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1.
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.

2.
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
3.
Intern Med ; 58(19): 2819-2824, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31243234

RESUMO

Congestive heart failure (CHF) is rare during pregnancy. We herein report a 35-year-old woman who developed CHF with severe left ventricular dysfunction at 35 weeks' gestation. She underwent emergency Caesarean section followed by intensive-care treatment for CHF. The diagnosis of Cushing's syndrome (CS) caused by adrenal adenoma was confirmed by endocrinological examinations and histology after adrenalectomy. She was discharged on heart failure medications and glucocorticoid replacement therapy. Both the symptoms and cardiac function had recovered after 12 months of follow-up. This case highlights the importance of considering CS-induced cardiomyopathy as a cause of CHF in pregnant women.


Assuntos
Adrenalectomia/métodos , Adenoma Adrenocortical/cirurgia , Cardiomiopatias/complicações , Cesárea/métodos , Síndrome de Cushing/complicações , Insuficiência Cardíaca/cirurgia , Complicações na Gravidez , Doença Aguda , Adenoma Adrenocortical/complicações , Adenoma Adrenocortical/diagnóstico , Adulto , Cardiomiopatias/diagnóstico , Síndrome de Cushing/diagnóstico , Ecocardiografia , Eletrocardiografia , Feminino , Insuficiência Cardíaca/etiologia , Humanos , Recém-Nascido , Laparoscopia , Gravidez , Tomografia Computadorizada por Raios X
4.
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.

5.
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
6.
Nephrology (Carlton) ; 24(9): 943-950, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30407693

RESUMO

AIM: Advanced glycation end products and their precursors cause vascular damage through oxidative stress. We investigated the hypothesis that methylglyoxal (MG), 3-deoxyglucosone (3-DG) and pentosidine influence outcomes of chronic kidney disease (CKD) patients. METHODS: We conducted a 3 years prospective observational study involving 150 outpatients at CKD stages 3-5. At enrolment, MG, 3-DG and pentosidine plasma concentrations were measured; patients were divided into tertiles according to the concentration of each substance. The primary endpoint was death, a cardiovascular event or end-stage renal disease. Survival analysis was performed using the Cox regression model. RESULTS: The patients' mean age was 62 ± 12 years, 97 were men, and 20 had diabetic nephropathy. The mean estimated glomerular filtration rate was 25.0 ± 12.1 mL/min per 1.73 m2 , which negatively correlated with MG but not with 3-DG and pentosidine. Forty-eight patients reached the primary endpoint. Compared with the lowest MG tertile, the hazard ratio for the primary endpoint was 7.57 (95% confidence interval (CI): 1.71-33.54) in the middle tertile and 27.00 (CI: 6.46-112.82) in the highest tertile. When adjusted for characteristics at baseline, the corresponding hazard ratio decreased to 2.09 (CI: 0.37-11.96) and 6.13 (CI: 0.97-38.82), but MG tertile remained an independent risk factor for the primary endpoint. However, 3-DG and pentosidine were not related to the primary outcome. CONCLUSION: Methylglyoxal has a close clinical association with CKD. Higher MG concentrations may contribute renal function deterioration in CKD. In CKD patients, MG concentration might be useful when determining the prognosis.


Assuntos
Nefropatias Diabéticas/sangue , Falência Renal Crônica/sangue , Aldeído Pirúvico/sangue , Insuficiência Renal Crônica/sangue , Idoso , Arginina/análogos & derivados , Arginina/sangue , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/mortalidade , Desoxiglucose/análogos & derivados , Desoxiglucose/sangue , Nefropatias Diabéticas/diagnóstico , Nefropatias Diabéticas/mortalidade , Progressão da Doença , Feminino , Humanos , Japão , Falência Renal Crônica/diagnóstico , Falência Renal Crônica/mortalidade , Lisina/análogos & derivados , Lisina/sangue , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Insuficiência Renal Crônica/diagnóstico , Insuficiência Renal Crônica/mortalidade , Fatores de Risco , Fatores de Tempo , Regulação para Cima
7.
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
8.
Surg Case Rep ; 4(1): 119, 2018 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-30225726

RESUMO

BACKGROUND: Ganglioneuroblastomas, particularly those that produce catecholamine, are extremely rare in adults. Here, we report an interesting surgical case of an adult patient with a catecholamine-producing ganglioneuroblastomas in her adrenal gland, suspected to be a pheochromocytoma, and with a cerebral aneurysm. CASE PRESENTATION: The patient was a 73-year-old woman under treatment for hypertension. During a health check-up, a cystic retroperitoneal tumor was incidentally found in the superior pole of her right kidney. Her blood adrenaline level was slightly elevated, and her urinary adrenaline, noradrenaline, and dopamine levels were above the upper reference limits. In addition, 24-h urinary excretion of metanephrine, normetanephrine, and vanillylmandelic acid were all increased. 123I-Meta-iodobenzylguanidine scintigraphy showed an abnormal accumulation of the marker in the cyst wall. She was, therefore, diagnosed with a pheochromocytoma and scheduled for tumor resection. However, preoperatively, 8-mm-diameter cerebral aneurysm was incidentally found in her basilar artery. This required careful preoperative discussion. The aneurysm was difficult to approach and treat, and based on its position, shape, and size, the risk of rupture was low. Because hypertension is a major risk factor for aneurysmal rupture, we decided to proceed with the tumor resection. A lumbar catheter was placed to monitor the cerebral aneurysm for intraoperative rupture, and her transcranial motor-evoked potential and somatosensory-evoked potentials were monitored to track her intraoperative neurological function. During surgery, we carefully monitored fluctuations in blood pressure and resected the tumor with minimal mobilization. Postoperatively, head computed tomography confirmed that there was no sign of rupture. Histopathologically, the tumor was diagnosed as a catecholamine-producing ganglioneuroblastoma. The postoperative course was good, and the patient's blood pressure improved. CONCLUSIONS: Careful perioperative management is needed for a patient with both a catecholamine-producing tumor and cerebral aneurysm.

9.
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
10.
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
11.
Eur J Radiol ; 98: 150-157, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29279155

RESUMO

OBJECTIVES: To compare image quality and radiation dose of right adrenal vein (RAV) imaging computed tomography (CT) among conventional, low kV, and low kV with reduced contrast medium protocols. METHODS: One-hundred-and-twenty patients undergoing adrenal CT were randomly assigned to one of three protocols: contrast dose of 600mgI/kg at 120-kV tube voltage setting (600-120 group), 600mgI/kg at 80kV (600-80 group), and 360mgI/kg at 80kV (360-80 group). Iterative reconstruction was used for 80-kV groups. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) of the RAV and size-specific dose estimates (SSDE) were measured. Three radiologists evaluated 4-point visualisation scores of RAV by consensus reading. RESULTS: The RAV detectability was 95%, 97.2%, and 97.3% for 600-120, 600-80, and 360-80 groups, respectively (p=1.000). Visualisation scores were not significantly different among the groups (p=0.152). There were no significant differences in CNR or SNR between the 600-120 and 360-80 groups. SSDE of the 360-80 group was significantly lower than that of the 600-120 group (5.86mGy±1.44 vs. 7.27mGy±1.81, p<0.001). CONCLUSIONS: 80-kV scans with 360 mgI/kg contrast media showed comparable detectability of RAV to conventional scans, while reducing 19% of SSDE.


Assuntos
Glândulas Suprarrenais/irrigação sanguínea , Glândulas Suprarrenais/diagnóstico por imagem , Meios de Contraste , Hiperaldosteronismo/diagnóstico por imagem , Doses de Radiação , Intensificação de Imagem Radiográfica/métodos , Tomografia Computadorizada por Raios X/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Razão Sinal-Ruído , Veias/diagnóstico por imagem
12.
Hypertension ; 70(2): 334-341, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28652474

RESUMO

Measurement of plasma aldosterone and renin concentration, or activity, is useful for selecting antihypertensive agents and detecting hyperaldosteronism in hypertensive patients. However, it takes several days to get results when measured by radioimmunoassay and development of more rapid assays has been long expected. We have developed chemiluminescent enzyme immunoassays enabling the simultaneous measurement of both aldosterone and renin concentrations in 10 minutes by a fully automated assay using antibody-immobilized magnetic particles with quick aggregation and dispersion. We performed clinical validation of diagnostic ability of this newly developed assay-based screening of 125 patients with primary aldosteronism from 97 patients with essential hypertension. Results of this novel assay significantly correlated with the results of radioimmunoassay (aldosterone, active renin concentration, and renin activity) and liquid chromatography-tandem mass spectrometry (aldosterone). The analytic sensitivity of this particularly novel active renin assay was 0.1 pg/mL, which was better than that of radioimmunoassay (2.0 pg/mL). The ratio of aldosterone-to-renin concentrations of 6.0 (ng/dL per pg/mL) provided 92.0% sensitivity and 76.3% specificity as a cutoff for differentiating primary aldosteronism from essential hypertension. This novel measurement is expected to be a clinically reliable alternative for conventional radioimmunoassay and to provide better throughput and cost effectiveness in diagnosis of hyperaldosteronism from larger numbers of hypertensive patients in clinical settings.


Assuntos
Aldosterona , Anti-Hipertensivos/uso terapêutico , Hiperaldosteronismo , Hipertensão , Medições Luminescentes/métodos , Renina , Adulto , Aldosterona/análise , Aldosterona/sangue , Cromatografia Líquida/métodos , Pesquisa Comparativa da Efetividade , Feminino , Humanos , Hiperaldosteronismo/sangue , Hiperaldosteronismo/diagnóstico , Hipertensão/tratamento farmacológico , Hipertensão/etiologia , Imunoensaio/métodos , Japão , Masculino , Programas de Rastreamento/métodos , Pessoa de Meia-Idade , Seleção de Pacientes , Testes Imediatos , Radioimunoensaio/métodos , Renina/análise , Renina/sangue , Reprodutibilidade dos Testes
13.
J Clin Endocrinol Metab ; 102(4): 1182-1192, 2017 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-28388725

RESUMO

Context: Approximately half of patients with primary aldosteronism (PA) have clinically evident disease according to clinical (hypertension) and/or laboratory (aldosterone and renin levels) findings but do not have nodules detectable in routine cross-sectional imaging. However, the detailed histopathologic, steroidogenic, and pathobiological features of cross-sectional image-negative PA are controversial. Objective: To examine histopathology, steroidogenic enzyme expression, and aldosterone-driver gene somatic mutation status in cross-sectional image-negative hyperaldosteronism. Methods: Twenty-five cross-sectional image-negative cases were retrospectively reviewed. In situ adrenal aldosterone production capacity was determined using immunohistochemistry (IHC) of steroidogenic enzymes. Aldosterone-driver gene somatic mutation status (ATP1A1, ATP2B3, CACNA1D, and KCNJ5) was determined in the CYP11B2 immunopositive areas [n = 35; micronodule, n = 32; zona glomerulosa (ZG), n = 3] using next-generation sequencing after macrodissection. Results: Cases were classified as multiple adrenocortical micronodules (MN; n = 13) or diffuse hyperplasia (DH) of ZG (n = 12) based upon histopathological evaluation and CYP11B2 IHC. Aldosterone-driver gene somatic mutations were detected in 21 of 26 (81%) of CYP11B2-positive cortical micronodules in MN; 17 (65%) mutations were in CACNA1D, 2 (8%) in KCNJ5, and 1 each (4% each) in ATP1A1 and ATP2B. One of 6 (17%) of nodules in DH harbored somatic aldosterone-driver gene mutations (CACNA1D); however, no mutations were detected in CYP11B2-positive nonnodular DH areas. Conclusion: Morphologic evaluation and CYP11B2 IHC enabled the classification of cross-sectional image-negative hyperaldosteronism into MN and DH. Somatic mutations driving aldosterone overproduction are common in micronodules of MN, suggesting a histological entity possibly related to aldosterone-producing cell cluster development.


Assuntos
Córtex Suprarrenal/patologia , Aldosterona/biossíntese , Hiperaldosteronismo/patologia , Mutação , Córtex Suprarrenal/metabolismo , Adulto , Idoso , Canais de Cálcio Tipo L/genética , Canais de Cálcio Tipo L/metabolismo , Feminino , 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 , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Hiperaldosteronismo/genética , Hiperaldosteronismo/metabolismo , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , ATPases Transportadoras de Cálcio da Membrana Plasmática/metabolismo , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismo
14.
Tohoku J Exp Med ; 240(3): 183-190, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27853054

RESUMO

Aldosterone-producing adrenocortical adenoma (APA) is responsible for the majority of cases clinically diagnosed as primary aldosteronism. Aldosterone synthase (CYP11B2) is one of the enzymes that play essential roles in aldosterone synthesis and is involved in the pathogenesis of APA. Recent studies have demonstrated that various factors and regulators influence the expression and function of CYP11B2 in APA. In particular, somatic mutations, such as gain-of-function and loss-of-function mutations, have been identified in several genes, each of which encodes a pivotal protein that affects the calcium signaling pathway, the expression of CYP11B2, and aldosterone production. The gain-of-function mutations were reported in KCNJ5 that encodes G-protein activated inward rectifier K+ channel 4 (Kir3.4) and in CACNA1D, encoding calcium channel, voltage-dependent, L type, alpha subunit Cav1.3. The loss-of-function mutations were found in ATP1A1 that encodes Na+/K+ ATPase α subunit and in ATP2B3, encoding Ca2+ ATPase. Furthermore, the aberrant expression of gonadotropin-releasing hormone receptor is associated with the overexpression of CYP11B2 and overproduction of aldosterone in APA with activating mutations in CTNNB1 encoding ß-catenin. On the other hand, CYP11B2 also catalyzes the conversion of cortisol to 18-hydroxycortisol and subsequently converts 18-hydroxycortisol to 18-oxocortisol. The recent studies have identified 18-oxocortisol as an important and distinct biomarker to diagnose primary aldosteronism. In this review, we summarize the recent findings on CYP11B2 and discuss the molecular pathogenesis of APA and the clinical significance of CYP11B2.


Assuntos
Neoplasias do Córtex Suprarrenal/enzimologia , Adenoma Adrenocortical/enzimologia , Aldosterona/biossíntese , Citocromo P-450 CYP11B2/metabolismo , Neoplasias do Córtex Suprarrenal/patologia , Adenoma Adrenocortical/patologia , Forma Celular , Citocromo P-450 CYP11B2/genética , Humanos , Mutação/genética , Fatores de Transcrição/metabolismo
15.
Eur J Endocrinol ; 173(4): 465-77, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26194502

RESUMO

OBJECTIVE AND DESIGN: Adrenal venous sampling (AVS) is critical to determine the subtype of primary aldosteronism (PA). Central AVS (C-AVS)--that is, the collection of effluents from bilateral adrenal central veins (CV)--sometimes does not allow differentiation between bilateral aldosterone-producing adenomas (APA) and idiopathic hyperaldosteronism. To establish the best treatment course, we have developed segmental AVS (S-AVS); that is, we collect effluents from the tributaries of CV to determine the intra-adrenal sources of aldosterone overproduction. We then evaluated the clinical utility of this novel approach in the diagnosis and treatment of PA. METHODS: We performed C-AVS and/or S-AVS in 297 PA patients and assessed the accuracy of diagnosis based on the results of C-AVS (n=138, 46.5%) and S-AVS (n=159, 53.5%) by comparison with those of clinicopathological evaluation of resected specimens. RESULTS: S-AVS demonstrated both elevated and attenuated secretion of aldosterone from APA and non-tumorous segments, respectively, in patients with bilateral APA and recurrent APA. These findings were completely confirmed by detailed histopathological examination after surgery. S-AVS, but not C-AVS, also served to identify APA located distal from the CV. CONCLUSIONS: Compared to C-AVS, S-AVS served to identify APA in some patients, and its use should expand the pool of patients eligible for adrenal sparing surgery through the identification of unaffected segments, despite the fact that S-AVS requires more expertise and time. Especially, this new technique could enormously benefit patients with bilateral or recurrent APA because of the preservation of non-tumorous glandular tissue.


Assuntos
Neoplasias do Córtex Suprarrenal/diagnóstico , Glândulas Suprarrenais/irrigação sanguínea , Adenoma Adrenocortical/diagnóstico , Aldosterona/metabolismo , Coleta de Amostras Sanguíneas/métodos , Hiperaldosteronismo/diagnóstico , Veias , Neoplasias do Córtex Suprarrenal/metabolismo , Neoplasias do Córtex Suprarrenal/cirurgia , Adrenalectomia/métodos , Adenoma Adrenocortical/metabolismo , Adenoma Adrenocortical/cirurgia , Feminino , Humanos , Hiperaldosteronismo/classificação , Hiperaldosteronismo/cirurgia , Masculino , Pessoa de Meia-Idade , Tratamentos com Preservação do Órgão
16.
Biochem Biophys Res Commun ; 435(3): 334-8, 2013 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-23624197

RESUMO

Discs large homolog 1 (DLG1/SAP97) is involved in the development and regulation of neuronal and immunological synapses. DLG1 is a member of the membrane associated guanylate kinase (MAGUK) family of proteins, which function as molecular scaffolds. The C-terminal guanylate kinase (GK) domain of DLG1 binds peptides with a phosphorylated serine residue. In this study, we solved the crystal structure of the GK domain of human DLG1. The C-terminal tail of DLG1 is bound to the peptide-binding site of an adjacent symmetry-related DLG1 GK molecule. The binding direction of the C-terminal tail to the peptide-binding site is opposite to that of the phosphorylated LGN peptide in complex with the rat DLG1 GK domain. The C-terminal tail forms a 310 helix, which is also different from the conformation of the phosphorylated LGN peptide. Nevertheless, the side chain interactions of the C-terminal tail with the DLG1 GK domain are similar to those of the phosphorylated LGN peptide.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas de Membrana/química , Animais , Sítios de Ligação , Cristalografia por Raios X , Guanilato Quinases/química , Humanos , Modelos Moleculares , Conformação Proteica , Domínios e Motivos de Interação entre Proteínas , Ratos , Proteínas Recombinantes/química , Especificidade da Espécie
17.
Cancer Sci ; 102(5): 934-41, 2011 May.
Artigo em Inglês | MEDLINE | ID: mdl-21272161

RESUMO

We previously reported that impaired retinoid signaling causes hepatocellular carcinoma (HCC) through oxidative stress. However, the interaction between oxidative stress and retinoid signaling has not been fully understood. To address this issue, the effects of hydrogen peroxide on the transcriptional activity of RAR/RXR heterodimers, RARα and RXRα proteins and intracellular signaling pathways were examined. The transcriptional activity of RAR/RXR examined by the DR5-tk-Luc reporter assay was significantly suppressed. The RARα protein level began to decrease at 6 h after treatment and declined thereafter. However, RARα mRNA were not changed. Activation of extracellular regulated kinases (ERK), p38, c-Jun N-terminal kinase (JNK) and Akt was observed after treatment of hydrogen peroxide. SP600125, an inhibitor of JNK, reversed the RARα protein level reduced by hydrogen peroxide. Anisomycin, an activator of JNK, reduced RARα protein. Transfection of wild-type JNK-constitutive actively expressing plasmid, but not kinase-negative JNK-expressing plasmid caused reduction of RARα protein. Proteasomal degradation of RARα was observed after anisomycin treatment; however, the mutant RARα, of which phosphorylation sites are replaced with alanines, was not degradated. In hepatitis C virus (HCV)-related human liver tissues, phospho-JNK and RARα reciprocally expressed with the progression of liver disease. Finally, the staining of 8-OHdG and thioredoxin was increased with the disease progression. These data indicate that JNK activation by oxidative stress suppresses retinoid signaling through proteasomal degradation of RARα, suggesting that a vicious cycle between aberrant retinoid signaling and oxidative stress accelerates hepatocarcinogenesis.


Assuntos
Ativação Enzimática/fisiologia , Hepatócitos/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Estresse Oxidativo/fisiologia , Complexo de Endopeptidases do Proteassoma/metabolismo , Receptores do Ácido Retinoico/metabolismo , Transdução de Sinais , Western Blotting , Humanos , Peróxido de Hidrogênio/farmacologia , Imuno-Histoquímica , Oxidantes/farmacologia , Receptor alfa de Ácido Retinoico , Receptores X Retinoide/metabolismo , Retinoides/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transcrição Genética
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