RESUMO
A series of studies have demonstrated that activation of the sympathetic nervous system (SNS) causes osteopenia via ß2-adrenoceptor (ß2-AR) signaling. However, in a recent study, we found an unexpected and generalized phenotype of high bone mass in female mice with chronic sympathetic hyperactivity, due to double gene inactivation of adrenoceptors that negatively regulate norepinephrine release, α2A-and α2C-AR (α2A/2C-AR-/-). These findings suggest that ß2-AR is not the single adrenoceptor involved in bone turnover regulation and show that α2-AR signaling may also mediate the SNS actions in the skeleton. In addition, we found that α2A/2C-AR-/- animals are resistant to the thyrotoxicosis-induced osteopenia, suggesting that thyroid hormone (TH), when in supraphysiological levels, interacts with the SNS to control bone mass and structure, and that this interaction may also involve α2-AR signaling. In the present study, to further investigate these hypotheses and to discriminate the roles of α2-AR subtypes, we have evaluated the bone phenotype of mice with the single gene inactivation of α2C-AR subtype, which mRNA expression was previously shown to be down regulated by triiodothyronine (T3). A cohort of 30 day-old female α2CAR-/- mice and their wild-type (WT) controls were treated with a supraphysiological dose of T3 for 30 or 90 days, which induced a thyrotoxic state in both mouse lineages. The micro-computed tomographic (µCT) analysis showed that α2C-AR-/- mice present lower trabecular bone volume (BV/TV) and number (Tb.N), and increased trabecular separation (Tb.Sp) in the femur compared with WT mice; which was accompanied by decreased bone strength (determined by the three-point bending test) in the femur and tibia. The opposite was observed in the vertebra, where α2C-AR-/- mice show increased BV/TV, Tb.N and trabecular thickness (Tb.Th), and decreased Tb.Sp, compared with WT animals. In spite of the contrasting bone phenotypes of the femur and L5, thyrotoxicosis negatively regulated most of the micro architectural features of the trabecular bone in both skeletal sites of WT, but not of α2C-AR-/- mice. T3 treatment also decreased biomechanical properties (maximum load and ultimate load) in the femur and tibia of WT, but not of knockout mice. The mRNA expression of osteocalcin, a marker of mature osteoblasts, and tartrate-resistant acid phosphatase, which is expressed by osteoclasts and is involved in collagen degradation, was increased by T3 treatment only in WT, and not in α2C-AR-/- mice. Altogether, these findings suggest that α2C-AR subtype mediates the effects of the SNS in the bone in a skeletal site-dependent manner, and that thyrotoxicosis depends on α2C-AR signaling to promote bone loss, which sustains the hypothesis of a TH-SNS interaction to modulate bone remodeling and structure.
Assuntos
Doenças Ósseas Metabólicas/etiologia , Receptores Adrenérgicos alfa 2/genética , Tireotoxicose/complicações , Animais , Fenômenos Biomecânicos , Doenças Ósseas Metabólicas/sangue , Remodelação Óssea , Feminino , Fêmur/metabolismo , Fêmur/fisiopatologia , Expressão Gênica , Camundongos Knockout , Fenótipo , Receptores Adrenérgicos alfa 2/metabolismo , Transdução de Sinais , Coluna Vertebral/metabolismo , Coluna Vertebral/fisiopatologia , Tireotoxicose/sangue , Tireotoxicose/genética , Tiroxina/sangue , Tíbia/metabolismo , Tíbia/fisiopatologia , Tri-Iodotironina/sangueRESUMO
Thyrotoxicosis is the most common cause of the acquired flaccid muscle paralysis in adults called thyrotoxic periodic paralysis (TPP) and is characterised by transient hypokalaemia and hypophosphataemia under high thyroid hormone levels that is frequently precipitated by carbohydrate load. The sulphonylurea receptor 1 (SUR1 (ABCC8)) is an essential regulatory subunit of the ß-cell ATP-sensitive K(+) channel that controls insulin secretion after feeding. Additionally, the SUR1 Ala1369Ser variant appears to be associated with insulin sensitivity. We examined the ABCC8 gene at the single nucleotide level using PCR-restriction fragment length polymorphism (RFLP) analysis to determine its allelic variant frequency and calculated the frequency of the Ala1369Ser C-allele variant in a cohort of 36 Brazilian TPP patients in comparison with 32 controls presenting with thyrotoxicosis without paralysis (TWP). We verified that the frequency of the alanine 1369 C-allele was significantly higher in TPP patients than in TWP patients (61.1 vs 34.4%, odds ratio (OR)=3.42, P=0.039) and was significantly more common than the minor allele frequency observed in the general population from the 1000 Genomes database (61.1 vs 29.0%, OR=4.87, P<0.005). Additionally, the C-allele frequency was similar between TWP patients and the general population (34.4 vs 29%, OR=1.42, P=0.325). We have demonstrated that SUR1 alanine 1369 variant is associated with allelic susceptibility to TPP. We suggest that the hyperinsulinaemia that is observed in TPP may be linked to the ATP-sensitive K(+)/SUR1 alanine variant and, therefore, contribute to the major feedforward precipitating factors in the pathophysiology of TPP.
Assuntos
Estudos de Associação Genética , Variação Genética , Resistência à Insulina/genética , Receptores de Sulfonilureias/genética , Tireotoxicose/genética , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Tireotoxicose/diagnóstico , Adulto JovemRESUMO
O bócio multinodular (BMN) é definido como um aumento da glândula tireóide secundário à proliferação multifocal de tireócitos e caracteriza-se pela heterogeneidade no crescimento e função das células foliculares. O BMN é considerado uma neoplasia benigna da tireóide. É uma doença comum, com aumento da prevalência em áreas com deficiência de iodo, sendo este o principal fator etiológico ambiental. A patogênese desta disfunção tireoidiana ainda não está inteiramente elucidada. Nesta revisão serão abordados os principais mecanismos envolvidos na patogênese, seguidos das implicações clínicas dessa patologia.
Multinodular goiter (MNG) is defined as an enlargement of the thyroid gland that is characterized by heterogeneity in growth and function of thyroid follicular cells. MNG is now considered a true thyroid neoplasm. It is a common disease, with higher prevalences in iodine deficiency areas. Iodine deficiency is the main environmental etiologic factor for MNG. The pathogenesis of multinodular goiter is not yet fully clarified. The purpose of this review is to summarize the current knowledge of MNG with respect to the pathology, etiologic and clinical characteristics.
Assuntos
Humanos , Criança , Adolescente , Bócio/complicações , Bócio/congênito , Bócio/diagnóstico , Bócio/etiologia , Bócio/genética , Bócio/patologia , Diagnóstico Clínico , Deficiência de Iodo/complicações , Deficiência de Iodo/diagnóstico , Deficiência de Iodo/etiologia , Deficiência de Iodo/metabolismo , Tireotoxicose/etiologia , Tireotoxicose/genética , Tireotoxicose/patologiaRESUMO
The RAS protooncogene has an important, although not yet established role in thyroid neoplasia. In this study, we evaluated the H-RAS mRNA and protein levels in human samples of nontoxic and toxic multinodular goiter samples, according to serum TSH levels. The mean of H-RAS mRNA levels in nodules of nontoxic nodular goiter were significantly increased compared to nonnodular tissue (1.49+/-1.21 vs. 0.94+/-0.81 AU, P=0.016). Nine of the 18 specimens (50%) of nontoxic multinodular goiter exhibited increased levels of H-RAS mRNA. The increased H-RAS mRNA levels were paralleled by inRAcreased H-Ras protein levels in about 90% of the cases. Interestingly, no differences were observed in H-RAS expression between nodules and adjacent nonnodular tissue in toxic nodular goiters (0.58+/-0.27 vs. 0.58+/-0.20 AU, P=0.88). None of the 10 samples from toxic multinodular goiters exhibited overexpression of H-RAS. The H-RAS expression was positively correlated with thyroglobulin expression (r2=0.51; P=0.04). In conclusion, we demonstrated increased levels of H-RAS mRNA and protein in samples of nontoxic multinodular goiter, indicating that it might be involved in goiter pathogenesis. In contrast, H-RAS overexpression was not detected in any of the samples of toxic multinodular goiter, suggesting different mechanisms for cell proliferation in nodular goiter according to thyroid status.
Assuntos
Expressão Gênica , Genes ras , Bócio Nodular/genética , Proteína Oncogênica p21(ras)/genética , Tireotoxicose/genética , Adulto , Idoso , Proliferação de Células , Análise Mutacional de DNA , Feminino , Bócio Nodular/metabolismo , Bócio Nodular/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Proteína Oncogênica p21(ras)/metabolismo , RNA Mensageiro/metabolismo , Estudos Retrospectivos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Tireoglobulina/metabolismo , Tireotoxicose/metabolismo , Tireotoxicose/patologia , Tireotropina/metabolismoRESUMO
Hypokalemic Periodic Paralyses comprise diverse diseases characterized by acute and reversible attacks of severe muscle weakness, associated with low serum potassium. The most common causes are Familial Hypokalemic Periodic Paralysis (FHypoKPP), an autosomal dominant disease, and Thyrotoxic Hypokalemic Periodic Paralysis (THypoKPP), secondary to thyrotoxicosis. Symptoms of paralysis are similar in both diseases, distinguished by thyrotoxicosis present in THypoKPP. FHypoKPP is caused by mutations in ionic channel genes calcium (CACN1AS), sodium (SCN4A) and potassium (KCNE3). Since both diseases are similar, we tested the hypothesis that THypoKPP could carry the same mutations described in FHypoKPP, being the paralysis a genetically conditioned complication of thyrotoxicosis. In 15 patients with THypoKPP, using target-exon PCR, CSGE screening, and direct sequencing, we excluded known mutations in CACN1AS and SCN4A genes. On the other hand, we were able to identify the R83H mutation in the KCNE3 gene in one sporadic case of THypoKPP, a man who had been asymptomatic until developing thyrotoxicosis caused by Graves' disease; we confirmed the disease-causing mutation in 2 of 3 descendants. R83H was recently found in two FHypoKPP unrelated families, in which the mutant decreased outward potassium flux, resulting in a more positive resting membrane potential. We, therefore, identified the first genetic defect in THypoKPP, a mutation in the KCNE3 gene.
Assuntos
Predisposição Genética para Doença , Paralisia Periódica Hipopotassêmica/genética , Mutação , Canais de Potássio de Abertura Dependente da Tensão da Membrana , Canais de Potássio/genética , Tireotoxicose/complicações , Tireotoxicose/genética , Adulto , Antitireóideos/uso terapêutico , Humanos , Paralisia Periódica Hipopotassêmica/tratamento farmacológico , Radioisótopos do Iodo/uso terapêutico , Masculino , Potenciais da Membrana , Metimazol/uso terapêutico , Linhagem , Reação em Cadeia da Polimerase , Cloreto de Potássio/uso terapêutico , Tireotoxicose/terapiaRESUMO
OBJECTIVE: To investigate whether patients with thyrotoxic hypokalaemic periodic paralysis (THPP) have the same molecular defect in the calcium channel gene described in familial hypokalaemic periodic paralysis (FHPP), as the symptoms of both diseases are comparable, we analysed, in patients with THPP, the presence of mutations R528H, R1239H and R1239G on the S4 voltage-sensing transmembrane segment of the alpha1 subunit of the calcium channel gene (Cav1.1). DESIGN AND PATIENTS: Genomic DNA was extracted from peripheral blood from 14 patients with THPP, 13 sporadic cases and one with a family history. An FHPP family was selected as a positive control. The exons bearing the described mutations were amplified by PCR, screened by single-strand conformation polymorphism (SSCP), and further sequenced. MEASUREMENTS: THPP was diagnosed both clinically and through laboratory tests, all patients having elevated levels of thyroid hormones (T4, T3 or free T4), suppressed TSH and plasma potassium below 3 small middle dot5 mmol/l. RESULTS: No evidence of the described mutations was found in patients with THPP. Furthermore, we did not detect any mutations in any of the four full S4 voltage-sensing transmembrane segments of Cav1 small middle dot1 (DIS4, DIIS4, DIIIS4 and DIVS4) by direct sequencing. However, close to the R528H mutation, we identified two single nucleotide polymorphisms at nucleotides 1551 and 1564 in both familial and sporadic cases with THPP. In addition, we were able to detect the R528H mutation in the DIIS4 transmembrane segment in all members of the FHPP family. CONCLUSION: Mutations linked to familial hypokalaemic periodic paralysis in the calcium channel alpha1 subunit gene (Cav1.1) are not associated with thyrotoxic hypokalaemic periodic paralysis. However, polymorphisms in nucleotides 1551 and 1564 in the exon 11 were found in patients with familial hypokalaemic periodic paralysis and thyrotoxic hypokalaemic periodic paralysis in higher frequency than in controls. The polymorphisms identified within the Cav1.1 gene are associated with thyrotoxic hypokalaemic periodic paralysis and represent a novel finding.
Assuntos
Canais de Cálcio Tipo L/genética , Paralisia Periódica Hipopotassêmica/genética , Mutação , Tireotoxicose/genética , Adulto , Sequência de Bases , Análise Mutacional de DNA , Feminino , Humanos , Paralisia Periódica Hipopotassêmica/sangue , Masculino , Dados de Sequência Molecular , Linhagem , Reação em Cadeia da Polimerase/métodos , Polimorfismo de Fragmento de Restrição , Polimorfismo Conformacional de Fita Simples , Hormônios Tireóideos/sangueRESUMO
Nonfamilial hypokalemic thyrotoxic periodic paralysis is rarely diagnosed among Caucasians and blacks in the western world but it is relatively common among Asiatics. Sudden paralysis occurring while at rest after a large carbohydrate meal or strenuous exercise in an undiagnosed mild thyrotoxic patient is a common presentation. A case illustrating such presentation is reported. Intracellular shifts of potassium triggered or facilitated by hyperthyroidism and hyperinsulinemia are the biochemical features. Correction of the thyrotoxic state is the definitive treatment for this disorder. Judicious administration of potassium is indicated during the hypokalemic episode to prevent life-threatening arrhythmias.