The conundrum of differentiating Cushing's syndrome from non-neoplastic hypercortisolism: a systematic review and meta-analysis.

CONTEXT: Once hypercortisolemia is confirmed, differential diagnosis between Cushing's syndrome (CS) due to neoplastic endogenous hypercortisolism and non-neoplastic hypercortisolism (NNH, pseudo-Cushing's syndrome) is crucial. Due to worldwide corticotropin-releasing hormone (CRH) unavailability, accuracy of alternative tests to dexamethasone (Dex)-CRH, is clearly needed. OBJECTIVE: Assess the diagnostic accuracy of Dex-CRH test, desmopressin stimulation test, midnight serum cortisol (MSC), and late-night salivary cortisol (LNSC) levels to distinguish CS from NNH. METHODS: Articles through March 2022 were identified from Scopus, Web of Science, MEDLINE, EMBASE, and PubMed. All steps through the systematic review were performed independently and in duplicate and strictly adhered to the updated PRISMA-DTA checklist. DATA SYNTHESIS: A total of 24 articles (1900 patients) were included. Dex-CRH had a pooled sensitivity and specificity of 91% (95%CI 87-94%; I2 0%) and 82% (73-88%; I2 50%), desmopressin test 86% (81-90%; I2 28%) and 90% (84-94%; I2 15%), MSC 91% (85-94%; I2 66%) and 81% (70-89%; I2 71%), and LNSC 80% (67-89%; I2 57%) and 90% (84-93%; I2 21%), respectively. Summary receiver operating characteristics areas under the curve were Dex-CRH 0.949, desmopressin test 0.936, MSC 0.942, and LNSC 0.950 without visual or statistical significance. The overall risk of studies bias was moderate. CONCLUSION: Dex-CRH, the desmopressin stimulation test, and MSC have similar diagnostic accuracy, with Dex-CRH and MSC having slightly higher sensitivity, and the desmopressin test being more specific. LNSC was the least accurate, probably due to high heterogeneity, intrinsic variability, different assays, and lack of consistent reported cutoffs. When facing this challenging differential diagnosis, the results presented here should increase clinicians' confidence when deciding which test to perform.

The risk of COVID-19 in Cushing's disease is independently related to disease activity (hypercortisolism) and obesity.

Objective: To evaluate the cumulative incidence, risk factors, and outcomes of COVID-19 in patients with Cushing's disease (CD). Subjects and methods: In all, 60 patients with CD following up in our outpatient clinic answered via phone interview a questionnaire about the occurrence of COVID-19 infection documented by RT-PCR (including the diagnosis date and clinical outcome) and vaccination status. Clinical and biochemical data on disease activity (hypercortisolism) and comorbidities (obesity, diabetes mellitus, and hypertension) were obtained from the patients' electronic medical records. Risk ratios (RRs) of risk factors were obtained using univariate and multivariate analyses. Results: The cumulative incidence of COVID-19 in patients with CD during the observation period was 31.7%, which was higher than that in the general reference population (9.5%). The cumulative incidence of COVID-19 was significantly higher in patients with hypercortisolism (57% versus 17% in those without hypercortisolism, p = 0.012) and obesity (54% versus 9% in those without obesity, p < 0.001) but not in patients with hypertension or diabetes mellitus. On multivariate analysis, hypercortisolism and obesity were each independent risk factors for COVID-19 (RR 2.18, 95% CI 1.06-4.46, p = 0.033 and RR 5.19, 95% CI 1.61-16.74, p = 0.006, respectively). Conclusion: The incidence of COVID-19 in patients with CD was associated with hypercortisolism, as expected, and obesity, a novel and unexpected finding. Thus, correction of hypercortisolism and obesity should be implemented in patients with CD during the current and future COVID-19 outbreaks.

Accuracy of the 10 µg desmopressin test for differential diagnosis of Cushing syndrome: a systematic review and meta-analysis.

We evaluated the accuracy of the 10 µg desmopressin test in differentiating Cushing disease (CD) from non-neoplastic hypercortisolism (NNH) and ectopic ACTH syndrome (EAS). A systematic review of studies on diagnostic test accuracy in patients with CD, NNH, or EAS subjected to the desmopressin test obtained from LILACS, PubMed, EMBASE, and CENTRAL databases was performed. Two reviewers independently selected the studies, assessed the risk of bias, and extracted the data. Hierarchical and bivariate models on Stata software were used for meta-analytical summaries. The certainty of evidence was measured using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation Working Group) approach. In total, 14 studies were included: 3 studies on differentiated CD versus NNH and 11 studies on differentiated CD versus EAS. Considering ΔACTH in 8 studies involving 429 patients, the pooled sensitivity for distinguishing CD from EAS was 0.85 (95% confidence interval [CI]: 0.80-0.89, I2 = 17.6%) and specificity was 0.64 (95% CI: 0.49-0.76, I2 = 9.46%). Regarding Δcortisol in 6 studies involving 233 participants, the sensitivity for distinguishing CD from EAS was 0.81 (95% CI: 0.74-0.87, I2 = 7.98%) and specificity was 0.80 (95% CI: 0.61-0.91, I2 = 12.89%). The sensitivity and specificity of the combination of ΔACTH > 35% and Δcortisol > 20% in 5 studies involving 511 participants were 0.88 (95% CI: 0.79-0.93, I2 = 35%) and 0.74 (95% CI: 0.55-0.87, I2 = 27%), respectively. The pooled sensitivity for distinguishing CD from NNH in 3 studies involving 170 participants was 0.88 (95% CI: 0.79-0.93) and the specificity was 0.94 (95% CI: 0.86-0.97). Based on the desmopressin test for differentiating CD from EAS, considering ΔACTH, Δcortisol, or both percent increments, 15%, 19%, or 20% of patients with CD, respectively, would be incorrectly classified as having EAS. For CD versus NNH, 11% of patients with CD would be falsely diagnosed as having NNH, whereas 7% of patients with NNH would be falsely diagnosed as having CD. However, in all hierarchical plots, the prediction intervals were considerably wider than the confidence intervals. This indicates low confidence in the estimated accuracy, and the true accuracy is likely to be different. Systematic review registration: https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=85634, identifier CRD42018085634; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=68317, identifier CRD42017068317.

The risk of COVID-19 in Cushing's disease is independently related to disease activity (hypercortisolism) and obesity

ABSTRACT Objective: To evaluate the cumulative incidence, risk factors, and outcomes of COVID-19 in patients with Cushing's disease (CD). Subjects and methods: In all, 60 patients with CD following up in our outpatient clinic answered via phone interview a questionnaire about the occurrence of COVID-19 infection documented by RT-PCR (including the diagnosis date and clinical outcome) and vaccination status. Clinical and biochemical data on disease activity (hypercortisolism) and comorbidities (obesity, diabetes mellitus, and hypertension) were obtained from the patients' electronic medical records. Risk ratios (RRs) of risk factors were obtained using univariate and multivariate analyses. Results: The cumulative incidence of COVID-19 in patients with CD during the observation period was 31.7%, which was higher than that in the general reference population (9.5%). The cumulative incidence of COVID-19 was significantly higher in patients with hypercortisolism (57% versus 17% in those without hypercortisolism, p = 0.012) and obesity (54% versus 9% in those without obesity, p < 0.001) but not in patients with hypertension or diabetes mellitus. On multivariate analysis, hypercortisolism and obesity were each independent risk factors for COVID-19 (RR 2.18, 95% CI 1.06-4.46, p = 0.033 and RR 5.19, 95% CI 1.61-16.74, p = 0.006, respectively). Conclusion: The incidence of COVID-19 in patients with CD was associated with hypercortisolism, as expected, and obesity, a novel and unexpected finding. Thus, correction of hypercortisolism and obesity should be implemented in patients with CD during the current and future COVID-19 outbreaks.

Long-term efficacy and safety of osilodrostat in patients with Cushing's disease: results from the LINC 4 study extension.

Objective: To evaluate the long-term efficacy and safety of osilodrostat in patients with Cushing's disease. Methods: The multicenter, 48-week, Phase III LINC 4 clinical trial had an optional extension period that was initially intended to continue to week 96. Patients could continue in the extension until a managed-access program or alternative treatment became available locally, or until a protocol amendment was approved at their site that specified that patients should come for an end-of-treatment visit within 4 weeks or by week 96, whichever occurred first. Study outcomes assessed in the extension included: mean urinary free cortisol (mUFC) response rates; changes in mUFC, serum cortisol and late-night salivary cortisol (LNSC); changes in cardiovascular and metabolic-related parameters; blood pressure, waist circumference and weight; changes in physical manifestations of Cushing's disease; changes in patient-reported outcomes for health-related quality of life; changes in tumor volume; and adverse events. Results were analyzed descriptively; no formal statistical testing was performed. Results: Of 60 patients who entered, 53 completed the extension, with 29 patients receiving osilodrostat for more than 96 weeks (median osilodrostat duration: 87.1 weeks). The proportion of patients with normalized mUFC observed in the core period was maintained throughout the extension. At their end-of-trial visit, 72.4% of patients had achieved normal mUFC. Substantial reductions in serum cortisol and LNSC were also observed. Improvements in most cardiovascular and metabolic-related parameters, as well as physical manifestations of Cushing's disease, observed in the core period were maintained or continued to improve in the extension. Osilodrostat was generally well tolerated; the safety profile was consistent with previous reports. Conclusion: Osilodrostat provided long-term control of cortisol secretion that was associated with sustained improvements in clinical signs and physical manifestations of hypercortisolism. Osilodrostat is an effective long-term treatment for patients with Cushing's disease. Clinical trial registration: ClinicalTrials.gov, identifier NCT02180217.

Prevalence of hypersomatotropism and hyperthyroidism in cats with diabetes mellitus from referral centers in Buenos Aires (2020-2022).

OBJECTIVES: The aim of this study was to estimate the prevalence of hypersomatotropism (HST) and hyperthyroidism in cats with diabetes mellitus (DM) from referral centers in Buenos Aires, Argentina. METHODS: This was a prospective study. Systematic screening of serum insulin-like growth factor 1 (IGF-1) and total thyroxine was performed in all cats diagnosed with DM at referral centers in Buenos Aires between February 2020 and February 2022. RESULTS: In total, 154 diabetic cats were evaluated (99 males and 55 females; median age 12 years [range 3-21]; mean body weight 5 kg [range 2-12]). Altogether, there were 115 (75%) domestic shorthairs and one domestic longhair; the remaining 38 cats were purebred (mainly Siamese, n = 25 [16%]). Twenty (12.9%) cats had IGF-1 concentrations >1000 ng/ml, and three (1.9%) had IGF-1 concentrations between 800 and 1000 ng/ml along with pituitary enlargement on CT, resulting in a 14.9% HST prevalence rate in diabetic cats. Intracranial imaging was performed in all cats with HST; median pituitary dorsoventral height was 5.8 mm (range 3.1-9.5). Fourteen of 23 (61%) cats had phenotypic changes consistent with acromegaly at the time of diagnosis of HST. Four of 154 (2.5%) cats had concurrent hyperthyroidism. CONCLUSIONS AND RELEVANCE: To date, this is the first study outside of Europe to have evaluated the prevalence of HST and hyperthyroidism in cats with DM. In Buenos Aires referral centers, feline HST is the most common concurrent endocrinopathy in cats with DM but with a lower prevalence than has previously been reported. Hyperthyroidism is a rare concurrent endocrinopathy in diabetic cats from referral centers in Buenos Aires.

El reto diagnóstico de la enfermedad de Cushing en pediatría: reporte de casos / The diagnostic challenge of Cushing's disease in pediatrics: cases report

Introducción: la enfermedad de Cushing (EC) se debe sospechar en el paciente pediátrico con retraso del crecimiento, aumento de peso y fenotipo característico. Se sugiere iniciar el protocolo diagnóstico, que consiste en: comprobación de hipercortisolemia, sitio de producción del cortisol e imágenes, para finalmente realizar el tratamiento quirúrgico curativo. Reporte de casos: se presentan los casos de tres pacientes con alteración de la velocidad de crecimiento, aumento de peso y fenotipo característico. Se realiza la secuencia diagnóstica para demostrar el hipercortisolismo, posteriormente se confirma EC y se realiza imagen por resonancia magnética nuclear (RMN) de hipófisis. Finalmente se lleva a cabo el tratamiento quirúrgico curativo. Conclusiones: la EC en pediatría sigue siendo un desafío diagnóstico. Un abordaje para su detección inicia con la sospecha clínica asociada a una adecuada interpretación de los estudios bioquímicos e imágenes, lo que permite realizar un diagnóstico oportuno y un tratamiento curativo definitivo.

Summary Introduction: Cushing's disease (CD) should always be suspected in a pediatric patient with growth delay, excessive weight gain and characteristic phenotype. It is suggested to start a diagnostic protocol sequence: verification of hypercortisolism, production site and images, to finally perform the definitive curative surgical treatment. Case reports: We report three CD patients with altered growth velocity, weight gain and characteristic phenotype. The diagnostic sequence was performed to demonstrate hypercortisolism. CD was subsequently confirmed, and a pituitary nuclear magnetic resonance (NMR) was performed. All patients underwent curative surgery. Conclusion: CD in pediatrics continues to be a diagnostic challenge for the clinician. An approach with high initial clinical suspicion, associated with paraclinical studies and obtaining the adequate images, are necessary to make an accurate diagnosis and a definitive curative treatment.

Evaluation of ketoconazole as a treatment for Cushing's disease in a retrospective cohort.

Objective: The first-line treatment for Cushing's disease is transsphenoidal surgery, after which the rates of remission are 60 to 80%, with long-term recurrence of 20 to 30%, even in those with real initial remission. Drug therapies are indicated for patients without initial remission or with surgical contraindications or recurrence, and ketoconazole is one of the main available therapies. The objective of this study was to evaluate the safety profile of and the treatment response to ketoconazole in Cushing's disease patients followed up at the endocrinology outpatient clinic of a Brazilian university hospital. Patients and methods: This was a retrospective cohort of Cushing's disease patients with active hypercortisolism who used ketoconazole at any stage of follow-up. Patients who were followed up for less than 7 days, who did not adhere to treatment, or who were lost to follow-up were excluded. Results: Of the 172 Cushing's disease patients who were followed up between 2004 and 2020, 38 received ketoconazole. However, complete data was only available for 33 of these patients. Of these, 26 (78%) underwent transsphenoidal surgery prior to using ketoconazole, five of whom (15%) had also undergone radiotherapy; seven used ketoconazole as a primary treatment. Ketoconazole use ranged from 14 days to 14.5 years. A total of 22 patients had a complete response (66%), three patients had a partial response (9%), and eight patients had no response to treatment (24%), including those who underwent radiotherapy while using ketoconazole. Patients whose hypercortisolism was controlled or partially controlled with ketoconazole had lower baseline 24-h urinary free cortisol levels than the uncontrolled group [times above the upper limit of normal: 0.62 (SD, 0.41) vs. 5.3 (SD, 8.21); p < 0.005, respectively] in addition to more frequent previous transsphenoidal surgery (p < 0.04). The prevalence of uncontrolled patients remained stable over time (approximately 30%) despite ketoconazole dose adjustments or association with other drugs, which had no significant effect. One patient received adjuvant cabergoline from the beginning of the follow-up, and it was prescribed to nine others due to clinical non-response to ketoconazole alone. Ten patients (30%) reported mild adverse effects, such as nausea, vomiting, dizziness, and loss of appetite. Only four patients had serious adverse effects that warranted discontinuation. There were 20 confirmed episodes of hypokalemia among 10/33 patients (30%). Conclusion: Ketoconazole effectively controlled hypercortisolism in 66% of Cushing's disease patients, being a relatively safe drug for those without remission after transsphenoidal surgery or whose symptoms must be controlled until a new definitive therapy is carried out. Hypokalemia is a frequent metabolic effect not yet described in other series, which should be monitored during treatment.

Growth hormone (GH) deficiency and GH replacement therapy in patients previously treated for Cushing's disease.

Several complications associated with active Cushing's disease may persist even years after complete and successful therapeutic remission of hypercortisolism. Growth hormone deficiency (GHD) shares many clinical features seen in patients with Cushing's disease, and its presence after disease remission (GHD-CR) might negatively influence and potentially worsen the systemic complications caused by previous hypercortisolism. GHD-CR is more prevalent in women, and compared to other causes of GHD, patients are younger at the onset of the pituitary disease, at diagnosis of GHD-CR and at start of GH therapy; prevalence of pituitary macroadenomas and visual abnormalities are lower, while prevalence of diabetes, hypertension, low bone mass, fractures, and worst quality of life, are higher. Serum IGF-1 levels are not useful for the diagnosis of GHD-CR and the application of GH stimulating tests requires some special attention in addition to the general recommendations for detecting GHD from other etiologies. In patients with active hypercortisolism, GH secretion is completely suppressed, but it may spontaneously and progressively recover over the years following successful therapy, meaning that GH testing may be performed at an appropriate time after remission for the correct diagnosis. Moreover, if the patient presents concomitant adrenal insufficiency, GH testing should only be carried out under adequate cortisol replacement therapy. GH therapy in children with GHD-CR improves adult height in the majority of patients, while GH therapy in adults has been associated with improvements in body composition, lipid profile and quality of life, but also with worsening of glucose metabolism.

Randomized Trial of Osilodrostat for the Treatment of Cushing Disease.

CONTEXT: Cushing disease, a chronic hypercortisolism disorder, is associated with considerable morbidity and mortality. Normalizing cortisol production is the primary treatment goal. OBJECTIVE: We aimed to evaluate the safety and efficacy of osilodrostat, a potent, orally available 11ßhydroxylase inhibitor, compared with placebo in patients with Cushing disease. METHODS: LINC 4 was a phase III, multicenter trial comprising an initial 12-week, randomized, double-blind, placebo-controlled (osilodrostat:placebo, 2:1) period followed by a 36-week, open-label treatment period (NCT02697734). Adult patients (aged 18-75 years) with confirmed Cushing disease and mean urinary free cortisol (mUFC) excretion ≥ 1.3 times the upper limit of normal (ULN) were eligible. The primary endpoint was the proportion of randomized patients with mUFC ≤ ULN at week 12. The key secondary endpoint was the proportion achieving mUFC ≤ ULN at week 36 (after 24 weeks' open-label osilodrostat). RESULTS: Seventy-three patients (median age, 39 years [range, 19-67]; mean/median mUFC, 3.1 × ULN/2.5 × ULN) received randomized treatment with osilodrostat (n = 48) or placebo (n = 25). At week 12, significantly more osilodrostat (77%) than placebo (8%) patients achieved mUFC ≤ ULN (odds ratio 43.4; 95% CI 7.1, 343.2; P < 0.0001). Response was maintained at week 36, when 81% (95% CI 69.9, 89.1) of all patients achieved mUFC ≤ ULN. The most common adverse events during the placebo-controlled period (osilodrostat vs placebo) were decreased appetite (37.5% vs 16.0%), arthralgia (35.4% vs 8.0%), and nausea (31.3% vs 12.0%). CONCLUSION: Osilodrostat rapidly normalized mUFC excretion in most patients with Cushing disease and maintained this effect throughout the study. The safety profile was favorable.

Discriminative Capacity of CT Volumetry to Identify Autonomous Cortisol Secretion in Incidental Adrenal Adenomas.

CONTEXT: Incidentally discovered adrenal adenomas are common. Assessment for possible autonomous cortisol excess (ACS) is warranted for all adrenal adenomas, given the association with increased cardiometabolic disease. OBJECTIVE: To evaluate the discriminatory capacity of 3-dimensional volumetry on computed tomography (CT) to identify ACS. METHODS: Two radiologists, blinded to hormonal levels, prospectively analyzed CT images of 149 adult patients with unilateral, incidentally discovered, adrenal adenomas. Diameter and volumetry of the adenoma, volumetry of the contralateral adrenal gland, and the adenoma volume-to-contralateral gland volume (AV/CV) ratio were measured. ACS was defined as cortisol ≥ 1.8 mcg/dL after 1-mg dexamethasone suppression test (DST) and a morning ACTH ≤ 15. pg/mL. RESULTS: We observed that ACS was diagnosed in 35 (23.4%) patients. Cortisol post-DST was positively correlated with adenoma diameter and volume, and inversely correlated with contralateral adrenal gland volume. Cortisol post-DST was positively correlated with the AV/CV ratio (r = 0.46, P < 0.001) and ACTH was inversely correlated (r = -0.28, P < 0.001). The AV/CV ratio displayed the highest odds ratio (1.40; 95% CI, 1.18-1.65) and area under curve (0.91; 95% CI, 0.86-0.96) for predicting ACS. An AV/CV ratio ≥ 1 (48% of the cohort) had a sensitivity of 97% and a specificity of 70% to identify ACS. CONCLUSION: CT volumetry of adrenal adenomas and contralateral adrenal glands has a high discriminatory capacity to identify ACS. The combination of this simple and low-cost radiological phenotyping can supplement biochemical testing to substantially improve the identification of ACS.

Cushing's syndrome caused by intra-adrenocortical adrenocorticotropic hormone in a dog.

A 13-year-old Labrador retriever was diagnosed with Cushing's syndrome (CS) caused by primary bilateral nodular adrenocortical hyperplasia with adrenocorticotropic hormone (ACTH) expression. The pituitary origin of CS was ruled out by suppression of plasma ACTH concentration and absence of a proliferative lesion on histological evaluation of the pituitary gland using periodic acid-Schiff (PAS) staining, reticulin staining, and immunostaining for ACTH. A pheochromocytoma also was found at necropsy examination. On histological evaluation of both adrenal glands, at the junction of the fascicular and glomerular zones, multiple cell clusters distributed in both hyperplastic adrenal cortices expressed ACTH, whereas the pheochromocytoma cells did not. These results indicate that a disease similar to primary bilateral macronodular adrenocortical hyperplasia in humans also occurs in dogs, with intra-adrenocortical expression of ACTH, glucocorticoids excess, and clinical signs of CS. Therefore, the term ACTH-independent could be inappropriate in some cases of bilateral adrenocortical hyperplasia and suppressed plasma ACTH concentration in dogs.

Manifestaciones clínicas predictivas del diagnóstico del hipercortisolismo endógeno / Clinical Manifestations Predicting Endogenous Hypercortisolism

Introducción: El diagnóstico clínico del hipercortisolismo endógeno puede ser complejo si las manifestaciones clínicas no son patognomónicas. Es importante conocer cuáles son las distintivas en nuestros pacientes, que permitan diagnosticar la enfermedad de forma precoz. Objetivo: Determinar sensibilidad, especificidad y valor predictivo positivo de las manifestaciones clínicas para diagnosticar el hipercortisolismo endógeno. Métodos: Estudio descriptivo transversal. Grupo I: 65 pacientes con hipercortisolismo endógeno y grupo II (comparación): 75 con sospecha clínica de hipercortisolismo endógeno a los que se les descartó la enfermedad. Se estudiaron pacientes con diagnóstico de hipercortisolismo endógeno (2004-2017), atendidos en el Instituto de Endocrinología. Se determinaron los valores de sensibilidad, especificidad y valor predictivo positivo para el diagnóstico de hipercortisolismo endógeno de cada síntoma y signo por separado, así como para las combinaciones de tres manifestaciones clínicas; además se realizó una regresión logística binaria para identificar las combinaciones de sintomatologías que mejor predicen la presencia de hipercortisolismo endógeno. Se consideró diferencia estadística significativa con p ≤ 0,05. Resultados: La mayoría de los síntomas presentó una sensibilidad inferior al 45 por ciento. La circunferencia de la cintura fue el único signo que mostró alta sensibilidad (76,9 por ciento), baja especificidad (28,6 por ciento) con valor predictivo positivo de 42,0 por ciento. Cuando se presentan dos o tres de estos signos: rubicundez, cara de "luna llena" e hirsutismo la posibilidad de tener hipercortisolismo endógeno es 75,4 por ciento, con valor predictivo positivo de 71 por ciento y, cuando no están presentes la probabilidad de no tenerlo es de 77,5 por ciento. Conclusiones: La combinación de sensibilidad, especificidad y valor predictivo positivo de los síntomas y signos de forma aislada no predice el diagnóstico de la enfermedad; sin embargo, la presencia de dos o tres de los síntomas y/o signos tiene una elevada sensibilidad y valor predictivo positivo para el diagnóstico del hipercortisolismo endógeno. Las combinaciones que mejor predicen la posibilidad de tener un hipercortisolismo endógeno son: piel fina, edema y acné; cara de "luna llena", hirsutismo y rubicundez, así como "giba de búfalo", hematomas y estrías(AU)

ABSTRACT Introduction: The clinical diagnosis of endogenous hypercortisolism can be complex if clinical manifestations are not pathognomonic. It is important to know what are distinctive in our patients, which allows to diagnose the disease early. Objective: To determine the sensitivity, specificity and positive predictive value of clinical manifestations for diagnosis. of endogenous hypercortisolism. Methods: Descriptive and cross-sectional study. Group I was made up of 65 patients with endogenous hypercortisolism; group II (comparison) was made up of 75 patients with clinical suspicion of endogenous hypercortisolism, finally ruled out. We studied patients diagnosed of endogenous hypercortisolism from 2004 to 2017, treated at the Endocrinology Institute. Sensitivity, specificity and positive predictive values were determined for the diagnosis of endogenous hypercortisolism for each symptom and sign separately, as well as for the combinations of three clinical manifestations; in addition, binary logistic regression was performed to identify the combinations of symptoms that best predict the presence of endogenous hypercortisolism. A statistically significant difference was considered with p ≤ 0.05. Results: Most of the symptoms presented a sensitivity lower than 45 percent. Waist circumference was the only sign that showed high sensitivity (76.9 percent), low specificity (28.6 percent), and positive predictive value of 42.0 percent. When two or three of these signs (redness, "full-moon" face, and hirsutism) are present, the possibility of having endogenous hypercortisolism is 75.4 percent, with positive predictive value of 71 percent; and, when they are not present, the probability of not having it is 77,5 percent. Conclusions: The combination of sensitivity, specificity and positive predictive value of the symptoms and signs in isolation does not predict the diagnosis of the disease; however, the presence of two or three of the symptoms and/or signs has a high sensitivity and positive predictive value for the diagnosis of endogenous hypercortisolism. The combinations that best predict the possibility of having an endogenous hypercortisolism are thin skin, edema and acne; "full-moon" face, hirsutism and redness; as well as "buffalo hump," bruises and stretch marks(AU)

Diabetes, Active Disease, and Afternoon Serum Cortisol Levels Predict Cushing's Disease Mortality: A Cohort Study.

CONTEXT: Cushing's disease (CD) is a life-threating disease, with increased mortality in comparison with the general population. OBJECTIVE: This study aimed to evaluate standardized mortality ratios (SMRs) in CD patients. We also analyzed independent risk factors related to increased mortality. DESIGN: We conducted a longitudinal cohort study in a 3rd level specialty center, from 1979 to 2018, in patients with CD. RESULTS: From 1375 cases with a pathology diagnosis of pituitary adenoma, 191 cases had the confirmed diagnosis of CD (14%). A total of 172 patients completed follow-up, with a mean age at diagnosis of 33 ±â€…11 years, female predominance (n = 154, 89.5%), majority of them with microadenoma (n = 136, 79%), and a median follow-up of 7.5 years (2.4-15). Eighteen patients (10.5%) died, 8 of them (44%) were with active CD, 8 (44%) were under remission, and 2 (11%) were under disease control. Estimated all-cause SMR = 3.1, 95% confidence interval (CI) 1.9-4.8, P < 0.001. Cardiovascular disease was the main cause of death (SMR = 4.2, 1.5-9.3, P = 0.01). Multivariate Cox regression models adjusted for potential cofounders showed that diabetes (HR = 5.2, IC 95% 1.8-15.4, P = 0.002), high cortisol levels after 1600 hours at diagnosis (3.4, 2.3-7.0, P = 0.02), and active CD (7.5, 3.8-17.3, P = 0.003) significantly increased the risk of mortality. CONCLUSIONS: Main cause of CD mortality was cardiovascular disease. Main risk factors for mortality were uncontrolled diabetes, persistently high cortisol levels after 1600 hours at diagnosis, and active disease at last follow-up.

Canine endogenous adrenocorticotrophic hormone preanalytical stability after sample shipping in dry ice or recyclable ice bars / Estabilidade pré-analítica do hormônio adrenocorticotrófico endógeno canino após remessa de amostras em gelo seco ou com barras de gelo reciclável

ABSTRACT: Endogenous adrenocorticotrophic hormone (eACTH) measurement is useful in hypercortisolism and hypoadrenocorticism investigation; however, since the hormone is highly unstable, blood samples require proper processing and storage, as well as shipping is often a step limiting since few laboratories offer this assay in Brazil. The aim of this note was to compare overnight dog´s eACTH preanalytical stability when frozen samples were shipped in dry ice (DI), or with recyclable ice bars (RIB). A total of 56 paired samples for eACTH measurement were analyzed. Blood samples were properly handled, plasma aliquots transferred into plastic microtubes, and stored at -80ºC. The fifty-six paired samples were overnight shipped in two thermic isolated boxes with DI or involved by RIB. Despite there was a high correlation between results from both shipping methods (r Spearman = 0.958, P<0.001), the Wilcoxon matched-pairs rank test showed that the shipping method may influence results (P<0.001). However, this difference does not affect results interpretation. By this way, when DI shipping was not possible, RIB shipping may represent a risk to eACTH preanalytical stability.

RESUMO: A mensuração do hormônio adrenocorticotrófico endógeno (ACTHe) é útil na investigação do hipercortisolismo e hipoadrenocorticismo. No entanto, como o hormônio é bastante instável, as amostras de sangue necessitam um manejo adequado no processamento e armazenamento, assim como o envio para laboratórios pode ser um passo limitante, uma vez que poucos laboratórios oferecem este ensaio no Brasil. O objetivo deste trabalho foi comparar a estabilidade pré-analítica do ACTHe durante longo período de envio de amostras congeladas em gelo seco (GS), ou com barras de gelo reciclável (BGR). Um total de 56 amostras pareadas para mensuração de ACTHe foram analisadas. As amostras de sangue foram adequadamente manejadas, sendo o plasma transferido para micro tubos plásticos estocados a -80ºC. Os 56 pares de amostras foram enviados à tarde para chegada ao laboratório na manhã seguinte em dois isopores, um com GS e outro com BGR. Apesar de uma alta correlação entre os resultados dos diferentes métodos de envio (r Spearman = 0,958, P<0,001), o teste de Wilcoxon para amostras pareadas mostrou que o método de envio influencia os resultados P<0,001). Apesar desta diferença, os resultados não afetaram a interpretação dos resultados. Desta forma, quando o envio em gelo seco não for possível, o envio das amostras com barras de gelo reciclável pode representar um risco à estabilidade pré-analítica do ACTHe.

Canine endogenous adrenocorticotrophic hormone preanalytical stability after sample shipping in dry ice or recyclable ice bars / Estabilidade pré-analítica do hormônio adrenocorticotrófico endógeno canino após remessa de amostras em gelo seco ou com barras de gelo reciclável

Endogenous adrenocorticotrophic hormone (eACTH) measurement is useful in hypercortisolism and hypoadrenocorticism investigation; however, since the hormone is highly unstable, blood samples require proper processing and storage, as well as shipping is often a step limiting since few laboratories offer this assay in Brazil. The aim of this note was to compare overnight dog´s eACTH preanalytical stability when frozen samples were shipped in dry ice (DI), or with recyclable ice bars (RIB). A total of 56 paired samples for eACTH measurement were analyzed. Blood samples were properly handled, plasma aliquots transferred into plastic microtubes, and stored at -80ºC. The fifty-six paired samples were overnight shipped in two thermic isolated boxes with DI or involved by RIB. Despite there was a high correlation between results from both shipping methods (r Spearman = 0.958, P<0.001), the Wilcoxon matched-pairs rank test showed that the shipping method may influence results (P<0.001). However, this difference does not affect results interpretation. By this way, when DI shipping was not possible, RIB shipping may represent a risk to eACTH preanalytical stability.(AU)

A mensuração do hormônio adrenocorticotrófico endógeno (ACTHe) é útil na investigação do hipercortisolismo e hipoadrenocorticismo. No entanto, como o hormônio é bastante instável, as amostras de sangue necessitam um manejo adequado no processamento e armazenamento, assim como o envio para laboratórios pode ser um passo limitante, uma vez que poucos laboratórios oferecem este ensaio no Brasil. O objetivo deste trabalho foi comparar a estabilidade pré-analítica do ACTHe durante longo período de envio de amostras congeladas em gelo seco (GS), ou com barras de gelo reciclável (BGR). Um total de 56 amostras pareadas para mensuração de ACTHe foram analisadas. As amostras de sangue foram adequadamente manejadas, sendo o plasma transferido para micro tubos plásticos estocados a -80ºC. Os 56 pares de amostras foram enviados à tarde para chegada ao laboratório na manhã seguinte em dois isopores, um com GS e outro com BGR. Apesar de uma alta correlação entre os resultados dos diferentes métodos de envio (r Spearman = 0,958, P<0,001), o teste de Wilcoxon para amostras pareadas mostrou que o método de envio influencia os resultados P<0,001). Apesar desta diferença, os resultados não afetaram a interpretação dos resultados. Desta forma, quando o envio em gelo seco não for possível, o envio das amostras com barras de gelo reciclável pode representar um risco à estabilidade pré-analítica do ACTHe.(AU)

A New Insight into the Surgical Treatment of Primary Macronodular Adrenal Hyperplasia.

PURPOSE: This prospective study presents the results of a new approach in the treatment of primary macronodular adrenal hyperplasia (PMAH), with simultaneous total adrenalectomy of the larger adrenal gland and partial adrenalectomy of the contralateral adrenal gland (adrenal-sparing surgery). MATERIALS AND METHODS: We performed a prospective study including 17 patients with PMAH treated surgically with adrenal-sparing surgery in a tertiary referral hospital, with a median follow-up of 41 months. Clinical, hormonal, and genetic parameters were evaluated before surgery and during follow-up. All patients had at least 1 radiological examination before and after the procedure. RESULTS: Among the 17 patients, all but 1 patient had complete hypercortisolism control, and 12 recovered normal adrenal function after surgery. Significant improvement in clinical parameters was observed: weight loss (P = .004); reduction of both systolic (P = .001) and diastolic (P = .001) blood pressure; and reduction in the number of antihypertensive drugs (P < .001). Intra-, peri-, and postoperative complications were not observed. CONCLUSION: Adrenal-sparing surgery is a safe and feasible procedure to treat patients with PMAH, providing a substantial chance of hypercortisolism control without the disadvantages of lifetime corticosteroid replacement.

Bone Evaluation by High-Resolution Peripheral Quantitative Computed Tomography in Patients With Adrenal Incidentaloma.

CONTEXT: Data regarding high-resolution peripheral quantitative computed tomography (HR-pQCT) in patients with adrenal incidentaloma (AI) are unknown. PURPOSE: To evaluate the areal bone mineral density (aBMD), microstructure, and fractures in patients with nonfunctioning AI (NFAI) and autonomous cortisol secretion (ACS). METHODS: We evaluated 45 patients with NFAI (1 mg dexamethasone suppression test [DST] ≤1.8 µg/dL) and 30 patients with ACS (1 mg DST 1.9-5.0 µg/dL). aBMD was measured using dual-energy X-ray absorptiometry; vertebral fracture by spine X-ray; and bone geometry, volumetric bone mineral density (vBMD), and microstructure by HR-pQCT. RESULTS: Patients with ACS showed lower aBMD values at the spine, femoral neck, and radius 33% than those with NFAI. Osteoporosis was frequent in both groups: NFAI (64.9%) and ACS (75%). Parameters at the distal radius by HR-pQCT were decreased in patients with ACS compared to those with NFAI: trabecular vBMD (Tb.vBMD, P = 0.03), inner zone of the trabecular region (Inn.Tb.vBMD, P = 0.01), the bone volume/tissue volume ratio (BV/TV, P = 0.03) and trabecular thickness (P = 0.04). As consequence, a higher ratio of the outer zone of the trabecular region/inner zone vBMD (Meta/Inn.vBMD, P = 0.003) was observed. A correlation between the cortisol levels after 1 mg DST and Meta/Inn.vBMD ratio was found (r = 0.29; P = 0.01). The fracture frequency was 73.7% in patients with ACS vs 55.6% in patients with NFAI (P = 0.24). CONCLUSION: Our findings point to an association between trabecular bone microarchitectural derangement at the distal radius and ACS. Our data suggest that AI have a negative impact on bone when assessed by HR-pQCT, probably associated to subclinical hypercortisolism.

Correlation Between Size and Function of Unilateral and Bilateral Adrenocortical Nodules: An Observational Study.

OBJECTIVE. Adrenal incidentalomas occur in 5% of adults and can produce autonomous cortisol secretion that increases the risk of metabolic syndrome and cardiovascular disease. The objective of our study was to evaluate the relationship between adrenal nodule size measured on CT and autonomous cortisol secretion. SUBJECTS AND METHODS. In a prospective study of 73 patients 22-87 years old with incidentalomas, unilateral in 52 patients and bilateral in 21 patients, we measured maximum nodule diameter on CT and serum cortisol levels at 8:00 am, 60 minutes after the adrenocorticotropic hormone stimulation test, and after the dexamethasone suppression test. We also studied 34 age-, sex-, and body mass index-matched control subjects. Statistics used were Spearman correlation coefficients, t tests, ANOVA test, and multivariate analysis. RESULTS. The mean maximum diameter of unilateral nodules measured on CT was larger on the right (2.47 ± 0.98 [SD] cm) than on the left (2.04 ± 0.86 cm) (p = 0.01). In the bilateral cases, the mean diameter of the right nodules was 2.69 ± 0.93 cm compared with 2.13 ± 0.89 cm on the left (p = 0.06). Mean baseline serum cortisol level was significantly higher in the patients with incidentalomas (bilateral, 13.1 ± 4.5 mcg/dL [p < 0.001]; unilateral, 9.7 ± 3.2 mcg/dL [p = 0.019]) than in the control subjects (7.5 ± 3.6 mcg/dL). After dexamethasone suppression test, serum cortisol levels were suppressed to less than 1.8 mcg/dL in 100% of control subjects, 33% of patients with bilateral incidentalomas, and 62% of patients with unilateral incidentalomas (p < 0.001). There were significant correlations between maximum nodule diameter on CT and serum cortisol levels after the dexamethasone suppression test (ρ = 0.500; p < 0.001) and at baseline (ρ = 0.373; p = 0.003). CONCLUSION. Increasing size of adrenal nodules is associated with more severe hyper-cortisolism and less dexamethasone suppression; these cases need further evaluation and possibly surgery because of increased risks of metabolic syndrome and cardiovascular mortality.

Epidemiological, clinical, and laboratory aspects in a case series of canine hyperadrenocorticism: 115 cases (2010-2014) / Aspectos epidemiológicos, clínicos e laboratoriais em uma série de cães com hiperadrenocorticismo: 115 casos (2010-2014)

Diseases' clinical-epidemiological characterization assists in directing the diagnosis. The objective of this study was to describe epidemiological, clinical and laboratorial aspects of a case series of canine hyperadrenocorticism (HAC). One-hundred fifteen records of dogs diagnosed by the low dose dexamethasone suppression test and/or ACTH stimulation test were evaluated. Of the cases, 81.3% were HAC ACTH-dependent and 18.7% HAC ACTH-independent. Females were more affected, representing 69.3% of the cases. The mean age was 10.3±2.5 years and 64.9% were gonadectomized. Most of the patients were small size dogs, weighting less than 10kg (73.9%). The most frequent breeds were: Poodle (27%), Dachshund (17.4%), and Yorkshire Terrier (10.4%). The most frequent clinical manifestations were polyphagia (86%), polydipsia (82.6%), polyuria (80%), abdominal enlargement (82.6%), thin skin (79.1%), muscular weakness (78.3%) and panting (74.8%). However, eventually unusual HAC-associated signs would be present in some dogs in a more important way compared with the classic disease´s clinical signs. The CBC showed neutrophilia (66%), eosinopenia (58.3%) and lymphopenia (42.6%) as main hematological abnormalities. The most common findings in serum biochemistry were increased alkaline phosphatase activity (81.74%), increased ALT activity (62.6%), hypercholesterolemia (66%) and hypertriglyceridemia (54.7%). Urinalysis revealed hyposthenuria in 14.9% and isostenuria in 13.5%; besides proteinuria in 50% of the cases. Abdominal ultrasound showed bilateral adrenal hyperplasia (92.2%) with adrenal asymmetry in 20.8% of the cases, in addition to hepatomegaly (80.9%), biliary sludge (67.8%) and hepatic hyperechogenicity (47.8%). It was concluded that small size gonadectomized female dogs, mainly Poodles and Dachshunds, presented higher frequency in the population studied, and that the main changes observed in clinical and complementary tests were polyphagia, polyuria, polydipsia, abdominal enlargement, adrenal hyperplasia, increased phosphatase alkaline and hyperlipidemia. These results corroborated to a better disease characterization at Brazil. This work concluded that the population studied resembles the profile describe in European and North American epidemiologic studies, and that the HAC dog´s clinical picture looks similar worldwide.(AU)

A caracterização clínica-epidemiológica de doenças auxilia no direcionamento do diagnóstico. O objetivo deste trabalho foi descrever aspectos epidemiológicos, clínicos e laboratoriais de uma série de casos de hiperadrenocorticismo (HAC) canino. Foram avaliados 115 prontuários de cães diagnosticados pelo teste de supressão por baixa dose de dexametasona e/ou teste de estimulação com ACTH. Os casos de HAC ACTH-dependentes representaram 81,3% da população, e 18,7% foram ACTH-independentes. As fêmeas foram mais acometidas, representando 69,3% dos casos. A média de idade foi 10,3 ± 2,5 anos e 64,9% eram gonadectomizados. A maioria dos cães foi de porte pequeno, de até 10 kg (73,9%). As raças mais frequentes foram Poodle (27%), Dachshund (17,4%) e Yorkshire (10,4%). As manifestações clínicas mais relatadas foram polifagia (86%), polidipsia (82,6%), poliúria (80%), abdome pendular (82,6%), atrofia cutânea (79,1%), fraqueza muscular (78,3%) e dispneia (74,8%). Entretanto, eventualmente sinais clínicos pouco associados ao HAC se manifestaram de forma mais importante que os sinais clássicos da doença. O hemograma revelou neutrofilia (66%), eosinopenia (58,3%) e linfopenia (42,6%) como principais alterações hematológicas. Na bioquímica sérica foi observado aumento de fosfatase alcalina (81,74% dos casos), aumento da atividade da ALT (62,6%), hipercolesterolemia (66%) e hipertrigliceridemia (54,7%). A urinálise revelou hipostenúria em 14,9% e isostenúria em 13,5%; além de proteinúria em 50% dos casos. A ecografia abdominal evidenciou hiperplasia bilateral de adrenal (92,2%) com assimetria de adrenais em 20,8% dos casos, além de hepatomegalia (80,9%), lama biliar (67,8%) e hiperecogenicidade hepática (47,8%). Concluiu-se que fêmeas castradas de pequeno porte, principalmente das raças Poodles e Dachshunds, apresentaram maior frequência na população estudada e que as principais alterações observadas clínicas e nos exames complementares foram polifagia, poliúria, polidipsia, aumento abdominal, hiperplasia da adrenal, aumento de fosfatase alcalina e hiperlipidemia. Estes resultados corroboram para melhor caracterização da doença no Brasil. Este estudo concluiu que a população estudada se assemelha ao perfil populacional de cães com HAC descrito em estudos Europeus e Norte Americanos de forma que o perfil dos casos ao redor do globo parece similar.(AU)