RESUMO
Endocrine disorders are the most common causes of secondary hypertension. Early diagnosis and specific treatment are crucial for improvement of the prognosis. This article provides an overview on which clinical constellations point to an increased risk of secondary causes of hypertension. These include spontaneous hypokalemia, young age at onset of hypertension, adrenal incidentaloma and therapy refractive arterial hypertension. The basic diagnostics include determination of the aldosterone to renin ratio, measurement of free plasma metanephrines and a 1â¯mg dexamethasone suppression test. Borderline results require repeated control testing and/or confirmatory testing under standardized test conditions. In cases of repeatedly conspicuous results referral to a specialized clinic should be considered for further clarification and confirmation of the diagnosis. Imaging diagnostics may constitute an adjunct to laboratory testing after the diagnosis has been confirmed. Therapeutic algorithms vary depending on the underlying endocrine disease.
Assuntos
Doenças do Sistema Endócrino/complicações , Hiperaldosteronismo/complicações , Hipertensão/etiologia , Algoritmos , Humanos , Hiperaldosteronismo/diagnóstico , Hipertensão/diagnósticoRESUMO
Untargeted, next generation sequencing approaches have provided deep insights into genetic events that result in unopposed steroidogenesis from the adrenal cortex. In particular, somatic mutations in the gene encoding the catalytic subunit α of protein kinase A (PKA) (PRKACA) were identified independently by several groups as the most frequently altered gene in cortisol-producing adenomas. Detailed functional studies could explore the molecular consequences of these hot-spot mutations and large international cohorts have provided the basis to explore the clinical characteristics associated with this mutation. Thereby, PRKACA mutations are highly specific for cortisol over-secretion, while they are absent or very rare in the context of other adrenal diseases. Patients carrying these somatic mutations are affected by a more severe phenotype and are identified at a younger age. Thus, these genotype/phenotype correlations provide further evidence for the importance of PKA-dependent pathways for adrenal physiology and disease.
Assuntos
Adenoma Adrenocortical , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico , Mutação , Proteínas de Neoplasias , Neoplasias do Córtex Suprarrenal/enzimologia , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/patologia , Adenoma Adrenocortical/enzimologia , Adenoma Adrenocortical/genética , Adenoma Adrenocortical/patologia , Animais , Humanos , Hidrocortisona/genética , Hidrocortisona/metabolismo , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismoRESUMO
The recently available genomic sequencing techniques have led to breakthroughs in understanding of the underlying genetic mechanisms in adrenocortical tumours. Disease-causing mutations have been described for aldosterone-producing adenomas, cortisol-producing adenomas and adrenocortical carcinomas. Further, knowledge gained from transcriptome analyses and methylation arrays has provided new insights into the development of these tumours. Elucidation of the genomic landscape of adrenocortical tumours and improved techniques may in the future be useful for early diagnosis through the detection of mutated DNA in the circulation. Moreover, compounds that bind specifically to altered proteins may be used as screening targets or therapeutic agents. Regulation of cortisol release by interaction with an altered subunit in adenylate cyclase may be more complex, but may provide a new option for regulating steroid release. Information about derangements in adrenocortical carcinoma is already helpful for determining patient prognosis. With further knowledge, we may be able to identify novel biomarkers that effectively and noninvasively help in differentiating between benign and malignant disease. It is clear that the next few years will provide much novel information that hopefully will aid in the treatment of patients with adrenocortical tumours.
Assuntos
Neoplasias do Córtex Suprarrenal/genética , Adenoma/genética , Adenoma/metabolismo , Carcinoma/genética , Análise Mutacional de DNA , Genômica , Glucocorticoides/metabolismo , Humanos , Hiperaldosteronismo/genéticaRESUMO
BACKGROUND: The clinical course of advanced adrenocortical carcinoma (ACC) is heterogeneous. Our study aimed primarily to refine and make headway in the prognostic stratification of advanced ACC. PATIENTS AND METHODS: Patients with advanced ENSAT ACC (stage III or stage IV) at diagnosis registered between 2000 and 2009 in the ENSAT database were enrolled. The primary end point was overall survival (OS). Parameters of potential prognostic relevance were selected. Univariate and multivariate analyses were carried out: model 1 'before surgery'; model 2 'post-surgery'. RESULTS: Four hundred and forty-four patients with advanced ENSAT ACC (stage III: 210; stage IV: 234) were analyzed. After a median follow-up of 55.2 months, the median OS was 24 months. A modified ENSAT (mENSAT) classification was validated: stage III (invasion of surrounding tissues/organs or the vena renalis/cava) and stage IVa, IVb, IVc (2, 3 or >3 metastatic organs, including N, respectively). Two- or 5-year OS was 73%, 46%, 26% and 15% or 50%, 15%, 14% and 2% for stages III, IVa, IVb and IVc, respectively. In the multivariate analysis, mENSAT stages (stages IVa, IVb, or IVc, respectively) were significantly correlated with OS (P < 0.0001), as well as additional parameters: age ≥ 50 years (P < 0.0001), tumor- or hormone-related symptoms (P = 0.01 and 0.03, respectively) in model 1 but also the R status (P = 0.001) and Grade (Weiss >6 and/or Ki67 ≥ 20%, P = 0.06) in model 2. CONCLUSION: The mENSAT classification and GRAS parameters (Grade, R status, Age and Symptoms) were found to best stratify the prognosis of patients with advanced ACC.
Assuntos
Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Neoplasias Ósseas/secundário , Neoplasias Hepáticas/secundário , Neoplasias Pulmonares/secundário , Recidiva Local de Neoplasia/patologia , Neoplasias do Córtex Suprarrenal/mortalidade , Carcinoma Adrenocortical/mortalidade , Neoplasias Ósseas/mortalidade , Europa (Continente) , Feminino , Seguimentos , Humanos , Neoplasias Hepáticas/mortalidade , Neoplasias Pulmonares/mortalidade , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Invasividade Neoplásica , Recidiva Local de Neoplasia/mortalidade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
Hypertension is a major cardiovascular risk factor that affects between 10-40% of the general population in an age dependent manner. The renin-angiotensin-aldosterone system (RAAS) regulates blood pressure, fluid volume, and the vascular response to injury and inflammation 1. Chronic RAAS activation in the presence of sufficient sodium consumption leads to persistent hypertension, setting off a cascade of inflammatory, thrombotic, and atherogenic effects eventually leading to end-organ damage 2 3. Accordingly, numerous studies have demonstrated that elevated renin and/or aldosterone levels are predictors of adverse outcome in hypertension 4, heart failure 5 6, myocardial infarction 7, and renal insufficiency 8 and influence insulin resistance 9. Primary aldosteronism (PA) is the most common secondary form of hypertension with an estimated prevalence between 4 and 12% of hypertensives 10 11 12 and 11-20% in patients that are resistant to combined antihypertensive medication 13 14. Given the severe cardiovascular adverse effects of aldosterone excess that are independent of high blood pressure levels 15 16 17 18 detection and treatment of PA has important impact on clinical outcome and survival.
Assuntos
Hiperaldosteronismo/patologia , Pesquisa Translacional Biomédica , Ensaios Clínicos como Assunto , Feminino , Humanos , Hiperaldosteronismo/complicações , Hiperaldosteronismo/genética , Mutação/genéticaRESUMO
Somatic mutations have been identified in the KCNJ5 gene (encoding the potassium channel GIRK4) in aldosterone-producing adenomas (APA). Most of these mutations are located in or near the selectivity filter of the GIRK4 channel pore and several have been shown to lead to the constitutive overproduction of aldosterone. KCNJ5 mutations in APA are more frequent in women; however, this gender dimorphism is a reported phenomenon of Western but not East Asian populations. In this review we discuss some of the issues that could potentially underlie this observation.
Assuntos
Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Mutação/genética , Seleção Genética , Caracteres Sexuais , Cloreto de Sódio na Dieta/efeitos adversos , Adenoma/genética , Aldosterona/biossíntese , Feminino , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/química , Humanos , MasculinoRESUMO
In depth analysis of key molecular mechanisms involved in functional autonomy of aldosterone secretion is hampered by the lack of tumor cell lines that reflect functional characteristics of aldosterone producing adenomas. Herein, we describe the characteristics of the adrenocortical carcinoma cell line NCI-H295R and its suitability as a model of hyperaldosteronism in relation to different culture conditions. Steroid profiling revealed that NCI-H295R cells predominantly secrete cortisol, while aldosterone and other steroids are released at much lower concentrations. However, aldosterone output specifically increased in response to different stimuli such as ACTH and angiotensin II, and in particular to potassium in a dose dependent manner. NCI-H295R cells readily formed spheroids under specific culture conditions, a method widely used for the enrichment of progenitor cells. Unexpectedly, spheroid cells excelled with higher aldosterone concentration and higher expression levels of the steroidogenic enzymes StAR, 3ßHSD, CYP17, SF-1, and the MC2-receptor. Further investigations revealed that this phenomenon is mainly attributed to epithelial growth factor (EGF) and particularly fibroblast growth factor (FGF), which are both essential ingredients in the spheroid culture medium. Aldosterone release under the combinatory influence of EGF and FGF was not higher than the effect of FGF alone. Spheroid growth per se, therefore, does not ensure an enrichment of less differentiated cell types in this cell line.
Assuntos
Neoplasias do Córtex Suprarrenal/patologia , Carcinoma Adrenocortical/patologia , Linhagem Celular Tumoral , Hiperaldosteronismo/patologia , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/metabolismo , Aldosterona/biossíntese , Aldosterona/metabolismo , Adesão Celular , Citocromo P-450 CYP11B2/biossíntese , Citocromo P-450 CYP11B2/genética , Citocromo P-450 CYP11B2/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Hidrocortisona/biossíntese , Hidrocortisona/metabolismo , Hiperaldosteronismo/enzimologia , Hiperaldosteronismo/metabolismo , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/metabolismo , Concentração Osmolar , Potássio/metabolismo , RNA Mensageiro/metabolismo , Esferoides Celulares/metabolismo , Esferoides Celulares/patologiaRESUMO
Primary aldosteronism (PA) is the most frequent cause of secondary arterial hypertension. To date 3 forms of familial hyperaldosteronism (FH) have been described accounting for a small percentage of all PA cases. In Germany, the prevalence of FH is currently unknown. Our aim was to determine the prevalence of familiarity in a large cohort of patients with PA. A total of 166 patients with apparently sporadic PA in Munich were investigated. FH types I, II, and III were identified using established clinical, biochemical, and molecular criteria. Among the 166 patients with PA, 2 patients (1.2%) reported a family history suggestive of FH. None of the 166 patients showed clinical, endocrine, or genetic evidence of FH type I. The 2 families had characteristic features of FH type II. Family A had 3 subjects affected out of 11 evaluated family members. Family B had 3 out of 4. Bilateral adrenal hyperplasia and unilateral adrenal adenoma were found within the same family. FH type I and FH type III are rare in Germany. With a prevalence of 1.2%, FH type II seems to be more common in apparently sporadic PA than had been assumed so far.
Assuntos
Hiperaldosteronismo/diagnóstico , Hiperaldosteronismo/epidemiologia , Linhagem , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Aldosterona/sangue , Criança , Estudos de Coortes , Feminino , Alemanha/epidemiologia , Humanos , Hiperaldosteronismo/genética , Hiperaldosteronismo/metabolismo , Masculino , Pessoa de Meia-Idade , Prevalência , Adulto JovemRESUMO
The melanocortin system is involved in central and peripheral regulation of energy homeostasis. In adipocytes, the melanocortin 2 receptor (MC2R) transmits ACTH-dependent signaling and its expression rises substantially during adipocyte differentiation. An in vitro system of retrovirally expressed shRNA directed against Mc2r mRNA in 3T3-L1 cells was established and effects of Mc2r knockdown (kd) in comparison to cells expressing non-targeting shRNA (control) were explored in differentiated adipocytes. Morphology, gene expression, lipolysis and fatty acid composition were analyzed. While gross morphology was unchanged extractable amount of lipids was reduced to 70-80% in kd cell lines (p<0.01). Moreover, expression changes of Pparγ2, aP2, and Pref1 indicated reduced differentiation in Mc2r kd cells. Intriguingly, not only ACTH, but also norepinephrine stimulated lipolysis were substantially reduced demonstrating functional significance of MC2R for general lipolysis pathway. Analysis of fatty acid composition in triglyceride and phospholipid fractions showed a lowered ratio of C16:1/C16:0 and C18:1/C18:0, but increased concentrations of arachidonic acid upon Mc2r knockdown. Reduction of mono-unsaturated fatty acids (MUFAs) was associated with lower expression of stearoyl-Coenzyme A desaturase 1 and 2 in kd cells (21 ± 8% vs. 100 ± 13%, p=0.01 and 32 ± 3% vs. 100 ± 15%, p=0.046). Conversely, high doses of ACTH resulted in gene expression changes, mirroring Mc2r knockdown (higher Pparγ2, Scd1, Hsl expression). MC2R plays an important role for regular lipolytic function and lipid composition in 3T3-L1 adipocytes. Of interest, desaturase expression was reduced and MUFA content accordingly altered in kd cells.
Assuntos
Adipócitos/citologia , Adipócitos/metabolismo , Diferenciação Celular , Lipídeos/química , Receptor Tipo 2 de Melanocortina/genética , Células 3T3-L1 , Adipócitos/química , Animais , Expressão Gênica , Técnicas de Silenciamento de Genes , Metabolismo dos Lipídeos , Lipólise , Camundongos , Receptor Tipo 2 de Melanocortina/metabolismo , Transdução de SinaisRESUMO
Pituicytoma is an exceptionally rare low-grade glioma (WHO grade I) of the neurohypophysis and infundibulum. We are reporting the case of a 48-year-old man who presented with severe Cushing's syndrome. Endocrinological evaluation unequivocally confirmed pituitary-dependent Cushing's syndrome (=Cushing's disease). Cranial MR-imaging displayed a conspicuous area in the dorsal and basal pituitary gland and a minimal bulging of the pituitary gland paramedian of the pituitary stalk on the right side. Transsphenoidal inspection revealed a small tumor in the basal and dorsal pituitary gland. Surprisingly, the definite postoperative histopathological diagnosis of the removed tumor was pituicytoma and not pituitary adenoma. Hence, the microadenoma responsible for Cushing's disease was not yet removed and persistent hypercortisolism necessitated transsphenoidal re-operation. During re-operation, hemihypophysectomy was performed on the right side. The non-tumorous specimen of the adeno-hypophysis showed signs of Crooke's hyalinization consistent with Cushing's disease. Undetectable postoperative ACTH- and cortisol levels provided clear evidence that the underlying ACTH-source was successfully removed during re-operation. Coincidence of pituicytoma and pituitary-dependent Cushing's disease has not previously been reported.
Assuntos
Hipersecreção Hipofisária de ACTH/diagnóstico , Neoplasias Hipofisárias/diagnóstico , Glioma/diagnóstico , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Neuro-HipófiseRESUMO
The urocortin (Ucn) family of neuropeptides is suggested to be involved in homeostatic coping mechanisms of the central stress response through the activation of corticotropin-releasing factor receptor type 2 (CRFR2). The neuropeptides, Ucn1 and Ucn2, serve as endogenous ligands for the CRFR2, which is highly expressed by the dorsal raphe serotonergic neurons and is suggested to be involved in regulating major component of the central stress response. Here, we describe genetically modified mice in which both Ucn1 and Ucn2 are developmentally deleted. The double knockout mice showed a robust anxiolytic phenotype and altered hypothalamic-pituitary-adrenal axis activity compared with wild-type mice. The significant reduction in anxiety-like behavior observed in these mice was further enhanced after exposure to acute stress, and was correlated with the levels of serotonin and 5-hydroxyindoleacetic acid measured in brain regions associated with anxiety circuits. Thus, we propose that the Ucn/CRFR2 serotonergic system has an important role in regulating homeostatic equilibrium under challenge conditions.
Assuntos
Ansiedade , Fenótipo , Serotonina/metabolismo , Urocortinas/deficiência , Adaptação Fisiológica/genética , Análise de Variância , Animais , Ansiedade/metabolismo , Ansiedade/patologia , Ansiedade/fisiopatologia , Encéfalo/metabolismo , Cromatografia Líquida de Alta Pressão/métodos , Hormônio Liberador da Corticotropina/genética , Modelos Animais de Doenças , Comportamento Exploratório/fisiologia , Feminino , Ácido Hidroxi-Indolacético/metabolismo , Sistema Hipotálamo-Hipofisário/patologia , Sistema Hipotálamo-Hipofisário/fisiopatologia , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Sistema Hipófise-Suprarrenal/patologia , Sistema Hipófise-Suprarrenal/fisiopatologiaRESUMO
Primary aldosteronism is the most prevalent cause of secondary hypertension. However, insights in pathophysiological mechanisms resulting in autonomous aldosterone secretion are limited. Although transcriptional regulators of aldosterone synthase (CYP11B2) including calcium-binding calmodulin kinase (CaMK) dependent pathways have been defined in vitro, it remains uncertain whether these mechanisms play a role in the context of dysregulated steroidogenesis in aldosterone producing adrenadenomas. Thus, we compared expression and activation of key components of CaMK pathways in aldosterone producing adenomas (APAs) with normal adrenals glands (NAGs). As expected, aldosterone synthase expression in APAs was significantly higher in comparison to NAGs, suggesting transcriptional activation as a contributing factor of aldosterone excess. Along the same line, CaMKI was significantly upregulated in APAs on the mRNA and protein level. Furthermore, immunohistochemistry revealed nuclear localization of CaMKI in these tumors. The phosphorylation of CREB, a target protein for CaMKI was increased, which could represent a further stimulation of aldosterone synthase transcription. In summary, this study provides indirect evidence for a causative involvement of the CaM kinase signaling pathway in human aldosterone producing adenomas.
Assuntos
Neoplasias do Córtex Suprarrenal/enzimologia , Adenoma Adrenocortical/enzimologia , Aldosterona/metabolismo , Proteína Quinase Tipo 1 Dependente de Cálcio-Calmodulina/metabolismo , Transdução de Sinais , Neoplasias do Córtex Suprarrenal/metabolismo , Adenoma Adrenocortical/metabolismo , Sequência de Bases , Proteína Quinase Tipo 1 Dependente de Cálcio-Calmodulina/genética , Citocromo P-450 CYP11B2/genética , Citocromo P-450 CYP11B2/metabolismo , Ativação Enzimática , Humanos , Dados de Sequência MolecularRESUMO
Over the last 30 years the prevalence of overweight and obesity has sharply increased in western industrialized countries. Accordingly, in Germany 15% of the adult population can be regarded as obese. The association between adiposity and increased morbidity and mortality has been well established but the individual metabolic risk is mainly dependent on the distribution of adipose depots. During the last two decades knowledge of the pathophysiology of obesity has increased substantially. However, current therapeutic options including life-style modifications and a few anti-obesity drugs show overall disappointing results in long-term body weight control indicating the need for therapeutic improvements. For patients with morbid obesity surgical therapies (bariatric surgery) can be considered. While long-lasting weight control and decrease of adiposity-related morbidity and mortality has been demonstrated only for these procedures, after bariatric surgery patients also require long-term follow up and treatment.
Assuntos
Fármacos Antiobesidade/uso terapêutico , Cirurgia Bariátrica/estatística & dados numéricos , Dietoterapia/estatística & dados numéricos , Obesidade/epidemiologia , Obesidade/terapia , Adulto , Alemanha/epidemiologia , Humanos , PrevalênciaRESUMO
Primary aldosteronism is considered the most prevalent form of secondary hypertension with pathophysiological and clinical features different from those of essential hypertension. Despite its high prevalence with the exception of the small subgroup of patients with familial hyperaldosteronism type I, the underlying genetic and molecular basis of this common disease is still largely unknown. In this context animal models can provide important insights in the physiology of aldosterone regulation that can serve as a starting point for investigation of mechanisms involved also in autonomous aldosterone secretion. Mouse models with defined genetic modification can further be utilized to prove functional relevance of these predefined candidate genes.Finally, animal models can be used to investigate cardiovascular and metabolic consequences of unopposed aldosterone secretion and potential restoration of these parameters through pharmacologic interventions. This review will provide a brief overview on animal models currently available for primary aldosteronism and describe in vivo screening strategies that are likely to aid in the elucidation of molecular and genetic mechanisms involved in autonomous aldosterone secretion.
Assuntos
Modelos Animais de Doenças , Hiperaldosteronismo , Aldosterona/metabolismo , Animais , Linhagem Celular , Hiperaldosteronismo/genética , Hiperaldosteronismo/fisiopatologia , Camundongos , Camundongos Knockout , Camundongos Transgênicos , Ratos , Sistema Renina-Angiotensina/fisiologiaRESUMO
Aldosterone excess in the context of primary aldosteronism (PA) has been associated with impaired glucose tolerance and diabetes mellitus. We retrospectively assessed the prevalence of diabetes mellitus in patients from the German Conn's Register and compared the data with those from hypertensive subjects of a population-based survey. In a case-control study, we have compared 638 patients with PA from the German Conn's registry who were treated in 6 German centers with 897 hypertensive control subjects from the population-based F3 survey of the Cooperative Health Research in the Region of Augsburg (KORA). The samples were matched for age, sex, and blood pressure in a 1:1 ratio. Risk factors associated with the presence of diabetes mellitus were calculated in 638 patients with PA and 897 hypertensive controls. In the case control study, the diabetes prevalence was calculated in 338 cases and controls. In patients with primary aldosteronism, age, BMI, and a higher number of antihypertensive drugs (lowest tertile vs. highest tertile) were variables associated with diabetes mellitus. In contrast, serum potassium and plasma aldosterone concentrations were not associated with higher diabetes prevalence, whereas diastolic blood pressure was inversely associated with diabetes mellitus. Diabetes mellitus was more prevalent in patients with PA than in 338 matched controls (23 vs. 10% in controls). Our data for the German population show that diabetes mellitus is more prevalent in patients with primary aldosteronism than in hypertensive controls.
Assuntos
Diabetes Mellitus/epidemiologia , Hiperaldosteronismo/epidemiologia , Sistema de Registros , Adulto , Idoso , Estudos de Casos e Controles , Complicações do Diabetes/epidemiologia , Feminino , Alemanha/epidemiologia , Humanos , Hiperaldosteronismo/complicações , Masculino , Pessoa de Meia-Idade , Prevalência , Sistema de Registros/estatística & dados numéricos , Estudos RetrospectivosRESUMO
Storage and tissue handling of surgical tumor specimen have been recognized as critical steps that can potentially affect reproducibility and comparability of molecular endpoints between laboratories. In the preparation of adrenal tumor tissue banking, three different protocols that simulate warm ischemia upon tumor removal (protocol I), thawing and refreezing cycles (protocol II), as well as storage of vital tumor samples (protocol III) were applied. For the first two protocols, samples were subdivided and either snap frozen or treated with a RNA preserving agent (RPA) while in protocol III different storage media were compared. Following these procedures, recovery and integrity of DNA, RNA, and protein by means of pulsed field electrophoresis, long-range PCR, real-time PCR, immunoblot, and immunohistochemistry (protocol I and II) as well as cell viability and steroidogenic capacity (protocol III) were investigated. While DNA integrity was not influenced by different treatment modalities, expression levels of adrenal marker genes were more affected in samples after snap freezing in comparison to RPA pretreatment. Moreover, storage at room temperature before and after freezing could be demonstrated to decrease the relative amount of protein phosphorylation (ERK) and enzymatic activity (succinate cytochrome c reductase) while overall protein levels were not significantly affected. Similarly, morphological or immunohistochemical evaluation was comparable between groups. For primary cell cultures generated after storage of tumor samples similar rates of viability were observable while steroid output varied between the groups. Overall, on the basis of the presented endpoints standardized operational procedures can be defined for a proposed European adrenal tumor biobank.
Assuntos
Neoplasias das Glândulas Suprarrenais/patologia , Glândulas Suprarrenais/patologia , Bancos de Espécimes Biológicos/organização & administração , Feocromocitoma/patologia , Manejo de Espécimes/normas , Neoplasias das Glândulas Suprarrenais/genética , Neoplasias das Glândulas Suprarrenais/metabolismo , Animais , Sobrevivência Celular , Criopreservação , DNA/análise , Europa (Continente) , Humanos , Técnicas Imunoenzimáticas , Antígeno Ki-67/metabolismo , Camundongos , Camundongos Nus , Proteínas Mitocondriais/metabolismo , Feocromocitoma/genética , Feocromocitoma/metabolismo , Controle de Qualidade , RNA/análise , Preservação de Tecido , Transplante HeterólogoRESUMO
Shortly after the first description of primary aldosteronism (PA) appeared in the 1950s by Jerome Conn, an association of the condition with diabetes mellitus was documented. However, a clear pathophysiological interrelationship linking the two entities has yet to be established. Nevertheless, so far, many mechanisms contributing to insulin resistance and dysregulation of glucose uptake have been described. At the same time, many observational studies have reported an increased prevalence of the metabolic syndrome (MetS) among patients with PA. Regarding the relationship between aldosterone levels and obesity, a vicious cycle of adipokine-induced aldosterone production and aldosterone adipogenic action may be further contributing to MetS manifestations in PA patients. However, whether aldosterone excess affects lipid metabolism is still under investigation. Also, recent findings of the coexistence of glucocorticoid excess in many cases of PA highlight the need for further studies to examine the presumed link between high aldosterone levels and various metabolic parameters. In the present review, our focus is to comprehensively present the spectrum of available research findings concerning the possible associations between aldosterone excess and metabolic alterations, including impaired glucose metabolism, insulin resistance and, consequently, diabetes, altered lipid metabolism and the development of fatty liver. In addition, the complex relationship between obesity and aldosterone is discussed in detail.
Assuntos
Aldosterona , Complicações do Diabetes , Hiperaldosteronismo , Síndrome Metabólica , Aldosterona/sangue , Aldosterona/metabolismo , Aldosterona/fisiologia , Glicemia , Humanos , Hiperaldosteronismo/complicações , Hiperaldosteronismo/fisiopatologia , Insulina , Resistência à Insulina , Síndrome Metabólica/complicações , Síndrome Metabólica/fisiopatologia , ObesidadeRESUMO
Primary aldosteronism (PA) is associated with vascular end organ damage. The aim of the study was to evaluate differences regarding comorbidities depending on tumor size in patients with aldosterone producing adenoma (APA). The retrospective cross-sectional study was done by collection from 6 German centers (German Conn's registry) between 1990 and 2007. Among the 640 registered patients with PA, 60 operated patients with APA were analyzed. The main outcome of measures was the comorbidities depending on tumor size. Thirty-one patients (17 men, 14 women) had an adenoma size <20 mm, and 29 patients (10 men, 19 women) had an adenoma size>/=20 mm. There was no difference in age, preoperative potassium, aldosterone, or creatinine levels, preoperative systolic and diastolic blood pressure, or duration of hypertension between the two groups. In the group with APA <20 mm, cerebrovascular events occurred with a prevalence of 12.9%, cardiac events 16.1%, peripheral vascular events 25.8%, renal insufficiency 16.1%, and sleep apnea 6.4%, respectively. There was no significant difference in comorbidities compared to the group with APA>/=20 mm. Subgroup analysis (n=22) of follow-up data on post-operative systolic and diastolic blood pressure showed no significant difference between these subgroups with regard to potassium, aldosterone or creatinine levels, blood pressure, duration of hypertension, or comorbidities. Our data indicate a high prevalence of comorbidities in patients with APA. However, adenoma size was not correlated with cardio- and cerebrovascular comorbidities, and does not seem to be a prognostic factor for blood pressure outcome.
Assuntos
Neoplasias do Córtex Suprarrenal/complicações , Adenoma Adrenocortical/complicações , Doenças Cardiovasculares/complicações , Transtornos Cerebrovasculares/complicações , Hiperaldosteronismo/complicações , Neoplasias do Córtex Suprarrenal/patologia , Adenoma Adrenocortical/patologia , Pressão Sanguínea/fisiologia , Doenças Cardiovasculares/patologia , Transtornos Cerebrovasculares/patologia , Estudos de Coortes , Estudos Transversais , Feminino , Humanos , Hiperaldosteronismo/patologia , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
With an average prevalence of 25% hypertension is one of the leading chronic diseases in westernized countries. Recent epidemiological data indicate a high proportion of patients with secondary hypertension due to primary aldosteronism that accounts for up to 8-12% of cases. Primary aldosteronism is caused by autonomous secretion of aldosterone by the adrenal cortex which results in hypertension with clinically, biochemically and therapeutically distinct features. With the exception of the small proportion of patients with familial hyperaldosteronism type I, the underlying genetic and molecular basis of this common disease is largely unknown. In this situation mouse models with targeted genetic modification can be utilized to define functional relevance of predefined candidate genes that are known or suspected to be involved in the regulation of aldosterone secretion. Moreover, animal models can aid in the identification of novel gene products that have not yet been identified to play a role in primary aldosteronism. This review will provide a brief overview on the animal models currently available for primary aldosteronism and describe in vivo screening strategies that are likely to provide insight in molecular and genetic mechanisms involved in autonomous aldosterone secretion.