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1.
Artigo em Inglês | MEDLINE | ID: mdl-32711725

RESUMO

BACKGROUND: Cross-sectional imaging regularly results in incidental discovery of adrenal tumours, requiring exclusion of adrenocortical carcinoma (ACC). However, differentiation is hampered by poor specificity of imaging characteristics. We aimed to validate a urine steroid metabolomics approach, using steroid profiling as the diagnostic basis for ACC. METHODS: We did a prospective multicentre study in adult participants (age ≥18 years) with newly diagnosed adrenal masses. We assessed the accuracy of diagnostic imaging strategies based on maximum tumour diameter (≥4 cm vs <4 cm), imaging characteristics (positive vs negative), and urine steroid metabolomics (low, medium, or high risk of ACC), separately and in combination, using a reference standard of histopathology and follow-up investigations. With respect to imaging characteristics, we also assessed the diagnostic utility of increasing the unenhanced CT tumour attenuation threshold from the recommended 10 Hounsfield units (HU) to 20 HU. FINDINGS: Of 2169 participants recruited between Jan 17, 2011, and July 15, 2016, we included 2017 from 14 specialist centres in 11 countries in the final analysis. 98 (4·9%) had histopathologically or clinically and biochemically confirmed ACC. Tumours with diameters of 4 cm or larger were identified in 488 participants (24·2%), including 96 of the 98 with ACC (positive predictive value [PPV] 19·7%, 95% CI 16·2-23·5). For imaging characteristics, increasing the unenhanced CT tumour attenuation threshold to 20 HU from the recommended 10 HU increased specificity for ACC (80·0% [95% CI 77·9-82·0] vs 64·0% [61·4-66.4]) while maintaining sensitivity (99·0% [94·4-100·0] vs 100·0% [96·3-100·0]; PPV 19·7%, 16·3-23·5). A urine steroid metabolomics result indicating high risk of ACC had a PPV of 34·6% (95% CI 28·6-41·0). When the three tests were combined, in the order of tumour diameter, positive imaging characteristics, and urine steroid metabolomics, 106 (5·3%) participants had the result maximum tumour diameter of 4 cm or larger, positive imaging characteristics (with the 20 HU cutoff), and urine steroid metabolomics indicating high risk of ACC, for which the PPV was 76·4% (95% CI 67·2-84·1). 70 (3·5%) were classified as being at moderate risk of ACC and 1841 (91·3%) at low risk (negative predictive value 99·7%, 99·4-100·0). INTERPRETATION: An unenhanced CT tumour attenuation cutoff of 20 HU should replace that of 10 HU for exclusion of ACC. A triple test strategy of tumour diameter, imaging characteristics, and urine steroid metabolomics improves detection of ACC, which could shorten time to surgery for patients with ACC and help to avoid unnecessary surgery in patients with benign tumours. FUNDING: European Commission, UK Medical Research Council, Wellcome Trust, and UK National Institute for Health Research, US National Institutes of Health, the Claire Khan Trust Fund at University Hospitals Birmingham Charities, and the Mayo Clinic Foundation for Medical Education and Research.

2.
J Bone Miner Res ; 2020 Apr 21.
Artigo em Inglês | MEDLINE | ID: mdl-32315096

RESUMO

Endogenous Cushing's syndrome (CS) is a rare cause of secondary osteoporosis. The long-term consequences for bone metabolism after successful surgical treatment remain largely unknown. We assessed bone mineral density and fracture rates in 89 patients with confirmed Cushing's syndrome at the time of diagnosis and 2 years after successful tumor resection. We determined five bone turnover markers at the time of diagnosis, 1 and 2 years postoperatively. The bone turnover markers osteocalcin, intact procollagen-IN-propeptide (PINP), alkaline bone phosphatase, CTX-I, and TrAcP 5b were measured in plasma or serum by chemiluminescent immunoassays. For comparison, 71 sex-, age-, and body mass index (BMI)-matched patients in whom Cushing's syndrome had been excluded were studied. None of the patients received specific osteoanabolic treatment. At time of diagnosis, 69% of the patients had low bone mass (mean T-score = -1.4 ± 1.1). Two years after successful surgery, the T-score had improved in 78% of patients (mean T-score 2 years postoperatively -1.0 ± 0.9). The bone formation markers osteocalcin and intact PINP were significantly decreased at time of diagnosis (p ≤ 0.001 and p = 0.03, respectively), and the bone resorption marker CTX-I and TrAcP 5b increased. Postoperatively, the bone formation markers showed a three- to fourfold increase 1 year postoperatively, with a moderate decline thereafter. The bone resorption markers showed a similar but less pronounced course. This study shows that the phase immediately after surgical remission from endogenous CS is characterized by a high rate of bone turnover resulting in a striking net increase in bone mineral density in the majority of patients. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

3.
J Clin Endocrinol Metab ; 105(6)2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31536622

RESUMO

CONTEXT: Adrenal venous sampling (AVS) is the key test for subtyping primary aldosteronism (PA), but its interpretation varies widely across referral centers and this can adversely affect the management of PA patients. OBJECTIVES: To investigate in a real-life study the rate of bilateral success and identification of unilateral aldosteronism and their impact on blood pressure outcomes in PA subtyped by AVS. DESIGN AND SETTINGS: In a retrospective analysis of the largest international registry of individual AVS data (AVIS-2 study), we investigated how different cut-off values of the selectivity index (SI) and lateralization index (LI) affected rate of bilateral success, identification of unilateral aldosteronism, and blood pressure outcomes. RESULTS: AVIS-2 recruited 1625 individual AVS studies performed between 2000 and 2015 in 19 tertiary referral centers. Under unstimulated conditions, the rate of biochemically confirmed bilateral AVS success progressively decreased with increasing SI cut-offs; furthermore, with currently used LI cut-offs, the rate of identified unilateral PA leading to adrenalectomy was as low as <25%. A within-patient pairwise comparison of 402 AVS performed both under unstimulated and cosyntropin-stimulated conditions showed that cosyntropin increased the confirmed rate of bilateral selectivity for SI cut-offs ≥ 2.0, but reduced lateralization rates (P < 0.001). Post-adrenalectomy outcomes were not improved by use of cosyntropin or more restrictive diagnostic criteria. CONCLUSION: Commonly used SI and LI cut-offs are associated with disappointingly low rates of biochemically defined AVS success and identified unilateral PA. Evidence-based protocols entailing less restrictive interpretative cut-offs might optimize the clinical use of this costly and invasive test. (J Clin Endocrinol Metab XX: 0-0, 2020).

4.
J Clin Endocrinol Metab ; 105(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31702016

RESUMO

CONTEXT: High dietary salt intake is known to aggravate arterial hypertension. This effect could be of particular relevance in the setting of primary aldosteronism (PA), which is associated with cardiovascular damage independent of blood pressure levels. The aim of this study was to determine the impact of therapy on salt intake in PA patients. PATIENTS AND METHODS: A total of 148 consecutive PA patients (66 with unilateral and 82 with bilateral PA) from the database of the German Conn's Registry were included. Salt intake was quantified by 24-hour urinary sodium excretion before and after initiation of PA treatment. STUDY DESIGN: Observational longitudinal cohort study. SETTING: Tertiary care hospital. RESULTS: At baseline, unilateral PA patients had a significantly higher urinary sodium excretion than patients with bilateral disease (205 vs 178 mmol/d, P = 0.047). Higher urinary sodium excretion correlated with an increased cardiovascular risk profile including proteinuria, impaired lipid, and glucose metabolism and was associated with higher daily doses of antihypertensive drugs to achieve blood pressure control. In unilateral disease, urinary sodium excretion dropped spontaneously to 176 mmol/d (P = 0.012) 1 year after unilateral adrenalectomy and remained low at 3 years of follow-up (174 mmol/d). In contrast, treatment with mineralocorticoid receptor antagonists (MRA) in bilateral PA patients was not associated with a significant change in urinary sodium excretion at follow-up (179 mmol/d vs 183 mmol/d). CONCLUSION: PA patients consuming a high-salt diet, estimated based on urinary sodium excretion, respond to adrenalectomy with a significant reduction of salt intake, in contrast to MRA treatment.

5.
J Clin Endocrinol Metab ; 105(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31665382

RESUMO

CONTEXT: Signs and symptoms of Cushing's syndrome (CS) overlap with common diseases, such as the metabolic syndrome, obesity, osteoporosis, and depression. Therefore, it can take years to finally diagnose CS, although early diagnosis is important for prevention of complications. OBJECTIVE: The aim of this study was to assess the time span between first symptoms and diagnosis of CS in different populations to identify factors associated with an early diagnosis. DATA SOURCES: A systematic literature search via PubMed was performed to identify studies reporting on time to diagnosis in CS. In addition, unpublished data from patients of our tertiary care center and 4 other centers were included. STUDY SELECTION: Clinical studies reporting on the time to diagnosis of CS were eligible. Corresponding authors were contacted to obtain additional information relevant to the research question. DATA EXTRACTION: Data were extracted from the text of the retrieved articles and from additional information provided by authors contacted successfully. From initially 3326 screened studies 44 were included. DATA SYNTHESIS: Mean time to diagnosis for patients with CS was 34 months (ectopic CS: 14 months; adrenal CS: 30 months; and pituitary CS: 38 months; P < .001). No difference was found for gender, age (<18 and ≥18 years), and year of diagnosis (before and after 2000). Patients with pituitary CS had a longer time to diagnosis in Germany than elsewhere. CONCLUSIONS: Time to diagnosis differs for subtypes of CS but not for gender and age. Time to diagnosis remains to be long and requires to be improved.

6.
J Clin Endocrinol Metab ; 105(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31665449

RESUMO

CONTEXT: Urine steroid metabolomics, combining mass spectrometry-based steroid profiling and machine learning, has been described as a novel diagnostic tool for detection of adrenocortical carcinoma (ACC). OBJECTIVE, DESIGN, SETTING: This proof-of-concept study evaluated the performance of urine steroid metabolomics as a tool for postoperative recurrence detection after microscopically complete (R0) resection of ACC. PATIENTS AND METHODS: 135 patients from 14 clinical centers provided postoperative urine samples, which were analyzed by gas chromatography-mass spectrometry. We assessed the utility of these urine steroid profiles in detecting ACC recurrence, either when interpreted by expert clinicians or when analyzed by random forest, a machine learning-based classifier. Radiological recurrence detection served as the reference standard. RESULTS: Imaging detected recurrent disease in 42 of 135 patients; 32 had provided pre- and post-recurrence urine samples. 39 patients remained disease-free for ≥3 years. The urine "steroid fingerprint" at recurrence resembled that observed before R0 resection in the majority of cases. Review of longitudinally collected urine steroid profiles by 3 blinded experts detected recurrence by the time of radiological diagnosis in 50% to 72% of cases, improving to 69% to 92%, if a preoperative urine steroid result was available. Recurrence detection by steroid profiling preceded detection by imaging by more than 2 months in 22% to 39% of patients. Specificities varied considerably, ranging from 61% to 97%. The computational classifier detected ACC recurrence with superior accuracy (sensitivity = specificity = 81%). CONCLUSION: Urine steroid metabolomics is a promising tool for postoperative recurrence detection in ACC; availability of a preoperative urine considerably improves the ability to detect ACC recurrence.

7.
J Clin Endocrinol Metab ; 105(1)2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31613324

RESUMO

CONTEXT: An important clinical feature of Cushing's syndrome (CS) is proximal muscle myopathy caused by glucocorticoid induced protein metabolism. However, interindividual differences cannot be explained solely by the pure extent of hypercortisolemia. OBJECTIVE: To evaluate the effects of glucocorticoid receptor (GR) polymorphisms (BclI, N363S, ER22/23EK and A3669G), which influence peripheral glucocorticoid sensitivity on muscular function in endogenous CS. METHODS: 205 patients with proven endogenous CS (128 central, 77 adrenal) from 3 centers of the German Cushing's Registry and 125 subjects, in whom CS was ruled out, were included. All subjects were assessed for grip strength (via hand grip dynamometer) and performed a chair-rising test (CRT). DNA samples were obtained from peripheral blood leukocytes for GR genotyping. RESULTS: In patients with active CS, normalized handgrip strength of the dominant and nondominant hand was higher in A3669G minor allele than in wildtype carriers (P = .006 and P = .021, respectively). CS patients in remission and ruled-out CS showed no differences in handgrip strength regarding A3669G minor allele and wildtype carriers. Male CS patients harboring the ER22/23EK wildtype presented lower hand grip strength than minor allele carriers (P = .049 dominant hand; P = .027 nondominant hand). The other polymorphisms did not influence handgrip strength. CRT showed no differences regarding GR polymorphisms carrier status. CONCLUSION: Handgrip strength seems to be more susceptible to hypercortisolism in A3669G wildtype than in A3669G minor allele carriers. This might partially explain the inter-individual differences of glucocorticoid-induced myopathy in patients with endogenous CS. ER22/23EK polymorphism seems to exert sex-specific differences.

8.
Artigo em Inglês | MEDLINE | ID: mdl-31787931

RESUMO

Cushing's syndrome (CS) is a classical rare disease: it is often suspected in patients who do not have the disease; at the same time, it takes a mean of 3 years to diagnose CS in affected individuals. The main reason is the extreme rarity (1-3/million/year) in combination with the lack of a single lead symptom. CS has to be suspected when a combination of signs and symptoms is present, which together make up the characteristic phenotype of cortisol excess. Unusual fat distribution affecting the face, neck, and trunk; skin changes including plethora, acne, hirsutism, livid striae, and easy bruising; and signs of protein catabolism such as thinned and vulnerable skin, osteoporotic fractures, and proximal myopathy indicate the need for biochemical screening for CS. In contrast, common symptoms like hypertension, weight gain, or diabetes also occur quite frequently in the general population and per se do not justify biochemical testing. First-line screening tests include urinary free cortisol excretion, dexamethasone suppression testing, and late-night salivary cortisol measurements. All three tests have overall reasonable sensitivity and specificity, and first-line testing should be selected on the basis of the physiologic conditions of the patient, drug intake, and available laboratory quality control measures. Two normal test results usually exclude the presence of CS. Other tests and laboratory parameters like the high-dose dexamethasone suppression test, plasma ACTH, the CRH test, and the bilateral inferior petrosal sinus sampling are not part of the initial biochemical screening. As a general rule, biochemical screening should only be performed if the pre-test probability for CS is reasonably high. This article provides an overview about the current standard in the diagnosis of CS starting with clinical scores and screenings, the clinical signs, relevant differential diagnoses, the first-line biochemical screening, and ending with a few exceptional cases.

9.
Hypertension ; 74(4): 800-808, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31476901

RESUMO

We sought to measure the clinical benefits of adrenal venous sampling (AVS), a test recommended by guidelines for primary aldosteronism (PA) patients seeking surgical cure, in a large registry of PA patients submitted to AVS. Data of 1625 consecutive patients submitted to AVS in 19 tertiary referral centers located in Asia, Australia, Europe, and North America were collected in a large multicenter international registry. The primary end points were the rate of bilateral success, ascertained lateralization of PA, adrenalectomy, and of cured arterial hypertension among AVS-guided and non AVS-guided adrenalectomy patients. AVS was successful in 80.1% of all cases but allowed identification of unilateral PA in only 45.5% by the criteria in use at each center. Adrenalectomy was performed in 41.8% of all patients and cured arterial hypertension in 19.6% of the patients, 2-fold more frequently in women than men (P<0.001). When AVS-guided, surgery provided a higher rate of cure of hypertension than when non-AVS-guided (40.0% versus 30.5%; P=0.027). Compared with surgical cases, patients treated medically needed more antihypertensive medications (P<0.001) and exhibited a higher rate of persistent hypokalemia requiring potassium supplementation (4.9% versus 2.3%; P<0.01). The low rate of adrenalectomy and cure of hypertension in PA patients seeking surgical cure indicates suboptimal AVS use, possibly related to issues in patient selection, technical success, and AVS data interpretation. Given the better outcomes of AVS-guided adrenalectomy, these results call for actions to improve the diagnostic use of this test that is necessary for detection of surgical PA candidates. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01234220.


Assuntos
Glândulas Suprarrenais/irrigação sanguínea , Adrenalectomia , Aldosterona/sangue , Hiperaldosteronismo/sangue , Adulto , Coleta de Amostras Sanguíneas , Feminino , Humanos , Hiperaldosteronismo/cirurgia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento
10.
J Clin Endocrinol Metab ; 104(11): 5658-5664, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31225874

RESUMO

CONTEXT: Primary aldosteronism (PA) represents a secondary form of arterial hypertension that can be cured by surgery. Evidence of adrenal insufficiency (AI) was recently found in patients with PA who had undergone unilateral adrenalectomy (uADX). OBJECTIVE: To study the incidence and long-term outcome of postoperative AI after uADX for PA. DESIGN: Prospective registry study (August 2014 until the end of 2018). SETTING: Tertiary referral center. PATIENTS: One hundred consecutive patients undergoing uADX for PA were included. All patients underwent postoperative ACTH stimulation testing. INTERVENTION: Postoperative ACTH stimulation testing to identify patients with AI. MAIN OUTCOME MEASURES: Incidence of patients with postoperative AI and definition of long-term outcome. RESULTS: Twenty-seven percent of patients developed postoperative AI. Of these, 48% had postoperative ACTH stimulation serum cortisol levels ≤13.5 µg/dL (severe AI); 52% were classified into the group with moderate AI (stimulated serum cortisol levels: 13.5 to 17 µg/dL). Patients with severe AI required significantly longer hydrocortisone replacement therapy than the moderate group (median [25th, 75th percentiles]: 353 [294, 476] days; 95% CI: 284 to 322 days; vs 74 [32, 293] days; 95% CI: 11 to 137 days; P = 0.016). One patient with severe AI was hospitalized for an acute adrenal crisis. With a cumulative follow-up of 14.5 years, this produced an incidence rate of 6.9 adrenal crises per 100 patient-years. CONCLUSION: We suggest performing postoperative ACTH stimulation tests in all patients who undergo uADX for PA.

11.
Endocr Connect ; 8(4): 407-415, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30865927

RESUMO

Primary aldosteronism is a natural model for chronic aldosterone excess in humans and associated with symptoms of anxiety and depression. Cognitive deficits are inherent to the symptomatology of depression and anxiety disorders. Mineralocorticoid receptors and aldosterone appear to play a role in memory. Aldosterone was additionally supposed to be a risk factor for cognitive decline in patients with essential hypertension. The objective of this study was to investigate possible effects of chronically high aldosterone concentrations on cognitive function. A range of cognitive dimensions were assessed in 19 patients (9 males, 10 females); mean age 47.1 (12.5) under standardized treatment and several rating scales for anxiety, depression, quality of life and sleep were administered. Cognitive parameters were compared to standard norms from a large, healthy standardization sample. Patients showed increased levels of anxiety and depression without meeting diagnostic criteria for a disorder. Besides a numerically lower attention score, patients did not show any significant differences in the cognitive dimensions. Anxiety and depression were negatively correlated with quantitative performance in males. In females, a negative correlation between sleep disturbances and abstract reasoning and a positive correlation with quantitative performance were found. Our data showed no specific effect of chronic aldosterone in the tested cognitive parameters overall at least in younger patients, but they indicate sexually dimorphic regulation processes.

12.
J Psychiatr Res ; 112: 52-60, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30852427

RESUMO

The mineralocorticoid receptor (MR)/glucocorticoid receptor balance plays an important role in the pathophysiology of anxiety and depression. Aldosterone, a primary MR ligand, seems to be related to the pathophysiology of anxiety and depressive symptoms. The objective of this study was to investigate effects of aldosterone excess on sleep EEG, as sleep EEG is a tool to gain insight into psychoneuroendocrine function. Here, 19 untreated patients (9 males, 10 females) suffering from primary aldosteronism were investigated using sleep EEG and several rating scales for anxiety, depression, quality of life and sleep before starting specific treatment. Parameters were compared to age and sex matched healthy controls and patients with depression and correlated with laboratory findings and blood pressure. Patients had higher values for anxiety and depression compared to the general population, although a psychiatric disorder in their history was ruled out. Although sleep disturbances were reported in the Pittsburgh sleep quality index, sleep EEG did not show significant changes between patients and healthy controls. No depression specific pattern in sleep EEG was found. But in contrast to females, several sleep-EEG parameters of male PA patients differed significantly from patients with depression. There was a significant correlation between blood pressure and the severity of depression and anxiety in females. Correlation analysis between blood pressure and rating scales indicate a relationship between blood pressure and anxiety in women. In conclusion, these data suggest gender related effects of aldosterone excess in males and females.

13.
J Clin Endocrinol Metab ; 103(12): 4543-4552, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30113683

RESUMO

Context: Primary aldosteronism (PA) represents the most frequent form of endocrine hypertension. Hyperaldosteronism and hypercortisolism both induce excessive left ventricular hypertrophy (LVH) compared with matched essential hypertensives. In recent studies frequent cosecretion of cortisol and aldosterone has been reported in patients with PA. Objective: Our aim was to investigate the impact of cortisol cosecretion on LVH in patients with PA. We determined 24-hour excretion of mineralocorticoids and glucocorticoids by gas chromatography-mass spectrometry and assessed cardiac remodeling using echocardiography initially and 1 year after initiation of treatment of PA. Patients: We included 73 patients from the Munich center of the German Conn's registry: 45 with unilateral aldosterone-producing adenoma and 28 with bilateral adrenal hyperplasia. Results: At the time of diagnosis, 85% of patients with PA showed LVH according to left ventricular mass index [(LVMI); median 62.4 g/m2.7]. LVMI correlated positively with total glucocorticoid excretion (r2 = 0.076, P = 0.018) as well as with tetrahydroaldosterone excretion (r2 = 0.070, P = 0.024). Adrenalectomy led to significantly reduced LVMI in aldosterone-producing adenoma (P < 0.001) whereas mineralocorticoid receptor antagonist therapy in bilateral adrenal patients with hyperplasia reduced LVMI to a lesser degree (P = 0.024). In multivariate analysis, the decrease in LVMI was positively correlated with total glucocorticoid excretion and systolic 24-hour blood pressure, but not with tetrahydroaldosterone excretion. Conclusion: Cortisol excess appears to have an additional impact on cardiac remodeling in patients with PA. Treatment of PA by either adrenalectomy or mineralocorticoid receptor antagonist improves LVMI. This effect was most pronounced in patients with high total glucocorticoid excretion.


Assuntos
Neoplasias do Córtex Suprarrenal/complicações , Adenoma Adrenocortical/complicações , Hidrocortisona/sangue , Hiperaldosteronismo/complicações , Hipertrofia Ventricular Esquerda/etiologia , Córtex Suprarrenal/metabolismo , Córtex Suprarrenal/cirurgia , Neoplasias do Córtex Suprarrenal/sangue , Neoplasias do Córtex Suprarrenal/terapia , Adrenalectomia , Adenoma Adrenocortical/sangue , Adenoma Adrenocortical/terapia , Adulto , Aldosterona/sangue , Aldosterona/metabolismo , Ecocardiografia , Feminino , Seguimentos , Ventrículos do Coração/diagnóstico por imagem , Humanos , Hidrocortisona/metabolismo , Hiperaldosteronismo/sangue , Hiperaldosteronismo/terapia , Hipertrofia Ventricular Esquerda/sangue , Hipertrofia Ventricular Esquerda/diagnóstico , Hipertrofia Ventricular Esquerda/epidemiologia , Masculino , Pessoa de Meia-Idade , Antagonistas de Receptores de Mineralocorticoides/uso terapêutico , Prevalência
14.
JCI Insight ; 2(8)2017 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-28422753

RESUMO

BACKGROUND: Adrenal aldosterone excess is the most common cause of secondary hypertension and is associated with increased cardiovascular morbidity. However, adverse metabolic risk in primary aldosteronism extends beyond hypertension, with increased rates of insulin resistance, type 2 diabetes, and osteoporosis, which cannot be easily explained by aldosterone excess. METHODS: We performed mass spectrometry-based analysis of a 24-hour urine steroid metabolome in 174 newly diagnosed patients with primary aldosteronism (103 unilateral adenomas, 71 bilateral adrenal hyperplasias) in comparison to 162 healthy controls, 56 patients with endocrine inactive adrenal adenoma, 104 patients with mild subclinical, and 47 with clinically overt adrenal cortisol excess. We also analyzed the expression of cortisol-producing CYP11B1 and aldosterone-producing CYP11B2 enzymes in adenoma tissue from 57 patients with aldosterone-producing adenoma, employing immunohistochemistry with digital image analysis. RESULTS: Primary aldosteronism patients had significantly increased cortisol and total glucocorticoid metabolite excretion (all P < 0.001), only exceeded by glucocorticoid output in patients with clinically overt adrenal Cushing syndrome. Several surrogate parameters of metabolic risk correlated significantly with glucocorticoid but not mineralocorticoid output. Intratumoral CYP11B1 expression was significantly associated with the corresponding in vivo glucocorticoid excretion. Unilateral adrenalectomy resolved both mineralocorticoid and glucocorticoid excess. Postoperative evidence of adrenal insufficiency was found in 13 (29%) of 45 consecutively tested patients. CONCLUSION: Our data indicate that glucocorticoid cosecretion is frequently found in primary aldosteronism and contributes to associated metabolic risk. Mineralocorticoid receptor antagonist therapy alone may not be sufficient to counteract adverse metabolic risk in medically treated patients with primary aldosteronism. FUNDING: Medical Research Council UK, Wellcome Trust, European Commission.

15.
Clin Endocrinol (Oxf) ; 86(3): 325-331, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27748964

RESUMO

OBJECTIVE: To evaluate volumetric and densitometric properties of the adrenal glands in patients with unilateral and bilateral disease in comparison with normal controls. DESIGN: A total of 77 patients (56 males and 21 females) diagnosed with primary aldosteronism (PA) with a mean age of 53 ± 10 years were prospectively enrolled. Unenhanced and contrast-enhanced computed tomography scans were analysed for adrenal volumes and mean densities. These values were compared with normal controls and between PA subtypes. RESULTS: Adrenals containing an aldosterone-producing adenoma (APA, n = 56) had on average higher attenuation values as compared to adrenals with bilateral adrenal hyperplasia (n = 21). Mean adrenal gland volume in PA patients was not significantly different between PA subtypes. In comparison with normal adrenal glands, volumes were significantly higher in PA patients (P < 0·0001) including adrenals contralateral to APAs, which were significantly larger in comparison with controls. CONCLUSION: Independent of subtype differentiation, adrenal volumetry reveals higher adrenal volumes in PA patients in comparison with normal controls. These findings provide indirect evidence for a general adrenal growth dysregulation in the context of PA.


Assuntos
Glândulas Suprarrenais/patologia , Hiperaldosteronismo/diagnóstico , Adenoma/metabolismo , Adenoma/patologia , Glândulas Suprarrenais/crescimento & desenvolvimento , Adulto , Idoso , Aldosterona/metabolismo , Estudos de Casos e Controles , Diagnóstico Diferencial , Feminino , Alemanha , Humanos , Hiperplasia , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Tomografia Computadorizada por Raios X , Adulto Jovem
16.
J Hypertens ; 34(10): 2066-73, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27442789

RESUMO

CONTEXT: Copeptin and high-sensitive C-reactive protein (hsCRP) are biomarkers associated with increased mortality in patients with cardiovascular and cerebrovascular disease as well as in the general population. No data exist regarding these markers in patients with primary aldosteronism. OBJECTIVE: To evaluate copeptin and hsCRP levels as cardiovascular risk markers in primary aldosteronism patients. METHODS: A total of 113 primary aldosteronism patients (64% male) from two centers of the prospective German Conn's Registry were identified, for whom a full data set and blood samples at baseline and follow-up (14 ±â€Š3.4 months) after initiation of specific primary aldosteronism treatment were available. These cases were matched 1 : 3 (n = 339) for sex, renal function, BMI, age and SBP with participants from the Cooperative Health Research in the Region of Augsburg F4 survey. Copeptin and hsCRP were determined by sandwich fluoroimmunoassay. RESULTS: HsCRP was significantly higher in primary aldosteronism patients at baseline compared with matched controls. Following specific therapy, hsCRP and copeptin decreased significantly in primary aldosteronism patients [median (25th and 75th percentile): 1.6 (0.8, 3.4) to 1.2 (0.6, 2.1) mg/l, P < 0.001; 7.8 (4.6, 13.5) to 5.0 (3.1, 8.9) pmol/l, P < 0.001, respectively]. Men had higher hsCRP and copeptin levels at baseline and follow-up compared with women. The combination of sex, hypokalemia, lateralization index and blood pressure were the best predictors of outcome. However, copeptin and hsCRP had no predictive value despite the association of lower copeptin levels with better outcome regarding cure of primary aldosteronism. CONCLUSION: Copeptin and hsCRP levels decrease following specific primary aldosteronism therapy reflecting successful cardiovascular risk reduction. However, they are no independent predictors regarding cure of primary aldosteronism.


Assuntos
Proteína C-Reativa/metabolismo , Doenças Cardiovasculares/sangue , Glicopeptídeos/sangue , Hiperaldosteronismo/sangue , Hiperaldosteronismo/terapia , Adulto , Idoso , Biomarcadores/sangue , Pressão Sanguínea , Estudos de Casos e Controles , Feminino , Humanos , Hipopotassemia/sangue , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Sistema de Registros , Fatores de Risco , Fatores Sexuais
17.
J Clin Endocrinol Metab ; 101(8): 3010-7, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27270477

RESUMO

CONTEXT: Somatic mutations have been found causative for endocrine autonomy in aldosterone-producing adenomas (APAs). Whereas mutations of PRKACA (catalytic subunit of protein kinase A) have been identified in cortisol-producing adenomas, the presence of PRKACA variants in APAs is unknown, especially in those that display cosecretion of cortisol. OBJECTIVE: The objective of the study was to investigate PRKACA somatic variants identified in APA cases. DESIGN: Identification of PRKACA somatic variants in APAs by whole-exome sequencing followed by in vitro analysis of the enzymatic activity of PRKACA variants and functional characterization by double immunofluorescence of CYP11B2 and CYP11B1 expression in the corresponding tumor tissues. SETTING AND PATIENTS: APA tissues were collected from 122 patients who underwent unilateral adrenalectomy for primary aldosteronism between 2005 and 2015 at a single institution. RESULTS: PRKACA somatic mutations were identified in two APA cases (1.6%). One APA carried a newly identified p.His88Asp variant, whereas in a second case, a p.Leu206Arg mutation was found, previously described only in cortisol-producing adenomas with overt Cushing's syndrome. Functional analysis showed that the p.His88Asp variant was not associated with gain of function. Although CYP11B2 was strongly expressed in the p.His88Asp-mutated APA, the p.Leu206Arg carrying APA predominantly expressed CYP11B1. Accordingly, biochemical Cushing's syndrome was present only in the patient with the p.Leu206Arg mutation. After adrenalectomy, both patients improved with a reduced number of antihypertensive medications and normalized serum potassium levels. CONCLUSIONS: We describe for the first time PRKACA mutations as rare findings associated with unilateral primary aldosteronism. As cortisol cosecretion occurs in a subgroup of APAs, other molecular mechanisms are likely to exist.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Adenoma Adrenocortical/genética , Adenoma Adrenocortical/metabolismo , Aldosterona/metabolismo , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/genética , Mutação de Sentido Incorreto , Neoplasias do Córtex Suprarrenal/sangue , Adenoma Adrenocortical/sangue , Adulto , Substituição de Aminoácidos , Células Cultivadas , Análise Mutacional de DNA , Feminino , Frequência do Gene , Células HEK293 , Humanos , Hiperaldosteronismo/genética , Hiperaldosteronismo/metabolismo , Metaboloma , Pessoa de Meia-Idade
18.
Hypertension ; 67(1): 139-45, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26573708

RESUMO

Primary aldosteronism comprises 2 main subtypes: unilateral aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia. Somatic KCNJ5 mutations are found in APA at a prevalence of around 40% that drive and sustain aldosterone excess. Somatic APA mutations have been described in other genes (CACNA1D, ATP1A1, and ATP2B3) albeit at a lower frequency. Our objective was to identify genotype-specific steroid profiles in adrenal venous (AV) and peripheral venous (PV) plasma in patients with APAs. We measured the concentrations of 15 steroids in AV and PV plasma samples by liquid chromatography-tandem mass spectrometry from 79 patients with confirmed unilateral primary aldosteronism. AV sampling lateralization ratios of steroids normalized either to cortisol or to DHEA+androstenedione were also calculated. The hybrid steroid 18-oxocortisol exhibited 18- and 16-fold higher concentrations in lateralized AV and PV plasma, respectively, from APA with KCNJ5 mutations compared with all other APA combined together (P<0.001). Lateralization ratios for the KCNJ5 group were also generally higher. Strikingly, we demonstrate that a distinct steroid signature can differentiate APA genotype in AV and PV plasma. Notably, a 7-steroid fingerprint in PV plasma correctly classified 92% of the APA according to genotype. Prospective studies are necessary to translate these findings into clinical practice and determine if steroid fingerprinting could be of value to select patients with primary aldosteronism who are particularly suitable candidates for adrenal venous sampling because of a high probability of having an APA.


Assuntos
Neoplasias do Córtex Suprarrenal/sangue , Adenoma Adrenocortical/sangue , Aldosterona/metabolismo , Hidrocortisona/sangue , Neoplasias do Córtex Suprarrenal/genética , Adenoma Adrenocortical/genética , Cromatografia Líquida , Análise Mutacional de DNA , DNA de Neoplasias/genética , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Genótipo , Humanos , Mutação , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , ATPases Transportadoras de Cálcio da Membrana Plasmática/metabolismo , Reação em Cadeia da Polimerase , Estudos Prospectivos , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismo , Espectrometria de Massas em Tandem
19.
Eur J Endocrinol ; 173(6): 757-64, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26346138

RESUMO

OBJECTIVE: Pheochromocytomas are rare chromaffin cell-derived tumors causing paroxysmal episodes of headache, palpitation, sweating and hypertension. Life-threatening complications have been described in case reports and small series. Systematic analyses are not available. We took an opportunity of a large series to make a survey. DESIGN AND METHODS: We analyzed records of patients diagnosed with pheochromocytomas in three geographically spread German referral centers between 2003 and 2012 (n=135). RESULTS: Eleven percent of the patients (ten women, five men) required in-hospital treatment on intensive care units (ICUs) due to complications caused by unsuspected pheochromocytomas. The main reasons for ICU admission were acute catecholamine induced Tako-Tsubo cardiomyopathy (n=4), myocardial infarction (n=2), acute pulmonary edema (n=2), cerebrovascular stroke (n=2), ischemic ileus (n=1), acute renal failure (n=2), and multi organ failure (n=1). One patient required extracorporeal membrane oxygenation due to a hypertensive crisis with lung edema occurring during delivery (n=1). Two patients died of refractory shock and pheochromocytomas were found postmortem. Two patients were treated by emergency surgery. Compared to pheochromocytoma patients without life-threatening events (n=120), patients with complications had a significant larger maximal tumor diameter (7.0 vs 4.5 cm, P<0.01), higher levels of catecholamines (20- vs ninefold upper limit of normal, P<0.01), and tended to be younger (42 vs 51 years, P=0.05). CONCLUSION: Although pheochromocytomas are rare, they are likely to be associated with a life-threatening situation. Clinicians have to be aware of these situations and perform a timely diagnosis.


Assuntos
Lesão Renal Aguda/etiologia , Neoplasias das Glândulas Suprarrenais/complicações , Isquemia Mesentérica/etiologia , Insuficiência de Múltiplos Órgãos/etiologia , Infarto do Miocárdio/etiologia , Feocromocitoma/complicações , Edema Pulmonar/etiologia , Cardiomiopatia de Takotsubo/etiologia , Adolescente , Neoplasias das Glândulas Suprarrenais/metabolismo , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Idoso , Catecolaminas/metabolismo , Estado Terminal , Oxigenação por Membrana Extracorpórea/estatística & dados numéricos , Feminino , Humanos , Íleus/etiologia , Unidades de Terapia Intensiva/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Feocromocitoma/metabolismo , Feocromocitoma/patologia , Gravidez , Complicações Neoplásicas na Gravidez , Estudos Retrospectivos , Acidente Vascular Cerebral , Carga Tumoral
20.
Eur J Endocrinol ; 173(5): 665-75, 2015 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-26311088

RESUMO

DESIGN: Abnormalities in glucose homeostasis have been described in patients with primary aldosteronism (PA) but most studies show inconsistent results. Therefore, we aimed to compare the prevalence of type 2 diabetes mellitus and metabolic syndrome (MetS) in newly diagnosed PA patients to a matched control cohort of the background population. METHODS: In total, 305 PA patients of the prospective German Conn's Registry were compared to the population-based Study of Health In Pomerania (SHIP1; n=2454). A 1:1 match regarding sex, age, and BMI resulted in 269 matched pairs regarding type 2 diabetes and 183 matched pairs regarding MetS. Of the total, 153 PA patients underwent oral glucose tolerance testing (OGTT) at diagnosis and 38 PA patients were reevaluated at follow-up. RESULTS: Type 2 diabetes and MetS were significantly more frequent in PA patients than in the control population (17.2% vs 10.4%, P=0.03; 56.8% vs 44.8%, P=0.02 respectively). Also, HbA1c levels were higher in PA patients than in controls (P<0.01). Of the total, 35.3% of non-diabetic PA patients showed an abnormal OGTT (» newly diagnosed type 2 diabetes and ¾ impaired glucose tolerance). PA patients with an abnormal OGTT at baseline presented with significantly improved 2 h OGTT glucose (P=0.01) at follow-up. We detected a negative correlation between 2 h OGTT glucose levels and serum potassium (P<0.01). CONCLUSIONS: Type 2 diabetes and MetS are more prevalent in patients with PA than in controls matched for sex, age, BMI, and blood pressure. This may explain in part the increased cardiovascular disease morbidity and mortality in PA patients.


Assuntos
Comorbidade/tendências , Diabetes Mellitus Tipo 2/epidemiologia , Hiperaldosteronismo/epidemiologia , Síndrome Metabólica/epidemiologia , Sistema de Registros/estatística & dados numéricos , Adulto , Feminino , Alemanha/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Prevalência , Estudos Prospectivos
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