Clinical Benefits of Unilateral Adrenalectomy in Patients with Subclinical Hypercortisolism Due to Adrenal Incidentaloma: Results from a Single Center.

INTRODUCTION: This study was designed to evaluate the results of unilateral laparoscopic adrenalectomy in patients with subclinical hypercortisolism (SH) due to adrenal incidentaloma (AI) concerning the main cardiometabolic disorders. METHODS: We have studied between January 2000 to December 2015, 645 patients with AI (283 males and 362 females; mean age 61.9 ± 10 years) and we found 70 patients with SH (27 males and 43 females; mean age 61.9 ± 8.4 years). Twenty-six (37%) SH patients (6 males and 20 females; mean age 58.7 ± 7.1 years) underwent unilateral laparoscopic adrenalectomy, whereas 44 SH patients (21 males and 23 females; mean age 63.9 ± 9.9 years) performed a conservative treatment. All SH patients were evaluated at diagnosis and after follow-up (mean 12 months; range 9-15 months). RESULTS: In only SH patients undergoing unilateral adrenalectomy we found a statistical significant reduction of the arterial hypertension and metabolic syndrome (p < 0.05, respectively). In particular we observed a reduction of 24-h systolic blood pressure and "non-dipper" pattern (p < 0.05, respectively) evaluated with ambulatory blood pressure monitoring (ABPM). CONCLUSIONS: Our study confirm the high prevalence of SH in AI, and the unilateral laparoscopic adrenalectomy seemed to have a beneficial effect on some cardiometabolic disorders.

A case report of subclinical hypercortisolism due to adrenal incidentaloma complicated by myasthenia gravis after adrenalectomy.

A 62-year-old woman was admitted for evaluation of an incidentally discovered adrenal mass and hypertension. CT scan revealed a 7 cm mass in the right adrenal gland. After careful examination, the patient was diagnosed with subclinical hypercortisolism (SH). Adrenalectomy was performed. Histopathological examination showed an adrenocortical adenoma. Symptoms and signs of myasthenia gravis appeared 5 months later. CT of the chest showed a solid tissue mass in the mediastinum. The patient underwent a sternotomy with excision of the tumor, which histologically proved to be a type 2B thymoma. We describe a rare case of SH due to an incidentally discovered adrenocortical adenoma in a patient who manifested myasthenia gravis after surgical remission of the cortisol excess.

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.

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.

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.

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.

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.

A pool of peptides extracted from wheat bud chromatin inhibits tumor cell growth by causing defective DNA synthesis.

BACKGROUND: We previously reported that a pool of low molecular weight peptides can be extracted by alkali treatment of DNA preparations obtained from prokaryotic and eukaryotic cells after intensive deproteinization. This class of peptides, isolated from wheat bud chromatin, induces growth inhibition, DNA damage, G2 checkpoint activation and apoptosis in HeLa cells. In this work we studied their mechanism of action by investigating their ability to interfere with DNA synthesis. METHODS: BrdUrd comet assays were used to detect DNA replication defects during S phase. DNA synthesis, cell proliferation, cell cycle progression and DNA damage response pathway activation were assessed using 3H-thymidine incorporation, DNA flow cytometry and Western blotting, respectively. RESULTS: BrdUrd labelling close to DNA strand discontinuities (comet tails) detects the number of active replicons. This number was significantly higher in treated cells (compared to controls) from entry until mid S phase, but markedly lower in late S phase, indicating the occurrence of defective DNA synthesis. In mid S phase the treated cells showed less 3H-thymidine incorporation with respect to the controls, which supports an early arrest of DNA synthesis. DNA damage response activation was also shown in both p53-defective HeLa cells and p53-proficient U2OS cells by the detection of the phosphorylated form of H2AX after peptide treatment. These events were accompanied in both cell lines by an increase in p21 levels and, in U2OS cells, of phospho-p53 (Ser15) levels. At 24 h of recovery after peptide treatment the cell cycle phase distribution was similar to that seen in controls and CDK1 kinase accumulation was not detected. CONCLUSION: The data reported here show that the antiproliferative effect exhibited by these chromatin peptides results from their ability to induce genomic stress during DNA synthesis. This effect seems to be S-phase specific since surviving cells are able to progress through their normal cell cycle when the peptide fraction is removed from the culture medium. It is likely that the subsequent apoptosis is a consequence of the failed attempt of the tumour cells to repair the DNA damage induced by the peptides.

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.

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.

TRIM proteins in cancer.

Some members of the tripartite motif (TRIM/RBCC) protein family are thought to be important regulators of carcinogenesis. This is not surprising as the TRIM proteins are involved in several biological processes, such as cell growth, development and cellular differentiation and alteration of these proteins can affect transcriptional regulation, cell proliferation and apoptosis. In particular, four TRIM family genes are frequently translocated to other genes, generating fusion proteins implicated in cancer initiation and progression. Among these the most famous is the promyelocytic leukaemia gene PML, which encodes the protein TRIM19. PML is involved in the t(15;17) translocation that specifically occurs in Acute Promyelocytic Leukaemia (APL), resulting in a PML-retinoic acid receptor-alpha (PML-RARalpha) fusion protein. Other members of the TRIM family are linked to cancer development without being involved in chromosomal re-arrangements, possibly through ubiquitination or loss of tumour suppression functions. This chapter discusses the biological functions of TRIM proteins in cancer.

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.

[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.

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.