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.

Hipertensión arterial secundaria a enfermedad de Cushing. Reporte de Caso / Hypertension secondary to Cushing´s Disease. Report of a clinical case

INTRODUCCIÓN: La Enfermedad de Cushing es una de las causas menos prevalentes de hipertensión arterial secundaria (HTA) (0,7 a 2,4 casos por millón de personas), sin embargo conlleva un aumento de la morbi-mortalidad que se relaciona con el tiempo de exposición al exceso de corticoides 6, lo cual representa un problema debido a que la inespecificidad de los síntomas y su baja prevalencia, llevan a un retraso diagnóstico de 2 a 4 años 6, generando un incremento del riesgo cardiovascular pese a una resolución completa de la enfermedad 6-9. Este artículo tiene como objetivo describir la presentación clínica de la Enfermedad de Cushing como causa de HTA secundaria. CASO CLÍNICO: Paciente femenina de 36 años con HTA de 7 años de evolución, a quien se identificó adenoma hipofisario productor de ACTH, con posterior exéresis transesfenoidal parcial, presentando enfermedad persistente, en quien se optó manejo farmacológico a base de inhibidor de la esteroidogénesis para control de la enfermedad. DISCUSIÓN: La HTA es un problema de salud pública considerado el principal factor de riesgo para discapacidad y muerte prematura 2, con las causas secundarias como responsables de gran afectación en la calidad de vida, tomando en cuenta que estas son potencialmente curables. El manejo de la enfermedad de Cushing (EC) es principalmente quirúrgico 6,13-14, pero en caso de enfermedad persistente existen alternativas para control de la enfermedad 6,15-16, siendo los fármacos inhibidores de la esteroidogénesis los más usados. CONCLUSIONES: La EC es una causa poco frecuente hipertensión arterial secundaria, pero implica un importante compromiso de la calidad de vida, al igual que otras etiologías secundarias, por lo que es fundamental tener en cuenta las características clínicas y bioquímicas que sugieran una etiología secundaria que lleven a un diagnóstico y tratamiento oportunos.

INTRODUCTION: Cushing's Disease is one of the least prevalent causes of secondary hypertension (0.7 to 2.4 cases per million people), however it entails an increase in morbidity and mortality that is related to the chronic exposure of corticosteroids 6, which represents a problem because the no specificity of the symptoms and their low prevalence lead to a diagnostic delay of 2 to 4 years 6, increasing the cardiovascular risk despite complete resolution of the disease 6 -9. The purpose of this article aims to describe the clinical presentation of Cushing Disease (CD) as a cause of secondary hypertension. CLINICAL CASE: 36-year-old female patient with hypertension of 7 years of evolution, in whom an ACTH-producing pituitary adenoma was identified, with subsequent partial transsphenoidal excision, presenting persistent disease, in whom pharmacological management based on a steroidogenesis inhibitor was chosen. for disease control. DISCUSSION: Hypertension is a public health problem, considered the main risk factor for disability and premature death 2, with secondary causes responsible for great impact on quality of life, considering that these are potentially curative. The management of CD is mainly surgical 6,13-14, but in cases of persistent disease there are alternatives to control the disease 6,15-16, with steroidogenesis inhibitor drugs being the most used. CONCLUSIONS: CD is a rare cause of secondary hypertension, but it implies a significant compromise in quality of life, like other secondary etiologies, so it is essential to consider the clinical and biochemical characteristics that suggest a secondary etiology, which can lead to timely diagnosis and treatment.

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.

Germline PRKACA amplification-associated primary pigmented nodular adrenocortical disease: a case report and literature review.

Primary pigmented nodular adrenocortical disease (PPNAD) is a rare adrenocorticotropin hormone (ACTH)-independent Cushing's syndrome (CS). Pediatric patients with PPNAD typically have unusual skin lesions and slow growth with unknown causes. We present a case of a female Chinese patient with PPNAD caused by the germline PRKACA gene copy number gain of chromosome 19. The patient initially presented with kidney stones, short stature, and obesity. After further testing, it was discovered that the patient had diabetes, mild hypertension, low bone mass, a low ACTH level, and hypercortisolemia, and neither the low-dose or high-dose dexamethasone suppression test was able to inhibit hematuric cortisol, which paradoxically increased. PPNAD was pathologically diagnosed after unilateral adrenalectomy. Chromosome microarrays and whole exon sequencing analyses of the peripheral blood, as well as testing of sectioned adrenal tissue, showed a rise in the copy number of the duplication-containing PRKACA gene on chromosome 19p13.13p13.12, a de novo but not heritable gene defect that causes disease. The clinical signs and symptoms supported the diagnosis of Carney complex (CNC). One significant mechanism of CNC pathogenesis may be the rise in germline PRKACA copy number of chromosome 19. When assessing PPNAD patients for CNC, the possibility of PRKACA gene amplification should be considered. The effect of PRKACA gene amplification on the clinical manifestations of CNC needs to be confirmed by more cases.

The Role of the Adrenal-Gut-Brain Axis on Comorbid Depressive Disorder Development in Diabetes.

Diabetic patients are more affected by depression than non-diabetics, and this is related to greater treatment resistance and associated with poorer outcomes. This increase in the prevalence of depression in diabetics is also related to hyperglycemia and hypercortisolism. In diabetics, the hyperactivity of the HPA axis occurs in parallel to gut dysbiosis, weakness of the intestinal permeability barrier, and high bacterial-product translocation into the bloodstream. Diabetes also induces an increase in the permeability of the blood-brain barrier (BBB) and Toll-like receptor 4 (TLR4) expression in the hippocampus. Furthermore, lipopolysaccharide (LPS)-induced depression behaviors and neuroinflammation are exacerbated in diabetic mice. In this context, we propose here that hypercortisolism, in association with gut dysbiosis, leads to an exacerbation of hippocampal neuroinflammation, glutamatergic transmission, and neuronal apoptosis, leading to the development and aggravation of depression and to resistance to treatment of this mood disorder in diabetic patients.

Overnight 1-mg Dexamethasone Suppression Test for Screening Cushing Syndrome and Mild Autonomous Cortisol Secretion (MACS): What Happens when Serum Dexamethasone Is Below Cutoff? How Frequent Is it?

OBJECTIVE: To determine the frequency of "invalid" 1-mg overnight dexamethasone (Dex) suppression tests (DSTs) (1-mg DST) on a large series of patients investigated for hypercortisolism and examine the interference of substances and clinical conditions that may explain low serum Dex levels. METHODS: A retrospective analysis of 1300 Dex-controlled 1-mg DST applied to patients screened for Cushing syndrome or mild autonomous cortisol secretion in a single center for which there were identified invalid tests and distinctive characteristics that may have interfered with the outcome. RESULTS: Among all tests, 146 (11.2%) were considered invalid (serum Dex levels <140 ng/dL, 36 [24.7%] of which were undetectable [<19.5 ng/dL]). In the Dex-undetectable group, 17% failed to take Dex correctly, 25% were on glucocorticoids (GCs), and 20% were on anticonvulsants and moderate CYP3A4 inducers. In the remaining 110 tests (serum Dex 20-140 ng/dL), 6.5% did not take Dex or were using GC, 22% were on anticonvulsants or CYP3A4 inducers, and another 13% had previous gastrointestinal tract abnormalities impairing drug absorption. CONCLUSION: Inappropriately low serum Dex levels during the 1-mg DST may lead to false-positive results. This is associated with recurrent use of CYP3A4-inducing drugs and/or gastrointestinal abnormalities. When serum Dex is undetectable, the key reason is failure to take the medication or the use of GC (when cortisol is suppressed). Simultaneous measurement of serum cortisol and Dex allows for DST validation, improving its accuracy and avoiding unnecessary repetitions. Adherence to verbal/written recommendations and actual use of medication are critical for interpreting the test.

Enhancing Cushing's disease diagnosis: exploring the impact of desmopressin on ACTH gradient during BIPSS.

Introduction: The differential diagnosis between Cushing's disease (CD) and ectopic ACTH syndrome (EAS) is complex, and bilateral inferior petrosal sinus sampling (BIPSS) is considered the gold-standard test. However, BIPSS with corticotropin-releasing hormone (CRH) stimulation is rarely available. Objective: This retrospective cohort study aimed to assess the accuracy of the inferior petrosal sinus to peripheral ACTH gradient (IPS:P) before and after desmopressin stimulation for the differential diagnosis of ACTH-dependent Cushing's syndrome (CS), applying different cutoff values. Methods: A total of 50 patients (48 with CD and 2 with EAS) who underwent BIPSS were included in this study. The sensitivity and specificity of IPS:P in BIPSS before and after desmopressin stimulation were evaluated. Various cutoff values for IPS:P were examined to determine their diagnostic accuracy. Results: Using the traditional IPS:P cutoff, the sensitivity was 85.1% before stimulation, 89.6% after stimulation, and a combined sensitivity of 91.7%. Applying cutoff values of IPS:P >1.4 before and >2.8 after stimulation, the sensitivity was 87.2% and 89.6%, respectively, with a combined sensitivity of 91.7%. Receiver operating characteristic (ROC) curve analysis determined optimal cutoff values of 1.2 before stimulation and 1.57 after stimulation, resulting in a sensitivity of 93.6% and 93.8%, respectively, with a combined sensitivity of 97.9%. Specificity remained at 100% throughout all analyses. Among the 43 patients who responded positively to stimulation, 42 (97.7%) did so within the first three minutes, and all 43 (100%) did so within the first five minutes. None of the assessed clinical variables predicted the ACTH response to stimulation in BIPSS with statistical significance. Discussion: ACTH stimulation with desmopressin during BIPSS improves the accuracy of IPS:P, making it a valuable tool for investigating ACTH-dependent Cushing's syndrome. Considering the low risk of complications, we recommend the use of desmopressin stimulation during BIPSS for the differential diagnosis of ACTH-dependent CS.

Severe osteoporosis in a young man with bilateral Cushing's syndrome: a case report.

BACKGROUND: The diagnosis of Cushing's syndrome is challenging; however, through the clinical picture and the search for secondary causes of osteoporosis, it was possible to reach the diagnosis of the case reported. There was an independent, symptomatic ACTH hypercortisolism manifested by typical phenotypic changes, severe secondary osteoporosis and arterial hypertension in a young patient. CASE PRESENTATION: A 20-year-old Brazilian man with low back pain for 8 months. Radiographs showed fragility fractures in the thoracolumbar spine, and bone densitometry showed osteoporosis, especially when evaluating the Z Score (- 5.6 in the lumbar spine). On physical examination, there were wide violaceous streaks on the upper limbs and abdomen, plethora and fat increase in the temporal facial region, hump, ecchymosis on limbs, hypotrophy of arms and thighs, central obesity and kyphoscoliosis. His blood pressure was 150 × 90 mmHg. Cortisol after 1 mg of dexamethasone (24.1 µg/dL) and after Liddle 1 (28 µg/dL) were not suppressed, despite normal cortisoluria. Tomography showed bilateral adrenal nodules with more severe characteristics. Unfortunately, through the catheterization of adrenal veins, it was not possible to differentiate the nodules due to the achievement of cortisol levels that exceeded the upper limit of the dilution method. Among the hypotheses for the differential diagnosis of bilateral adrenal hyperplasia are primary bilateral macronodular adrenal hyperplasia, McCune-Albright syndrome and isolated bilateral primary pigmented nodular hyperplasia or associated with Carney's complex. In this case, primary pigmented nodular hyperplasia or carcinoma became important etiological hypotheses when comparing the epidemiology in a young man and the clinical-laboratory-imaging findings of the differential diagnoses. After 6 months of drug inhibition of steroidogenesis, blood pressure control and anti-osteoporotic therapy, the levels and deleterious metabolic effects of hypercortisolism, which could also impair adrenalectomy in the short and long term, were reduced. Left adrenalectomy was chosen, given the possibility of malignancy in a young patient and to avoid unnecessary definitive surgical adrenal insufficiency if the adrenalectomy was bilateral. Anatomopathology of the left gland revealed expansion of the zona fasciculate with multiple nonencapsulated nodules. CONCLUSION: The early identification of Cushing's syndrome, with measures based on the assessment of risks and benefits, remains the best way to prevent its progression and reduce the morbidity of the condition. Despite the unavailability of genetic analysis for a precise etiological definition, it is possible to take efficient measures to avoid future damage.

Ketoconazole as second-line treatment for Cushing's disease after transsphenoidal surgery: systematic review and meta-analysis.

Introduction: The first-line treatment for Cushing's disease is transsphenoidal surgery for pituitary tumor resection. Ketoconazole has been used as a second-line drug despite limited data on its safety and efficacy for this purpose. The objective of this meta-analysis was to analyze hypercortisolism control in patients who used ketoconazole as a second-line treatment after transsphenoidal surgery, in addition to other clinical and laboratory criteria that could be related to therapeutic response. Methods: We searched for articles that evaluated ketoconazole use in Cushing's disease after transsphenoidal surgery. The search strategies were applied to MEDLINE, EMBASE, and SciELO. Independent reviewers assessed study eligibility and quality and extracted data on hypercortisolism control and related variables such as therapeutic dose, time, and urinary cortisol levels. Results: After applying the exclusion criteria, 10 articles (one prospective and nine retrospective studies, totaling 270 patients) were included for complete data analysis. We found no publication bias regarding reported biochemical control or no biochemical control (p = 0.06 and p = 0.42 respectively). Of 270 patients, biochemical control of hypercortisolism occurred in 151 (63%, 95% CI 50-74%) and no biochemical control occurred in 61 (20%, 95% CI 10-35%). According to the meta-regression, neither the final dose, treatment duration, nor initial serum cortisol levels were associated with biochemical control of hypercortisolism. Conclusion: Ketoconazole can be considered a safe and efficacious option for Cushing's disease treatment after pituitary surgery. Systematic review registration: https://www.crd.york.ac.uk/prospero/#searchadvanced, (CRD42022308041).

Atrial myxoma and associated Cushing syndrome: Carney complex.

A 33-year-old woman with a history of high blood pressure since she was 8 years old, hypothyroidism, polycystic ovary syndrome, metabolic syndrome, multiple nevi, and a maternal family history of death at age 50 due to malignant high blood pressure and heart failure. Cushing's syndrome secondary to a secretory pituitary microadenoma was diagnosed, being the cause of secondary arterial hypertension, and ruling out other causes such as renal stenosis and coarctation of the aorta. A transthoracic and transesophageal echocardiogram was performed, which detected a left atrial myxoma. Given the presence of an atrial myxoma, Cushing's syndrome and polycystic ovary syndrome, a diagnosis of Carney Complex was made due to the presence of positive Stratakis criteria. The cardiac tumor was resected, and pathology confirmed that it was an atrial myxoma. She evolved clinically stable in outpatient controls in a 6-month follow-up. Resection of the pituitary microadenoma is planned as a curative treatment for Cushing's syndrome and arterial hypertension.

Mujer de 33 años, con antecedentes de hipertensión arterial desde los 8 años, hipotiroidismo, síndrome de ovario poliquístico, síndrome metabólico, nevos múltiples y antecedente familiar materno de muerte a los 50 años por hipertensión arterial maligna e insuficiencia cardiaca. Se diagnosticó síndrome de Cushing secundario a un microadenoma hipofisario secretor, siendo la causa de la hipertensión arterial secundaria, y descartándose otras causas como estenosis renal y coartación de aorta. Se realizó u n ecocardiograma transtorácico y transesofágico que detectaron un mixoma auricular izquierdo. Ante la presencia de un mixoma auricular, síndrome de Cushing y síndrome de ovario poliquístico se llegó al diagnóstico de Complejo de Carney por la presencia de criterios de Stratakis positivos. Se realizó la resección del tumor cardiaco, y la anatomía patológica confirmó que se trataba de un mixoma auricular. Evolucionó clínicamente estable en controles ambulatorios en un seguimiento de 6 meses, y se planifica la resección del microadenoma hipofisario como tratamiento curativo del síndrome de Cushing y la hipertensión arterial.

QT interval instability and variability in dogs with naturally-occurring hypercortisolism.

Hypercortisolism is one of the most common endocrine diseases in dogs. In humans, it is clearly associated with a higher risk of cardiovascular events, but studies in dogs are scarce. To investigate the arrhythmogenic risk of dogs with naturally-occurring hypercortisolism (NOHC), indices of variability and instability of the QT interval were retrospectively studied in 38 dogs with NOHC and prospectively studied in 12 healthy dogs: variance (QTv), total instability (TI), short-term (STI) and long-term (LTI), and mean (QTm). Except for QTm, all parameters studied were higher in the NOHC group than in the control group. In addition, STI and QTv showed moderate positive correlation with left ventricle wall thickness. The NOHC group was subdivided according to cortisol suppression pattern in the low-dose dexamethasone suppression test. All electrocardiographic indices of partial and absent suppression patterns were numerically higher than healthy dogs. QTv and TI were lower in the control group than in both NOHC subgroups. LTI and STI were lower in the CG than in the group with the partial suppression pattern. There was no statistical difference between sex groups in any of the electrocardiographic parameters studied. This result might indicate that the etiology of NOHC, and its consequent influence on hypothalamus-pituitary-adrenal axis could interfere on the heterogeneity of ventricular repolarization parameters in different ways, especially in the short-term and the long-term stability; however further studies are necessary to understand the role of cortisol on electrical instability in dogs.

["Herbalist" supplements maliciously expanding from Mexico to the world. Artriking and company]. / Complementos "herbolarios" expandiéndose maliciosamente de México para el mundo. Artriking y compañíal.

This letter aims to inform the medical community about herbal supplements that have steroidal and non-steroidal drugs hidden in their formulation, entailing risks to the health of consumers, in addition to the fact that they are not regulated at the local level and the producers of these supplements try to sell them internationally, which would bring serious consequences, since it would become a serious global health problem; these supplements have provoked Cushing's syndrome, diabetes mellitus, sepsis, pneumonitis and invasive helminthiasis.

La presente carta pretende informar a la comunidad médica sobre los complementos herbolarios que tienen de manera oculta en su formulación fármacos esteroideos y no esteroideos, lo cual conlleva riesgos a la salud de los consumidores, además de que no hay una regulación de los mismos a nivel local y quienes los producen buscan que se diseminen en forma global, lo cual traería consecuencias graves, dado que se convertiría en un problema de salud pública mundial; estos complementos han condicionado síndrome de Cushing, diabetes mellitus, sepsis, neumonitis y helmintiasis invasivas.

Cardiovascular indicators and mitral valve disease in dogs with spontaneous hypercortisolism - prospective evaluation

Background: Canine hypercortisolism (HC) is the most prevalent endocrinopathy in dogs in southern Brazil. The prognosis depends on several factors including the general health status, owners´ commitment, and the development of disease complications and comorbidities occurrence, such as cardiovascular complications including mitral valve disease (MVD), systemic arterial hypertension, and left ventricular hypertrophy. The main objective of the present study was to assess cardiovascular parameters in canine HC, based on investigating survival-related variables. The study also aimed to evaluate the influence of concurrent preclinical (MVD) on dogs` survival and the impact of HC on MVD progression. Materials, Methods & Results: A total of 25 dogs with spontaneous HC were enrolled and divided into 2 subgroups accordingly to their echocardiographic findings: group HC (normal echocardiography at first evaluation, n = 16); and group HC + MVD (concurrent presence of stages B1 and B2 MVD diagnosed at the first evaluation, n = 9). The patients were evaluated at diagnosis (T0); 6 months after treatment begging (T1); and after 12 months of treatment (T2). The owners were further contacted by phone or e-mail for 1 more year after T2 regarding survival information. A control group (CG, n = 20) was also evaluated at T0 and T1. At each evaluation, dogs were submitted to a complete clinical evaluation and physical exam, associated with a minimum database (CBC, serum biochemistry, and urine analysis) and cardiovascular evaluation composed of systolic blood pressure determination, electrocardiogram (ECG), and echodopplercardiography. In the HC group, 11/16 dogs underwent the evaluation at T2, while 4/9 dogs from the HC + MVD group and 17/20 dogs from the CG underwent the evaluation at T2. Five dogs (31.25%) from the HC group and 4 dogs (44.44%) from the HC + MVD group died before the end of the follow-up period. In the control group, only 1 dog (5.26%) died before the end of the study. Despite the higher mortality in the HC + MVD group during the follow-up period, there was no significant difference (P = 0.632) in survival when compared with the HC group. The MVD of 4 dogs included in the HC + MVD group was classified as stage B1, while the other 5 dogs were classified as stage B2. Only 1 dog from the CG developed stage B1 MVD in the period studied; however, progression of the MVD stage was documented in 1/4 of dogs in the HC + MVD group and MVD development was documented in 3/11 of dogs from the HC group from T0 to T2. The odds ratio (OR) and respective 95% confidence interval (95%CI) for HC as a risk factor for MVD progression were 4.267 (0.4268 - 42.65; P = 0.342). Exercise intolerance (12/16 dogs) and dyspnea (6/16 dogs) were the cardiorespiratory clinical signs with the highest incidence in the HC group at T0. When compared to the control group, both exercise intolerance (P < 0.001) and dyspnea (P = 0.03) occurrence were significantly higher in the HC group. The age (P = 0.001) and the occurrence of dyspnea (P = 0.036) at diagnosis were significantly higher in dogs with HC that died during the follow-up than those that remained alive. Regarding the occurrence of cardiac arrhythmias verified by ECG, no statistically significant differences were observed among groups. Discussion: The study suggests that systemic hypertension and altered echocardiographic measurements did not interfere with dogs' survival; however, dyspnea was associated with a worse prognosis. Finally, it is possible to conclude that mitral valve degeneration is a common comorbidity in dogs with HC, however, it was not evidenced their interference in the survival of dogs with this endocrine disease or even a role of the HC in the progression of the MVD.

The promising role of risk scoring system for Cushing syndrome: Time to reconsider current screening recommendations.

Despite the current screening approach for Cushing syndrome (CS), delayed diagnosis is common due to broad spectrum of presentation, poor discriminant symptoms featured in diabetes and obesity, and low clinical index of suspicion. Even if initial tests are recommended to screen CS, divergent results are not infrequent. As global prevalence of type 2 diabetes and obesity increases, CS may not be frequent enough to back routine screening to avoid false-positive results. This represents a greater challenge in countries with limited health resources. The development of indexes incorporates clinical features and biochemical data that are largely used to provide a tool to predict the presence of disease. In clinical endocrinology, indexes have been used in Graves' ophthalmology, hirsutism, and hypothyroidism. The use of clinical risk scoring system may assist clinicians in discriminating CS in the context of at-risk populations and, thus, may provide a potential intervention to decrease time to diagnosis. Development and validation of clinical model to estimate pre-test probability of CS in different geographic source population may help to establish regional prediction model for CS. Here, we review on the latest progress in clinical risk scoring system for CS and attempt to raise awareness for the use, validation, and/or development of clinical risk scores in CS.

Preparation of ICD and overdenture in patients with Cushing's Syndrome: five-year follow-up / Preparo de PTI e overdenture em pacientes com Síndrome de Cushing: cinco anos de acompanhamento

The aim of this study is to report a clinical case of a patient with Cushing's syndrome, low self-esteem and need for oral rehabilitation. A 50-year-old female patient with hypercortisolism sought care at School of Dentistry of the Federal University of Minas Gerais. During anamnesis, the patient reported painful symptoms and mobility of the upper and lower teeth. On clinical examination, absence of many teeth were observed, periodontal disease and caries lesions. After discussion of the case, the planning involved the extraction of all teeth, and the preparation of Maxillary Immediate Complete Dentures (ICD's) and Immediate Mandibular Implant-retained Overdenture (IMIO). The treatment proposed allowed the restored aesthetics, phonetics and chewing(AU)

O objetivo desse estudo é relatar um caso clínico de uma paciente com síndrome de Cushing, baixa autoestima e necessidade de reabilitação oral. Paciente do sexo feminino, 50 anos de idade e com hipercortisolismo, procurou atendimento na Faculdade de Odontologia da Universidade Federal de Minas Gerais. Durante a anamnese, a paciente relatou sintomas dolorosos e mobilidade dos dentes superiores e inferiores. No exame clínico, foi observada a ausência de muitos dentes, doença periodontal e lesões cariosas. Após a discussão do caso, o planejamento envolveu a extração de todos os dentes, e o preparo de Prótese Total Imediata maxilar (PTI), e Overdenture Implantorretida Imediata mandibular. O tratamento proposto permitiu que restaurasse a estética, fonética e mastigação(AU)

Evidence of Cushing's syndrome in a pre-Columbian Mexican statue?

INTRODUCTION: In the absence of skeletons or written narrations, information about diseases in past societies may be acquired from icono-diagnosis. From the observation of a masterpiece presenting pathological features, we tried to make retrospective diagnosis. MATERIAL AND METHOD: A pre-Columbian Mexican statuette originating from the Chupicuaro culture and dated 600 BC to 200 AD - conserved in the Louvre Museum in Paris (Section of the quai Branly - Jacques Chirac museum) was examined; it was found to display a huge spinal curvature with excessive dorsal kyphosis and obesity. RESULTS: The appearance of the figurine with large head, shortened stature and limbs, may suggest a form of dwarfism; however, many statuettes in the Chupicuaro culture were found displaying large head and relatively short limbs, suggesting that these pictorial features are more of an artistic style. On the contrary, uncommon kyphosis and obesity led us to diagnose a case of either Pott disease associated with neuro-endocrine complications, or of Cushing's disease. CONCLUSION: Although icono-diagnosis could have allowed us to contribute to the health mapping of ancient Americas and propose the presence of complicated tuberculosis in central Mexico between 600 BC and 200 AD, we believe "Choupi" portrays here an individual having suffered from hypercortisolism (Cushing's disease). Even though considerations related to cultural and artistic context may constitute limitations to interpretation, iconotopsy/iconodiagnosis are important for a better description of the natural history of diseases, as a complement to morphological analyses of human remains (paleopathology) and laboratory exams (DNA or immunology testing).

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.

Osilodrostat para el síndrome de Cushing endógeno / Osilodrostat for Cushing's syndrome endogenous

INTRODUCCIÓN: El síndrome de Cushing endógeno es un trastorno endocrino severo y multiorgánico causado por la hiperproducción de cortisol por parte de las glándulas adrenales. Las manifestaciones clínicas más habituales incluyen síndrome metabólico, resistencia a la insulina, obesidad visceral, diabetes, hipertensión, dislipemia, osteoporosis, cambios en la piel, daños en el sistema inmune (aumento del riesgo de infecciones), trastornos neuropsiquiátricos, hipogonadismo, desórdenes menstruales en mujeres y un estado de hipercoagulabilidad. Debido a las complicaciones metabólicas y cardiovasculares asociadas, los pacientes mal controlados o sin tratamiento presentan un incremento en la mortalidad. El manejo terapéutico puede incluir cirugía hipofisaria o suprarrenal, tratamiento médico y/o radioterapia. La cirugía es la terapia de elección, cualquiera que sea la causa de base, y que consiste en la resección quirúrgica del tumor subyacente, excepto en los pacientes que presenten un carcinoma suprarrenal metastásico o cuya enfermedad sea de origen desconocido. La segunda línea terapéutica es la irradiación sobre la hipófisis, la suprarrenalectomía bilateral y el tratamiento farmacológico (inhibidores de la enzima adrenal, etomidato, antagonistas de los receptores de glucocorticoides). Algunos de los fármacos mencionados no tienen autorización de comercialización del país aún. TECNOLOGÍA: Osilodrostat (Isturisa®) es un inhibidor de la 11ß-hidroxilasa (CYP11B1), enzima responsable de la etapa final de la biosíntesis de cortisol en la glándula suprarrenal. OBJETIVO: El objetivo del presente informe es evaluar rápidamente los parámetros de eficacia, seguridad, costos y recomendaciones disponibles acerca del empleo de osilodrostat para el tratamiento de adultos con síndrome de Cushing endógeno. MÉTODOS: Se realizó una búsqueda bibliográfica en las principales bases de datos tales como PUBMED, LILACS, BRISA, COCHRANE, SCIELO, EMBASE, TRIPDATABASE como así también en sociedades científicas, agencias reguladoras, financiadores de salud y agencias de evaluación de tecnologías sanitarias. Se priorizó la inclusión de revisiones sistemáticas, ensayos clínicos controlados aleatorizados, evaluación de tecnología sanitaria y guías de práctica clínica de alta calidad metodológica. En PubMed se utilizó la estrategia de búsqueda que se detalla en el Anexo I. La fecha de búsqueda de información fue hasta el 19 de octubre de 2022. Para la búsqueda en Pubmed se utilizó la siguiente estrategia de búsqueda: (osilodrostat [Supplementary Concept] OR Isturisa [tiab] OR LCI699 [tiab]) AND ("Cushing Syndrome" [MESH] OR "Cushing Syndrome" [tiab] OR Hypercortisolism [tiab]). RECOMENDACIONES: No se hallaron guías de práctica clínica actualizadas en Argentina que mencionen la tecnología en la indicación evaluada. Un consenso de expertos internacional publicado en 2021 menciona la utilización de osilodrostat como una opción terapéutica junto con otros inhibidores de la esteroidogénesis como el ketoconzol, etomidato, mitotano, metirapona, (estos últimos tres no se encuentran disponibles en nuestro país) o pasireotida, mifepristona. En España se ha emitido resolución de financiación de osilodrostat para el tratamiento del síndrome de Cushing endógeno en adultos, limitando su utilización al tratamiento tras fracaso o contraindicación a otras alternativas farmacológicas. No se hallaron documentos referentes al uso de osilodrostat en la indicación especificada por parte de otras entidades de evaluación de tecnologías sanitarias a nivel mundial como Instituto Nacional para la Excelencia en Salud y Atención (del inglés, National Institute for Health and Care Excellence) de Reino Unido y la Agencia Canadiense de Medicamentos y Tecnologías en Salud (del inglés, Canadian Agency for Drugs & Technologies in Health). CONCLUSIONES: La evidencia que sustenta la aprobación de comercialización de osilodrostat por parte de las agencias regulatorias relevadas para el tratamiento de personas adultas con síndrome de Cushing endógeno con enfermedad recurrente o persistente, se basa en ensayos clínicos frente a placebo con un bajo número de pacientes y corto seguimiento. El cuerpo de la evidencia mostraría que el uso de osilodrostat podría normalizar los valores de cortisol libre urinario y mejorar la calidad de vida de forma importante frente a placebo al mediano plazo. Sin embargo, estos estudios mostrarían una elevada incidencia de eventos adversos y de discontinuación del tratamiento por eventos adversos. La seguridad y eficacia frente a otras opciones terapéuticas disponibles no pudo ser establecida debido a que solo se hallaron estudios que comparan osilodrostat contra placebo. Las agencias regulatorias relevadas han autorizado recientemente la comercialización, junto con la designación de medicamento huérfano y vigilancia adicional. No se hallaron guías de práctica clínica actualizadas en Argentina que mencionen la tecnología en la indicación evaluada, mientras que una recomendación internacional la menciona como una opción entre otras alternativas. Agencias de Reino Unido y Canadá no hay evaluado su cobertura hasta el momento, y en España su cobertura se haya limitada al tratamiento del síndrome de Cushing endógeno que ha fracasado o tiene contraindicación a otras alternativas farmacológicas. No se hallaron evaluaciones económicas publicadas, aunque el costo del fármaco es muy elevado.

Enfermedad de Cushing recurrente con hipercortisolismo catastrófico: reporte de caso y revisión de literatura / Catastrophic hypercortisolism and recurrence in Cushing´s disease: a case report and literature review / Doença de Cushing recorrente com hipercortisolismo catastrófico: relato de caso e revisão da literatura

Resumen: Presentamos un caso de una paciente femenina de 27 años, con síndrome de Cushing ACTH dependiente con hipercortisolismo severo, causado por un macroadenoma hipofisario recurrente y resistente pese a dos cirugías transesfenoidales, radioterapia y terapia médica. Dada la falla en las diferentes terapias se realiza una adrenalectomía bilateral como tratamiento definitivo. La paciente fallece en el posoperatorio por causa no clara. Si bien la adrenalectomía bilateral ha sido reportada como un tratamiento efectivo en pacientes con enfermedad de Cushing, se ha relacionado con una mortalidad significativa vinculada con la severidad del hipercortisolismo y las comorbilidades presentes. En este caso la adrenalectomía izquierda se tuvo que convertir a cielo abierto, asociada con mayor morbimortalidad.

Abstract: The study presents the case of a 27-year-old female patient with adrenocorticotropic hormone (ACTH) dependent Cushing's disease and severe hypercortisolism caused by recurrent pituitary macroadenoma that was resistant to treatment despite two transsphenoidal surgeries, radiotherapy and medical treatment. Upon failure of the different therapies a bilateral adrenalectomy was performed as the final treatment. The patient died in after surgery although the case of death was not clear. Despite bilateral adrenalectomy having been reports as an effective treatment in patients with Cushing's disease, it has been related to significant mortality rates in connection with the severity of hypercortisolism and existing comorbilities. In this case the left adrenalectomy ended up being an open surgery, which is associated to a higher mortality rate.

Resumo: Apresentamos o caso de uma paciente de 27 anos com síndrome de Cushing ACTH-dependente com hipercortisolismo grave causado por macroadenoma hipofisário, recorrente e resistente, apesar de haver sido submetida a duas cirurgias transesfenoidal, radioterapia e terapia medicamentosa. Diante do fracasso das diferentes terapias, foi realizada adrenalectomia bilateral como tratamento definitivo. A paciente faleceu no pós-operatório por causa não esclarecida. Embora a adrenalectomia bilateral tenha sido relatada como tratamento eficaz em pacientes com doença de Cushing, ela tem sido associada a mortalidade significativa relacionada à gravidade do hipercortisolismo e às comorbidades presentes. Neste caso, a adrenalectomia esquerda teve que ser convertida para cirurgia aberta, associada a maior morbimortalidade.