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1.
Horm Metab Res ; 2020 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-32403152

RESUMO

Primary aldosteronism (PA) was reported to frequently harbor not only cardiovascular diseases but also some metabolic disorders including secondary calcium metabolic diseases. Recently, the potential association between aldosterone producing cells and systemic calcium metabolism has been proposed. For instance, PA is frequently associated with hypercalciuria or hypocalcemia, which subsequently stimulates parathyroid hormone (PTH) secretion. This altered calcium metabolism in PA patients could frequently result in secondary osteoporosis and fracture in some patients. On the other hand, extracellular calcium itself directly acts on adrenal cortex and has been also proposed as an independent regulator of aldosterone biosynthesis in human adrenals. However, it is also true that both PTH and vitamin D pathways stimulate endocrine functions of adrenal cortical adenomas to co-secret both aldosterone and cortisol. Therefore, it has become pivotal to explore the potential crosstalk between aldosterone and systemic calcium metabolism. We herein reviewed recent advances in these fields.

2.
Endocr J ; 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32378529

RESUMO

This phase 2, single-arm, open-label, dose-titration, multicenter study evaluated osilodrostat (11ß-hydroxylase inhibitor) in Japanese patients with endogenous Cushing's syndrome (CS) caused by adrenal tumor/hyperplasia or ectopic adrenocorticotropic hormone syndrome. The primary endpoint was percent change from baseline to week 12 in mean urinary free cortisol (mUFC) at the individual patient level. Of the nine patients enrolled in the study, seven completed the 12-week core treatment period and two discontinued at or prior to week 12 due to adverse events (AEs). Of the seven patients who completed 12 weeks of study treatment, two completed 48 weeks of study treatment. Median osilodrostat exposure was 12 weeks. Median (range) average dose including dose interruption (0 mg/day) was 2.143 (1.16-7.54) mg/day. Median (range, population) percentage change in mUFC was -94.47% (-99.0% to -52.6%, n = 7) at week 12. At week 12, 6/9 patients were complete responders (mUFC ≤ upper limit of normal [ULN]) and 1/9 was a partial responder (mUFC > ULN but decreased by ≥50% from baseline). Most frequent AEs were adrenal insufficiency (n = 7), gamma-glutamyl transferase increase, malaise, and nasopharyngitis (n = 3 each). Serious AEs were seen in four patients. No deaths occurred in this study. In conclusion, osilodrostat treatment led to a reduction in mUFC in all nine patients with endogenous CS other than Cushing's disease (CD), regardless of disease type, with >80% reduction seen in 6/7 patients at week 12. The safety profile was consistent with previous reports in CD patients, and the reported AEs were manageable.

3.
BMC Nephrol ; 21(1): 144, 2020 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-32321450

RESUMO

BACKGROUND: Aciduria caused by urinary excretion of acidic metabolic wastes produced in daily life is known to be augmented in patients with chronic kidney disease (CKD). To evaluate the reno-protective effect of oral alkalizing agents for the improvement of metabolic acidosis and neutralization of intratubular pH in the patients with mild stages of CKD. Also, to identify reno-protective surrogate markers in the serum and urine that can closely associate the effect of urine alkalization. METHODS: In this single-centered, open-labeled, randomized cohort study, patients with CKD stages G2, G3a and G3b, who visited and were treated at Tohoku University Hospital during the enrollment period were registered. We administered sodium bicarbonate or sodium-potassium citrate as the oral alkalinizing agents. A total of 150 patients with CKD will be randomly allocated into the following three groups: sodium bicarbonate, sodium-potassium citrate and standard therapy group without any alkalinizing agents. The data of performance status, venous blood test, spot urine test, venous blood-gas test, electrocardiogram, renal arterial ultrasonography and chest X-ray will be collected at 0, 6, 12 and 24 weeks (short-term study) from starting the interventions. These data will be also collected at 1 and 2 years (long-term study). The samples of plasma and serum and early-morning urine at every visit will be acquired for the analysis of renal function and surrogate uremic biomarkers. The recruitment for this cohort study terminated in March, 2018, and the follow-up period for all the enrolled subjects will be terminated in December, 2020. The primary endpoint will be the development of originally-defined significant renal dysfunction or the occurrence of any cerebrovascular disease in the short-term study. The secondary endpoint will be the same endpoints as in the long-term study, or the patients with significant changes in the suggested the surrogate biomarkers. DISCUSSION: The findings of this study will address the importance of taking oral alkalizing agents in the patients with early stages of CKD, furthermore they could address any new surrogate biomarkers that can be useful from early stage CKD. TRIAL REGISTRATION: Registered Report Identifier: UMIN000010059 and jRCT021180043. The trial registration number; 150. Date of registration; 2013/02/26.

4.
J Clin Endocrinol Metab ; 105(3)2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31789380

RESUMO

CONTEXT: Aldosterone-producing adrenocortical adenomas (APAs) are mainly composed of clear (lipid rich) and compact (eosinophilic) tumor cells. The detailed association between these histological features and somatic mutations (KCNJ5, ATP1A1, ATP2B3, and CACNA1D) in APAs is unknown. OBJECTIVE: To examine the association between histological features and individual genotypes in APAs. METHODS: Examination of 39 APAs subjected to targeted next-generation sequencing (11 KCNJ5, 10 ATP1A1, 10 ATP2B3, and 8 CACNA1D) and quantitative morphological and immunohistochemical (CYP11B2 and CYP17A1) analyses using digital imaging software. RESULTS: KCNJ5- and ATP2B3-mutated APAs had clear cell dominant features (KCNJ5: clear 59.8% [54.4-64.6%] vs compact 40.2% (35.4-45.6%), P = .0022; ATP2B3: clear 54.3% [48.2-62.4 %] vs compact 45.7% (37.6-51.8 %), P = .0696). ATP1A1- and CACNA1D-mutated APAs presented with marked intratumoral heterogeneity. A significantly positive correlation of immunoreactivity was detected between CYP11B2 and CYP17A1 in tumor cells of KCNJ5-mutated APAs (P = .0112; ρ = 0.7237), in contrast, significantly inverse correlation was detected in ATP1A1-mutated APAs (P = .0025; ρ = -0.8667). CONCLUSION: KCNJ5-mutated APAs, coexpressing CYP11B2 and CYP17A1, were more deviated in terms of zonation-specific differentiation of adrenocortical cells than ATP1A1- and ATP2B3-mutated APAs.

5.
J Hypertens ; 38(1): 3-12, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31385870

RESUMO

OBJECTIVES: In experimental animal models, exogenous aldosterone excess has been linked to the progression of renal disease. However, the evidence of an increased risk of renal damage in patients affected by primary aldosteronism remains controversial. We aimed at evaluating the association between primary aldosteronism and renal damage through a meta-analysis. METHODS: We performed a quantitative review of studies evaluating parameters of renal function in patients affected by primary aldosteronism compared with hypertensive patients without primary aldosteronism and in patients affected by primary aldosteronism before and after treatment. We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials from January 1960 up to April 2019. RESULTS: Forty-six studies including 6056 patients with primary aldosteronism and 9733 patients affected by arterial hypertension without primary aldosteronism were included. After 8.5 years from hypertension diagnosis, patients with primary aldosteronism had an increased estimated glomerular filtration rate (eGFR) compared with hypertensive patients without primary aldosteronism [by 3.37 ml/min IQR (0.82-5.93)] and a more severe albuminuria [standard mean difference 0.55 (0.19-0.91)], resulting into an association with microalbuminuria [odds ratio (OR) 2.09 (1.40; 3.12)] and proteinuria [OR 2.68 (1.89;3.79)]. Following primary aldosteronism treatment, after a median follow-up of 12 months, a reduction in eGFR was observed [by -10.69 ml/min (-13.23; -8.16)], consistent in both medically and surgically treated patients. Similarly, a reduction in albumin excretion and an increase in serum creatinine were observed after treatment. CONCLUSION: Patients affected by primary aldosteronism, compared with patients affected by arterial hypertension without primary aldosteronism, display a more pronounced target organ damage, which can be mitigated by the specific treatment.

6.
Tohoku J Exp Med ; 249(3): 223-229, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31776301

RESUMO

Hypothalamic obesity is a clinical syndrome characterized by severe and refractory obesity that is caused by hypothalamic function impairment. Recently, bariatric surgery has been attempted for patients with hypothalamic obesity after craniopharyngioma, but experiences have not yet been accumulated in other hypothalamic disorders. Here, we report the case of a 39-year-old male patient with panhypopituitarism who received laparoscopic sleeve gastrectomy (LSG) after intracranial germinoma treatment. The patient was diagnosed with intracranial germinoma at age 15 and achieved complete remission after radiotherapy (total 50 Gy). He was obese during diagnosis [body mass index (BMI), 29.2 kg/m2], and his obesity gradually worsened after the intracranial germinoma treatment, and LSG was considered when his BMI was 48.6 kg/m2. After 1 month of hospitalized diet-exercise program, LSG was performed. After LSG, his BMI gradually decreased and reached 38.8 kg/m2 on the day of discharge (6 weeks after the surgery). Five months after LSG, his insulin resistance improved, but insulin hypersecretion remained. Fifteen months after the surgery, his BMI was 31.2 kg/m2, with marked decrease in visceral and subcutaneous fat areas (from 393.8 cm2 and 168.2 cm2 before the surgery to 111.5 cm2 and 56.3 cm2, respectively.). To our knowledge, this is the first case of LSG for hypothalamic obesity after intracranial germinoma treatment. Although the pathophysiology of hypothalamic obesity is different from that of primary obesity, LSG could be a successful therapeutic choice for patients with hypothalamic obesity after the intracranial germinoma treatment.

7.
Endocr J ; 66(12): 1063-1072, 2019 Dec 25.
Artigo em Inglês | MEDLINE | ID: mdl-31511435

RESUMO

We recently conducted an open-label phase I/II study to evaluate the efficacy and safety of preoperative and chronic treatment with metyrosine (an inhibitor of catecholamine synthesis) in pheochromocytoma/paraganglioma (PPGL) in Japan. We compared creatinine-corrected metanephrine fractions in spot urine and 24-hour urine samples (the current standard for the screening and diagnosis of PPGLs) from 16 patients to assess the therapeutic effect of metyrosine. Percent changes from baseline in urinary metanephrine (uMN) or normetanephrine (uNMN) were compared between spot and 24-hour urine samples. Mean percent changes in uMN or uNMN in spot and 24-hour urine were -26.36% and -29.27%, respectively. The difference in the percent change from baseline between uMN or uNMN in spot and 24-hour urine was small (-2.90%). The correlation coefficient was 0.87 for percent changes from baseline between uMN or uNMN measured in spot and 24-hour urine. The area under the receiver operator characteristic (ROC) curve of uMN or uNMN measured in spot urine vs. 24-hour urine (reference standard) to assess the efficacy of metyrosine treatment was 0.93. Correlations and ROCs between 24-hour urinary vanillylmandelic acid, adrenaline, and noradrenaline and 24-hour uMN or uNMN were similar to those between spot uMN or uNMN and 24-hour uMN or uNMN. No large difference was observed between spot and 24-hour urine for the assessment of metyrosine treatment by quantifying uMN or uNMN in Japanese patients with PPGLs. These results suggest that spot urine samples may be useful in assessing the therapeutic effect of metyrosine.

8.
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, identification of unilateral aldosteronism and 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 (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-stimulation conditions showed that cosyntropin increased the confirmed rate of bilateral selectivity for SI cut-offs ≥ 2.0, but with 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.

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 Steroid Biochem Mol Biol ; 193: 105434, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31351131

RESUMO

Intracellular calcium (Ca) levels play pivotal roles in aldosterone biosynthesis. Several somatic mutations of ion channels associated with aldosterone over-production were reported to result in over-inflow of Ca ion. Recently, the main regulators of extracellular Ca including VDR, CaSR and PTH1R were also reported to regulate steroidogenesis including aldosterone production. Therefore, not only intracellular but also extracellular Ca levels could regulate aldosterone biosynthesis. In addition, primary aldosteronism (PA) is clinically associated with not only more frequent cardiovascular events but also secondary metabolic disorders including abnormal calcium metabolism, osteoporosis and others. However, the details of Ca metabolic abnormalities associated with, including the potential correlation between those abnormalities and aldosterone overproduction, have remained virtually unknown. Therefore, in this study, we first immunolocalized Ca metabolism-related receptors (CaSR, VDR and PTH1R) in normal adrenal glands (NAs), aldosterone-producing adenomas (APAs) and cortisol-producing adenoma (CPA). We then compared the findings with clinicopathological parameters of these patients and the patterns of KCNJ5 somatic mutation of the tumors among APA patients. In vitro study was also performed to further explore the potential effects of extracellular Ca, PTH, Vitamin D and ionophore on aldosterone production. Ca metabolism-related receptors were predominantly localized in aldosterone-producing cells (ZG and APA) in both immunohistochemistry and qRT-PCR analysis. CYP11B2 mRNA was significantly increased by CaCl2 treatment and further by adding ionophore. All the key enzymes related to aldosterone and cortisol biosynthesis including CYP11B2, CYP17A1 and CYP11B1 were upregulated by PTH treatment in this model and PTH could serve as a co-stimulator of ANG II to increase CYP11B2 expression. VDR mRNA levels were positively correlated with those of CYP11B2, CYP17A1 and CYP11B1 in APA tumor tissues and significantly higher in KCNJ5 mutated APAs than wild type. CYP11B1 levels were also significantly increased by VitD treatment. PTH1R mRNA levels were positively correlated with those of CYP17A1 and CYP11B1, both involved in cortisol production. In addition, the status of VDR was correlated with TRACP-5b levels, and that of PTH1R with serum Ca levels as well as urinary Ca excretion, respectively. Results of our present study did firstly demonstrate that aldosterone-producing cells were more sensitive to the fluctuations of extracellular Ca levels and Ca metabolism could directly influence steroidogenesis, especially "neoplastic" co-secretion of aldosterone and cortisol in APA patients.


Assuntos
Glândulas Suprarrenais/metabolismo , Aldosterona/metabolismo , Cálcio/metabolismo , Hiperaldosteronismo/metabolismo , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Adenoma Adrenocortical/genética , Adenoma Adrenocortical/metabolismo , Adulto , Idoso , Linhagem Celular Tumoral , Sistema Enzimático do Citocromo P-450/genética , Feminino , Humanos , Hiperaldosteronismo/genética , Masculino , Pessoa de Meia-Idade , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Receptores de Calcitriol/metabolismo , Receptores de Detecção de Cálcio/metabolismo , Adulto Jovem
11.
Hypertension ; 73(6): 1283-1290, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31006333

RESUMO

Peripheral 18-oxocortisol (18oxoF) level could contribute to the detection of aldosterone-producing adenoma (APA) in patients with primary aldosteronism. However, peripheral 18oxoF varies among such patients, which is a big drawback concerning its clinical application. We studied 48 cases of APA, 35 harboring KCNJ5 mutation, to clarify the significance of clinical and pathological parameters about peripheral 18oxoF. Peripheral 18oxoF concentration ranged widely from 0.50 to 183.13 ng/dL and correlated positively with intratumoral areas stained positively for steroidogenic enzymes ( P<0.0001). The peripheral 18oxoF level also correlated significantly with that of circulating aldosterone ( P<0.0001) but not with that of cortisol, a precursor of 18oxoF. However, a significant correlation was detected between peripheral 18oxoF and intratumoral glucocorticoids ( P<0.05). In addition, peripheral 18oxoF correlated positively with the number of hybrid cells double positive for 11ß-hydroxylase and aldosterone synthase ( P<0.0001). Comparing between the cases with and those without KCNJ5 mutation, the KCNJ5-mutated group demonstrated a significantly higher concentration of peripheral 18oxoF (28.4±5.6 versus 3.0±0.9 ng/dL, P<0.0001) and a larger intratumoral environment including the hybrid cells ( P<0.001), possibly representing a deviation from normal aldosterone biosynthesis. After multivariate analysis, KCNJ5 mutation status turned out to be the most associated factor involved in 18oxoF synthesis in APA ( P<0.0001). Results of our present study first revealed that enhanced 18oxoF synthesis in APA could come from a functional deviation of aldosterone biosynthesis from the normal zona glomerulosa and the utility of peripheral 18oxoF measurement could be influenced by the prevalence of KCNJ5 mutation in an APA.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Adenoma Adrenocortical/genética , Aldosterona/metabolismo , DNA de Neoplasias/genética , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Hidrocortisona/análogos & derivados , Mutação/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Adenoma Adrenocortical/metabolismo , Análise Mutacional de DNA , Feminino , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/metabolismo , Humanos , Hidrocortisona/biossíntese , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
12.
Endocr Connect ; 8(5): 454-461, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-30959487

RESUMO

Objective: Regional differences in cardiac magnetic resonance, which can reveal catecholamine-induced myocardial injury in patients with pheochromocytoma, have not yet been assessed using 3T magnetic resonance imaging. We evaluated these differences using myocardial T1-mapping and strain analysis. Design and Methods: We retrospectively reviewed 16 patients newly diagnosed with catecholamine-producing tumors (CPT group) and 16 patients with essential hypertension (EH group), who underwent cardiac magnetic resonance imaging between May 2016 and March 2018. We acquired 3T magnetic resonance cine and native T1-mapping images and performed feature-tracking-based strain analysis in the former. Results: Global cardiac function, morphology, global strain and peak strain rate were similar, but end-diastolic wall thickness differed between groups (CPT vs EH: 10.5 ± 1.7 vs 12.6 ± 2.8 mm; P < 0.05). Basal, but not apical, circumferential strain was significantly higher in the CPT than the EH group (19.4 ± 3.2 vs 16.8 ± 3.6 %; P < 0.05). Native T1 values were significantly higher in CPT than in EH patients, in both the basal septum (1307 ± 48 vs 1241 ± 45 ms; P < 0.01) and the apical septum (1377 ± 59 vs 1265 ± 58 ms; P < 0.01) mid-walls. In the CPT, but not in the EH group, native T1 values in the apical wall were significantly higher than those in the basal wall (P < 0.01). Conclusion: 3T magnetic resonance-based T1-mapping can sensitively detect subclinical catecholamine-induced myocardial injury; the influence of catecholamines may be greater in the apical than in the basal wall.

13.
Ann Surg ; 2019 Jan 18.
Artigo em Inglês | MEDLINE | ID: mdl-30672800

RESUMO

MINI: Clinical remission after unilateral adrenalectomy to treat unilateral primary aldosteronism is achieved in less than half of patients. A linear discriminant model with 6 presurgical predictors of clinical remission was used to build a 25-point prediction score of postsurgical clinical outcomes. The prediction score was integrated into a user-friendly online tool which can be used in a clinical setting to differentiate patients who are likely to be clinically cured after surgery from those who will need continuous surveillance after surgery due to remnant hypertension. OBJECTIVE: To develop a prediction model for clinical outcomes after unilateral adrenalectomy for unilateral primary aldosteronism. SUMMARY BACKGROUND DATA: Unilateral primary aldosteronism is the most common surgically curable form of endocrine hypertension. Surgical resection of the dominant overactive adrenal in unilateral primary aldosteronism results in complete clinical success with resolution of hypertension without antihypertensive medication in less than half of patients with a wide between-center variability. METHODS: A linear discriminant analysis model was built using data of 380 patients treated by adrenalectomy for unilateral primary aldosteronism to classify postsurgical clinical outcomes. The total cohort was then randomly divided into training (280 patients) and test (100 patients) datasets to create and validate a score system to predict clinical outcomes. An online tool (Primary Aldosteronism Surgical Outcome predictor) was developed to facilitate the use of the predictive score. RESULTS: Six presurgical factors associated with complete clinical success (known duration of hypertension, sex, antihypertensive medication dosage, body mass index, target organ damage, and size of largest nodule at imaging) were selected based on classification performance in the linear discriminant analysis model. A 25-point predictive score was built with an optimal cut-off of greater than 16 points (accuracy of prediction = 79.2%; specificity = 84.4%; sensitivity = 71.3%) with an area under the curve of 0.839. CONCLUSIONS: The predictive score and the primary aldosteronism surgical outcome predictor can be used in a clinical setting to differentiate patients who are likely to be clinically cured after surgery from those who will need continuous surveillance after surgery due to persistent hypertension.

14.
J Hypertens ; 37(3): 603-611, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30431526

RESUMO

: Nowadays most patients diagnosed with surgically curable primary aldosteronism have small or micro aldosterone-producing adenoma or unilateral micronodular hyperplasia, which are undetectable with available imaging technologies. Therefore, a negative imaging test by no means excludes unilateral primary aldosteronism. Moreover, about 10% of the subjects above the age of 35 years have nonfunctioning adrenal tumors, regardless of being hypertensive or not, with a prevalence that raises with aging. Hence, the finding of an adrenal mass at imaging does not reliably detect the culprit of primary aldosteronism. On the other hand, when primary aldosteronism patients are selected for adrenalectomy on the basis of demonstration of lateralized aldosterone excess at adrenal vein sampling (AVS), close to 100% are biochemically cured from the hyperaldosteronism, about 45% are cured of arterial hypertension and an additional 52% are markedly improved in terms of blood pressure control. By contrast, patients referred for surgery based on imaging alone often fail to reach these successful outcomes, indicating that surgery was unnecessary or, even worse, performed on the wrong side. For these reasons, and because of the lack of accurate and widely available alternative methods, all current guidelines recommend that AVS be offered to all primary aldosteronism patients with only few exceptions, mainly in patients unable or unwilling to undergo surgery and those with germ-line mutations causing familial primary aldosteronism. The main argument against systematic use of AVS entails its suboptimal performance, partly justified by its intrinsic technical difficulty, and its limited availability. This led to propose skipping AVS strategies for predicting surgically curable primary aldosteronism, but success has been inconsistent. The most urgent standing issue is, therefore, not to find loopholes to avoid AVS, but rather to improve its use, which means improving the rate of AVS success, through formal training of interventionists, selection of appropriate cutoffs and exploitation of a standardized procedure.

15.
Hypertension ; 72(4): 874-880, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30354720

RESUMO

Primary aldosteronism affects ≈5% to 10% of hypertensive patients and has unilateral and bilateral forms. Most unilateral primary aldosteronism is caused by computed tomography-detectable aldosterone-producing adenomas, which express CYP11B2 (aldosterone synthase) and frequently harbor somatic mutations in aldosterone-regulating genes. The cause of the most common bilateral form of primary aldosteronism, idiopathic hyperaldosteronism (IHA), is believed to be diffuse hyperplasia of aldosterone-producing cells within the adrenal cortex. Herein, a multi-institution cohort of 15 IHA adrenals was examined with CYP11B2 immunohistochemistry and next-generation sequencing. CYP11B2 immunoreactivity in adrenal glomerulosa harboring non-nodular hyperplasia was only observed in 4/15 IHA adrenals suggesting that hyperplasia of CYP11B2-expressing cells may not be the major cause of IHA. However, the adrenal cortex of all IHA adrenals harbored at least 1 CYP11B2-positive aldosterone-producing cell cluster (APCC) or micro-aldosterone-producing adenomas. The number of APCCs per case (and individual APCC area) in IHA adrenals was significantly larger than in normotensive controls. Next-generation sequencing of DNA from 99 IHA APCCs demonstrated somatic mutations in genes encoding the L-type calcium voltage-gated channel subunit α 1-D ( CACNA1D, n=57; 58%) and potassium voltage-gated channel subfamily J-5 ( KCNJ5, n=1; 1%). These data suggest that IHA may result from not only hyperplasia but also the accumulation or enlargement of computed tomography-undetectable APCC harboring somatic aldosterone-driver gene mutations. The high prevalence of mutations in the CACNA1D L-type calcium channel provides a potential actionable therapeutic target that could complement mineralocorticoid blockade and inhibit aldosterone overproduction in some IHA patients.


Assuntos
Aldosterona , Canais de Cálcio Tipo L/genética , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Hiperaldosteronismo , Hipertensão , Zona Glomerulosa , Aldosterona/biossíntese , Aldosterona/genética , Citocromo P-450 CYP11B2/metabolismo , Feminino , Regulação da Expressão Gênica , Humanos , Hiperaldosteronismo/complicações , Hiperaldosteronismo/genética , Hiperaldosteronismo/metabolismo , Hiperplasia , Hipertensão/etiologia , Hipertensão/metabolismo , Imuno-Histoquímica , Masculino , Mutação , Zona Glomerulosa/metabolismo , Zona Glomerulosa/patologia
16.
Hypertension ; 72(3): 632-640, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-30354756

RESUMO

Aldosterone-producing adenomas (APAs) harbor marked intratumoral heterogeneity in terms of morphology, steroidogenesis, and genetics. However, an association of biological significance of morphologically identified tumor cell subtypes and genotypes is virtually unknown. KCNJ5 mutation is most frequently detected and generally considered a curable phenotype by adrenalectomy. Therefore, to explore the biological significance of KCNJ5 mutation in APA based on intracellular hormonal activities, 35 consecutively selected APAs (n=18; KCNJ5 mutated, n=17; wild type) were quantitatively examined in the whole tumor areas by newly developed digital image analysis incorporating their histological and ultrastructural features (14 cells from 2 KCNJ5-mutated APAs and 15 cells from 1 wild type) and CYP11B2 immunoreactivity. Results demonstrated that KCNJ5-mutated APAs had significantly lower nuclear/cytoplasm ratio and more abundant clear cells than wild type. CYP11B2 immunoreactivity was not significantly different between these genotypes, but a significant correlation was detected between the proportion of clear cells and CYP11B2 immunoreactivity in all of the APAs examined. CYP11B2 was predominantly immunolocalized in clear cells in KCNJ5-mutated APAs. Quantitative ultrastructural analysis revealed that KCNJ5-mutated APAs had significantly more abundant and smaller-sized mitochondria with well-developed cristae than wild type, whereas wild type had more abundant lipid droplets per unit area despite the small number of the cases examined. Our results did provide the novel insights into the morphological features of APA based on their biological significance. KCNJ5-mutated APAs were characterized by predominance of enlarged lipid-rich clear cells possibly resulting in increased neoplastic aldosterone biosynthesis.


Assuntos
Neoplasias do Córtex Suprarrenal/genética , Adenoma Adrenocortical/genética , Aldosterona/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Mutação , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/ultraestrutura , Adenoma Adrenocortical/metabolismo , Adenoma Adrenocortical/ultraestrutura , Adulto , Citocromo P-450 CYP11B2/metabolismo , Feminino , Humanos , Gotículas Lipídicas/ultraestrutura , Masculino , Microscopia Eletrônica de Transmissão , Pessoa de Meia-Idade , Mitocôndrias/ultraestrutura
17.
Endocr Pathol ; 29(4): 302-309, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30155766

RESUMO

In chromaffin cells, tyrosine hydroxylase (TH), aromatic L-amino acid decarboxylase (AADC), dopamine ß-hydroxylase (DBH), and phenylethanolamine N-methyltransferase (PNMT) are mainly involved in catecholamine synthesis. In this study, we evaluated the association between the status of catecholamine-synthesizing enzymes and histopathological features of pheochromocytoma and extraadrenal paraganglioma with special emphasis upon their postoperative clinical behavior. Immunohistochemical evaluation of TH, DBH, AADC, PNMT, Ki 67, and S-100 was performed in 29 pheochromocytoma and 10 extraadrenal paraganglioma and one lymph node harboring metastatic pheochromocytoma. Among these cases, metastasis was subsequently developed in three cases. Urinary normetanephrine (U-NM) levels were significantly higher in clinical metastatic cases than non-metastatic ones. Ki 67 labeling index was significantly higher in both clinical metastatic cases and the Adrenal Gland Scaled Score (PASS) score of ≧ 4 cases than PASS < 4 cases, although this score was originally used in pheochromocytoma. H-score of AADC and DBH were significantly lower in PASS ≧ 4 cases than those with < 4 cases, and in the cases associated with intratumoral necrosis (n = 4), the presence of spindle shaped tumor cells (n = 4), and large nests of cells or diffuse growth (n = 5). Lower status of intratumoral AADC could be related to poor differentiation of tumor cells in both catecholamine production and morphology and could be related to aggressive biological behavior of both pheochromocytoma and extraadrenal paraganglioma.


Assuntos
Neoplasias das Glândulas Suprarrenais/enzimologia , Catecolaminas/biossíntese , Paraganglioma Extrassuprarrenal/enzimologia , Feocromocitoma/enzimologia , Neoplasias das Glândulas Suprarrenais/patologia , Adulto , Descarboxilases de Aminoácido-L-Aromático/análise , Descarboxilases de Aminoácido-L-Aromático/metabolismo , Doenças do Sistema Nervoso Autônomo/metabolismo , Dopamina beta-Hidroxilase/análise , Dopamina beta-Hidroxilase/deficiência , Dopamina beta-Hidroxilase/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Norepinefrina/análise , Norepinefrina/deficiência , Norepinefrina/metabolismo , Paraganglioma Extrassuprarrenal/patologia , Feniletanolamina N-Metiltransferase/análise , Feniletanolamina N-Metiltransferase/metabolismo , Feocromocitoma/patologia , Tirosina 3-Mono-Oxigenase/análise , Tirosina 3-Mono-Oxigenase/metabolismo
18.
Hypertension ; 72(3): 641-649, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29987100

RESUMO

Unilateral primary aldosteronism is the most common surgically correctable form of endocrine hypertension and is usually differentiated from bilateral forms by adrenal venous sampling (AVS) or computed tomography (CT). Our objective was to compare clinical and biochemical postsurgical outcomes of patients with unilateral primary aldosteronism diagnosed by CT or AVS and identify predictors of surgical outcomes. Patient data were obtained from 18 internationally distributed centers and retrospectively analyzed for clinical and biochemical outcomes of adrenalectomy of patients with surgical management based on CT (n=235 patients, diagnosed from 1994-2016) or AVS (526 patients, diagnosed from 1994-2015) using the standardized PASO (Primary Aldosteronism Surgical Outcome) criteria. Biochemical outcomes were highly different according to surgical management approach with a smaller proportion in the CT group achieving complete biochemical success (188 of 235 [80%] patients versus 491 of 526 [93%], P<0.001) and a greater proportion with absent biochemical success (29 of 235 [12%] versus 10 of 526 [2%], P<0.001). A diagnosis by CT was associated with a decreased likelihood of complete biochemical success compared with AVS (odds ratio, 0.28; 0.16-0.50; P<0.001). Clinical outcomes were not significantly different, but the absence of a postsurgical elevated aldosterone-to-renin ratio was a strong marker of complete clinical success (odds ratio, 14.81; 1.76-124.53; P=0.013) in the CT but not in the AVS group. In conclusion, patients diagnosed by CT have a decreased likelihood of achieving complete biochemical success compared with a diagnosis by AVS.


Assuntos
Glândulas Suprarrenais/irrigação sanguínea , Coleta de Amostras Sanguíneas/métodos , Hiperaldosteronismo/diagnóstico por imagem , Hiperaldosteronismo/cirurgia , Tomografia Computadorizada por Raios X/métodos , Adrenalectomia/métodos , Adulto , Aldosterona/sangue , Biomarcadores/sangue , Feminino , Humanos , Hiperaldosteronismo/sangue , Masculino , Pessoa de Meia-Idade , /estatística & dados numéricos , Renina/sangue , Estudos Retrospectivos , Veias
19.
Endocr J ; 65(10): 991-999, 2018 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-30012912

RESUMO

Acromegalic arthropathy is a common complication of acromegaly and harms the quality of life of the patients even after acromegaly is in long-term remission. A recent study demonstrated by knee MRI the characteristic structural features of acromegalic arthropathy. However, the effects of treatment for acromegaly on such structural features are almost unknown. This study was undertaken to analyze the effects of transsphenoidal surgery (TSS) on acromegalic arthropathy and elucidate whether knee MRI findings are reversible or irreversible. We analyzed 22 patients with acromegaly (63.7% females, median age 58 years) by knee MRI at diagnosis. Out of these 22 patients, 16 who underwent TSS (68.9% female, median age 58 years) were also subjected to knee MRI 2 months after TSS. As for X-ray undetectable findings, MRI detected synovial thickening, bone marrow lesion, ligament injury and meniscus injury in 22.7%, 22.7%, 4.7% and 59.1% of the patients, respectively. With respect to the 16 patients who underwent TSS, clinical and structural improvements were observed respectively in 100%, 66.7% and 66.7% of the patients who showed knee joint pain, synovial thickening and bone marrow lesion before TSS. However, no patient showed structural improvement of meniscus injury after TSS. In acromegalic arthropathy, synovial thickening and bone marrow lesions are reversible while meniscus injury is irreversible. Because all those findings are associated with the exacerbation of arthropathy, they may be therapeutic targets for preventing the progression of arthropathy by endocrinological and orthopedic intervention.


Assuntos
Acromegalia/cirurgia , Artropatias/diagnóstico por imagem , Articulação do Joelho/diagnóstico por imagem , Joelho/diagnóstico por imagem , Membrana Sinovial/diagnóstico por imagem , Acromegalia/diagnóstico por imagem , Idoso , Feminino , Humanos , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Osso Esfenoide/cirurgia
20.
Am J Hypertens ; 31(5): 522-531, 2018 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-29534182

RESUMO

Primary aldosteronism (PA) is now considered as one of leading causes of secondary hypertension, accounting for 5-10% of all hypertensive patients and more strikingly 20% of those with resistant hypertension. Importantly, those with the unilateral disease could be surgically cured when diagnosed appropriately. On the other hand, only a very limited portion of those suspected to have PA has been screened, diagnosed, or treated to date. With current advancement in medical technologies and genetic research, expanding knowledge of PA has been accumulated and recent achievements have also been documented in the care of those with PA. This review is aimed to have focused description on updated topics of the following; importance of PA screening both in the general and specialized settings and careful interpretation of screening data, recent achievements in hormone assays and sampling methods and their clinical relevance, and expanding knowledge on PA genetics. Improvement in workup processes and novel treatment options, as well as better understanding of the PA pathogenesis based on genetic research, might be expected to result in increased cure and better care of the patients.


Assuntos
Hiperaldosteronismo/terapia , Humanos , Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/etiologia , Hiperaldosteronismo/genética
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