocols for inferior petrosal sinus sampling (IPSS) during the workup of hypercortisolemia require adrenocorticotrophic hormone (ACTH) measurement at multiple time points with corticotropic-releasing hormone (CRH) used as a stimulator. Modernized evidence-based protocols must also reflect the increased utilization of desmopressin (DDAVP) for ACTH stimulation as the manufacturing shortage of traditionally used CRH continues. We model the diagnostic accuracy and potential economic savings of DDAVP utilization and reduced time point sampling. METHODS: A single-institution, retrospective review of patients undergoing IPSS between 2007 and 2021 was performed. A computational search for the minimal set of time points which preserves conventional diagnostic accuracy was performed by testing all 1 through 5-point combinations generated using a binomial expansion. Economic savings were modeled using a publicly available hospital chargemaster. RESULTS: A total of 50 patients qualified for inclusion, 47 of whom were diagnosed with Cushing disease and 3 with ectopic Cushing syndrome. Single-point diagnostic accuracy for DDAVP-stimulated tests was 71.4%-92.9%, and seven 2-point combinations (5-25 procedural minutes) were found, which preserved conventional diagnostic accuracy. Single-point accuracy for CRH-stimulated tests was 67.9%-89.3%, and two 2-point combinations ( t = -15, t = +2 and t = -15, t = +10) preserved accuracy. For every time point removed, the cost of ACTH laboratory tests was reduced by $507 from $3042 for 6-point IPSS). The shortest and most economical stimulator and time point combination that preserved conventional accuracy was DDAVP sampling at t = 0 and t = +5 or t = +2 and t = +5 minutes, which cost $2028 total compared with the most expensive 6-point IPSS option with CRH ($6392). CONCLUSION: DDAVP is a cost-efficient and effective alternative to CRH during IPSS. Our results encourage prospective evaluation of potentially fewer sampling time points in the interest of time and cost efficiency balanced with preserved accuracy.

Assessment of the diagnostic performance of the 1 mg dexamethasone suppression test in class 3 obese patients.

Objective. This study was aimed to evaluate the prevalence of Cushing's syndrome and the diagnostic performance of the 1 mg dexamethasone suppression test in class 3 obese patients. Methods. Anthropometric measurements and other laboratory data, including 1 mg dexamethasone suppression test of 753 class 3 obese patients, who applied to the Endocrinology and Metabolism Outpatient Clinic for the pre-bariatric surgery evaluation between 2011 and 2020, were evaluated retrospectively. Results. An abnormal response to the 1 mg dexamethasone suppression test (cortisol ≥1.8 mcg/dl) was observed in 24 patients and the presence of Cushing's syndrome was confirmed by additional tests in 6 patients. The prevalence of abnormal dexamethasone suppression test was 3.18% and the prevalence of Cushing's syndrome 0.79%. The specificity value was determined as 97.5% for 1 mg dexamethasone suppression test with cortisol threshold value ≥1.8 mcg/dl. Conclusions. The prevalence of Cushing's syndrome was found to be low in class 3 obese patients and 1 mg of dexamethasone suppression test had a very sufficient performance for Cushing's syndrome screening in this patient group.

Interpretation of Abnormal Dexamethasone Suppression Test is Enhanced With Use of Synchronous Free Cortisol Assessment.

CONTEXT: Interpretation of dexamethasone suppression test (DST) may be influenced by dexamethasone absorption and metabolism and by the altered cortisol binding. OBJECTIVE: We aimed to determine the normal ranges of free cortisol during DST in participants without adrenal disorders and to identify the population of patients where post-DST free cortisol measurements add value to the diagnostic workup. DESIGN AND SETTING: Cross-sectional study conducted in a tertiary medical center. PARTICIPANTS: Adult volunteers without adrenal disorders (n = 168; 47 women on oral contraceptive therapy [OCP], 66 women not on OCP, 55 men) and patients undergoing evaluation for hypercortisolism (n = 196; 16 women on OCP). MEASUREMENTS: Post-DST dexamethasone and free cortisol (mass spectrometry) and total cortisol (immunoassay). MAIN OUTCOME MEASURES: Reference range for post-DST free cortisol, diagnostic accuracy of post-DST total cortisol. RESULTS: Adequate dexamethasone concentrations (≥0.1 mcg/dL) were seen in 97.6% volunteers and 96.3% patients. Only 25.5% of women volunteers on OCP had abnormal post-DST total cortisol (>1.8 mcg/dL). In volunteers, the upper post-DST free cortisol range was 48 ng/dL in men and women not on OCP, and 79 ng/dL in women on OCP. When compared with post-DST free cortisol, diagnostic accuracy of post-DST total cortisol was 87.3% (95% CI, 81.7-91.7); all false-positive results occurred in patients with post-DST cortisol between 1.8 and 5 mcg/dL. OCP use was the only factor associated with false-positive results (21.1% vs 4.9%, P = 0.02). CONCLUSIONS: Post-DST free cortisol measurements are valuable in patients with optimal dexamethasone concentrations and post-DST total cortisol between 1.8 and 5 mcg/dL.

Assessment of non-traumatic vertebral fractures in Cushing's syndrome patients.

PURPOSE: Hypercortisolism has detrimental effects on bone metabolism with the consequences of bone loss and bone fractures. We aimed to evaluate the frequency of vertebral fragility fractures and to determine the factors associated with Cushing's syndrome (CS). METHODS: A total of 135 patients diagnosed with Cushing's syndrome [108 patients with Cushing's disease and 27 patients with adrenocortical adenoma] and 107 healthy controls were included in this cross-sectional study. The available clinical, laboratory, and radiologic data of patients with CS were recorded, retrospectively. Lateral vertebral radiograms were evaluated for vertebral fragility fractures according to Genant's semi-quantitative method. Bone mineral density (BMD) was determined using a Dual-energy X-ray absorptiometry (DEXA). RESULTS: Vertebral fragility fractures (VFs) were observed in 75.3% (n = 61) of the patients. The median number of VFs was six (min-max: 2-12). All patients with vertebral fractures had thoracic VF, and 50.7% of the patients had lumbar fragility fractures. Thirty-three (40.7%) patients with vertebral fractures had normal bone densitometry values. Osteoporosis and osteopenia were observed in 16.2% and 40.7% of the patients, respectively. The duration of active disease, the presence of ACTH-secreting pituitary adenoma, and 24-h urinary cortisol did not influence the presence of vertebral fractures. Vertebral fractures were independently associated with age, FSH, LH levels, and lumbar BMD (R2 = 68.18%, p = 0.028). The femoral neck BMD (but not lumbar BMD) was independently associated with age, BMI, and PTH levels (R2 = 48.48%, p < 0.001). CONCLUSION: Vertebral fracture frequency was higher in CS patients. Most of the patients with vertebral fractures had multiple fractures. Although low lumbar BMD was associated with VF, patients with CS with normal bone densitometry could experience VF. Vertebral radiograph evaluations as a part of routine evaluation for silent vertebral fractures may help to prevent further fractures in patients with CS.

Early assessment of postoperative adrenal function is necessary after adrenalectomy for mild autonomous cortisol secretion.

BACKGROUND: The diagnostic threshold for mild autonomous cortisol secretion using low dose, overnight, dexamethasone suppression testing is recognized widely as a serum cortisol ≥1.8 mcg/dL. The degree to which these patients require postoperative glucocorticoid replacement is unknown. METHODS: We reviewed adult patients with corticotropin (ACTH)-independent hypercortisolism who underwent unilateral laparoscopic adrenalectomy for benign disease with a dexamethasone suppression testing ≥1.8 mcg/dL at our institution from 1996 to 2018. Patients with a dexamethasone suppression testing of 1.8 to 5 mcg/dL were compared with those with a dexamethasone suppression testing >5 mcg/dL. RESULTS: We compared 68 patients with a preoperative dexamethasone suppression testing of 1.8 to 5 mcg/dL to 53 patients with a preoperative dexamethasone suppression testing >5 mcg/dL. Preoperative serum ACTH (mean 10.0 vs 9.2 pg/mL), adenoma size (mean 3.4 vs 3.5 cm), and side of adrenalectomy (37 and 47% right) were similar between groups (P > .05 each). Patients with a dexamethasone suppression testing 1.8 to 5 mcg/dL were older (mean values 58 ± 11 vs 52 ± 16 years ; P = .01), less likely to be female (63 vs 81%; P = .03), had greater body mass indexes (33.1 ± 8.4 vs 29.1 ± 5.6; P = .01), and had lesser 24 hour preoperative urine cortisol excretions (32.6 ± 26.7 vs 76.1 ± 129.4 mcg; P = .03). Postoperative serum cortisol levels were compared in 22 patients with a dexamethasone suppression testing of 1.8 to 5 mcg/dL to 14 patients with a dexamethasone suppression testing >5 mcg/dL. Those with dexamethasone suppression testing 1.8 to 5 mcg/dL had greater postoperative serum cortisol levels (8.0 ± 5.7 vs 5.0 ± 2.6 mcg/dL; P = .03), were less likely to be discharged on glucocorticoid replacement (59% vs 89%; P = .003), and had a decreased duration of treatment (4.4 ± 3.8 vs 10.7 ± 18.0 months; P = .04). CONCLUSION: Assessment of early postoperative adrenal function with mild autonomous cortisol secretion is necessary to minimize unnecessary glucocorticoid replacement.

Adrenal Venous Sampling for Assessment of Autonomous Cortisol Secretion.

Context: Autonomous cortisol secretion (ACS) can be unilateral or bilateral irrespective of the presence of an adrenal tumor. A reliable method to distinguish between unilateral and bilateral ACS is lacking. Objective: Evaluate the use of adrenal venous sampling (AVS) to distinguish between unilateral and bilateral ACS. Design and Methods: This was a prospective study of AVS in patients with adrenal tumors who received a diagnosis of ACS or adrenal Cushing syndrome (CS). Unilateral secretion was defined as >2.3-fold difference in cortisol levels between the two adrenal veins. Metanephrine levels were used to ascertain correct catheter position. Results were correlated with findings on CT and iodine-131-cholesterol scintigraphy. Results: Thirty-nine patients underwent AVS; there were no complications. The procedure was inconclusive in six patients and repeated with success in one, giving a success rate of 85%, and leaving 34 procedures for evaluation (adrenal CS, n = 2; ACS, n = 32). Of 14 patients with bilateral tumors, 10 had bilateral and 4 had unilateral overproduction. Of 20 patients with unilateral tumors, 11 had lateralization to the side of the tumor and the remaining had bilateral secretion. Cholesterol scintigraphy findings were concordant with those of AVS in 13 of 18 cases (72%) and discordant in 5 (28%). Conclusion: Laterality of ACS does not always correspond to findings on CT images. AVS is a safe and valuable tool for differentiation between unilateral and bilateral cortisol secretion and should be considered when operative treatment of ACS is a possibility.

Proopiomelanocortin interference in the measurement of adrenocorticotrophic hormone: a United Kingdom National External Quality Assessment Service study.

OBJECTIVE: It is recognized that measurement of ACTH-precursor peptides including proopiomelanocortin (POMC) has clinical utility in identifying the aetiology of Cushing's syndrome. Recent data have also demonstrated cross-reactivity of POMC in ACTH immunoassays used in clinical laboratories. The aim of this study was to assess the cross-reactivity of POMC in the main commercial immunoassays for ACTH and to survey the awareness of laboratory professionals to this potential interference. METHOD: To assess cross-reactivity, specimens containing ACTH and/or POMC were prepared by the UK National External Quality Assessment Service (UK NEQAS) [Edinburgh]. A separate interpretative exercise was also sent to participating laboratories. RESULTS: Eighty-seven laboratories measured 'total' ACTH (i.e. ACTH and/or POMC) in their assays. Cross-reactivity of POMC varied from a mean of 1·6-4·7% (reflected in a large percentage increase in measured ACTH of up to 261% due to POMC cross-reactivity) depending on the manufacturer. Major differences in the clinical interpretation of test results were observed in returned responses to the interpretative exercise. CONCLUSION: An appraisal of POMC cross-reactivity in currently available ACTH immunoassays has been achieved. Cross-reactivity was sufficient to detect ACTH precursors at concentrations that could be found in patients with ectopic ACTH syndrome. These data will assist laboratories in interpreting results when assessing the hypothalamic-pituitary-adrenal axis. Endocrinologists and laboratory professionals should be aware of the degree of cross-reactivity in ACTH immunoassay in order to minimize the risk of misinterpretation of results and/or potentially delayed treatment.

Incidence of Cushing's syndrome and Cushing's disease in commercially-insured patients <65 years old in the United States.

PURPOSE: To estimate the incidence of Cushing's syndrome (CS) and Cushing's disease (CD) in the US. METHODS: MarketScan Commercial database 2007-2010 (age <65 years) was used. CS patients were defined with ≥2 claims of CS diagnosis, while CD patients were defined with CS plus a benign pituitary adenoma diagnosis or hypophysectomy in the same calendar year. Annual incidence was calculated by dividing the number of CS or CD cases by the total number of members with the same enrollment requirement during the calendar years. RESULTS: CS incidence rates per million person-years were 48.6 in 2009 and 39.5 in 2010. The lowest rates of CS were in ≤17-year-olds and highest rates were in 35 to 44-year-olds. CD incidence rates were 7.6 in 2009 and 6.2 in 2010. The lowest rates of CD were in ≤17-year-olds and highest rates were in 18 to 24-year-olds. The rates varied by sex (2.3-2.7 in males, 9.8-12.1 in females). In females, lowest rates ranged 2.5-4.0 in ≤17-year-olds and highest 16.7-27.2 in 18-24 year olds. In males, there were too few cases to report estimates by age. CONCLUSIONS: In the first large US-based study, the annual incidence of CS in individuals <65 years old was nearly 49 cases per million, substantially higher than previous estimates, which were based primarily on European data. Using similar methods, we estimated the incidence of CD at nearly 8 cases per million US population. These estimates, if confirmed in other epidemiologic databases, represent a new data reference in these rare conditions.

Fracture risk assessment before and after resolution of endogenous hypercortisolism: is the FRAX® algorithm useful?

PURPOSE: Fracture risk data following curative treatment of Cushing's syndrome (CS) are scarce and the role of bisphosphonates in bone recovery after remission is controversial. We evaluated the effects of hypercortisolism remission in bone recovery in CS. Then, we assessed if the FRAX(®) algorithm calculated before the cure can predict fracture risk after cure. METHODS: Thirty-six patients with CS were retrospectively investigated. Bone turnover markers, bone mineral density (BMD) at the lumbar spine (L1-L4) and left femur (both neck and total hip were considered), and fracture risk using FRAX(®) algorithm with femoral neck BMD were evaluated at diagnosis and after a median follow-up of 24 months (range 12-108 months) from hypercortisolism remission. Data about bone active therapy were analyzed. RESULTS: Hypercortisolism remission was associated with the improvement of all densitometric parameters and with the reduction of fracture risk. The percentage change in BMD and the fracture risk were not significantly different in bisphosphonate-treated vs. untreated patients. During follow-up, three fractured patients at baseline exhibited a new vertebral fracture. A baseline 10-year probability of major osteoporotic fractures (FRAX(®) Major) of 17 % was able to predict the occurrence of a new vertebral fracture during follow-up after cure with 100 % sensitivity, 77 % specificity, 81 % positive predictive value and 100 % negative predictive value. CONCLUSIONS: Osteoporosis and fracture risk may be reversible after curative treatment of CS, regardless of bisphosphonate therapy. We suggest applying the FRAX(®) algorithm to all active CS patients using a baseline FRAX(®) Major of 17 % as "intervention threshold".

Electrochemical sensing of cortisol: a recent update.

Psychological stress caused by everyday lifestyle contributes to health disparities experienced by individuals. It affects many biomarkers, but cortisol - "a steroid hormone" - is known as a potential biomarker for psychological stress detection. Abnormal levels of cortisol are indicative of conditions such as Cushing's syndrome Addison's disease, adrenal insufficiencies and more recently post-traumatic stress disorder (PTSD). Chromatographic techniques, which are traditionally used to detect cortisol, are a complex system requiring multistep extraction/purification. This limits its application for point-of-care (POC) detection of cortisol. However, electrochemical immunosensing of cortisol is a recent advancement towards POC application. This review highlights simple, low-cost, and label-free electrochemical immunosensing platforms which have been developed recently for sensitive and selective detection of cortisol in bio-fluids. Electrochemical detection is utilized for the detection of cortisol using Anti-Cortisol antibodies (Anti-Cab) covalently immobilized on nanostructures, such as self-assembled monolayer (SAM) and polymer composite, for POC integration of sensors. The observed information can be used as a prototype to understand behavioral changes in humans such as farmers and firefighters. Keeping the future directions and challenges in mind, the focus of the BioMEMS and Microsystems Research Group at Florida International University is on development of POC devices for immunosensing, integration of these devices with microfluidics, cross validation with existing technologies, and analysis of real sample.

Adrenal incidentalomas.

The term adrenal incidentaloma (AI) is usually defined as an adrenal mass unexpectedly detected through an imaging procedure performed for reasons a priori unrelated to adrenal dysfunction or suspected dysfunction. The preferred approach to their management in terms of diagnosis, follow-up, and treatment remain controversial despite a state-of-the-science conference sponsored by the U.S. National Institutes of Health. Although most experts' recommendations tend to be relatively minor variations of the conference's approach, dissenting voices have been heard. Despite their frequent appearance, the challenge remains to recognize and treat the small percentage of AI that do pose a significant risk, either because of their hormonal activity or because of their malignant histology, while leaving the rest alone. Although the differential diagnosis of an incidentally discovered mass is quite extensive, most AIs are non-secreting cortical adenomas. The noninvasive differentiation of benign and malignant lesions depends upon imaging characteristics, and sometimes radiologic diagnosis can be definitive, but often it is not, Among function lesions, autonomous cortisol production seems to be the most common and may be associated with increased cardiovascular risk and clinical features of the "metabolic syndrome." Follow-up of cases in which a specific diagnosis is not made initially involves assessment for growth and development of hormonal function, but even here, controversy about the extent of evaluation persists.

Budget impact of using midnight salivary cortisol in the diagnosis of hypercortisolism.

BACKGROUND: A single midnight serum cortisol (MSC) test has been reported to possess the best sensitivity and specificity for diagnosing Cushing's syndrome (CS). However, this test requires patient hospitalization, making it costly. This paper aims to compare the hospital budget impact and accuracy of using midnight salivary cortisol (MSVC), as opposed to MSC, in the diagnosis of hypercortisolism. METHODS: 77 patients with at least two high urinary free cortisol (UFC) values (>360 nmol/24 h) were selected from 611 patients with clinical symptoms of CS. The costs of the method to confirm the diagnosis of hypercortisolism was calculated comparing Option A using MSC (UFCx2, low-dose dexamethasone suppression test [LDDST]) that requires patient hospitalization versus Option B using MSVC (UFCx2, LDDST) in which the evaluation is done outside the Hospital. A budget impact analysis for one year was developed, and a sensitivity analysis in different scenarios was performed. Reproducibility and diagnostic performance of MSVC and MSC were also measured. RESULTS: Salivary cortisol is a sound analytical method for evaluating free serum cortisol due to its classification accuracy, good imprecision, linearity, and stability. AUC(ROC) comparison between MSVC and MSC shows no significant differences. The substitution of the MSC for MSVC in our hospital could save between €16,762 and €132,804 in one year. CONCLUSIONS: The use of MSVC in the diagnosis of hypercortisolism can result in a substantial decrease in the budget impact, without losing diagnosis accuracy and reliability, a significant advantage considering the current emphasis on reducing the financial burden of health care.

High prevalence of subclinical hypercortisolism in patients with bilateral adrenal incidentalomas: a challenge to management.

OBJECTIVE: The prevalence of subclinical hypercortisolism (SH) in unilateral incidentalomas (UI) has been extensively studied; however, patients with bilateral incidentalomas (BI) have not been thoroughly investigated. We therefore aimed to describe the characteristics of patients with BI compared to their unilateral counterparts. The surgical outcome in a small number of patients is reported. DESIGN: Observational retrospective study in a single secondary/tertiary centre. PATIENTS: One hundred and seventy-two patients with adrenal incidentalomas (41 with BI). MEASUREMENTS: Morning cortisol (F), ACTH, dehydroepiandrosterone sulphate (DHEA-S), midnight F, 24-h urine collection for cortisol (UFC), low-dose dexamethasone suppression test (LDDST), fasting glucose, insulin, and oral glucose tolerance test (OGTT). Primarily, SH was defined as F-post-LDDST>70 nmol/l and one more abnormality; several diverse cut-offs were also examined. RESULTS: No difference was noted in age, body mass index, or prevalence of diabetes and impaired glucose tolerance between patients with UI and those with BI. Patients with BI had higher F-post-LDDST (119·3 ± 112·8 vs 54·3 ± 71·5 nmol/l, P<0·001) and lower DHEA-S (1·6 ± 1·5 vs 2·5 ± 2·3 µmol/l, P=0·003) but similar UFC, ACTH and midnight F levels, compared to UI. SH was significantly more prevalent in BI (41·5%vs 12·2%, P<0·001). Fourteen patients were operated on; four underwent bilateral interventions. In 10 patients, unilateral adrenalectomy on the side of the largest lesion resulted in significant improvement in F-post-LDDST (P=0·008) and a decrease in midnight F (P=0·015) levels. CONCLUSIONS: Subclinical hypercortisolism is significantly more prevalent in bilateral incidentaloma patients, posing great dilemmas for its optimum management.

Assessment of bilateral inferior petrosal sinus sampling in the diagnosis and surgical treatment of the ACTH-dependent Cushing's syndrome: a comparison with other tests.

BACKGROUND: Bilateral inferior petrosal sinus sampling (BIPSS), currently, is the gold standard test for the differential diagnosis of Cushing's syndrome (CS), but few data are available on the efficacy and accuracy of BIPSS in the qualitative diagnosis of ACTH-dependent CS and lateralization of Cushing's disease (CD); especially, the evaluation of BIPSS in all CD patients with transsphenoidal surgery (TSS). As a result, we investigated whether such invasive test compared other noninvasive tests may affect the efficacy and accuracy of diagnosis and TSS treatment in ACTH-dependent CS. OBJECTIVE: We investigated the efficacy and lateralized accuracy of diagnostic and therapeutic of BIPSS in ACTH-dependent CS. SETTINGS: A retrospective analysis was conducted at a single care center in Ruijin Hospital, Shanghai City. PARTICIPANTS: CD was confirmed by histopathology in one hundred and nineteen patients, include sixty-four patients with BIPSS procedure; and ectopic ACTH syndrome (EAS) also was histological confirmed in five patients. MAIN INTERVENTIONS AND OUTCOMES: Sixty-nine patients were all administrated with BIPSS test. Additionally, other noninvasive tests included endocrine examinations, low and high dose dexamethasone suppression test (LDDST and HDDST); imagine examinations include magnetic resonance imaging (MRI) and positron emission tomography and computerized tomography (PET-CT).Gradients of inferior petrosal sinus (IPS) to peripheral (IPS/P) ACTH were calculated before and after BIPSS procedure completed five minutes. RESULTS: In patients with proven pituitary cases, stringent response criteria in MRI and HDDST testing were fully by 51.6% and 60.3% respectively. While BIPSS, gave direct evidence of CD in 90.6% of these cases. The sensitivity for a basal IPS/P gradient greater than 2 was 89.1%, with 100% specificity and a diagnostic accuracy of 87.5%. A subgroup of 14 patients (all were CD) had contradictory responses to routine test with HDDST; while the sensitivity, specificity and accuracy of BIPSS were 100% respectively. Compared with the MRI and DST, we accepted Receiver Operating Characteristic (ROC) curve analysis showed that BIPSS performance is the best efficacy diagnosis tool in CS. In total, 57 of 64 patients with CD had an IPS/P gradient greater than 2, resulting in the sensitivity, specificity and diagnostic accuracy are 90.5%, 100%, 95.2% respectively. Additionally, the accuracy value of BIPSS in indicating dominant side should also be stressed in adenoma lateralization of CD. Finally, BIPSS test contributed most in the remission efficacy of TSS; then remission rate of underwent BIPSS group is 92.2% compared to the rate of 80% in without BIPSS group (p<0.01), Compared with other noninvasive tests, turn out the highest accuracy rate in remission. CONCLUSIONS: The application of BIPSS is associated with efficacy and accuracy of ACTH-dependent CS and lateralization of CD, what's more, all above, we can conclude that BIPSS is associated with the surgical therapy in CD patients. Therefore, BIPSS dedicate to the diagnosis, treatment and intraoperation administration of ACTH-dependent CS.

Specificity of first-line tests for the diagnosis of Cushing's syndrome: assessment in a large series.

CONTEXT: The diagnosis of Cushing's syndrome requires highly sensitive screening tests. Therefore, diagnostic cutoffs have been lowered to maximize sensitivity and identify all patients. However, few studies have investigated the impact of these refinements on the specificity of first-line tests. OBJECTIVE: The aim of the study was the assessment of the specificity of three widely used screening tests in a large series of Cushing's syndrome suspects referred to our endocrine service. PATIENTS: We retrospectively reviewed the results of urinary free cortisol (UFC), 1-mg dexamethasone suppression test [overnight suppression test (OST)], and serum cortisol at midnight in 3,461, 357, and 864 patients, respectively, with clinical features suggestive of Cushing's syndrome but in whom this diagnosis was subsequently excluded. RESULTS: UFC and OST at the 5-microg/dl cutoff exhibited the highest specificities [91% (95% confidence intervals [CI] 90.2-92.1%) and 97% (95% CI 96.3-98.5%), respectively]. Conversely, midnight serum cortisol yielded 87% (95% CI 84.3-91.1%) specificity only with the 7.5-microg/dl cutoff, whereas the 1.8-microg/dl threshold resulted in an unacceptably high proportion of false positives at only 20% specificity (95% CI 16.0-24.4%). Gender and age may lead to misleading results in all three screening tests. CONCLUSIONS: Specificity of tests for Cushing's syndrome varies considerably, with OST and UFC presenting the best performances, and circadian rhythm appearing heavily impaired by lowering of diagnostic cutoffs. Indeed, the vast majority of individuals in our series presented midnight serum cortisol values greater than 1.8 microg/dl; thus, caution has to be exercised when this criterion is used to exclude Cushing's syndrome.

Assessment of bilateral inferior petrosal sinus sampling (BIPSS) in the diagnosis of Cushing's disease.

BACKGROUND: The differential diagnosis of adrenocorticotropin (ACTH)-dependent Cushing's syndrome (CS) remains a challenging issue for clinical endocrinologists. In this respect, bilateral inferior petrosal sinus sampling (BIPSS) appears to be the most sensitive and specific test. Here, we report our 15-year experience of analyzing the performance of BIPSS, both in the correct diagnosis and in the precise lateralization of tumors in patients with Cushing's disease (CD). METHODS: Between 1992 and 2006, 18 patients with CD (16 females, 2 males; age range, 14-56 years) were admitted to Taipei Veterans General Hospital and subjected to BIPSS plus ovine corticotropin-releasing hormone (oCRH) stimulation. Four of them had previously undergone transsphenoidal hypophysectomy (TSH) and had a recurrence thereafter. BIPSS was performed by inserting a catheter in the right and left inferior petrosal sinus for ACTH assay via a femoral vein puncture. An inferior petrosal sinus/peripheral ACTH ratio (C/P ratio) > or = 2 at baseline > or = 3 after oCRH injection indicated a pituitary origin of ACTH secretion, and an interpetrosal ACTH gradient (IPS ratio) > or = 1.4 at baseline or after oCRH indicated evidence of lateralization. RESULTS: Positive BIPSS results were found in 16 patients at baseline and in 17 patients after oCRH injection. In 17 out of 18 patients, TSH was subsequently carried out and a pituitary source was confirmed on histopathologic examination. The only 1 false-negative test result was noted in a patient who had undergone previous TSH. Thus, the sensitivities of BIPSS for the diagnosis of CD before and after oCRH stimulation were 89% and 94%, respectively. Moreover, using an IPS ratio > or = 1.4 as a criterion, BIPSS correctly lateralized the tumor in 9 of 17 and 10 of 17 patients at baseline and after oCRH stimulation, respectively, including in 2 patients who had a centrally located tumor and who had an IPS ratio < 1.4. Thus, the sensitivities of lateralization of BIPSS were 53% and 59%, respectively. None of the 4 patients who had previous TSH were precisely localized by BIPSS. If these 4 patients were excluded, the sensitivities of BIPSS for localizing in the patients who had not undergone previous operation increased to 70% (9/13) at baseline and 77% (10/13) after oCRH stimulation, respectively. CONCLUSION: BIPSS combined with oCRH stimulation is a safe and reliable examination both in the differential diagnosis of CD and in the correct lateralization of pituitary microadenoma in patients without previous pituitary surgery. Nevertheless, this procedure may provide misleading results in patients who have received previous pituitary surgery.

External quality assessment of urinary steroid profile analysis.

BACKGROUND: Clinical samples were distributed on 10 occasions to six UK laboratories that perform urinary steroid profile analysis. Urine samples were from normal adult men and women, normal children and neonates. Samples from patients with Cushing's syndrome, virilization, adrenarche, obesity and congenital adrenal hyperplasia (21 and 17-hydroxylase defects) were also used for evaluation. METHODS: Samples were analysed by capillary column gas chromatography (all laboratories) after hydrolysis of conjugates and derivative formation (five laboratories) or by variation of 17-oxogenic steroid methodology (one laboratory). RESULTS: For each distribution of samples, the performance of the participants was compared for quantitative analysis, and user comments were summarized. Quantitative results showed variation without necessarily biasing the result. Comments varied considerably in length. The interpretations did not always lead to a clear diagnosis or advise about appropriate further tests. CONCLUSIONS: This pilot urine steroid profiling scheme has clearly identified the requirement for external quality assessment. It is now hoped to offer this scheme worldwide in collaboration with the European Research Network for the Evaluation and Improvement of Screening, Diagnosis and Treatment of Inherited Disorders of Metabolism (ERNDIM).