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Aspects of hypertension in endocrine diseaseRitchie, Catherine Marian January 1986 (has links)
No description available.
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An Enzymology and Inhibition Study of a cAMP-Dependent Protein Kinase Linked to ACTH-Independent Cushing's SyndromeLuzi, Nicole 01 January 2019 (has links)
Cyclic-AMP dependent protein kinase (PKA) is a key intracellular signal transduction kinase that is modulated by Gs- and Gi-coupled GPCRs. Under normal physiological conditions, PKA exists as an inactive holoenzyme made up of two catalytic subunits and two regulatory subunits. Upon cAMP binding to the regulatory subunits, the catalytic subunits (PKACa) are released to perform various downstream phosphorylation events. However, aberrant PKA activation can cause various diseases including Cushing’s Syndrome, which is an endocrine disorder caused by the overproduction of cortisol by the hypothalamus-pituitary-adrenal hormone system. This disorder can be caused by pituitary adenomas that release unregulated amounts of ACTH, adrenal adenomas that release unregulated amounts of cortisol without ACTH stimulation, and ectopic tumors outside the hypothalamus-pituitary-adrenal axis that produce ACTH. In recent genomic studies of patients with ACTH-independent Cushing’s Syndrome, the L205R-PKACamutant has been discovered. Through various studies on the mutant enzyme multiple research groups learned that the single point mutation causes a loss in sensitivity to cAMP signaling, a loss in binding to PKA regulatory subunits, and unregulated phosphorylation of PKACasubstrates, which ultimately leads to the increased cortisol biosynthesis in these patients.
The first part of this work describes the enzymology and inhibition studies of known inhibitors against both wt- and L205R-PKACa. Early in the enzymology studies we developed at medium throughput endpoint assay that used Rhodamine-kemptide as the substrate and as a chromophore separating substrate and phosphorylated product using a reverse-phase HPLC method. The analysis of the substrate peptide against both wild-type and mutant enzyme showed a 6-fold decrease in the KMand a 2-fold decrease in kcat, and a similar but lower order of magnitude effect was observed for the studies with ATP. The inhibition studies were performed using the substrate competitive inhibitor PKI(5-24), which showed a 253-fold higher potency towards the wild-type enzyme over the mutant while the ATP-competitive inhibitor was determined to be equipotent. Using this information we used modeling studies to aid in the development of mutant selective functional inhibitors for the substrate-binding pocket. Additionally, we begun to explore the use of Proteolysis Targeting Chimeras, or PROTACs, as another means for targeting the L205R mutant enzyme.
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Mechanisms underlying glucocorticoid-induced protein wasting and potential treatment with anabolic hormonessBurt, Morton Garth, St Vincent's Clinical School, UNSW January 2007 (has links)
Protein wasting is a complication of glucocorticoid (GC) therapy. It causes substantial morbidity and there is no treatment. This thesis investigates the metabolic mechanisms underlying GC-induced protein wasting and the potential for anabolic hormones to reverse protein loss. The models of GC excess were Cushing's syndrome and GC therapy. Whole body protein metabolism was assessed using the leucine turnover technique and body composition by dual-energy X-ray absorptiometry to estimate lean body mass (LBM) and fat mass (FM). As previous studies demonstrated that LBM and FM influenced rates of protein metabolism, the magnitude of body compositional abnormality in Cushing's syndrome was determined. After accounting for the greater FM (30%) and lesser LBM (15%), protein metabolism in Cushing's syndrome was characterised by a significant increase in protein oxidation, an abnormality that leads to irreversible protein loss. Successful treatment of Cushing's syndrome normalised protein oxidation. Studies of the acute and chronic effects of therapeutic GCs revealed a time-dependent effect on protein metabolism. GCs acutely increased protein oxidation. However, the rate of protein oxidation during chronic therapy at a similar dose was not significantly different to untreated control subjects. This time-dependent change suggests that GC-induced stimulation of protein oxidation does not persist and could represent a metabolic adaptation to limit protein loss. This finding contrasts with that in Cushing's syndrome, where protein oxidation is persistently elevated. This difference may represent a dose effect. Studies in GH-deficient subjects revealed that GH induced a fall in protein oxidation that was significantly correlated with a subsequent gain in LBM. This suggests that the anabolic potential of a therapeutic substance can be predicted by its ability to suppress protein oxidation acutely. Finally, the potential for GH and androgens to reverse the metabolic effects of GCs was assessed. A preliminary study in GC users revealed that a GH dose of 0.8 mg/d was effective in reducing protein oxidation. In a subsequent study, the GH-induced reduction in protein oxidation in women on GCs was enhanced by combined treatment with dehydroepiandrosterone, an androgen. In summary, GCs induce protein loss by stimulating protein oxidation. GH reverses this effect and this action is enhanced by coadministration of androgens. GH and androgens may be used therapeutically to prevent protein loss induced by GCs.
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Biosynthesis of Various Steroids in vitro by Isolated Adrenal Cells in Primary Aldosteronism, Cushing's Syndrome, and Adrenogenital Syndrome due to Adrenocortical AdenomaFUNAHASHI, HIROOMI, MIZUNO, SHIGERU 11 1900 (has links)
No description available.
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Systemic POMC Overexpression Increases Visceral Fat Accumulation in MiceTang, Chia-Hua 16 February 2011 (has links)
Proopiomelanocortin (POMC) is a polypeptide precursor with 241 amino acid residues which undergoes extensive post-translational modification to yield a range of smaller, biological active peptides including £\-, £] -, £^-melanocyte-stimulating hormone (£\-MSH, £]-MSH, £^-MSH )¡A£]-endorphin (£]-EP) and adrenocorticotrophic hormone (ACTH). POMC-derived peptides play important roles in appetite and energy homeostasis. Recently, the peripheral POMC system is under active investigation to delineate their pathogenic roles in metabolic diseases such as Cushing¡¦s syndrome and obesity. In the present study, we utilized adenovirus gene delivery system to achieve systemic POMC overexpression in adult C57/BL6 mice for at least 30 days. Subsequently, the plasma and abdominal adipose tissue of mice were collected and analyzed by biochemical assays and weight determination respectively. POMC overexpression did not increase in the food uptake and body weight. These results imply that local POMC gene delivery induced the visceral fat accumulation and altered the metabolism in mice. It was observed that systemic POMC overexpression significantly elevated the triglyceride and the cholesterol levels in mice. However, POMC gene delivery also induced elevated plasma glucose concentration at weeks 1-4 and evoked glucose tolerance in mice at week 4. Interestingly, insulin resistance was readily detected in POMC-transduced in mice at as early as week 1. Besides, Micro-CT scanning and histological studies demonstrated that the visceral fat was significantly increased in POMC over-expressing mice compared with control animals. These data indicate that hepatic POMC gene delivery causes systemic ACTH rise and insulin resistance, which recapitulates the clinical features of Cushing¡¦s syndrome. In summary, POMC gene delivery induces systemic POMC overexpression and results in visceral fat accumulation and insulin resistance, which may facilitates a mice model for Cushing¡¦s-like metabolic syndrome.
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Mechanisms underlying glucocorticoid-induced protein wasting and potential treatment with anabolic hormonessBurt, Morton Garth, St Vincent's Clinical School, UNSW January 2007 (has links)
Protein wasting is a complication of glucocorticoid (GC) therapy. It causes substantial morbidity and there is no treatment. This thesis investigates the metabolic mechanisms underlying GC-induced protein wasting and the potential for anabolic hormones to reverse protein loss. The models of GC excess were Cushing's syndrome and GC therapy. Whole body protein metabolism was assessed using the leucine turnover technique and body composition by dual-energy X-ray absorptiometry to estimate lean body mass (LBM) and fat mass (FM). As previous studies demonstrated that LBM and FM influenced rates of protein metabolism, the magnitude of body compositional abnormality in Cushing's syndrome was determined. After accounting for the greater FM (30%) and lesser LBM (15%), protein metabolism in Cushing's syndrome was characterised by a significant increase in protein oxidation, an abnormality that leads to irreversible protein loss. Successful treatment of Cushing's syndrome normalised protein oxidation. Studies of the acute and chronic effects of therapeutic GCs revealed a time-dependent effect on protein metabolism. GCs acutely increased protein oxidation. However, the rate of protein oxidation during chronic therapy at a similar dose was not significantly different to untreated control subjects. This time-dependent change suggests that GC-induced stimulation of protein oxidation does not persist and could represent a metabolic adaptation to limit protein loss. This finding contrasts with that in Cushing's syndrome, where protein oxidation is persistently elevated. This difference may represent a dose effect. Studies in GH-deficient subjects revealed that GH induced a fall in protein oxidation that was significantly correlated with a subsequent gain in LBM. This suggests that the anabolic potential of a therapeutic substance can be predicted by its ability to suppress protein oxidation acutely. Finally, the potential for GH and androgens to reverse the metabolic effects of GCs was assessed. A preliminary study in GC users revealed that a GH dose of 0.8 mg/d was effective in reducing protein oxidation. In a subsequent study, the GH-induced reduction in protein oxidation in women on GCs was enhanced by combined treatment with dehydroepiandrosterone, an androgen. In summary, GCs induce protein loss by stimulating protein oxidation. GH reverses this effect and this action is enhanced by coadministration of androgens. GH and androgens may be used therapeutically to prevent protein loss induced by GCs.
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Steroidní metabolom ve fyziologii a patofyziologii člověka. / Steroid metabolome in human physiology and pathophysiology.Hána, Václav January 2019 (has links)
Many studies have shown steroid hormone changes in adrenal incidentalomas with subclinical hypercortisolism and various forms of Cushing's syndrome. The aim of our work was to measure, using novel steroid GC-MS/MS measurement procedure, complex picture of many steroids in these patients. With the knowledge of these changes we could better explain causal pathophysiologic changes. In the study on patients with adrenal incidentalomas we described complex steroid changes in patients with subclinical hypercortisolism. Previous studies showed decrease of DHEAS in subclinical hypercortisolism. We confirmed this finding and described a decrease in other androgens and their metabolites. We also evaluated their sensitivity and specificity when compared to routinely used parameters for diagnosis of subclinical hypercortisolism. Furthermore, we looked at the alterations in all measured steroids and their changes in the 1 mg dexamethasone suppression test. In another study, we analyzed steroid changes in various forms of Cushing's syndrome. We confirmed the decrease of adrenal androgens in the ACTH independent forms and mild increase in the ACTH dependent forms. We also described elevations of mineralocorticoid precursors in central and ectopic forms of ACTH secretion. In the distinction of ectopic and central...
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The Effects of Excess Corticosterone on LKB1 and AMPK Signaling in Skeletal Muscle of RatsNakken, Gary N. 04 December 2008 (has links) (PDF)
Cushing's syndrome and glucocorticoid therapy lead to central obesity, insulin resistance, and symptoms of altered energy regulation similar to those observed in the metabolic syndrome. We hypothesized that excess glucocorticoids alter energy sensing/signaling in skeletal muscle through mediation of the LKB1/AMPK signaling pathway. To test this hypothesis, three 100 mg pellets of corticosterone were implanted subcutaneously in each of nine rats for two weeks. Responses were compared with sham operated controls fed ad libitum or food restricted to produce the body weights similar to the treatment group rats. After the treatment period, animals were anesthetized and the right gastrocnemius-plantaris and soleus were removed for analysis. After tibial nerve stimulation for 5 min, the left gastrocnemius-plantaris and soleus were also removed. We assessed AMPK activity and subunit expression, as well as several metabolic indicators including ATP, creatine phosphate, creatine, glycogen, and malonyl-CoA levels in rested and stimulated gastrocnemius-plantaris and soleus muscles. We found that high levels of glucocorticoids decreased AMPKγ3 subunit expression in the gastrocnemius-plantaris. We also observed reduced AMPKα2 activity in the stimulated gastrocnemius-plantaris, but not the soleus; and that this decreased activity corresponded to a significant reduction in phosphorylated TBC1D1, a protein involved in signaling GLUT-4 translocation. Finally, in the gastrocnemius-plantaris, we also noted an increase in glycogen stores in the hypercorticosteronemic rats. Our data suggest that altered energy sensing/signaling associated with high levels of glucocorticoids may be due in part to inhibition of AMPKα2 activity and the high energy state produced by increased glycogen stores. We also conclude that high levels of glucocorticoids decrease the levels of AMPKγ3 and diminish insulin/contraction signaling through phosphorylated TBC1D1.
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Aspectos clínicos e moleculares da hiperplasia adrenal macronodular independente de ACTH em sua forma familial / Clinical and molecular aspects of familial ACTH-independent macronodular adrenal hyperplasiaAlencar, Guilherme Asmar 14 October 2013 (has links)
INTRODUÇÃO: A hiperplasia adrenal macronodular independente de ACTH (AIMAH) é uma doença rara, caracterizada pela presença de macronódulos funcionantes nas adrenais e por uma produção aumentada, autônoma e sustentada de cortisol. Constitui uma causa incomum de síndrome de Cushing (SC). A forma esporádica da doença parece ser a mais frequente, no entanto, se desconhece a real prevalência de sua forma familial. Apesar de ser uma entidade clínica conhecida há quase 50 anos, o processo fisiopatológico que culminaria com a AIMAH, as alterações genéticas predisponentes e aspectos clínicos, laboratoriais e radiológicos relevantes da doença ainda não foram elucidados de forma clara. O diagnóstico recente de uma grande família portadora da doença viabilizou a realização do presente trabalho. OBJETIVOS: 1) Caracterizar a evolução da AIMAH em sua forma familial, correlacionando as manifestações clínicas, os dados laboratoriais e os achados radiológicos; 2) investigar a possível associação entre a AIMAH e a ocorrência de meningiomas intracranianos; 3) avaliar a atividade metabólica das adrenais hiperplasiadas na AIMAH; 4) definir o padrão de herança genética da doença na família estudada; e 5) mapear regiões cromossômicas e loci potencialmente relacionados à etiologia genética da AIMAH familial. MÉTODOS: 96 membros da família estudada foram inicialmente submetidos a uma avaliação clínica e laboratorial pormenorizada. Em seguida, foram realizados exames de tomografia computadorizada para a caracterização radiológica das adrenais. Exames de ressonância magnética e de tomografia por emissão de pósitrons com fluordesoxiglicose marcada, acoplada à tomografia computadorizada (18F-FDGPET/CT) foram realizados em pacientes com as formas familial e esporádica da doença para, respectivamente, investigar a presença de meningiomas intracranianos e caracterizar a atividade metabólica das adrenais hiperplasiadas. Foram também realizados testes in vivo para a pesquisa de receptores hormonais aberrantes nos pacientes com a forma familial da doença. Em uma outra etapa do estudo, diferentes técnicas de biologia molecular foram empregadas para a investigação da etiologia genética da AIMAH familial. Desta forma, realizou-se: o sequenciamento do gene do receptor do ACTH (MC2R), um estudo de ligação genética utilizando microssatélites específicos, um estudo de ligação genética em escala genômica utilizando polimorfismos de nucleotídeo único (SNPs) e o sequenciamento de genes suspeitos. RESULTADOS: A avaliação dos indivíduos pertencentes à genealogia permitiu o diagnóstico de 15 casos da doença (7 mulheres e 8 homens) em três gerações consecutivas. A AIMAH era transmitida para as gerações subsequentes tanto pelo sexo masculino como feminino e acometia cerca de metade dos irmãos em alguns segmentos da família. A idade média ao diagnóstico da doença foi de 52,8 +-11,3 anos (32 a 74 anos) e cerca de 86% (12/14) desses pacientes apresentavam SC subclínica. As dosagens do cortisol salivar à meia-noite e do cortisol em urina de 24 horas demonstraram baixa sensibilidade (21% e 14%, respectivamente) para o diagnóstico da doença em sua forma familial. O valor do ACTH plasmático encontrava-se baixo ( < 10 pg/mL) em 46% (5/11) dos pacientes doentes. Em cerca de 62% (8/13) dos casos, foi demonstrada uma redução do valor sérico do sulfato de desidroepiandrosterona (SDHEA). Por regressão logística simples, foi observado que a probabilidade (odds ratio) de um indivíduo apresentar a doença na família era maior diante da presença de pletora, após o diagnóstico de diabetes ou pré-diabetes ou diante do relato de ganho ponderal progressivo. O espessamento de ambas as adrenais associado à presença de nódulos bilaterais foi o achado radiológico mais frequente na forma familial da doença. No entanto, em um terço dos pacientes (5/15) foram encontradas alterações radiológicas em somente uma das adrenais. Durante os testes in vivo para pesquisa de receptores hormonais aberrantes, foram observadas, com frequência, respostas distintas entre os indivíduos doentes pertencentes à família. Nos pacientes submetidos ao exame de ressonância magnética, foram demonstradas imagens típicas de meningiomas intracranianos em um terço (5/15) dos casos. No exame 18F-FDG-PET/CT, foi observado um aumento da atividade metabólica das adrenais hiperplasiadas, tanto nos pacientes com SC manifesta como naqueles com a forma subclínica da doença. O estudo molecular permitiu delimitar nos cromossomos 16 e 11 algumas regiões genômicas potencialmente relacionadas à etiologia genética da AIMAH familial. O sequenciamento de alguns genes suspeitos (GPR56, GPR97 e GPR114), localizados nessas regiões, não demonstrou a presença de mutações. CONCLUSÕES: Na genealogia estudada, o padrão de transmissão da AIMAH foi autossômico dominante, e a SC subclínica foi a forma mais frequente de manifestação da doença. O teste de supressão com 1 mg de dexametasona via oral à meia-noite demonstrou ser o exame laboratorial de escolha para a avaliação inicial dos pacientes suspeitos de apresentarem AIMAH familial, em função, sobretudo, da baixa sensibilidade do cortisol salivar à meia-noite e do cortisol urinário para o diagnóstico da doença. Valores normais do ACTH plasmático foram um achado laboratorial frequente na AIMAH familial e valores baixos do SDHEA sérico demonstraram ser um indício relativamente precoce da SC subclínica associada à doença. Diferentes padrões radiológicos foram demonstrados nas tomografias das adrenais dos pacientes com AIMAH familial, não sendo infrequente a presença de assimetria entre as duas glândulas. Os resultados dos testes in vivo para a pesquisa de receptores hormonais aberrantes foram mais condizentes com a hipótese de que a expressão desses receptores seria um epifenômeno do processo fisiopatológico, resultante da proliferação e desdiferenciação celular. Uma alta prevalência de meningiomas intracranianos foi observada nos pacientes com AIMAH, tanto na forma familial da doença como na forma esporádica. Demonstrou-se também, pela primeira vez, que as adrenais na AIMAH podem exibir uma captação aumentada de 18F-FDG no exame de PET/CT, de forma semelhante às metástases e aos carcinomas da glândula. Por fim, foram delimitadas no cromossomo 16 (16p12.1, 16p11.2, 16q12.1, 16q13 e 16q21) e no cromossomo 11 (11q23.1) as principais regiões do genoma suspeitas de estarem ligadas à etiologia genética da AIMAH familial (genoma de referência: NCBI36/hg18) / INTRODUCTION: ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a rare disease characterized by functioning adrenal macronodules and increased, autonomous and sustained cortisol production. This condition is an uncommon cause of Cushing\'s syndrome (CS). While the sporadic form of the disease appears to be the most frequent, the true prevalence of its familial form is unknown. Despite being a known clinical entity for almost 50 years, the pathophysiological process that leads to AIMAH, the predisposing genetic alterations and important clinical, laboratory and radiological aspects of the disease have not been fully clarified. The recent identification of a large group of relatives with familial AIMAH allowed the accomplishment of the present study. OBJECTIVES: The following were the aims of this study: 1) characterize the development of familial AIMAH through correlations between clinical manifestations, laboratory data and radiological findings; 2) investigate the possible association between AIMAH and the occurrence of intracranial meningioma; 3) characterize the metabolic activity of the adrenal glands in this disease; 4) define the inheritance pattern of the disease in the family studied; and 5) map chromosomal regions and loci potentially related to the genetic etiology of familial AIMAH. METHODS: 96 members of the family studied were initially subjected to a detailed clinical and laboratory evaluation. Computed tomography (CT) scans were performed for the radiological characterization of the adrenal glands. Magnetic resonance imaging scans and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) scans were performed on patients with both forms of the disease (familial and sporadic) to investigate the presence of intracranial meningioma and characterize the metabolic activity of the adrenal glands, respectively. In vivo studies for aberrant hormone receptors were also conducted on those patients with familial AIMAH. In another phase of the study, different molecular biology techniques were employed to investigate the genetic etiology of familial AIMAH. For such, sequencing of the ACTH receptor gene (MC2R), a linkage study using specific microsatellite markers, a single nucleotide polymorphism (SNP)-based genome-wide linkage study and the sequencing of suspect genes were performed. RESULTS: The evaluation of the family revealed the diagnosis of 15 cases of the disease (7 women and 8 men) in three consecutive generations. AIMAH was transmitted to subsequent generations by both genders and half of the siblings were affected in some segments of the family. Mean age at diagnosis was 52.8 +-11.3 years (range: 32 to 74 years) and about 86% (12/14) of the patients exhibited subclinical CS. Both midnight salivary cortisol and 24-hour urinary cortisol demonstrated low sensitivity (21% and 14%, respectively) for the diagnosis of familial AIMAH. Plasma ACTH levels were low ( < 10 pg/ml) in 46% (5/11) of patients with the disease. In about 62% (8/13) of cases, serum dehydroepiandrosterone sulphate (DHEAS) levels were below the normal range. Simple logistic regression models revealed that the probability (odds ratio) of an individual having the disease in the family was greater in the presence of plethora, progressive weight gain or after the diagnosis of diabetes or prediabetes. Adrenal thickening associated with the presence of bilateral nodules was the most common radiological finding in familial AIMAH. However, radiological abnormalities were found in only one of the adrenal glands in one third of the patients (5/15). Throughout the in vivo studies for aberrant hormone receptors, distinct responses were frequently observed among the individuals with familial AIMAH. One third (5/15) of the patients who underwent magnetic resonance imaging scans had typical images of intracranial meningiomas. The 18F-FDG-PET/CT scan revealed increased metabolic activity of the hyperplastic adrenals in patients with both overt and subclinical CS. The molecular studies delimited genomic regions on chromosomes 16 and 11 potentially related to the genetic cause of familial AIMAH. Some suspected genes (GPR56, GPR97 and GPR114), located in these genomic regions, were sequenced, but no mutations were found. CONCLUSIONS: In the extended family studied, AIMAH followed an autosomal dominant pattern of inheritance and subclinical CS was the most common presentation of the disease. The 1 mg overnight dexamethasone suppression test proved to be the screening test of choice for the initial evaluation of patients suspected to have familial AIMAH, due mainly to the low sensitivity of midnight salivary cortisol and 24-hour urinary cortisol as screening tests. A normal level of plasma ACTH was a common laboratory finding in familial AIMAH. Low serum levels of DHEAS proved to be a relatively early finding associated with the subclinical CS determined by the disease. Adrenal CT scans revealed different radiological patterns among patients with familial AIMAH, with a fairly frequent rate of asymmetry between glands. The distinct responses observed throughout the in vivo studies for aberrant hormone receptors, among family members, favor the hypothesis that these receptors may be an epiphenomenon resulting from cell proliferation and dedifferentiation. An increased prevalence of intracranial meningioma was demonstrated in both the familial and sporadic forms of AIMAH. For the first time, it was shown that AIMAH may exhibit increased 18FFDG uptake on the PET/CT scan, similarly to adrenal carcinoma and metastasis. The main genomic regions potentially associated with familial AIMAH were delimited on chromosome 16 (16p12.1, 16p11.2, 16q12.1, 16q13 and 16q21) and chromosome 11 (11q23.1) (reference genome: NCBI36/hg18)
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Aspectos clínicos e moleculares da hiperplasia adrenal macronodular independente de ACTH em sua forma familial / Clinical and molecular aspects of familial ACTH-independent macronodular adrenal hyperplasiaGuilherme Asmar Alencar 14 October 2013 (has links)
INTRODUÇÃO: A hiperplasia adrenal macronodular independente de ACTH (AIMAH) é uma doença rara, caracterizada pela presença de macronódulos funcionantes nas adrenais e por uma produção aumentada, autônoma e sustentada de cortisol. Constitui uma causa incomum de síndrome de Cushing (SC). A forma esporádica da doença parece ser a mais frequente, no entanto, se desconhece a real prevalência de sua forma familial. Apesar de ser uma entidade clínica conhecida há quase 50 anos, o processo fisiopatológico que culminaria com a AIMAH, as alterações genéticas predisponentes e aspectos clínicos, laboratoriais e radiológicos relevantes da doença ainda não foram elucidados de forma clara. O diagnóstico recente de uma grande família portadora da doença viabilizou a realização do presente trabalho. OBJETIVOS: 1) Caracterizar a evolução da AIMAH em sua forma familial, correlacionando as manifestações clínicas, os dados laboratoriais e os achados radiológicos; 2) investigar a possível associação entre a AIMAH e a ocorrência de meningiomas intracranianos; 3) avaliar a atividade metabólica das adrenais hiperplasiadas na AIMAH; 4) definir o padrão de herança genética da doença na família estudada; e 5) mapear regiões cromossômicas e loci potencialmente relacionados à etiologia genética da AIMAH familial. MÉTODOS: 96 membros da família estudada foram inicialmente submetidos a uma avaliação clínica e laboratorial pormenorizada. Em seguida, foram realizados exames de tomografia computadorizada para a caracterização radiológica das adrenais. Exames de ressonância magnética e de tomografia por emissão de pósitrons com fluordesoxiglicose marcada, acoplada à tomografia computadorizada (18F-FDGPET/CT) foram realizados em pacientes com as formas familial e esporádica da doença para, respectivamente, investigar a presença de meningiomas intracranianos e caracterizar a atividade metabólica das adrenais hiperplasiadas. Foram também realizados testes in vivo para a pesquisa de receptores hormonais aberrantes nos pacientes com a forma familial da doença. Em uma outra etapa do estudo, diferentes técnicas de biologia molecular foram empregadas para a investigação da etiologia genética da AIMAH familial. Desta forma, realizou-se: o sequenciamento do gene do receptor do ACTH (MC2R), um estudo de ligação genética utilizando microssatélites específicos, um estudo de ligação genética em escala genômica utilizando polimorfismos de nucleotídeo único (SNPs) e o sequenciamento de genes suspeitos. RESULTADOS: A avaliação dos indivíduos pertencentes à genealogia permitiu o diagnóstico de 15 casos da doença (7 mulheres e 8 homens) em três gerações consecutivas. A AIMAH era transmitida para as gerações subsequentes tanto pelo sexo masculino como feminino e acometia cerca de metade dos irmãos em alguns segmentos da família. A idade média ao diagnóstico da doença foi de 52,8 +-11,3 anos (32 a 74 anos) e cerca de 86% (12/14) desses pacientes apresentavam SC subclínica. As dosagens do cortisol salivar à meia-noite e do cortisol em urina de 24 horas demonstraram baixa sensibilidade (21% e 14%, respectivamente) para o diagnóstico da doença em sua forma familial. O valor do ACTH plasmático encontrava-se baixo ( < 10 pg/mL) em 46% (5/11) dos pacientes doentes. Em cerca de 62% (8/13) dos casos, foi demonstrada uma redução do valor sérico do sulfato de desidroepiandrosterona (SDHEA). Por regressão logística simples, foi observado que a probabilidade (odds ratio) de um indivíduo apresentar a doença na família era maior diante da presença de pletora, após o diagnóstico de diabetes ou pré-diabetes ou diante do relato de ganho ponderal progressivo. O espessamento de ambas as adrenais associado à presença de nódulos bilaterais foi o achado radiológico mais frequente na forma familial da doença. No entanto, em um terço dos pacientes (5/15) foram encontradas alterações radiológicas em somente uma das adrenais. Durante os testes in vivo para pesquisa de receptores hormonais aberrantes, foram observadas, com frequência, respostas distintas entre os indivíduos doentes pertencentes à família. Nos pacientes submetidos ao exame de ressonância magnética, foram demonstradas imagens típicas de meningiomas intracranianos em um terço (5/15) dos casos. No exame 18F-FDG-PET/CT, foi observado um aumento da atividade metabólica das adrenais hiperplasiadas, tanto nos pacientes com SC manifesta como naqueles com a forma subclínica da doença. O estudo molecular permitiu delimitar nos cromossomos 16 e 11 algumas regiões genômicas potencialmente relacionadas à etiologia genética da AIMAH familial. O sequenciamento de alguns genes suspeitos (GPR56, GPR97 e GPR114), localizados nessas regiões, não demonstrou a presença de mutações. CONCLUSÕES: Na genealogia estudada, o padrão de transmissão da AIMAH foi autossômico dominante, e a SC subclínica foi a forma mais frequente de manifestação da doença. O teste de supressão com 1 mg de dexametasona via oral à meia-noite demonstrou ser o exame laboratorial de escolha para a avaliação inicial dos pacientes suspeitos de apresentarem AIMAH familial, em função, sobretudo, da baixa sensibilidade do cortisol salivar à meia-noite e do cortisol urinário para o diagnóstico da doença. Valores normais do ACTH plasmático foram um achado laboratorial frequente na AIMAH familial e valores baixos do SDHEA sérico demonstraram ser um indício relativamente precoce da SC subclínica associada à doença. Diferentes padrões radiológicos foram demonstrados nas tomografias das adrenais dos pacientes com AIMAH familial, não sendo infrequente a presença de assimetria entre as duas glândulas. Os resultados dos testes in vivo para a pesquisa de receptores hormonais aberrantes foram mais condizentes com a hipótese de que a expressão desses receptores seria um epifenômeno do processo fisiopatológico, resultante da proliferação e desdiferenciação celular. Uma alta prevalência de meningiomas intracranianos foi observada nos pacientes com AIMAH, tanto na forma familial da doença como na forma esporádica. Demonstrou-se também, pela primeira vez, que as adrenais na AIMAH podem exibir uma captação aumentada de 18F-FDG no exame de PET/CT, de forma semelhante às metástases e aos carcinomas da glândula. Por fim, foram delimitadas no cromossomo 16 (16p12.1, 16p11.2, 16q12.1, 16q13 e 16q21) e no cromossomo 11 (11q23.1) as principais regiões do genoma suspeitas de estarem ligadas à etiologia genética da AIMAH familial (genoma de referência: NCBI36/hg18) / INTRODUCTION: ACTH-independent macronodular adrenal hyperplasia (AIMAH) is a rare disease characterized by functioning adrenal macronodules and increased, autonomous and sustained cortisol production. This condition is an uncommon cause of Cushing\'s syndrome (CS). While the sporadic form of the disease appears to be the most frequent, the true prevalence of its familial form is unknown. Despite being a known clinical entity for almost 50 years, the pathophysiological process that leads to AIMAH, the predisposing genetic alterations and important clinical, laboratory and radiological aspects of the disease have not been fully clarified. The recent identification of a large group of relatives with familial AIMAH allowed the accomplishment of the present study. OBJECTIVES: The following were the aims of this study: 1) characterize the development of familial AIMAH through correlations between clinical manifestations, laboratory data and radiological findings; 2) investigate the possible association between AIMAH and the occurrence of intracranial meningioma; 3) characterize the metabolic activity of the adrenal glands in this disease; 4) define the inheritance pattern of the disease in the family studied; and 5) map chromosomal regions and loci potentially related to the genetic etiology of familial AIMAH. METHODS: 96 members of the family studied were initially subjected to a detailed clinical and laboratory evaluation. Computed tomography (CT) scans were performed for the radiological characterization of the adrenal glands. Magnetic resonance imaging scans and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) scans were performed on patients with both forms of the disease (familial and sporadic) to investigate the presence of intracranial meningioma and characterize the metabolic activity of the adrenal glands, respectively. In vivo studies for aberrant hormone receptors were also conducted on those patients with familial AIMAH. In another phase of the study, different molecular biology techniques were employed to investigate the genetic etiology of familial AIMAH. For such, sequencing of the ACTH receptor gene (MC2R), a linkage study using specific microsatellite markers, a single nucleotide polymorphism (SNP)-based genome-wide linkage study and the sequencing of suspect genes were performed. RESULTS: The evaluation of the family revealed the diagnosis of 15 cases of the disease (7 women and 8 men) in three consecutive generations. AIMAH was transmitted to subsequent generations by both genders and half of the siblings were affected in some segments of the family. Mean age at diagnosis was 52.8 +-11.3 years (range: 32 to 74 years) and about 86% (12/14) of the patients exhibited subclinical CS. Both midnight salivary cortisol and 24-hour urinary cortisol demonstrated low sensitivity (21% and 14%, respectively) for the diagnosis of familial AIMAH. Plasma ACTH levels were low ( < 10 pg/ml) in 46% (5/11) of patients with the disease. In about 62% (8/13) of cases, serum dehydroepiandrosterone sulphate (DHEAS) levels were below the normal range. Simple logistic regression models revealed that the probability (odds ratio) of an individual having the disease in the family was greater in the presence of plethora, progressive weight gain or after the diagnosis of diabetes or prediabetes. Adrenal thickening associated with the presence of bilateral nodules was the most common radiological finding in familial AIMAH. However, radiological abnormalities were found in only one of the adrenal glands in one third of the patients (5/15). Throughout the in vivo studies for aberrant hormone receptors, distinct responses were frequently observed among the individuals with familial AIMAH. One third (5/15) of the patients who underwent magnetic resonance imaging scans had typical images of intracranial meningiomas. The 18F-FDG-PET/CT scan revealed increased metabolic activity of the hyperplastic adrenals in patients with both overt and subclinical CS. The molecular studies delimited genomic regions on chromosomes 16 and 11 potentially related to the genetic cause of familial AIMAH. Some suspected genes (GPR56, GPR97 and GPR114), located in these genomic regions, were sequenced, but no mutations were found. CONCLUSIONS: In the extended family studied, AIMAH followed an autosomal dominant pattern of inheritance and subclinical CS was the most common presentation of the disease. The 1 mg overnight dexamethasone suppression test proved to be the screening test of choice for the initial evaluation of patients suspected to have familial AIMAH, due mainly to the low sensitivity of midnight salivary cortisol and 24-hour urinary cortisol as screening tests. A normal level of plasma ACTH was a common laboratory finding in familial AIMAH. Low serum levels of DHEAS proved to be a relatively early finding associated with the subclinical CS determined by the disease. Adrenal CT scans revealed different radiological patterns among patients with familial AIMAH, with a fairly frequent rate of asymmetry between glands. The distinct responses observed throughout the in vivo studies for aberrant hormone receptors, among family members, favor the hypothesis that these receptors may be an epiphenomenon resulting from cell proliferation and dedifferentiation. An increased prevalence of intracranial meningioma was demonstrated in both the familial and sporadic forms of AIMAH. For the first time, it was shown that AIMAH may exhibit increased 18FFDG uptake on the PET/CT scan, similarly to adrenal carcinoma and metastasis. The main genomic regions potentially associated with familial AIMAH were delimited on chromosome 16 (16p12.1, 16p11.2, 16q12.1, 16q13 and 16q21) and chromosome 11 (11q23.1) (reference genome: NCBI36/hg18)
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