[Adrenal pheochromocytoma associated with "tako-tsubo" syndrome]. / Un caso di feocromocitoma surrenalico manifestatosi con un quadro di cardiomiopatia tipo "tako-tsubo".

"Tako-tsubo" cardiomyopathy is a condition characterized by a transitory left ventricular asinergia, induced by physical and emotional stress. In literature there are few cases of association between cardiomyopathy and pheochromocytoma. We described a case of a 72 year-old woman admitted in Emergency Room for chest pain associated with high blood pressure: the ECG showed non-ST elevation in leads III, AVF and V1. An echocardiogram showed global reduction in contractility (EF 40%) with apical akinesia. The coronary angiography showed coronary without stenosis while left ventriculography showed an average apical akinesia of the anterior wall with enhanced contractility of basal segments. Subsequently, the patient continued to present episodes of tremors associated with high blood pressure and therefore was made the determination of urinary metanephrines and urinary vanilmandelic acid that were both high. A subsequent abdomen MRI showed a 32 mm left adrenal lesion with arterial phase impregnation. The diagnosis of left adrenal pheochromocytoma was made and the tumor, after appropriate preoperative pharmacological preparation with α-blockers, was removed surgically. In conclusion, the unexplained transitory left ventricular asinergia alert the clinician of an underlying disorder, such as pheochromocytoma, the early detection of which is crucial to the prognosis.

Role of growth factors on human parathyroid adenoma cell proliferation.

INTRODUCTION: Primary hyperparathyroidism (pHPT) is caused by a single monoclonal adenoma in more than 80% of patients. Biomolecular mechanisms causing pHPT are still not completely known, even if a great amount of studies have been developed recently, mainly regarding angiogenesis and growth factors. Among the latter, insulin-like growth factor 1 (IGF-1), basic fibroblastic growth factor (bFGF), vascular endothelial growth factor (VEGF), and transforming growth factor beta 1 (TGF-beta1) and their effects have been extensively evaluated in different kinds of endocrine disease. METHODS: Parathyroid cell cultures were prepared from six human adenomatous parathyroid glands that were surgically removed. After 7 days of culture, the cells were refed with DMEM supplemented with 2% FCS alone (control group), or containing hrTGFbeta1, or hrIGF-I, or hrbFGF, or hrVEGF. Then, after 48-hour incubation, cell count was performed by a particle count and size analyzer, and prevalence of cell cycle was analyzed by using a flow cytometer. RESULTS: Cell count (x10000) in the control group was 3.73 +/- 0.32. Low-dose TGF-beta1 stimulation resulted in 5.25 +/- 0.38 cells, and high-dose TGF-beta1 stimulation resulted in 2.35 +/- 0.37 cells. IGF-1 stimulation resulted in 5.4 +/- 0.65 cells, bFGF stimulation in 5.68 +/- 0.86 cells, and VEGF stimulation resulted in 6.03 +/- 1.03 cells. Statistical analysis revealed significant differences in the control group compared with the growth factor-stimulated groups. Cytometry showed different results in the percentage of cells in S-phase, in particular 22.65 +/- 4.98% of IGF-1-stimulated cells were found in S-phase compared with 7.55 +/- 3.2% of control group cells (p < 0.0001). CONCLUSIONS: Growth factors seem to play an important role in parathyroid adenoma cell proliferation; IGF-1, bFGF, VEGF, and low-dose TGF-beta1 promote cell proliferation, whereas high-dose TGF-beta1 inhibits these phenomena.

Surgical management of abdominal manifestations of type 1 neurofibromatosis: experience of a single center.

Neurofibromatosis type 1 (NF1) is a genetic disease characterized by neoplastic and nonneoplastic disorders involving tissues of neuroectodermal and mesenchymal origin. The mainly involved districts are skin, the central nervous system, and eye and there is a wide range of severity of clinical presentations. Abdominal manifestations of NF1 include five kinds of tumors: neurogenic tumors (neurofibromas, malignant peripheral nerve sheath tumors [MPNSTs], and ganglioneuromas); neuroendocrine tumors (pheochromocytomas and carcinoids); nonneurogenic gastrointestinal stromal tumors (GISTs); embryonal tumors; and miscellaneous. The present experience depends on the participation in the National Project for Diagnosis and Treatment of Rare Diseases. In the group of patients with a diagnosis of von Recklinghausen disease, 10 patients underwent surgical treatment for gastrointestinal and retroperitoneal tumors associated with NF1. Three patients underwent adrenalectomy for pheochromocytoma (in one case associated with jejunal wall neurofibroma); two patients were found to be affected by MPNST (recurrent and unresectable in one case). One patient was affected by giant gastric GIST and jejunal neurofibroma; two patients were affected by extraperitoneal neurofibroma (pararenal and pararectal position); one patient was affected by giant colic neurofibroma and one patient was affected by retroperitoneal bilateral plexiform neurofibromas. Early diagnosis of these abdominal manifestations is very important because of the risk of malignancy, organic complications (such as pheochromocytoma), or hemorrhagic-obstructive complications such as in case of tumors of the gastrointestinal tract (GISTs and neurofibromas). The importance of an annual clinical evaluation on the part of a multidisciplinary pool of clinicians in highly specialized centers allows early detection of complications and of neoplastic transformation. Genetic screening allows preclinical diagnosis with a sensibility of 95 per cent. Further studies are necessary to detect predictive factors of malignant tumor development of severe clinical conditions.

Clinical experience with pheochromocytoma in a single centre over 16 years.

BACKGROUND: Pheochromocytoma and paraganglioma are rare tumours of neuroectodermal origin. Pheochromocytoma occurs in 0.1-2% of people with hypertension, while the incidence rises to 4-5% in patients with incidental adrenal mass. AIM: To analyse the presentation, diagnosis and localization, pathology, molecular genetic aspects, surgical management and long-term outcome of a large series of patients with pheochromocytoma referred to a single centre. METHODS: From 1992 to 2008, we observed 91 patients with pheochromocytoma, 70 (77%) with the sporadic form and 21 (23%) with the hereditary form. In the group with the hereditary form, the mean age at diagnosis was significantly lower than the mean age of the group with the sporadic form (38 vs 48 years; p < 0.001). RESULTS: Eighty (88%) patients with pheochromocytoma were symptomatic and the classical triad of palpitations, headache and diaphoresis was present in 30% of patients. In 12% of patients, the pheochromocytoma was discovered during radiological images (adrenal incidentaloma). The unilateral adrenal localization was observed in 78% of patients, bilateral in 15% and extra-adrenal in 7% of patients. All pheochromocytoma patients underwent surgical procedure and the laparotomic approach was used in 49 (53%) patients, while the laparoscopic approach was performed in 42 (47%) patients. Pheochromocytoma was benign in 86 patients (93%) [mean size was 4.3 cm] and the malignant form was found in five patients (7%) [mean size was 10 cm]. CONCLUSIONS: These data from a large cohort of patients are consistent with those reported in the literature and show that pheochromocytoma is an in important challenge for clinicians.

Comparisons of microvascular and macrovascular changes in aldosteronism-related hypertension and essential hypertension.

Case-control observational study to evaluate the microvascular and macrovascular changes in patients with hypertension secondary to primary aldosteronism (PA), essential hypertension (EH) and healthy subjects. Measurements of arterial stiffness including augmentation index (AIx) and pulse wave velocity (PWV) were assessed using a TensioClinic arteriograph system. Retinal microcirculation was imaged by a Retinal Vessel Analyzer (RVA) and a non-midriatic camera (Topcon-TRC-NV2000). IMEDOS software analyzed the retinal artery diameter (RAD), retinal vein diameters (RVD) and arteriole-to-venule ratio (AVR) of the vessels coming off the optic disc. Thirty, 39 and 35 patients were included in the PA, EH and control group, respectively. The PA group showed higher PWV values compared only with the control group. The mean brachial and aortic AIx values did not show significant difference between groups. In the PA group, the mean RVD and AVR values were significantly lower than in the EH and control groups, whereas the parameters did not differ between the EH and control groups. In conclusion, AVR appears significantly modified in the PA group compared with the EH group and could represent an early and more reliable indicator of microvascular remodeling.

Adrenal Pheochromocytoma Incidentally Discovered in a Patient With Parkinsonism.

To evaluate the diagnostic route of pheochromocytoma (PHEO) in a patient under dopaminergic treatment.A 70-year-old man with Parkinsonism and under treatment with levodopa and carbidopa came to our observation for evaluation of arterial hypertension and right adrenal mass discovered incidentally.To evaluate adrenal hormone levels we performed a dexamethasone suppression test, plasma aldosterone levels and 24-hr urinary metanephrine, which revealed elevated levels of catecholamines metabolities. 123-I-metaiodobenzylguanidine SPECT scintiscan revealed raised activity within the right adrenal gland concordant with the mass. The diagnosis of PHEO was posed and an elective laparoscopic adrenalectomy was performed; histopathological examination confirmed the PHEO diagnosis.Recently the coexistence of PHEO and Parkinsonism is a very rare association of diseases, with only 3 cases reported in literature. In this article, another case is reported and diagnostic procedures are discussed.

Subclinical Atherosclerosis in Patients with Cushing Syndrome: Evaluation with Carotid Intima-Media Thickness and Ankle-Brachial Index.

BACKGROUND: Cushing syndrome (CS) has been described as a killing disease due its cardiovascular complications. In fact, chronic cortisol excess leads to a constellation of complications, including hypertension, hyperglycemia, adiposity, and thromboembolism. The main vascular alteration associated with CS is atherosclerosis. METHODS: Aim of this study was to analyze carotid intima-media thickness (cIMT) and ankle-brachial index (ABI), two surrogate markers of subclinical atherosclerosis in a consecutive series of CS patients, compared to patients with essential hypertension (EH) and health subjects (HS). RESULTS: Patients with CS showed a significant increase (P<0.05) of cIMT (0.89±0.17 mm) compared to EH (0.81±0.16 mm) and HS (0.75±0.4 mm), with a high prevalence of plaque (23%; P<0.03). Moreover, CS patients showed a mean ABI values (1.07±0.02) significantly lower respect to HS (1.12±0.11; P<0.05), and a higher percentage (20%) of pathological values of ABI (≤0.9; P<0.03). CONCLUSION: In conclusion, we confirmed and extended the data of cIMT in CS, and showed that the ABI represent another surrogate marker of subclinical atherosclerosis in this disease.

Leptin and adiponectin mRNA expression from the adipose tissue surrounding the adrenal neoplasia.

CONTEXT: Interplay between adipose tissue and adrenal glands has been recently suggested, without well-founded actions of locally adipose tissue surrounding the adrenal glands. OBJECTIVE: We hypothesized that the local expression of leptin and adiponectin can be associated with pathological changes of the adrenal glands. PATIENTS AND MAIN OUTCOME MEASURES: We evaluated RT-PCR of leptin and adiponectin mRNA expression from the adipose tissue surrounding adrenal glands in 30 patients, collecting adipose tissue surrounding the adrenal neoplasms, peri-renal and subcutaneous depots. RESULTS: Leptin mRNA levels from adrenal neoplasia and peri-renal fat were significantly higher in aldosterone-producing adenoma than in nonfunctioning adenomas (P < 0.001 and P < 0.02, respectively). In patients with Cushing's syndrome leptin mRNA levels were significantly higher in adrenal fat than in peri-renal (P < 0.05) and subcutaneous adipose tissue (P < 0.001). Adiponectin mRNA expression from adrenal neoplasia was significantly lower than that from peri-renal and subcutaneous fat depots (P < 0.05). Leptin and adiponectin plasma levels significantly correlated with their mRNA expression from the fat depot surrounding the adrenal neoplasia. CONCLUSIONS: Our findings suggest an active role of the fat depot surrounding the adrenal neoplasia, with local secretion of leptin and adiponectin.

Electrical and Myocardial Remodeling in Primary Aldosteronism.

OBJECTIVE AND DESIGN: Primary aldosteronism (PA) represents the most common cause of secondary hypertension. A higher risk of cardiovascular events has been reported in patients with PA than in otherwise similar patients with essential hypertension (EH). So far, only a few studies investigated the electrocardiographic changes in PA patients compared to EH patients. METHODS: To investigate the electrocardiographic changes and heart remodeling in PA, we enrolled 61 consecutive patients, 30 with PA [12 with aldosterone-producing adrenal cortical adenoma (APA) and 18 with bilateral adrenal hyperplasia-idiopathic adrenal hyperplasia] and 30 with EH. In all subjects, electrocardiographic parameters were evaluated from 12-lead electrocardiograms and heart remodeling with echocardiogram. RESULTS: No significant differences in age, sex, body mass index, and blood pressure were found in two groups. The P wave and PR interval duration were significantly prolonged in patients with PA respect to EH (p < 0.003 and <0.002, respectively). A first degree atrio-ventricular block was present in 16% of the patients with PA and only in 3.2% of those with EH. In PA patients, the interventricular septum thickness (IVST) correlated with PR duration (r = 0.51; p < 0.03). Left ventricular hypertrophy was present in 53% of the patients with PA and in 26% of the patients with EH (χ(2), p < 0.03). CONCLUSION: In this case-control study, patients with PA show more anatomic and electrical heart remodeling than those with EH. We hypothesize that in patients with PA these cardiac changes may play a role for the increased risk of future cardiovascular events.

Oxidative stress in patients affected by primary aldosteronism.

OBJECTIVE: Primary aldosteronism, an important form of secondary hypertension, is associated with significant increase of cardiovascular risk (ischaemic heart, cerebrovascular events, arrhythmias) (relative risk 4.6). The specific treatment of primary aldosteronism significantly reduces cardiovascular risk. In addition to high blood pressure values and direct action of aldosterone, new mechanisms such as increased oxidative stress are involved in the development of organ damage, metabolic, endothelial and coagulation complications. METHODS: The aim of the study was to evaluate parameters of oxidative stress in 38 patients (21 men, 17 women, mean age 53.3 ±â€Š4.7 years) with primary aldosteronism [11 aldosterone-producing adenoma (APA) (4 men, 7 women, mean age 50.2 ±â€Š4.5 years) and 27 idiopathic adrenal hyperplasia (IHA) (17 men, 10 women, mean age 54.5 ±â€Š5.3 years)] at diagnosis and after specific treatment (surgical or pharmacological), with respect to 50 patients with essential hypertension (26 men, 24 women, mean age 49 ±â€Š7.4 years) and 50 healthy individuals (28 men, 22 women, mean age 48.7 ±â€Š4.4 years). RESULTS: Patients with primary aldosteronism showed significant increase of NADPH oxidase (Nox2-dp) plasma levels and urinary isoprostanes (34.9 ±â€Š4.3 µg/dl and 216.3 ±â€Š15.7 ng/mg, respectively; P < 0.05) than essential hypertensive patients (27.1 ±â€Š3.7 µg/dl and 144.8 ±â€Š9.4 ng/mg, respectively; P < 0.05). In APA patients undergoing adrenalectomy, we observed significant reduction of both circulating levels of Nox2-dp (29 ±â€Š2.1  vs. 22,4 ±â€Š1.7 µg/dl; P < 0.05) and urinary levels of isoprostanes (221.1 ±â€Š10.5 vs. 132.6 ±â€Š8.7 ng/mg; P < 0.05). CONCLUSIONS: This is the first study showing an increased oxidative stress in primary aldosteronism, characterized by increased serum levels of Nox2-dp and urinary excretion of isoprostanes. After APA removal with laparoscopic adrenalectomy, we found reduction of serum Nox2-dp and urinary isoprostanes.

Bone and mineral metabolism in patients with primary aldosteronism.

Primary aldosteronism represents major cause of secondary hypertension, strongly associated with high cardiovascular morbidity and mortality. Aldosterone excess may influence mineral homeostasis, through higher urinary calcium excretion inducing secondary increase of parathyroid hormone. Recently, in a cohort of PA patients a significant increase of primary hyperparathyroidism was found, suggesting a bidirectional functional link between the adrenal and parathyroid glands. The aim of this study was to evaluate the impact of aldosterone excess on mineral metabolism and bone mass density. In 73 PA patients we evaluated anthropometric and biochemical parameters, renin-angiotensin-aldosterone system, calcium-phosphorus metabolism, and bone mineral density; control groups were 73 essential hypertension (EH) subjects and 40 healthy subjects. Compared to HS and EH, PA subjects had significantly lower serum calcium levels and higher urinary calcium excretion. Moreover, PA patients showed higher plasma PTH, lower serum 25(OH)-vitamin D levels, higher prevalence of vitamin D deficiency (65% versus 25% and 25%; P < 0.001), and higher prevalence of osteopenia/osteoporosis (38.5 and 10.5%) than EH (28% and 4%) and NS (25% and 5%), respectively. This study supports the hypothesis that bone loss and fracture risk in PA patients are potentially the result of aldosterone mediated hypercalciuria and the consecutive secondary hyperparathyroidism.

KCNJ5 gene somatic mutations affect cardiac remodelling but do not preclude cure of high blood pressure and regression of left ventricular hypertrophy in primary aldosteronism.

OBJECTIVE: Aldosterone exerts detrimental cardiovascular effects, and patients with an aldosterone-producing adenoma (APA) carrying somatic mutations in the KCNJ5 K(+) channel (mutAPA) have higher plasma aldosterone concentration than wild-type APA (wtAPA) patients. We therefore investigated whether mutAPA patients develop a more prominent cardiovascular damage than wtAPA patients. METHODS AND FINDINGS: From 257 consecutive primary aldosteronism patients, we identified 176 who had both a diagnosis of APA by the 'four corners' criteria and high-quality echocardiographic data. Of them, 129 with KCNJ5 sequencing information and long-term follow-up data were compared for echocardiographic changes according to presence (mutAPA, 26%) or absence (wtAPA, 74%) of the KCNJ5 mutations. At baseline, the mutAPA were similar to the wtAPA for blood pressure (BP) and need for antihypertensive medications. However, they had higher left ventricular mass index (59 ± 19 vs. 51 ± 13 g/h(2.7); P < 0.05) and plasma aldosterone concentration [49 (32-68) vs. 36 (25-52) ng/dl); P = 0.048] than the wtAPA patients. In spite of their more prominent cardiac involvement, the mutAPA patients exhibited a fall of BP and plasma aldosterone similar to wtAPA, and a regression of left ventricular mass index. CONCLUSIONS: Compared to the wild-type APA patients those with KCNJ5 mutations showed more prominent cardiovascular damage. Notwithstanding this, their chances of being cured from the hyperaldosteronism and the high BP, and of regression of left ventricular hypertrophy after adrenalectomy, were not compromised by the presence of these mutations.

Primary aldosteronism with concurrent primary hyperparathyroidism in a patient with arrhythmic disorders.

A 25-year-old Caucasian woman was admitted to our department with severe hypokalemia that was associated with hypercalcemia. An endocrinological investigation showed the coexistence of primary hyperparathyroidism (PHPT) and primary aldosteronism (PA), arising from an adenoma of the left cortical adrenal gland. The patient underwent left laparoscopic adrenalectomy, but refused the surgical neck exploration that would be required for parathyroidectomy. The post-operative course was uneventful, and the patient realized a normalization of her potassium serum level and a reduction of her blood pressure values. We herein report the important issues regarding the management of a severe electrolyte imbalance, in view of the reciprocal interaction between aldosterone and parathyroid hormone, and their combined potential for causing cardiovascular damage.

von Hippel Lindau disease with colon adenocarcinoma, renal cell carcinoma and adrenal pheochromocytoma.

von Hippel-Lindau (VHL) disease is an autosomal dominant inherited tumor syndrome characterized by the presence of heterogeneous tumors derived from different organs. VHL is caused by germline mutations in the VHL tumor suppressor gene located on chromosome 3p25-26. The loss of functional VHL protein contributes to tumorigenesis. VHL tumors are most frequently derived from the kidneys, adrenal gland, central nervous system, eyes, inner ear, epididymis and pancreas. We herein describe the case of a 64-year-old man carrying the VHL gene mutation affected by simultaneous colon adenocarcinoma, renal clear cell carcinoma and adrenal pheochromocytoma.

Brown fat expresses adiponectin in humans.

The presence of brown adipose tissue (BAT) in humans is unclear. Pheochromocytomas (PHEO) are rare tumors of neuroectodermal origin which occur in 0.1-0.2% of patients with hypertension. We sought to evaluate the presence and activity of BAT surrounding adrenal PHEO in a well-studied sample of 11 patients who were diagnosed with PHEO and then underwent adrenalectomy. Areas of white fat (WAT) and BAT surrounding PHEO were obtained by Laser Capture Microdissection for analysis of uncoupling protein (UCP)-1 and adiponectin mRNA expression. Adiponectin and UCP-1 mRNA levels were significantly higher in BAT than in WAT (0.62 versus 0.15 and 362.4 versus 22.1, resp., P < 0.01 for both). Adiponectin mRNA levels significantly correlated with urinary metanephrines (r = 0.76, P < 0.01), vanilly mandelic acid (VMA) (r = 0.95, P < 0.01), and serum adiponectin levels (r = 0.95, P < 0.01). Serum adiponectin levels significantly decreased (24.2 ± 2 µ g/mL versus 18 ± 11 µ g/mL, P < 0.01) after adrenalectomy in PHEO subjects. This study provides the following findings: (1) BAT surrounding PHEO expresses adiponectin and UCP-1 mRNA, (2) expression of adiponectin mRNA is significantly higher in BAT than in WAT surrounding PHEO, and (3) catecholamines and serum adiponectin levels significantly correlate with BAT UCP-1 and adiponectin mRNA.

Epicardial fat thickness and left ventricular mass in subjects with adrenal incidentaloma.

Emerging evidences indicate that patients diagnosed with adrenal incidentaloma may present with cardiovascular complications. Epicardial fat is known to play a role in left ventricle (LV) changes. Whether epicardial fat can be associated with LV mass (LVM) in patients with incidentaloma is unknown. We test the hypothesis that echocardiographic epicardial fat thickness is independently related to LVM in a well-studied group of subjects with adrenal incidentaloma. 46 consecutive patients (age 59 ± 9 years) with imaging diagnosis of adrenal incidentaloma and 30 healthy controls underwent echocardiogram for epicardial fat thickness and LVM measurement. Non-functional incidentaloma was confirmed in 40 subjects, whereas 6 patients were actually diagnosed with mild Cushing's syndrome. Epicardial fat thickness was significantly higher in patients with incidentaloma and mild Cushing's syndrome when compared to controls, (p < 0.01 for both). LVM(h2.7) was higher in subjects with adrenal incidentaloma than in controls and higher in subjects with mild Cushing's syndrome than in those with adrenal incidentaloma (p < 0.05 and p < 0.01). Multiple regression analysis showed that epicardial fat thickness was the best correlate (R (2) = 0.36, ß 2.8, p < 0.01) of LVM in overall study patients. We showed for the first time that (1) epicardial fat thickness and LVM are higher in subjects with adrenal incidentaloma and (2) epicardial fat thickness independently correlates with LVM. Echocardiographic epicardial fat may serve as non-invasive marker of visceral fat and earlier cardiac abnormalities in patients with adrenal incidentaloma.

Bone mineral metabolism in patients with neurofibromatosis type 1 (von Recklingausen disease).

The neurofibromatosis type 1 (NF1) is characterized by specific cutaneous features (neurofibromas, "café-au-lait" spots of the skin) and alterations of several tissue (nervous, vascular) and bone deformities, such as scoliosis, congenital pseudoarthrosis and bone dysplasia of tibia. Moreover, several studies have shown systemic involvement of bone tissue in NF1 patients, leading to reduced bone mass. The aim of our study was to evaluate some bone mineral metabolism parameters before and after calcium and vitamin D supplementation in NF1 patients. We evaluated in 70 NF1 consecutive patients the mineral metabolism and bone mineral density compared with 40 normal subjects. We showed bone alterations in 35% of patients and the increase of bone formation markers, such as bone isoenzyme of alkaline phosphatase (41.2 ± 15.5 vs. 25.6 ± 8.7 UI; P < 0.05, respectively) and osteocalcin (18.1 ± 5.6 vs. 7.6 ± 1.9 ng/ml; P < 0.05) and reduction of circulating levels of (25OH)-vitamin D (21.8 ± 12.3 ng/ml) with an high percentage of hypovitaminosys D (>60%). Moreover, we revealed a significant reduction of bone mass density at spine (L1-L4) (0.935 ± 0.13 vs. 1.110 ± 0.17 g/cm(2); P < 0.001) and femoral neck side (0.765 ± 0.09 vs. 0.839 ± 0.12 g/cm(2); P < 0.02), with high prevalence of osteopenia (44%) and osteoporosis (18%). After 12 months of calcium (1,200 mg/die) and cholecalciferol (800 UI/die) supplementation, we found a significant increase of (25) OH-vitamin D level (21.8 ± 12.3 vs. 35 ± 13 ng/ml; P < 0.01), without changes in bone mass density. In conclusion, NF1 patients may present a mineral bone involvement, with vitamin D deficiency; calcium and vitamin D supplementation is necessary to restore these bone mineral metabolic alterations.

Prevalence, clinical, and molecular correlates of KCNJ5 mutations in primary aldosteronism.

Primary aldosteronism is the most common form of secondary hypertension. Mutations in the KCNJ5 gene have been described recently in aldosterone-producing adenomas (APAs). The aim of this study was to investigate the prevalence of KCNJ5 mutations in unselected patients with primary aldosteronism and their clinical, biological and molecular correlates. KCNJ5 sequencing was performed on somatic (APA, n=380) and peripheral (APA, n=344; bilateral adrenal hyperplasia, n=174) DNA of patients with primary aldosteronism, collected through the European Network for the Study of Adrenal Tumors. Transcriptome analysis was performed in 102 tumors. Somatic KCNJ5 mutations (p.Gly151Arg or p.Leu168Arg) were found in 34% (129 of 380) of APA. They were significantly more prevalent in females (49%) than males (19%; P<10(-3)) and in younger patients (42.1±1.0 versus 47.6±0.7 years; P<10(-3)) and were associated with higher preoperative aldosterone levels (455±26 versus 376±17 ng/L; P=0.012) but not with therapeutic outcome after surgery. Germline KCNJ5 mutations were found neither in patients with APA nor those with bilateral adrenal hyperplasia. Somatic KCNJ5 mutations were specific for APA, because they were not identified in 25 peritumoral adrenal tissues or 16 cortisol-producing adenomas. Hierarchical clustering of transcriptome profiles showed that APAs with p.Gly151Arg or p.Leu168Arg mutations were indistinguishable from tumors without KCNJ5 mutations. In conclusion, although a large proportion of sporadic APAs harbors somatic KCNJ5 mutations, germline mutations are not similarly causative for bilateral adrenal hyperplasia. KCNJ5 mutation carriers are more likely to be females; younger age and higher aldosterone levels at diagnosis suggest that KCNJ5 mutations may be associated with a more florid phenotype of primary aldosteronism.

Neurofibromatosis type 1 (NF1) and pheochromocytoma: prevalence, clinical and cardiovascular aspects.

The aim of the study was to evaluate the prevalence of pheochromocytoma (PHEO) in patients with neurofibromatosis type 1 (NF1), and to analyze the behavior of some anthropometric and cardiovascular parameters. In 48 consecutive NF1 patients, urinary metanephrines and vanillylmandelic acid excretion were assessed. The body mass index (BMI), waist circumference (WC), ambulatory blood pressure monitoring (ABPM), echocardiography and ultrasound carotid arterial wall evaluation were performed. In NF1 patients, 11 (29.3%) had arterial hypertension, 7 (14.6%) had a PHEO. Four (57%) NF1 patients with PHEO were symptomatic at the diagnosis. In PHEO-NF1 patients, we revealed a lower BMI and WC values with respect to NF1 patients without PHEO and normal subjects (NSs) (p < 0.05), respectively. The nocturnal non-dipping pattern at the ABPM was present in 40.4% of NF1 patients, and in particular this phenomenon was present in PHEO-NF1 patients (71.4%). Left ventricular mass index and intima media thickness were significantly higher in NF1 patients as compared to NS (p < 0.05), particularly in NF1-PHEO patients (p < 0.05). In conclusions, these findings revealed high prevalence of PHEO in NF1 patients and suggest that, in addition to blood pressure, humoral factors (increased sympathetic activity or neurofibromin), influence the pathogenesis of remodeling of cardiovascular system.

Adipokines and cardiometabolic profile in primary hyperaldosteronism.

CONTEXT: Primary aldosteronism (PA) has been recently associated with an unfavorable cardiometabolic profile. However, whether pro- and antiinflammatory adipokines levels can vary in PA is unknown. OBJECTIVE: We evaluated the circulating levels of resistin, leptin, and adiponectin, echocardiographic left ventricle (LV) parameters, and the prevalence of metabolic syndrome (SM) in subjects with PA. PATIENTS: Seventy-five subjects with established diagnosis of PA and 232 consecutive individuals with known or suspected hypertension were enrolled. MAIN OUTCOME MEASURES: Plasma adipokine levels and echocardiographic parameters were calculated. Prevalence of SM was also estimated. RESULTS: Among the 75 PA subjects, 37 patients were affected by aldosterone-producing adenoma and 38 by idiopathic hyperaldosteronism; 40 subjects were affected by essential hypertension (EH) and SM (EH SM+); 152 subjects were affected by EH without SM (EH SM-); and 40 subjects were normotensive (NT). Subjects with PA had the highest plasma resistin levels among the four groups (P < 0.01). Plasma resistin concentration was significantly higher in PA subjects when compared with EH SM+ individuals (P < 0.01) and EH SM- subjects (P < 0.01). PA subjects showed the higher LV mass and left atrium than EH individuals, irrespectively of the presence of SM (P < 0.01 for both). Plasma resistin levels was significantly correlated with ejection fraction and LV end-diastolic volume. The prevalence of SM was higher in PA subjects than in those with EH (25.4 vs. 20.3%). CONCLUSIONS: Our data suggest that elevated aldosterone levels is associated with elevated circulating resistin levels and cardiac morphological changes independently of the presence of SM.