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Adrenocortical Hyperfunction
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Annals of internal medicine 
Background: Primary aldosteronism is recognized as a severe form of renin-independent aldosteronism that results in excessive mineralocorticoid receptor (MR) activation. Objective: To investigate whether a spectrum of subclinical renin-independent aldosteronism that increases risk for hypertension exists among normotensive persons. Design: Cohort study. Setting: National community-based study. Participants: 850 untreated normotensive participants in MESA (Multi-Ethnic Study of Atherosclerosis) with measurements of serum aldosterone and plasma renin activity (PRA). Measurements: Longitudinal analyses investigated whether aldosterone concentrations, in the context of physiologic PRA phenotypes (suppressed, ≤0.50 µg/L per hour; indeterminate, 0.51 to 0.99 µg/L per hour; unsuppressed, ≥1.0 µg/L per hour), were associated with incident hypertension (defined as systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or initiation of antihypertensive medications). Cross-sectional analyses investigated associations between aldosterone and MR activity, assessed via serum potassium and urinary fractional excretion of potassium. Results: A suppressed renin phenotype was associated with a higher rate of incident hypertension than other PRA phenotypes (incidence rates per 1000 person-years of follow-up: suppressed renin phenotype, 85.4 events [95% CI, 73.4 to 99.3 events]; indeterminate renin phenotype, 53.3 events [CI, 42.8 to 66.4 events]; unsuppressed renin phenotype, 54.5 events [CI, 41.8 to 71.0 events]). With renin suppression, higher aldosterone concentrations were independently associated with an increased risk for incident hypertension, whereas no association between aldosterone and hypertension was seen when renin was not suppressed. Higher aldosterone concentrations were associated with lower serum potassium and higher urinary excretion of potassium, but only when renin was suppressed. Limitation: Sodium and potassium were measured several years before renin and aldosterone. Conclusion: Suppression of renin and higher aldosterone concentrations in the context of this renin suppression are associated with an increased risk for hypertension and possibly also with increased MR activity. These findings suggest a clinically relevant spectrum of subclinical primary aldosteronism (renin-independent aldosteronism) in normotension. Primary Funding Source: National Institutes of Health.
Cardiovascular Diseases (9)
Hypertension (8), Hyperaldosteronism (7), Atherosclerosis (1), more mentions
European journal of endocrinology
OBJECTIVE: Recently, the European Society of Endocrinology (ESE), in collaboration with the European Network for the Study of Adrenal Tumors (ENSAT), asserted that adrenal incidentalomas (AIs) <4 cm and ≤10 Hounsfield units (HU) do not require further follow-up imaging. To validate the clinical application of the follow-up strategies suggested by the 2016 ESE-ENSAT guidelines, we explored the clinical characteristics and natural course of AIs in a single center over 13 years. DESIGN AND METHODS: This retrospective cohort study included a total of 1149 patients diagnosed with AIs between 2000 and 2013 in a single tertiary center. Hormonal examination and radiological evaluations were performed at the initial diagnosis of AI and during the follow-up according to the appropriate guidelines. RESULTS: The mean age at diagnosis was 54.2 years, and the majority of AIs (68.0%) were nonfunctional lesions. Receiver operating curve analysis was used to discriminate malignant from benign lesions; the optimal cut-off value for mass size was 3.4 cm (sensitivity: 100%; specificity: 95.0%), and that for the pre-contrast HU was 19.9 (sensitivity: 100%; specificity: 67.4%). The majority of nonfunctional lesions did not change in size during the 4-year follow-up period. Applying a cut-off value of 1.8 μg/dL after a 1-mg overnight dexamethasone suppression test, 28.0% of all nonfunctional AIs progressed to autonomous cortisol secretion during the follow-up period. However, we observed no development of overt Cushing's syndrome in the study. CONCLUSIONS: We advocate that no follow-up imaging is required if the detected adrenal mass is <4 cm and has clear benign features. However, prospective studies with longer follow-up are needed to confirm the appropriate follow-up strategies.
Neoplasms (2), Cushing Syndrome (2), Pheochromocytoma (1), more mentions
RATIONALE: Typical pulmonary carcinoid is a kind of low-grade malignancy neuroendocrine tumor. Cushing's syndrome is a very rare clinical feature of typical pulmonary carcinoid caused by hypercorticism. Complete tumor resection is the standard curative treatment for primary typical pulmonary carcinoid. However, our knowledge on the gene level of typical pulmonary carcinoid is limited. PATIENT CONCERNS: A 42-year-old man was admitted to our hospital for progressive weight gain within one year. No other obvious symptoms were obsessed in this patient. He was clinical diagnosed with ectopic adrenocorticotropic hormone syndrome through hormonal tests and imaging exams. Positron emission tomography-computed tomography detected a pulmonary nodule localized in the middle lobe of the lung and it is thought to be the ectopic source. INTERVENTION: This patient received a pulmonary wedge resection. After the surgery, a genetic sequencing was performed and it reported a mutation (S1240Cfs*21) in the BCOR gene. DIAGNOSIS: Postoperative pathology confirmed the diagnosis of ACTH-producing typical pulmonary carcinoid. OUTCOMES: The patient had a smooth postoperative course and no recurrence of the tumor was found for 3 years. LESSONS: Mutation in BCOR gene is quite common in pulmonary neuroendocrine tumor and it has been proven to play a role in the development of some tumor. We herein first report BCOR gene mutation in Cushing's syndrome secondary to TPC and it may become a promising therapeutic target in the future.
Carcinoid Tumor (7), Cushing Syndrome (4), Neoplasms (3), more mentions
Journal of clinical pathology
Primary aldosteronism (PA) is the most common form of secondary hypertension and is critical to identify because when caused by an aldosterone-producing adenoma (APA) or another unilateral form, it is potentially curable, and even when caused by bilateral disease, antihypertensives more specific to PA treatment can be employed (ie, aldosterone antagonists). Identification of unilateral forms is not generally accomplished with imaging because APAs may be small and elude detection, and coincidental identification of a non-functioning incidentaloma contralateral to an APA may lead to removal of an incorrect gland. For this reason, the method of choice for identifying unilateral forms of PA is selective adrenal venous sampling (AVS) followed by aldosterone and cortisol analysis on collected samples. This procedure is technically difficult from a radiological standpoint and, from the laboratory perspective, is fraught with opportunities for preanalytical, analytical and postanalytical error. We review the process of AVS collection, analysis and reporting. Suggestions are made for patient preparation, specimen labelling practices and nomenclature, analytical dilution protocols, which numerical results to report, and the necessary subsequent calculations. We also identify and explain frequent sources of confusion in the aldosterone and cortisol results and provide an example of tabular reporting to facilitate interpretation and communication between laboratorian, radiologist and clinician.
Cardiovascular Diseases (2)
Hyperaldosteronism (3), Hypertension (2), Adenoma (1), more mentions
Clinical endocrinology
Cushing's Syndrome (CS) is critical to identify because of the numerous and sometimes irreversible sequelae. Surreptitious glucocorticoid use is usually a straightforward consideration in the Cushingoid patient having suppressed ACTH levels, in the absence of adrenal mass or hyperplasia, and in whom screening tests for CS have unexpectedly low or high results depending on the specific steroid used and vulnerability of the assay employed to analytical cross-reactivity. We present a case of a patient with factitious hypercortisolism without suppressed ACTH. This article is protected by copyright. All rights reserved.
Cushing Syndrome (3), Hyperplasia (1), more mentions
Endocrine practice : official journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists
OBJECTIVE: To evaluate the diagnostic efficacy of various screening tests for the diagnosis of Cushing's syndrome (CS). METHODS: 35 patients of Cushing's syndrome and 16 patients of pseudo-Cushing's syndrome were enrolled. Assessment of 24h urinary free cortisol (UFC), late night salivary cortisol (LNSC), over night dexamethasone suppression test (ONDST), late night plasma cortisol (LNPC) and ACTH on outpatient basis, and during sleep as well as in awake state after 48 hours of hospital admission. RESULTS: 24h UFC performed the best among screening tests with sensitivity, specificity and AUC of 96.0 %, 99% and 0.988, respectively at a cut-off of 144.6 μg/24h.A cut-off of 10.5 nmol/L for LNSC had sensitivity 85.7%, specificity 88.2 % and AUC 0.897.A cut-off of 412.4 nmol/L for MNC on outpatient basis had sensitivity 88.2%,specificity 91.2% and AUC 0.957.A cut-off of 215 nmol/L and 243.3nmol/L for MNC during sleep and awake state after acclimatization had sensitivity, specificity and AUC of 94.1%, 88.2%, 0.958 respectively for each. ONDST at a cut-off of 94.6 nmol/L provided sensitivity, specificity and AUC of 96.0 %, 99.03% and 0.995, respectively. A cut-off of 30.3 pg/ml for late night ACTH on outpatient basis had sensitivity 67.6%, specificity 99.9% and AUC 0.796.A cut-off of 22.6 pg/ml for ACTH during sleep state after acclimatization had sensitivity, specificity and AUC of 73.5%, 99.2 %, 0.827, respectively. CONCLUSION: UFC is the best screening test for CS. Further, a single LNPC and ACTH level helps to establish the diagnosis and ACTH-dependency of CS. ABBREVIATIONS: CS = Cushing's syndrome; UFC = Urinary free cortisol; LNSC = Late night salivary cortisol; ONDST = Overnight dexamethsone suppression test; LDDST = Low dose dexamethasone suppression test; ACTH = Adrenocorticotropic hormone; HPA = Hypothalamo-pituitary-adrenal axis; CBG = Corticotropin binding globulin; CEMRI = Contrast enhanced magnetic resonance imaging sella; CECT = Contrast enhanced computerized tomography; ECLIA = Electro-chemiluminescence-immuno-assay; BIPSS = Bilateral inferior petrosal sinus sampling.
Cushing Syndrome (6), more mentions
Clinical endocrinology
CONTEXT: Abdominal visceral adiposity and central sarcopenia are markers of increased cardiovascular risk and mortality. OBJECTIVE: To assess whether central sarcopenia and adiposity can serve as a marker of disease severity in patients with adrenal adenomas and glucocorticoid secretory autonomy. DESIGN: Retrospective cohort study. PATIENTS: Twenty-five patients with overt Cushing syndrome (CS), 48 patients with mild autonomous cortisol excess (MACE), and 32 patients with a non-functioning adrenal tumor (NFAT) were included. METHODS: Medical records were reviewed and body composition measurements (visceral fat [VAT], subcutaneous fat [SAT], visceral/total fat [V/T], visceral/subcutaneous [V/S] and total abdominal muscle mass) were calculated based on abdominal computed tomography (CT). RESULTS: In patients with overt CS, when compared to patients with NFAT, the V/T fat and the V/S ratio were increased by 0.08 (P<0.001) and by 0.3 (P<0.001); however, these measurements were decreased by 0.04 (P=0.007) and 0.2 (P=0.01), respectively in patients with MACE. Total muscle mass was decreased by -10 cm(2) (P =0.02) in patients with overt CS compared to patients with NFAT.Correlation with morning serum cortisol concentrations after dexamethasone suppression testing revealed that for every 28nmol/L cortisol increase there was a 0.008 increase in V/T (P<0.001), 0.02 increase in the V/S fat ratio (P<0.001), and a 1.2 cm(2) decrease in mean total muscle mass (P=0.002). CONCLUSIONS: The severity of hypercortisolism was correlated with lower muscle mass and higher visceral adiposity. These CT-based markers may allow for a more reliable and objective assessment of glucocorticoid-related disease severity in patients with adrenal adenomas. This article is protected by copyright. All rights reserved.
Cushing Syndrome (4), Adenoma (3), Sarcopenia (2), more mentions
OBJECTIVE: To evaluate the cut-off value of the ratio of 24 h urinary free cortisol (24 h UFC) levels post-dexamethasone to prior-dexamethasone in dexamethasone suppression test (DST) during the diagnosis of primary pigmented nodular adrenocortical disease in Chinese adrenocorticotropic hormone-independent Cushing syndrome. DESIGN: Retrospective study. PARTICIPANTS: The patients diagnosed with primary pigmented nodular adrenocortical disease (PPNAD, n = 25), bilateral macronodular adrenal hyperplasia (BMAH, n = 27), and adrenocortical adenoma (ADA, n = 84) were admitted to the Peking Union Medical College Hospital from 2001 to 2016. ESTIMATIONS: Serum cortisol, adrenocorticotropic hormone (ACTH), and 24 h UFC were measured before and after low-dose dexamethasone suppression test (LDDST) and high-dose dexamethasone suppression test (HDDST). RESULTS: After LDDST and HDDST, 24 h UFC elevated in patients with PPNAD (paired t-test, P = 0.007 and P = 0.001), while it remained unchanged in the BMAH group (paired t-test, P = 0.471 and P = 0.414) and decreased in the ADA group (paired t-test, P = 0.002 and P = 0.004). The 24 h UFC level after LDDST was higher in PPNAD and BMAH as compared to ADA (P < 0.017), while no significant difference was observed between PPNAD and BMAH. After HDDST, 24 h UFC was higher in patients with PPNAD as compared to that of ADA and BMAH (P < 0.017). The cut-off value of 24 h UFC (Post-L-Dex)/(Pre-L-Dex) was 1.16 with 64.0% sensitivity and 77.9% specificity, and the cut-off value of 24 h UFC (Post-H-Dex)/(Pre-H-Dex) was 1.08 with 84.0% sensitivity and 75.6% specificity. CONCLUSION: The ratio of post-dexamethasone to prior-dexamethasone had a unique advantage in distinguishing PPNAD from BMAH and ADA.
Cushing Syndrome (3), Carney Complex (1), Adrenocortical Adenoma (1), more mentions
Clinical endocrinology
BACKGROUND: Bilateral inferior petrosal sinus sampling (IPSS) with corticotropin-releasing hormone (CRH) is currently the gold standard in the diagnosis of Cushing's disease (CD) and has also been used in tumour lateralization. Our objective was to determine the diagnostic value and lateralization accuracy of IPSS with desmopressin. METHODS: We retrospectively analyzed 91 patients with Cushing's syndrome who had either negative findings on pituitary dynamic enhanced magnetic resonance imaging (MRI) or non-suppressed high dose dexamethasone suppression tests (HDDST). Thin-slice thoracoabdominal computed tomography (CT) and octreotide receptor imaging of whole body were also negative to rule out ectopic adrenocorticotropin hormone (ACTH) syndrome. All patients went through IPSS with desmopressin. Afterwards, transsphenoidal pituitary surgery, light microscope pathology and immunohistological staining for ACTH were performed in all patients. RESULTS: 1. Diagnosis of CD. Among the 91 patients included, 90 were confirmed with CD, of whom 89 had positive IPSS findings, therefore the sensitivity was 98.9%. The one patient who was negative for CD also had negative IPSS findings, therefore the specificity was 100%. 2. Tumour lateralization. Among the 51 patients who were ultimately diagnosed with CD and whose lateralization by IPSS and surgery was either left or right, 37 had IPSS lateralization in concordance with surgery, therefore the concordance rate was 72.5%. Patients in the concordant group had a higher frequency of right lateralization by surgery. CONCLUSIONS: IPSS with desmopressin is a sensitive approach in the diagnosis of CD and has moderate accuracy in tumour lateralization, making it an alternative choice to IPSS with CRH. This article is protected by copyright. All rights reserved.
Cushing Syndrome (2), ACTH-Secreting Pituitary Adenoma (1), more mentions
Hypertension (Dallas, Tex. : 1979)
Aldosterone-producing adenoma (APA), a major subtype of primary hyperaldosteronism, the main curable cause of human endocrine hypertension, involves somatic mutations in the potassium channel Kir3.4 (KCNJ5) in 30% to 70% of cases, typically the more florid phenotypes. Because KCNJ5 mutated channels were reported to be specifically sensitive to inhibition by macrolide antibiotics, which concentration dependently blunts aldosterone production in HAC15 transfected with the G151R and L168R mutated channel, we herein tested the effect of clarithromycin on aldosterone synthesis and secretion in a pure population of aldosterone-secreting cells obtained by immunoseparation (CD56(+) cells) from APA tissues with/without the 2 most common KCNJ5 mutations. From a large cohort of patients with an unambiguous APA diagnosis, we recruited those who were wild type (n=3) or had G151R (n=2) and L168R (n=2) mutations. We found that clarithromycin concentration dependently lowered CYP11B2 gene expression (by 60%) and aldosterone secretion (by 70%; P<0.001 for both) in CD56(+) cells isolated ex vivo from KCNJ5 mutated APAs, although it was ineffective in CD56(+) cells from wild-type APAs. By proving the principle that the oversecretion of aldosterone can be specifically blunted in APA cells ex vivo with G151R and L168R mutations, these results provide compelling evidence of the possibility of specifically correcting aldosterone excess in patients with APA carrying the 2 most common KCNJ5 somatic mutations.
Cardiovascular Diseases (2), Infectious Diseases (1)
Adenoma (2), Hypertension (2), Hyperaldosteronism (1), more mentions
PURPOSE: To compare long-term outcomes in patients with adrenal incidentalomas (AIs) with the response to a 1 mg overnight dexamethasone suppression test (DST). METHODS: Consecutive patients with "non-functional" AIs (n = 365) were examined. Patients with overt hormone excess, adrenocortical cancer and known malignancy had been excluded. Patients were classified to normal cortisol secretion group (n = 204, DST ≤ 50 nmol/l), possible autonomous cortisol secretion group (n = 128, DST 51-138 nmol/l) and autonomous cortisol secretion group (n = 33, DST ≥ 138 nmol/l). RESULTS: Thirty-seven patients (10.1%) deceased during the follow-up period (5.2 ± 2.3 years): 16(7.8%) in the non-secreting group (time from diagnosis to death: 3.9 ± 2.9 years), 15 in the possible autonomous cortisol secretion group (11.7%, 3.2 ± 1.8 years) and 6 in the autonomous cortisol secretion group (18.2%, 2.3 ± 1.5 years), respectively (P = 0.019). Multivariate analysis only found significant association with age and the tumour size but if cortisol levels post-DST were analysed as a continuous variable it was significant as well. All deaths in autonomous cortisol secretion group were due to cancer not related to adrenal glands. Hypertension, cardiovascular disease and medications were more common in the possible and autonomous cortisol secretion group, especially in the former. More bilateral AIs and larger AI size were found in the two latter groups. CONCLUSIONS: Patients with autonomous cortisol secretion had higher mortality than those with non-functioning AIs though cortisol levels post-DST as a continuous variable, age and tumour size were better predictor of mortality. Cardiovascular disease and osteoporosis medication seemed more prevalent in the possible and autonomous cortisol secretion groups, especially in the former.
Cardiovascular Diseases (3), Oncology (3), Muscular and Skeletal Diseases (1)
Cardiovascular Diseases (2), Neoplasms (2), Osteoporosis (1), more mentions
12. Genetics of Cushing's disease.  
Date: 08/29/2017
Clinical endocrinology
Cushing's disease (CD) is a rare disabling condition caused by ACTH-secreting adenomas of the pituitary. The majority of corticotropic adenomas are monoclonal and occur sporadically. Only rarely does CD arise in the context of genetic familial syndromes. Targeted sequencing of oncogenes and tumour-suppressor genes commonly mutated in other tumours did not identify recurrent mutations. In contrast, next generation sequencing allowed us recently to clarify the genetic basis of CD: We identified somatic driver mutations in the ubiquitin-specific protease 8 (USP8) gene in a significant portion of corticotropinomas. These mutations represent a novel and unique mechanism leading to ACTH excess. Inhibition of USP8 or its downstream signalling pathways could represent a new therapeutic approach for the management of CD. In this review we will focus on this new evidence and its implication for clinical care of affected patients. This article is protected by copyright. All rights reserved.
Adenoma (2), Cushing Syndrome (1), Pituitary Adenoma (1), more mentions