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  • 1
    In: Journal of the Endocrine Society, The Endocrine Society, Vol. 4, No. Supplement_1 ( 2020-05-08)
    Abstract: Primary aldosteronism (PA) is the most common cause of endocrine hypertension. PA subtypes include bilateral hyperplasia and unilateral PA, typically aldosterone-producing adenomas. Adrenal venous (AV) sampling (AVS) is a key step to define PA subtype and guide PA management. According current PA guidelines, most PA patients should undergo AVS, which is a challenging procedure, especially in terms of successfully cannulating the right AV. The aim of this study was to report a single tertiary center experience with AVS in PA patients. We retrospectively evaluated 84 AVS from 1984 to 2019. Sequential AVS was performed by an experienced interventional radiologist. AV and inferior vena cava (IVC) samples were obtained under cosyntropin continuous infusion. Successful catheterization was defined by a selectivity index [SI= AV/IVC cortisol (C) concentrations] ≥5. Unilateral disease was defined by a lateralization index [LI= aldosterone (A)/C ratio in the dominant AV divided by A/C in the non-dominant AV] ≥4. The relative aldosterone secretion index (RASI= A/C ratio in AV divided by A/C in IVC) was calculated in each side. A RASI & lt;1 was defined as contralateral suppression (CS). In patients with unsuccessful AV catheterization (mostly right AV) or undetermined LI (3-4), CS was used to indicate adrenalectomy. The biochemical cure of PA after adrenalectomy was defined as the gold standard parameter to confirm unilateral disease. Successful bilateral AV catheterization was achieved in 75% of the cases. After 2015, the use of intra-procedural rapid cortisol assay improved angiographer experience and increased AVS successful rate from 52 to 80%. LI revealed unilateral and bilateral aldosterone excess in 68 and 32% of the cases, respectively. A LI ≥4 had a sensitivity of 100% and specificity of 98% to define unilateral PA among patients with successful catheterization. In addition, RASI in the non-dominant AV was significantly lower in unilateral PA according the LI when compared to bilateral cases [0.12 (0.03 to 1.18) vs. 1.1 (0.04 to 4.56), p= 0.0001]. RASI in the non-dominant AV was inversely correlated with LI (r= -0.81, p= 0.0001). A CS index ≤0.5 had a high sensitivity (90%) and specificity (94%) to define unilateral aldosterone excess. In conclusion, the LI is the most valuable parameter in AVS for PA subtyping. Additionally, CS (cut-off of 0.5) is very useful to define lateralization and can be used in cases of borderline LI or unsuccessful AV catheterization.CAPES Grant to Freitas TC.
    Type of Medium: Online Resource
    ISSN: 2472-1972
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2020
    detail.hit.zdb_id: 2881023-5
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  • 2
    In: Endocrine-Related Cancer, Bioscientifica, Vol. 28, No. 1 ( 2021-01), p. 1-13
    Abstract: Familial primary aldosteronism (PA) is rare and mostly diagnosed in early-onset hypertension (HT). However, ‘sporadic’ bilateral adrenal hyperplasia (BAH) is the most frequent cause of PA and remains without genetic etiology in most cases. Our aim was to investigate new genetic defects associated with BAH and PA. We performed whole-exome sequencing (paired blood and adrenal tissue) in six patients with PA caused by BAH that underwent unilateral adrenalectomy. Additionally, we conducted functional studies in adrenal hyperplastic tissue and transfected cells to confirm the pathogenicity of the identified genetic variants. Rare germline variants in phosphodiesterase 2A ( PDE2A ) and 3B ( PDE3B ) genes were identified in three patients. The PDE2A heterozygous variant (p.Ile629Val) was identified in a patient with BAH and early-onset HT at 13 years of age. Two PDE3B heterozygous variants (p.Arg217Gln and p.Gly392Val) were identified in patients with BAH and HT diagnosed at 18 and 33 years of age, respectively. A strong PDE2A staining was found in all cases of BAH in zona glomerulosa and/or micronodules (that were also positive for CYP11B2). PKA activity in frozen tissue was significantly higher in BAH from patients harboring PDE2A and PDE3B variants. PDE2A and PDE3B variants significantly reduced protein expression in mutant transfected cells compared to WT. Interestingly, PDE2A and PDE3B variants increased SGK1 and SCNN1G/ENaCg at mRNA or protein levels. In conclusion, PDE2A and PDE3B variants were associated with PA caused by BAH. These novel genetic findings expand the spectrum of genetic etiologies of PA.
    Type of Medium: Online Resource
    ISSN: 1351-0088 , 1479-6821
    Language: Unknown
    Publisher: Bioscientifica
    Publication Date: 2021
    detail.hit.zdb_id: 2010895-3
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  • 3
    In: European Journal of Endocrinology, Oxford University Press (OUP), Vol. 171, No. 3 ( 2014-09), p. 335-342
    Abstract: To date, no evidence of robust genotype–phenotype correlation or disease modifiers for multiple endocrine neoplasia type 1 (MEN1) syndrome has been described, leaving the highly variable clinical presentation of patients unaccounted for. Design As the CDKN1B ( p27 ) gene causes MEN4 syndrome and it is transcriptionally regulated by the product of the MEN1 gene (menin), we sought to analyze whether p27 influences the phenotype of MEN1 -mutated patients. The cohort consisted of 100 patients carrying germline MEN1 gene mutations and 855 population-matched control individuals. Methods Genotyping of the coding p27 c.326T 〉 G (V109G) variant was performed by sequencing and restriction site digestion, and the genotypes were associated with clinical parameters by calculating odds ratios (ORs) and their 95% CIs using logistic regression. Results There were significant differences in p27 V109G allele frequencies between controls and MEN1 -mutated patients (OR=2.55, P =0.019, CI=1.013–5.76). Among patients who are ≥30 years old carrying truncating MEN1 mutations, the T allele was strongly associated with susceptibility to tumors in multiple glands (three to four glands affected vs one to two glands affected; OR=18.33; P =0.002, CI=2.88–16.41). This finding remained significant after the Bonferroni's multiple testing correction, indicating a robust association. No correlations were observed with the development of MEN1-related tumors such as hyperparathyroidism, pituitary adenomas, and enteropancreatic and adrenocortical tumors. Conclusions Our study suggests that the p27 tumor suppressor gene acts as a disease modifier for the MEN1 syndrome associated with MEN1 germline mutations. If confirmed in independent patient cohorts, this finding could facilitate the management of this clinically complex disease.
    Type of Medium: Online Resource
    ISSN: 0804-4643 , 1479-683X
    RVK:
    Language: Unknown
    Publisher: Oxford University Press (OUP)
    Publication Date: 2014
    detail.hit.zdb_id: 1485160-X
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  • 4
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 108, No. 5 ( 2023-04-13), p. 1143-1153
    Abstract: Primary aldosteronism (PA) screening relies on an elevated aldosterone to renin ratio with a minimum aldosterone level, which varies from 10 to 15 ng/dL (277-415.5 pmol/L) using immunoassay. Objective To evaluate intra-individual coefficient of variation (CV) of aldosterone and aldosterone to direct renin concentration ratio (A/DRC) and its impact on PA screening. Methods A total of 671 aldosterone and DRC measurements were performed by the same chemiluminescence assays in a large cohort of 216 patients with confirmed PA and at least 2 screenings. Results The median intra-individual CV of aldosterone and A/DRC was 26.8% and 26.7%. Almost 40% of the patients had at least one aldosterone level & lt;15 ng/dL, 19.9% had at least 2 aldosterone levels & lt;15 ng/dL, and 16.2% had mean aldosterone levels & lt;15 ng/dL. A lower cutoff of 10 ng/dL was associated with false negative rates for PA screening of 14.3% for a single aldosterone measurement, 4.6% for 2 aldosterone measurements, and only 2.3% for mean aldosterone levels. Considering the minimum aldosterone, true positive rate of aldosterone thresholds was 85.7% for 10 ng/dL and 61.6% for 15 ng/dL. An A/DRC & gt;2 ng/dL/µIU/mL had a true positive rate for PA diagnosis of 94.4% and 98.4% when based on 1 or 2 assessments, respectively. CV of aldosterone and A/DRC were not affected by sex, use of interfering antihypertensive medications, PA lateralization, hypokalemia, age, and number of hormone measurements. Conclusion Aldosterone concentrations had a high CV in PA patients, which results in an elevated rate of false negatives in a single screening for PA. Therefore, PA screening should be based on at least 2 screenings with concomitant aldosterone and renin measurements.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    RVK:
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2023
    detail.hit.zdb_id: 2026217-6
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  • 5
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 104, No. 10 ( 2019-10-01), p. 4695-4702
    Abstract: Primary aldosteronism (PA) is the most common cause of endocrine hypertension (HT). HT remission (defined as blood pressure 〈 140/90 mm Hg without antihypertensive drugs) has been reported in approximately 50% of patients with unilateral PA after adrenalectomy. HT duration and severity are predictors of blood pressure response, but the prognostic role of somatic KCNJ5 mutations is unclear. Objective To determine clinical and molecular features associated with HT remission after adrenalectomy in patients with unilateral PA. Methods We retrospectively evaluated 100 patients with PA (60 women; median age at diagnosis 48 years with a median follow-up of 26 months). Anatomopathological analysis revealed 90 aldosterone-producing adenomas, 1 carcinoma, and 9 unilateral adrenal hyperplasias. All patients had biochemical cure after unilateral adrenalectomy. KCNJ5 gene was sequenced in 76 cases. Results KCNJ5 mutations were identified in 33 of 76 (43.4%) tumors: p.Gly151Arg (n = 17), p.Leu168Arg (n = 15), and p.Glu145Gln (n = 1). HT remission was reported in 37 of 100 (37%) patients. Among patients with HT remission, 73% were women (P = 0.04), 48.6% used more than three antihypertensive medications (P = 0.0001), and 64.9% had HT duration 〈 10 years (P = 0.0015) compared with those without HT remission. Somatic KCNJ5 mutations were associated with female sex (P = 0.004), larger nodules (P = 0.001), and HT remission (P = 0.0001). In multivariate analysis, only a somatic KCNJ5 mutation was an independent predictor of HT remission after adrenalectomy (P = 0.004). Conclusion The presence of a KCNJ5 somatic mutation is an independent predictor of HT remission after unilateral adrenalectomy in patients with unilateral PA.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    RVK:
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2019
    detail.hit.zdb_id: 2026217-6
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  • 6
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, ( 2024-03-05)
    Abstract: The role for hormone parameters at adrenal venous sampling (AVS) in predicting clinical and biochemical outcome remains controversial. Objective To investigate the impact of hormone parameters at AVS under cosyntropin stimulation on lateralization and on complete biochemical and clinical outcome. Methods We retrospectively evaluated 150 sequential AVS under cosyntropin infusion. Bilateral successful cannulation rate was 83.3% (n = 140), 47.9% bilateral and 52.1% unilateral. The lateralization index (LI), aldosterone/cortisol ratio (A/C) in the dominant adrenal vein (AV), relative aldosterone secretion index (RASI = A/C in AV divided by A/C in inferior vena cava) were assessed. The contralateral suppression (CS) percentage was defined by (1 – nondominant RASI) *100. Results A nondominant RASI & lt;0.5 (CS & gt;50%) had 86.84% sensitivity and 92.96% specificity to predict contralateral lateralization. An A/C ratio in dominant AV & gt;5.9 (74.67% sensitivity and 80% specificity) and dominant RASI & gt;4.7 (35.21% sensitivity and 88.06% specificity) had a worst performance to predict ipsilateral lateralization. Complete biochemical and clinical cure were significantly more frequent in the patients with CS & gt;50% [98.41% vs. 42.86% (p & lt; 0.001) and 41.94% vs. 0% (p & lt; 0.001)]. CS correlated with high aldosterone at diagnosis (p & lt; 0.001) and low postoperative aldosterone levels at 1 month (p = 0.019). Postoperative biochemical hypoaldosteronism was more frequent in patients with CS & gt;50% (70% vs. 16.67%, p = 0.014). In multivariable analysis, a CS & gt;50% was associated with complete biochemical cure (OR 125, 95%CI 11.904–5,000; p = 0.001) and hypertension remission (OR 12.19, 95%CI 2.074–250; p = 0.023). Conclusion A CS & gt;50% was an independent predictor of complete clinical and biochemical cure. Moreover, it can predict unilateral PA and postoperative biochemical hypoaldosteronism. Our findings underscore the usefulness of CS for clinical decision-making.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    RVK:
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2024
    detail.hit.zdb_id: 2026217-6
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  • 7
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 108, No. 8 ( 2023-07-14), p. 2105-2114
    Abstract: Limited information is available concerning the genetic spectrum of pheochromocytoma and paraganglioma (PPGL) patients in South America. Germline SDHB large deletions are very rare worldwide, but most of the individuals harboring the SDHB exon 1 deletion originated from the Iberian Peninsula. Objective Our aim was to investigate the spectrum of SDHB genetic defects in a large cohort of Brazilian patients with PPGLs. Methods Genetic investigation of 155 index PPGL patients was performed by Sanger DNA sequencing, multiplex ligation-dependent probe amplification, and/or target next-generation sequencing panel. Common ancestrality was investigated by microsatellite genotyping with haplotype reconstruction, and analysis of deletion breakpoint. Results Among 155 index patients, heterozygous germline SDHB pathogenic or likely pathogenic variants were identified in 22 cases (14.2%). The heterozygous SDHB exon 1 complete deletion was the most frequent genetic defect in SDHB, identified in 8 out of 22 (36%) of patients. Haplotype analysis of 5 SDHB flanking microsatellite markers demonstrated a significant difference in haplotype frequencies in a case-control permutation test (P = 0.03). More precisely, 3 closer/informative microsatellites were shared by 6 out of 8 apparently unrelated cases (75%) (SDHB-GATA29A05-D1S2826-D1S2644 | SDHB-186-130-213), which was observed in only 1 chromosome (1/42) without SDHB exon 1 deletion (X2 = 29.43; P & lt; 0.001). Moreover, all cases with SDHB exon 1 deletion had the same gene breakpoint pattern of a 15 678 bp deletion previously described in the Iberian Peninsula, indicating a common origin. Conclusion The germline heterozygous SDHB exon 1 deletion was the most frequent genetic defect in the Brazilian PPGL cohort. Our findings demonstrated a founder effect for the SDHB exon 1 deletion in Brazilian patients with paragangliomas.
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    RVK:
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2023
    detail.hit.zdb_id: 2026217-6
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  • 8
    In: Journal of the Endocrine Society, The Endocrine Society, Vol. 7, No. Supplement_1 ( 2023-10-05)
    Abstract: Disclosure: M.A. Stumpf: None. N.L. Queiroz: None. V.C. Souza: None. A.W. Maciel: None. G.F. Fagundes: None. V. Srougi: None. F.Y. Tanno: None. J.L. Chambo: None. M.A. Pereira: None. A. Pio-Abreu: None. L.A. Bortolotto: None. A. Latronico: None. M.B. Fragoso: None. L.F. Drager: None. B.B. Mendonca: None. M.Q. Almeida: None. Background: Primary aldosteronism (PA) is a very prevalent disease, characterized by an autonomous aldosterone secretion. Unilateral PA accounts for approximately 40% of the cases and is preferentially treated with surgery. Several studies reported decrease in renal function following unilateral adrenalectomy, but the risk factors associated with this decline remain to be better elucidated. Aim: Our aim was to investigate predictive factors of the decrease in renal function after unilateral adrenalectomy for PA. Methods: We retrospectively evaluated 89 PA patients submitted to unilateral adrenalectomy. Serum aldosterone, direct renin concentration, estimated glomerular filtration rate (eGFR), and electrolytes were determined at the pre-operative period and at 1 week, 1, 3 and 6 months (m) after unilateral adrenalectomy. The primary endpoint was the DELTAeGFR (eGFR after surgery at different times – eGFR before surgery). Results: Thirty-seven patients (41.6%) were men and 52 (58.4%) were women, with a median age of diagnosis of 49 years (range, 20 to 74 years). At diagnosis, the median aldosterone and renin levels were 29.8 ng/dl (7.3 - 217) and 4 μIU/mL (4 – 8.2), respectively. Hypokalemia at diagnosis was evidenced in 75 out of 89 (84.3%) of the patients. Unilateral PA was confirmed in 78 out of 89 cases (87.6%) by biochemical cure after adrenalectomy. The mean pre-operative creatinine and eGFR were 1.14 ± 0.48 mg/dL and 53.5 ± 17.1 mL/min, respectively. After adrenalectomy, the DELTAeGFR was −6.7 ± 12.1 mL/min at 1 week (p= 0.001), 0.17 ± 10 mL/min at 1m (p= 0.91), −2 ± 8.7 mL/min at 3m (p= 0.13) and −1.8 ± 10.9 mL/min at 6m (p= 0.24). Interestingly, aldosterone levels at diagnosis were significantly associated with the DELTAeGFR at 1 week (p= 0.024). PA patients with aldosterone levels & gt;50 ng/dL (n= 13) at diagnosis presented a higher deterioration in renal function at 1 week when compared to those with aldosterone & lt;50 ng/dL (n= 76) (αeGFR −12 ± 8.6 mL/min vs. −5.9 ± 12.5 mL/min, respectively; p= 0.032). Moreover, the patients with hypoaldosteronism (aldosterone & lt;5 ng/dl) at 1 week had a lower decrease in renal function (DELTAeGFR −4.4 ± 12mL/min (n= 41) vs. −9.9 ± 11.6 mL/min (n= 42), respectively; p= 0.014) and lower levels of aldosterone at diagnosis (31.5 ± 21.1 ng/dL vs. 50.4 ± 44.4 ng/dL, respectively; p= 0.008). The post-operative decline in renal function did not correlate with age, hypokalemia, number of anti-hypertensive medications at diagnosis, immediate pre-operative and post-operative renin, and hypertension remission after surgery. Conclusion: The renal function decreased precociously after adrenalectomy but returned to basal levels after 1m. Aldosterone levels at diagnosis and at 1 week after surgery were significantly associated with decline in renal function. Support: This work was supported by the Sao Paulo Research Foundation (FAPESP) grant 2019/15873-6. Presentation: Friday, June 16, 2023
    Type of Medium: Online Resource
    ISSN: 2472-1972
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 2023
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  • 9
    In: Hormone and Metabolic Research, Georg Thieme Verlag KG, Vol. 56, No. 05 ( 2024-05), p. 350-357
    Abstract: Few studies demonstrated a percentage decrease in the estimated glomerular filtration rate (eGFR) at a single time and the rate of hypoaldosteronism after adrenalectomy for primary aldosteronism (PA). Our aim was to investigate the evolution of renal function and the hypoaldosteronism risk after adrenalectomy for PA. Aldosterone, renin, eGFR, and electrolyte levels were determined before and at 1 week, 1, 3 and 6 months after unilateral adrenalectomy in 94 PA patients (40 men and 54 women). The main outcome was the postoperative eGFR decline using analysis of covariance with the preoperative eGFR as a covariate. eGFR decreased during first postoperative week compared to 3 months before surgery. During the first 6 months, eGFR remained stable at similar levels to the first week after surgery. Age (p=0.001), aldosterone levels (p=0.021) and eGFR 3 months before surgery (p+ 〈 +0.0001) had a significant correlation with eGFR during first postoperative week. High aldosterone levels at diagnosis were correlated with decline in renal function in the univariate model (p=0.033). In the multivariate analysis, aldosterone levels at diagnosis had a tendency to be an independent predictor of renal function after surgery (p=0.059). Postoperative biochemical hypoaldosteronism was diagnosed in 48% of the cases after adrenalectomy, but prolonged hyperkalemia occurred in only 4 cases (4.5%). Our findings showed a decrease of eGFR after unilateral adrenalectomy for PA. Additionally, aldosterone levels at diagnosis correlated with postoperative renal function. Postoperative biochemical hypoaldosteronism occurred in almost half of the patients, but prolonged hyperkalemia with fludrocortisone replacement was less frequent.
    Type of Medium: Online Resource
    ISSN: 0018-5043 , 1439-4286
    RVK:
    Language: English
    Publisher: Georg Thieme Verlag KG
    Publication Date: 2024
    detail.hit.zdb_id: 2056576-8
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  • 10
    In: Endocrine, Springer Science and Business Media LLC, Vol. 72, No. 2 ( 2021-05), p. 586-590
    Type of Medium: Online Resource
    ISSN: 1355-008X , 1559-0100
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
    detail.hit.zdb_id: 2074043-8
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