RESUMO
CONTEXT: Recent studies have identified that the somatic PRKACA L206R mutation can cause cortisol-producing adenomas (CPAs). This study investigated the prevalence and characteristics of PRKACA, GNAS and CTNNB1 mutations in adrenal lesions in patients from a single centre in China. DESIGN, PATIENTS AND MEASUREMENTS: We sequenced PRKACA, GNAS and CTNNB1 genes in 108 patients, including 60 patients with CPAs (57 with unilateral and three with bilateral adenomas), 13 with nonfunctional adenomas, 12 with adrenocortical carcinomas (ACCs), 15 with primary bilateral macronodular hyperplasia (PBMAH) and eight with aldosterone and cortisol cosecreting adenomas. Mutations in PRKACA, GNAS and CTNNB1 were examined, and clinical characteristics were compared. RESULTS: Among the unilateral CPAs, we identified somatic mutations in PRKACA (L206R) in 23 cases (40·4%), GNAS (R201C and R201H) in six cases (10·5%), CTNNB1 (S45C, L46P and S45P) in six cases (10·5%) and CTNNB1 plus GNAS in two cases (3·5%). PRKACA and GNAS mutations were mutually exclusive. Among the patients with nonfunctional adenoma, two carried CTNNB1 mutations. Among the patients with ACC, two carried GNAS and CTNNB1 mutations but none carried PRKACA mutations. One patient showed bilateral CPA, and one PBMAH patient carried PRKACA mutations. No mutations in PRKACA, GNAS or CTNNB1 were identified in the eight patients with aldosterone and cortisol cosecreting adenomas. PRKACA-mutant adenomas were associated with young age, overt Cushing's syndrome and high cortisol levels compared with non-PRKACA-mutant or CTNNB1-mutant lesions. CONCLUSIONS: PRKACA mutations are present in CPAs and bilateral adrenal macronodular hyperplasia. PRKACA mutation is associated with more severe autonomous cortisol secretion.
Assuntos
Neoplasias das Glândulas Suprarrenais/patologia , Subunidades Catalíticas da Proteína Quinase Dependente de AMP Cíclico/genética , Mutação , Adenoma , Glândulas Suprarrenais/patologia , Adulto , Idoso , China , Cromograninas/genética , Feminino , Subunidades alfa Gs de Proteínas de Ligação ao GTP/genética , Humanos , Hidrocortisona/metabolismo , Hiperplasia , Masculino , Pessoa de Meia-Idade , Análise de Sequência de DNA , Adulto Jovem , beta Catenina/genéticaRESUMO
OBJECTIVE: To evaluate the outcomes of intravenous glucocorticoid therapy with or without orbital radiotherapy for moderate-to-severe Graves' ophthalmopathy. METHODS: A total of 83 patients with moderate-to-severe Graves' ophthalmopathy were retrospectively analyzed. Intravenous glucocorticoid was given to patients for 3 consecutive days every four weeks in 1-3 circles. The regimens included intravenous glucocorticoid alone (n = 36) and intravenous glucocorticoid plus orbital radiotherapy (n = 47). Photophobia, lacrimation, eye pain, soft tissue congestion, edema, exophthalmos and diplopia were compared before and after treatment. The symptoms and efficacies were compared between two groups. RESULTS: During a 12-week follow-up, clinical activity score (CAS), exophthalmos and diplopia all improved after treatment (P < 0.05). However, the changes of CAS, exophthalmos or diplopia showed no inter-group differences (P > 0.05). The overall clinical response was 50% in glucocorticoid group and 63.8% in glucocorticoid plus orbital radiotherapy group. And there was no statistical difference (P > 0.05). CONCLUSION: Moderate-to-severe Graves' ophthalmopathy may be relieved by pulsed intravenous glucocorticoid with or without orbital radiotherapy. There is no inter-group difference in short-term efficacies.
Assuntos
Oftalmopatia de Graves , Administração Intravenosa , Glucocorticoides , Humanos , Estudos RetrospectivosRESUMO
OBJECTIVE: To investigate the clinical characteristics of patients with different gender who diagnosed as differentiated thyroid cancers (DTC). METHODS: A cohort of patients with DTC underwent surgery in Chinese PLA General Hospital from October 2001 to may 2011 was retrospectively studied. RESULTS: (1) A total of 1 756 patients with DTC were enrolled in the study and a marked female preponderance was found with the female/male ratio of 2.32: 1. The peak incidence was 35-45 years old in both genders.Higher prevalence of DTC was observed in the male patients with a single nodule than in the males with multinodulars (36.42% vs 28.90%, P < 0.01), while no statistical difference was found in the female patients (33.60% vs 31.77%, P > 0.05). (2) Ultrasound examination revealed that, the female DTC patients with microcalcification thyroid nodules were more than the male patients (69.26% vs 62.62%, P < 0.05), while less in female patients with undefined boundary thyroid nodules (57.79% vs 72.01%, P < 0.01). The tumor size was shown to be smaller in the women than in the men [(1.6 ± 1.3) cm vs (1.8 ± 1.5) cm, P < 0.01]. (3) Higher rates of III/IV TNM Stage, lymph node metastasis and extrathyroidal invasion were found in the men than in the women (21.74% vs 14.51%, P < 0.01, 33.27% vs 23.80%, P < 0.01 and 10.59% vs 7.17%, P < 0.01). CONCLUSION: There is significant gender-related difference of clinical characteristics in the patients with DTC.
Assuntos
Carcinoma/patologia , Neoplasias da Glândula Tireoide/patologia , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Fatores Sexuais , Nódulo da Glândula Tireoide/patologiaRESUMO
OBJECTIVE: To investigate the association between DBil with normal range and serum lipid in type 2 diabetic patients. METHODS: A total of 979 subjects with type 2 diabetes admitted to the Department of Endocrinology of Chinese PLA General Hospital from June 2012 to June 2013 were included for the study. Serum DBil, TC, TG, HDL-C and LDL-C levels were collected for the analyses. Subjects were divided into four groups based on the DBil levels: Q1 group (<2.2 µmol/L), Q2 group (2.2-< 2.9 µmol/L), Q3 group (2.9-< 3.9 µmol/L) and Q4 group ( ≥ 3.9 µmol/L) . RESULTS: (1) TC, TG, LDL-C levels were significantly lower in Q4 group than those in the other three Q groups after adjustment of age, gender, duration of diabetes, BMI, smoking, drinking, glycosylated hemoglobin A1c (HbA1c) , fasting plasma glucose (FPG), medication, ALT, AST and fatty liver. No difference could be viewed in HDL-C level between each group (P = 0.65). (2) Pearson correlation analyses showed that DBil was inversely correlated with TC (r = -0.33, P < 0.01), TG (r = -0.23, P < 0.01), LDL-C (r = -0.18, P < 0.01), and positively correlated with HDL-C level in men (r = 0.14, P < 0.01), respectively. Multiple linear regression analyses showed DBil was an independent impact factor for TC, TG and LDL-C. (3) Compared with Q1 group, the odds ratio (OR) for dyslipidemia was 0.54 (95%CI 0.35-0.82, P < 0.01), 0.56 (95%CI 0.37-0.85, P < 0.01) and 0.44 (95%CI 0.29-0.69, P < 0.01) in Q2, Q3 and Q4 group, respectively, after age, gender, duration of diabetes, BMI, smoking, drinking, HbA1c, FPG, medication, ALT, AST and fatty liver were adjusted. Moreover, the OR for dyslipidemia was much lower in Q4 man subjects with age<55 years , HbA1c ≥ 6.5%, BMI<25 kg/m(2), and with no fatty liver. CONCLUSION: DBil in normal range was closely associated with lipid profile in type 2 diabetes. It might play a protective effect in dyslipidemia.
Assuntos
Bilirrubina/sangue , Diabetes Mellitus Tipo 2/sangue , Dislipidemias , Hemoglobinas Glicadas , Humanos , Fator de Impacto de Revistas , Lipídeos/sangue , Testes de Função Hepática , MasculinoRESUMO
OBJECTIVE: To summarize the disease distribution characteristics of adrenal lesions and analyze the changes of disease spectrum so as to further guide clinical practices. METHODS: All clinical data of adrenal lesion patients hospitalized between 1993 and 2013 were collected. Their profiles of gender ratio, visiting age, final diagnosis and year of hospitalization were retrospectively analyzed. RESULTS: A total of 4 049 patients with adrenal lesions were admitted. There were 2 004 males and 2 045 females with a mean age of 46.82 ± 13.36 years. The number of cases gradually increased year-on-year. And the visiting age was 30-60 years. The annual proportion of adrenal incidentaloma out of total adrenal lesions gradually increased with advancing age. Among them, 3 014 received endocrine function assessments. And there were non-functional lesions (n = 1 503, 49.88%) , adrenal Cushing's syndrome (n = 259, 8.60%), primary aldosteronism (n = 665, 22.04%) and pheochromocytoma (n = 235, 7.80%) . The proportion of non-functional lesions rose from 20.97% to 54.11% (P < 0.05). The proportion of primary aldsteronism declined from 29.84% to 20.43% (P < 0.05). And the proportion of adrenal Cushing syndrome changed slightly (P > 0.05). The proportion of pheochromocytoma declined from 18.55% to 6.99% (P < 0.05). CONCLUSION: The number of patients gradually increased over the last two decades.So did the proportion of adrenal incidentaloma. The disease spectrum of adrenal lesions has changed. And the proportion of non-functional lesions increased while that of functional lesions declined.
Assuntos
Neoplasias das Glândulas Suprarrenais , Hiperaldosteronismo , Feocromocitoma , Adulto , Feminino , Humanos , Achados Incidentais , Masculino , Pessoa de Meia-Idade , Estudos RetrospectivosRESUMO
OBJECTIVE: To explore the imaging features of congenital adrenal cortex hyperplasia (CAH). METHODS: A total of 45 patients clinically confirmed as CAH were retrospectively analyzed to investigate the imaging features and strengthening way of the multi-detector-row Computed tomography. RESULTS: The imaging features of all the cases presented as following: 25 with bilateral adrenal hyperplasia, 6 with unilateral adrenal hyperplasia, 6 with adrenal nodular hyperplasia, 2 with adrenal hyperplasia and unilateral solid cystic lesion, 2 with adrenal hyperplasia and double side real cystic lesion, 1 with adrenal hyperplasia and unilateral cystic changes and 3 with normal adrenal. The unilateral or bilateral hyperplasia adrenal could be homogeneously enhanced, while the enhanced performance of other cases was inequitable. CONCLUSIONS: The adrenal imaging features of CAH by multi-detector-row CT are variable, with the bilateral adrenal hyperplasia as the main form, which could be restored to normal morphology after hormone replacement therapy.No regression of the tumor size is observed in cases with adrenal mass. CT scanning combined with clinical manifestation and biochemical examination could facilitate the diagnosis of CAH.
Assuntos
Hiperplasia Suprarrenal Congênita/diagnóstico por imagem , Tomografia Computadorizada Espiral , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Estudos Retrospectivos , Adulto JovemRESUMO
MicroRNAs (miRNAs or miRs) are a class of short, non-coding RNAs that participate in various oncological processes. This study aims to explore the roles of microRNA-34a (miR-34a) in invasive urothelial bladder carcinoma. miR-34a was transfected into bladder cancer cell lines 253J and J82. The miR-34a expression levels in tissues and cells were detected by using qRT-PCR. The Notch1 expression was detected by qRT-PCR and Western blotting. Cell migratory and invasive abilities were measured by Transwell chamber assay. Bioinformatics and luciferase assay were performed to predict and analyze the binding sites between miRNA-34a and Notch1. It was found that there was aberrant expression of miR-34a in bladder cancer tissues. Moreover, we revealed that ectopic expression of miR-34a suppressed cell migration and invasion, while forced expression of Notch1 increased cell migratory and invasive abilities. Finally, we observed that miR-34a transfection significantly down-regulated luciferase activity and reduced the mRNA and protein levels of Notch1. Our study concluded that microRNA-34a antagonizes Notch1 and inhibits cell migration and invasion of bladder cancer cells, which indicates the tumor-suppressive function of microRNA-34a in bladder cancer.
Assuntos
MicroRNAs/genética , Receptor Notch1/fisiologia , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/fisiopatologia , Adulto , Idoso , Movimento Celular/genética , Regulação para Baixo/genética , Feminino , Marcação de Genes , Humanos , Masculino , Pessoa de Meia-Idade , Invasividade Neoplásica , Transfecção , Células Tumorais CultivadasRESUMO
This study examined the association of polymorphisms in angiotensin II receptor genes (AT (1) R and AT (2) R) with the risk for aldosterone-producing adenoma (APA) in a Chinese Han population. Four polymorphisms including rs5182 (573T/C) in exon 4, rs5186 (1166A/C) in 3'-untranslated region (3'-UTR) in AT (1) R gene and rs5194 (2274G/A) in 3'-UTR, rs1403543 (1675G/A) in intron 1 in AT (2) R gene were detected in 148 APA patients and 192 normal subjects (serving as control) by using a MGB-Taqman probe. The distribution of genotypes of each locus was in accordance with Hardy-Weinberg Equilibrium (HWE) in the APA and control groups (P>0.05). The allele A frequency at rs5194 was significantly higher in the APA group (0.49) than in the control group (0.35) (χ (2)=12.08, P=0.001). Subjects with homozygotic genotype AA and heterozygotic genotype GA were at an increased risk for APA as compared to those with GG genotype (OR=2.66, 95% CI=1.45-4.87; OR=1.67, 95% CI=1.02-2.74). Furthermore, rs5194 single-nucleotide polymorphism (SNP) at AT (2) R gene was significantly associated with APA in additive (OR=1.64, 95% CI=1.21-2.20, P=0.001), dominant (OR=1.94, 95% CI=1.23-3.06, P=0.003), and recessive model (OR=2.01, 95% CI=1.17-3.45, P=0.01). It was concluded that rs5194 polymorphism at AT (2) R gene was associated with the risk for APA, which may constitute a genetic marker of APA.
Assuntos
Adenoma/genética , Neoplasias do Córtex Suprarrenal/genética , Aldosterona/metabolismo , Polimorfismo Genético , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/genética , Adenoma/metabolismo , Neoplasias do Córtex Suprarrenal/metabolismo , Adulto , Estudos de Casos e Controles , China/etnologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
The expression of angiotensin II type 1 receptor (AT1R) and angiotensin II type 2 receptor (AT2R) in aldosterone-producing adenoma (APA) of the adrenal gland was detected, and their relationship with clinical indexes of APA was analyzed. The mRNA expression of AT1R and AT2R in 50 cases of APA and tissues adjacent to tumors and 12 cases of normal adrenal tissues was detected by using reverse transcriptase polymerase chain reaction (RT-PCR). The expression of AT1R and AT2R proteins in paraffin-embedded slices of tissue was detected by immunohistochemistry. The expression of AT1R in adenoma, tissues adjacent to tumor, and normal tissues of the adrenal gland showed no significant differences. The expression of AT2R in APA tissue was lower than that in normal adrenal gland tissues (P<0.05). Correlation analysis of the mRNA expression level of AT2R and clinical data from patients demonstrated that AT2R expression was negatively related to plasma aldosterone concentration (PAC) (r=-0.467, P<0.05), but positively related with plasma renin activity (PRA) (r=0.604, P<0.05). It is concluded that down-regulation of the AT2R expression is possibly related with the tumorigenesis of APA.
Assuntos
Adenoma/metabolismo , Neoplasias das Glândulas Suprarrenais/metabolismo , Aldosterona/sangue , Receptor Tipo 1 de Angiotensina/metabolismo , Receptor Tipo 2 de Angiotensina/metabolismo , Regulação para Baixo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptor Tipo 1 de Angiotensina/genética , Receptor Tipo 2 de Angiotensina/genéticaRESUMO
This study aimed to determine whether aldosterone could induce vascular cell apoptosis in vivo. Thirty-two male rats were randomly divided into 4 groups: vehicle (control), aldosterone, aldosterone plus eplerenone or hydralazine. They were then implanted with an osmotic mini-pump that infused either aldosterone or the vehicle. Systolic blood pressure (SBP) was measured weekly by the tail-cuff method. After 8 weeks, plasma aldosterone concentration (PAC) and renin activity (PRA) were determined by radioimmunoassay. Aortic apoptosis was examined by TUNEL assay. The levels of cytochrome c and caspase-3 were determined by Western blotting and the expression of Bax and Bcl-2 was detected by immunohistochemistry and Western blotting. The results showed that as compared with control group, aldosterone-infused rats exhibited: (1) an increase in SBP; (2) significantly elevated PAC with depressed PRA; (3) elevated aortic vascular cell apoptosis accompanied with higher levels of cytochrome c and activated caspase-3; and (4) significantly up-regulated Bax protein with down-regulated Bcl-2. These effects of aldosterone were significantly inhibited after co-administration with eplerenone but not with hydralazine. It was concluded that aldosterone induced vascular cell apoptosis by its direct effect on the aorta via mineralocorticoid receptors and independently of blood pressure, which may contribute to aldosterone-mediated vascular injury.
Assuntos
Aorta/patologia , Apoptose/fisiologia , Células Endoteliais/patologia , Hiperaldosteronismo/patologia , Receptores de Mineralocorticoides/metabolismo , Aldosterona/sangue , Animais , Masculino , Distribuição Aleatória , Ratos , Ratos Sprague-DawleyRESUMO
PURPOSE: We compared the clinical outcomes of retroperitoneoscopic and open adrenalectomy for pheochromocytoma. MATERIALS AND METHODS: Clinical data on 56 patients who underwent retroperitoneoscopic lateral adrenalectomy were retrospectively compared with those on 50 who underwent open adrenalectomy for pheochromocytoma, including patient demographic data, perioperative indexes and clinical outcomes. RESULTS: Demographic data on patients were similar in the 2 groups. In the retroperitoneoscopic group such perioperative indexes were significantly different from those of the open group (each p <0.05), including operative time (mean +/- SD 52 +/- 22 vs 120 +/- 42 minutes), estimated blood loss (74 +/- 34 vs 187 +/- 64 ml), resumption of oral intake (1 vs 2 days), postoperative hospital stay (5.2 +/- 1.7 vs 8.3 +/- 1.8 days), incidence of intraoperative hypertension (17.0% or 9 of 53 patients vs 36.0% or 18 of 50) and number of patients requiring blood transfusion(1.8% or 1 of 53 vs 16.0% or 8 of 50). The incidence of systemic inflammatory response syndrome was much less in the retroperitoneoscopic group (20.8% or 11 of 53 patients vs 42.0% or 21 of 50, p <0.05). However, the duration of systemic inflammatory response syndrome and postoperative complications were similar in the 2 groups (p >0.05). Blood pressure returned to normal 3 months after the operation in 81% of the patients in the retroperitoneoscopic group and in 84% in the open group. During the followup of 5 to 36 months no tumor recurrence and/or metastasis developed. CONCLUSIONS: Compared with open surgery retroperitoneoscopic lateral adrenalectomy for pheochromocytoma is a safe, minimally invasive and effective procedure.
Assuntos
Neoplasias das Glândulas Suprarrenais/cirurgia , Adrenalectomia/métodos , Laparoscopia , Feocromocitoma/cirurgia , Adulto , Feminino , Humanos , Masculino , Estudos RetrospectivosRESUMO
Context: KCNJ5 mutation is a major cause of aldosterone-producing adenomas (APAs). The development of APA apart from KCNJ5 mutation is less investigated. Objective: To investigate other mechanisms affecting aldosterone secretion apart from KCNJ5. Patients and Methods: Six pairs of KCNJ5-mutated, high and low aldosterone-secreting APAs, five non-KCNJ5-mutated APAs, and four normal adrenal glands were assayed by Affymetrix GeneChip Human Transcriptome Array 2.0. A total of 113 APA samples were investigated to explore the expression of glutathione-S-transferase A1 (GSTA1). H295R cells were used to verify the function of GSTA1. Results: GSTA1 was the top gene downregulated in high-aldosterone KCNJ5-mutated APAs. GSTA1 was also downregulated in KCNJ5-mutated APAs compared with wild-type KCNJ5 APAs. Accordingly, mutant KCNJ5 decreased GSTA1 messenger RNA and protein expression levels. GSTA1 overexpression suppressed aldosterone secretion whether in wild-type or mutant KCNJ5 H295R cells. Adding ethacrynic acid or silencing of GSTA1 increased aldosterone secretion by increasing reactive oxygen species (ROS), superoxide, H2O2 levels, and Ca2+ influx. The expression of the transcription factors NR4A1, NR4A2, and CAMK1 and intracellular Ca2+ were significantly upregulated by GSTA1 inhibition. The reduced form of NAD phosphate oxidase inhibitor or H2O2 scavenger or blocking calmodulin or calcium channels could significantly reduce aldosterone secretion in GSTA1-inhibited cells. Conclusions: (1) GSTA1 expression is reversely correlated with aldosterone level in KCNJ5-mutated APAs, (2) GSTA1 regulates aldosterone secretion by ROS and Ca2+ signaling, and (3) KCNJ5 mutation downregulates GSTA1 expression, and overexpression of GSTA1 reverses increased aldosterone in KCNJ5-mutated adrenal cells.
Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Adenoma Adrenocortical/metabolismo , Aldosterona/metabolismo , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Glutationa Transferase/biossíntese , Neoplasias do Córtex Suprarrenal/genética , Adenoma Adrenocortical/genética , Adulto , Aldosterona/biossíntese , Cálcio/fisiologia , Citocromo P-450 CYP11B2/biossíntese , Citocromo P-450 CYP11B2/genética , Regulação para Baixo , Feminino , Regulação Neoplásica da Expressão Gênica , Glutationa Transferase/genética , Humanos , Peróxido de Hidrogênio/metabolismo , Masculino , Pessoa de Meia-Idade , Mutação , RNA Mensageiro/genética , RNA Neoplásico/genética , RNA Interferente Pequeno/genética , Espécies Reativas de Oxigênio/metabolismo , Superóxidos/metabolismo , Células Tumorais CultivadasRESUMO
BACKGROUND: Prolonged gonadal hormone deficiency in patients with idiopathic hypogonadotropic hypogonadism (IHH) may produce adverse effects on the endocrine homeostasis and metabolism. This study aimed to compare basal serum adrenocorticotropic hormone (ACTH) and cortisol levels between male IHH patients and healthy controls. Moreover, this study compared the basal hypothalamic-pituitary-adrenal (HPA) axis in patients with and without nonalcoholic fatty liver disease (NAFLD), and also evaluated the relationship between basal HPA axis and NAFLD in male IHH patients. METHODS: This was a retrospective case-control study involving 75 Chinese male IHH patients (mean age 21.4 ± 3.8 years, range 17-30 years) and 135 healthy controls after matching for gender and age. All subjects underwent physical examination and blood testing for serum testosterone, luteinizing hormone, follicle-stimulating hormone, ACTH, and cortisol and biochemical tests. RESULTS: Higher basal serum ACTH levels (8.25 ± 3.78 pmol/L vs. 6.97 ± 2.81 pmol/L) and lower cortisol levels (366.70 ± 142.48 nmol/L vs. 452.82 ± 141.53 nmol/L) were observed in male IHH patients than healthy subjects (all p<0.05). IHH patients also showed higher metabolism parameters and higher prevalence rate of NAFLD (34.9% vs. 4.4%) than the controls (all P < 0.05). Basal serum ACTH (9.91 ± 4.98 pmol/L vs. 7.60 ± 2.96 pmol/L) and dehydroepiandrosterone sulfate (2123.7 ± 925.8 µg/L vs. 1417.1 ± 498.4 µg/L) levels were significantly higher in IHH patients with NAFLD than those without NAFLD (all P < 0.05). We also found that basal serum ACTH levels were positively correlated with NAFLD (r = 0.289,p<0.05) and triglyceride levels (r = 0.268, P< 0.05) in male IHH patients. Furthermore, NAFLD was independently associated with ACTH levels in male IHH patients by multiple linear regression analysis. CONCLUSIONS: The male IHH patients showed higher basal serum ACTH levels and lower cortisol levels than matched healthy controls. NAFLD was an independent associated factor for ACTH levels in male IHH patients. These preliminary findings provided evidence of the relationship between basal serum ACTH and NAFLD in male IHH patients.
Assuntos
Hormônio Adrenocorticotrópico/sangue , Hidrocortisona/sangue , Hipogonadismo/sangue , Hepatopatia Gordurosa não Alcoólica/sangue , Adolescente , Adulto , Humanos , Modelos Lineares , Masculino , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Estudos Retrospectivos , Adulto JovemRESUMO
Recently somatic mutations of KCNJ5, ATP1A1, ATP2B3, and CACNA1D have been identified in patients with aldosterone-producing adenoma (APA). The present study sequenced the DNA in the tissues and blood samples from Chinese patients with APA for KCNJ5, ATP1A1, ATP2B3, and CACNA1D gene mutations.Among the 114 patients, 86 (75.4%) were identified with KCNJ5 somatic mutations, including 3 previously reported (G151R, L168R, T158A) and 2 other unreported mutations. One patient presented with both a point mutation (E147) and an insertion mutation, whereas another had a 36-base duplication, G153_G164dup. No mutation of ATP1A1 and ATP2B3 in the known hotspots was identified and only 1 male patient was detected with a novel CACNA1D mutation, V748I. Unlike other studies, male and female patients had similar KCNJ5 mutation rates (76.9% vs 74.2%). Mutation carriers were younger and had lower preoperative potassium level, whereas male (but not female) mutation carriers had higher preoperative plasma aldosterone concentration and preoperative blood pressures. Mutation carriers also had higher LV mass index (LVMI) than nonmutation carriers. After surgery, LVMI improved significantly in the KCNJ5 mutation group but not in the nonmutation group. The mRNA expression of KCNJ5, CYP11B2, and ATP2B3 was higher in the KCNJ5-mutated APA tissues. Functional characterization of the 2 novel KCNJ5 mutations showed that they were associated with decreased proliferation, membrane depolarization, elevated secretion of aldosterone, and increased expression of CYP11B1 and CYP11B2.In conclusion, Chinese APA patients appear to have a high frequency of somatic KCNJ5 mutation. Mutation prevalence rates are similar among men and women and 2 novel mutations are identified. KCNJ5-mutated patients benefit more from surgical resection of APA than nonmutated patients.
Assuntos
Adenoma/genética , Aldosterona/metabolismo , Adulto , Fatores Etários , Povo Asiático , Canais de Cálcio Tipo L/genética , Técnicas de Cultura de Células , China/epidemiologia , Feminino , Canais de Potássio Corretores do Fluxo de Internalização Acoplados a Proteínas G/genética , Perfilação da Expressão Gênica , Heterozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Mutação , ATPases Transportadoras de Cálcio da Membrana Plasmática/genética , Reação em Cadeia da Polimerase , Prevalência , RNA Mensageiro/biossíntese , Fatores Sexuais , ATPase Trocadora de Sódio-Potássio/genéticaRESUMO
BACKGROUND: Hypertension often persists after adrenalectomy for primary aldosteronism (PA). Many studies have analyzed the outcomes of adrenalectomy for aldosterone-producing adenomas (APA) to identify predictive factors for persistent hypertension. However, differentially expressed genes in persistent postoperative hypertension remain unknown. Our aim was to describe gene expression profile of persistent postoperative hypertension patients with APA. METHODS: In this study, we described and compared gene expression profiles in persistent postoperative hypertension and postoperative normotension in Chinese patients with APA using microarray analysis. Confirmation was performed with quantitative real time-polymerase chain reaction analysis. Bioinformatic analysis (gene ontology analysis, pathway analysis and network analysis) was used for further research. RESULTS: Microarray analysis identified a total of 99 differentially expressed genes, including 18 up-regulated and 81 down-regulated genes. Among the dysregulated genes were fat atypical cadherin 1 as well as fatty acid binding protein 4 and other genes that have not been previously studied in persistent postoperative hypertension with APA. Bioinformatics analysis indicated that differentially expressed genes were associated with lipid metabolic process, metal ion binding, and cell differentiation. Pathway analysis determined that five pathways corresponded to the dysregulated transcripts. The mRNAs-ncRNAs co-expression network was composed of 49 network nodes and 72 connections between 18 coding genes and 31 noncoding genes. CONCLUSIONS: This study revealed differentially expressed genes in persistent postoperative hypertension with APA and provided a resource of candidate genes for exploration of possible drug targets and prognostic markers.
Assuntos
Adenoma/metabolismo , Adenoma/fisiopatologia , Aldosterona/metabolismo , Perfilação da Expressão Gênica/métodos , Adenoma/cirurgia , Adrenalectomia , Pressão Sanguínea/fisiologia , Humanos , Hiperaldosteronismo/metabolismo , Hiperaldosteronismo/fisiopatologia , Hiperaldosteronismo/cirurgia , Complicações Pós-Operatórias , Estudos RetrospectivosRESUMO
OBJECTIVE: Pituitary stalk interruption syndrome (PSIS) is characterized by the absence of pituitary stalk, pituitary hypoplasia, and ectopic posterior pituitary. Due to the rarity of PSIS, clinical data are limited, especially in Chinese people. Herein, we analyzed the clinical characteristics of patients diagnosed with PSIS from our center over 10 years. PATIENTS AND METHODS: We retrospectively analyzed the clinical manifestations and laboratory and MRI findings in 55 patients with PSIS. RESULTS: Of the 55 patients with PSIS, 48 (87.3%) were male. The average age was 19.7±6.7 years and there was no familial case. A history of breech delivery was documented in 40 of 45 patients (88.9%) and 19 of 55 patients (34.5%) had a history of dystocia. Short stature was found in 47 of 55 patients (85.5%) and bone age delayed 7.26±5.37 years. Secondary sex characteristics were poor or undeveloped in most patients. The prevalence of deficiencies in growth hormone, gonadotropins, corticotropin, and thyrotropin were 100%, 95.8%, 81.8%, 76.3%, respectively. Hyperprolactinemia was found in 36.4% of patients. Three or more pituitary hormone deficiencies were found in 92.7% of the patients. All patients had normal posterior pituitary function and absent pituitary stalk on imaging. The average height of anterior pituitary was 28 mm, documented anterior pituitary hypoplasia. Midline abnormalities were presented in 9.1% of patients. CONCLUSIONS: The clinical features of our Chinese PSIS patients seem to be different from other reported patients in regarding to the higher degree of hypopituitarism and lower prevalence of midline defects. In addition, our patients were older at the time of case detection and the bone age was markedly delayed. We also had no cases of familial PSIS.
Assuntos
Povo Asiático , Doenças da Hipófise/patologia , Hipófise/patologia , Adolescente , Adulto , Criança , China , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Doenças da Hipófise/diagnóstico , Síndrome , Adulto JovemRESUMO
OBJECTIVES: The expression of steroidogenic factor-1 (SF-1) was elevated in adrenal aldosterone-producing adenoma (APA). The influence of SF-1 on adrenal tumorigenesis by adrenocortical cell line H295R cells was investigated. MATERIALS AND METHODS: Real-time PCR and Western blotting were used to detect SF-1 expression in 16 APA samples and 12 normal adrenal samples. Specific SF-1-shRNA plasmid was transfected into H295R cells to inhibit SF-1 expression. Western blotting and real-time PCR were used to verify the effects of RNAi on SF-1 inhibition. Subsequently, WST-1 and cell count were applied to evaluate cell proliferation at different SF-1 levels. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was used to measure cell apoptosis, and proliferation marker Ki-67 was studied by immunohistochemistry. RESULTS: Compared with normal adrenal samples, SF-1 mRNA and protein levels in APA samples were significantly higher. It was 10.48:1 at SF-1 mRNA and 0.87 ± 0.05 vs. 0.39 ± 0.07 at protein levels, respectively (P < 0.01). A decreased SF-1 significantly inhibited cell proliferation in the experimental and control cells. These results were supported by weaker Ki-67 staining in SF-1-inhibited cells [(36.9% ± 4.17%) vs. (58.48% ± 7.16%) (P < 0.01)]. Moreover, SF-1 inhibition induced a 2.7-fold increase in the percentage of apoptotic H295R cells (P < 0.01). CONCLUSIONS: Elevated SF-1 may play an important role in APA formation and primary aldosteronism. SF-1 acts as an oncogenic factor, and its inhibition provides new insight into the understanding and treatment of related adrenal diseases.
Assuntos
Neoplasias do Córtex Suprarrenal/metabolismo , Adenoma Adrenocortical/metabolismo , Aldosterona/biossíntese , Fator Esteroidogênico 1/metabolismo , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/patologia , Adenoma Adrenocortical/genética , Adenoma Adrenocortical/patologia , Apoptose , Western Blotting , Linhagem Celular , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Antígeno Ki-67/análise , Microscopia de Fluorescência , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator Esteroidogênico 1/genéticaRESUMO
OBJECTIVES: Hypertension often persists after adrenalectomy for primary aldosteronism. Traditional factors associated with postoperative hypertension were evaluated, but whether genetic determinants were involved remains poorly understood. The aim of this study was to investigate the association of DNA polymorphisms within steroid synthesis genes (CYP11B2, CYP11B1) and the postoperative resolution of hypertension in Chinese patients undergoing adrenalectomy for aldosterone-producing adenomas (APA). METHODS: Ninety-three patients with APA were assessed for postoperative resolution of hypertension. All patients were genotyped for rs1799998 (C-344 T), intron 2 conversion, rs4539 (A2718G) within CYP11B2 and rs6410 (G22 5A), rs6387 (A2803G) within CYP11B1. The associations between CYPB11B2/CYP11B1 polymorphisms and persistent postoperative hypertension were assessed by multivariate analysis. RESULTS: CYP11B2-CYP11B1 haplotype was associated with persistent postoperative hypertension in Chinese patients undergoing adrenalectomy with APA (P = .006). Specifically, the rs4539 (AA) polymorphism was associated with persistent postoperative hypertension (P = .002). Multivariate logistic regression revealed the common haplotypes H1 (AGACT), H2 (AGAWT), and H3 (AGAWC) were associated with the persistent postoperative hypertension (P = .01, 0.03, 0.005 after Bonferroni correction). Additional predictors of persistent postoperative hypertension included duration of hypertension (P <.0005), family history of hypertension (P = .001), and elevated systolic blood pressure (P = .015). CONCLUSIONS: The rs4539 (AA), H1, H2, and H3 are genetic predictors for postoperative persistence of hypertension for Chinese patients treated by adrenalectomy with APA. DNA polymorphisms at CYP11B2/B1 locus may confer susceptibility to postoperative hypertension of patients with APA.
Assuntos
Neoplasias do Córtex Suprarrenal/cirurgia , Adrenalectomia , Adenoma Adrenocortical/cirurgia , Aldosterona/metabolismo , Citocromo P-450 CYP11B2/genética , Hiperaldosteronismo/genética , Hipertensão/genética , Polimorfismo de Nucleotídeo Único , Complicações Pós-Operatórias/etiologia , Esteroide 11-beta-Hidroxilase/genética , Neoplasias do Córtex Suprarrenal/epidemiologia , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Adenoma Adrenocortical/epidemiologia , Adenoma Adrenocortical/genética , Adenoma Adrenocortical/metabolismo , Adulto , China/epidemiologia , Éxons/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Hiperaldosteronismo/epidemiologia , Hiperaldosteronismo/etiologia , Hiperaldosteronismo/cirurgia , Hipertensão/epidemiologia , Hipertensão/etiologia , Íntrons/genética , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Estudos RetrospectivosRESUMO
Several frequent polymorphisms in the CYP11B2 gene are suggested to be associated with essential hypertension and aldosterone secretion. In this study, we investigated the association of polymorphisms in CYP11B2 and CYP11B1 genes with the risk of primary hyperaldosteronism (PH). Three polymorphisms in the CYP11B2 gene (intron 2 conversion, rs1799998 and rs4539) and two polymorphisms in the CYP11B1 gene (rs6410 and rs6387) were analyzed in patients with PH and in the normal population. The rs6410 allelic frequencies in patients with aldosterone-producing adenoma (APA) and idiopathic hyperaldosteronism (IHA) were significantly different from those in controls at P=1.09 x 10(-5) and 0.015, respectively. There was a relative excess of AA homozygotes and AG heterozygotes of the rs6410 allele in the APA group as compared with the control group (P=2.19 x 10(-4)). There were significantly different genotypes, AA and AG, of the rs6410 allele between the patients with IHA and the controls only after adjustments for age, gender and body mass index (odds ratio (OR)=4.06, 95% confidence interval (CI) 1.31-12.66; OR=2.41, 95% CI 1.02-5.72). One susceptible haplotype, AAAWT, was identified to be significantly associated with APA (OR=1.44, 95% CI 1.19-1.76), and three susceptible haplotypes, AAAWT, AGGWT and AGAWC, were identified to be significantly associated with IHA (OR=1.55, 95% CI 1.23-1.96; OR=1.49, 95% CI 1.17-1.89; OR=1.40, 95% CI 1.04-1.88). In contrast, one protective haplotype, GGAWT, showed a significant difference between the patients with APA and controls (OR=0.73, 95% CI 0.55-0.97). Several haplotypes were associated with ARR in both the controls and cases. Our data demonstrated that there was a significant association between polymorphisms in the CYP11B2 and CYP11B1 genes and a genetic predisposition to PH. The association with IHA seemed closer compared with APA.
Assuntos
Neoplasias do Córtex Suprarrenal/genética , Adenoma Adrenocortical/genética , Citocromo P-450 CYP11B2/genética , Hiperaldosteronismo/genética , Esteroide 11-beta-Hidroxilase/genética , Alelos , Análise de Variância , Distribuição de Qui-Quadrado , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Variação Genética , Genótipo , Haplótipos , Reação em Cadeia da Polimerase , Polimorfismo GenéticoRESUMO
OBJECTIVES: To evaluate the effectiveness and safety of retroperitoneal laparoscopic adrenalectomy for pheochromocytoma and report our experience in adrenalectomy without previous control of the adrenal vein. METHODS: From January 2000 to December 2005, 56 patients underwent 58 retroperitoneal laparoscopic adrenalectomy procedures for the treatment of pheochromocytoma. Adequate preoperative antihypertensive preparation was performed. Intraoperative hemodynamic changes were documented in detail. During surgery, the adrenal vein was identified and ligated after dissection and mobilization of the adrenal gland. RESULTS: One patient required conversion to open surgery. The mean operative time and estimated blood loss was 50.4 +/- 19.8 minutes (range 25 to 150) and 76.4 +/- 23.5 mL (range 20 to 300), respectively. A systolic blood pressure greater than 200 mm Hg or less than 80 mm Hg was observed in 6 and 3 patients, respectively. Moreover, an upward fluctuation of systolic blood pressure (20 mm Hg or greater) was recorded during laparoscopic manipulation in 21 patients (37.5%), and in 8 of them, it was 50 mm Hg or greater. The mean diameter of the excised masses was 4.6 +/- 1.7 cm (range 1.5 to 10.0). The mean hospital stay was 5.2 +/- 1.3 days (range 3 to 9). No patients had a major complication and none died. During the follow-up period of 5 months to 3 years, 36 patients recovered normal blood pressure without antihypertensive drugs. No tumor recurrences developed. CONCLUSIONS: Retroperitoneal laparoscopic adrenalectomy without previous control of the adrenal vein is effective and safe for ablation of pheochromocytoma. For experienced surgeons, the tumors larger than 6 cm in diameter can also be removed using the retroperitoneal endoscopic approach.