Giorgio Arnaldi

AME Position Statement on Adrenal Incidentaloma.

OBJECTIVE To assess currently available evidence on adrenal incidentaloma and provide recommendations for clinical practice. DESIGN A panel of experts (appointed by the Italian Association of Clinical Endocrinologists (AME)) appraised the methodological quality of the relevant studies, summarized their results, and discussed the evidence reports to find consensus. RADIOLOGICAL ASSESSMENT Unenhanced computed tomography (CT) is recommended as the initial test with the use of an attenuation value of ≤10 Hounsfield units (HU) to differentiate between adenomas and non-adenomas. For tumors with a higher baseline attenuation value, we suggest considering delayed contrast-enhanced CT studies. Positron emission tomography (PET) or PET/CT should be considered when CT is inconclusive, whereas fine needle aspiration biopsy may be used only in selected cases suspicious of metastases (after biochemical exclusion of pheochromocytoma). HORMONAL ASSESSMENT: Pheochromocytoma and excessive overt cortisol should be ruled out in all patients, whereas primary aldosteronism has to be considered in hypertensive and/or hypokalemic patients. The 1 mg overnight dexamethasone suppression test is the test recommended for screening of subclinical Cushings syndrome (SCS) with a threshold at 138 nmol/l for considering this condition. A value of 50 nmol/l virtually excludes SCS with an area of uncertainty between 50 and 138 nmol/l. MANAGEMENT Surgery is recommended for masses with suspicious radiological aspects and masses causing overt catecholamine or steroid excess. Data are insufficient to make firm recommendations for or against surgery in patients with SCS. However, adrenalectomy may be considered when an adequate medical therapy does not reach the treatment goals of associated diseases potentially linked to hypercortisolism.

Clinically Guided Genetic Screening in a Large Cohort of Italian Patients with Pheochromocytomas and/or Functional or Nonfunctional Paragangliomas

PURPOSE The aim of the study was to define the frequency of hereditary forms and the genotype/phenotype correlations in a large cohort of Italian patients with pheochromocytomas and/or functional or nonfunctional paragangliomas. DESIGN We examined 501 consecutive patients with pheochromocytomas and/or paragangliomas (secreting or nonsecreting). Complete medical and family histories, as well as the results of clinical, laboratory, and imaging studies, were recorded in a database. Patients were divided into different groups according to their family history, the presence of lesions outside adrenals/paraganglia considered syndromic for VHL disease, MEN2, and NF1, and the number and types of pheochromocytomas and/or paragangliomas. Germ-line mutations in known susceptibility genes were investigated by gene sequencing (VHL, RET, SDHB, SDHC, SDHD) or diagnosed according to phenotype (NF1). In 160 patients younger than 50 yr with a wild-type profile, multiplex ligation-dependent probe amplification assays were performed to detect genomic rearrangements. RESULTS Germline mutations were detected in 32.1% of cases, but frequencies varied widely depending on the classification criteria and ranged from 100% in patients with associated syndromic lesions to 11.6% in patients with a single tumor and a negative family history. The types and number of pheochromocytomas/paragangliomas as well as age at presentation and malignancy suggest which gene should be screened first. Genomic rearrangements were found in two of 160 patients (1.2%). CONCLUSIONS The frequency of the hereditary forms of pheochromocytoma/paraganglioma varies depending on the family history and the clinical presentation. A positive family history and an accurate clinical evaluation of patients are strong indicators of which genes should be screened first.

High cardiovascular risk in patients with Cushing's syndrome according to 1999 WHO/ISH guidelines

objective  In patients with Cushings syndrome (CS) cardiovascular complications determine a mortality rate four times higher than in an age‐ and gender‐matched population. Therefore, we calculated the global cardiovascular risk in patients with CS.

Approach to the Patient with Possible Cushing's Syndrome

Clinical decision making for patients with suspect hypercortisolism involves a complex diagnostic assessment. Cushings syndrome remains one of the most challenging endocrine pathologies. Most clinical features overlap with those of common diseases found in the general population, and some patients have an atypical clinical presentation with only isolated symptoms. Recently, several studies have suggested that the prevalence of Cushings syndrome is higher than previously thought. Therefore, efficient screening tests are needed to identify the few uncovered patients also among unselected high-risk ambulatory patients with disorders potentially related to cortisol excess. The recommended diagnostic tests are 24-h urinary free cortisol, 1-mg overnight dexamethasone suppression test, and late-night salivary cortisol. Once the diagnosis of Cushings syndrome is established, the next step is the measurement of plasma ACTH. Then, dynamic test and appropriate imaging procedures are the most useful noninvasive investigations for the differential diagnosis. Patients with Cushings disease are generally responsive to the CRH test and to high-dose glucocorticoid feedback. Bilateral inferior petrosal sinus sampling is considered the gold standard for establishing the origin of ACTH secretion, and it is recommended in patients with ACTH-dependent Cushings syndrome whose clinical, biochemical, or radiological studies are discordant or equivocal. The present clinical case shows that even if rare, the ectopic ACTH secretion should be considered also in those cases where the pretest probability is low. The management of Cushings syndrome depends on the exact knowledge of its various causes, paying attention to the many potential diagnostic pitfalls. The choice of test, the modality of specimen collection (blood, urine, and saliva), the quality of measurement (assay methodology and standardization), and close dialogue among endocrinologists, chemical pathologists, and neuroradiologists are key factors for optimal care of patients.

AMP-activated protein kinase mediates glucocorticoid-induced metabolic changes: a novel mechanism in Cushing’s syndrome

Chronic exposure to glucocorticoid hormones, resulting from either drug treatment or Cushings syndrome, results in insulin resistance, central obesity, and symptoms similar to the metabolic syndrome. We hypothesized that the major metabolic effects of corticosteroids are mediated by changes in the key metabolic enzyme adenosine monophosphate‐activated protein kinase (AMPK) activity. Activation of AMPK is known to stimulate appetite in the hypothalamus and stimulate catabolic processes in the periphery. We assessed AMPK activity and the expression of several metabolic enzymes in the hypothalamus, liver, adipose tissue, and heart of a rat glucocorticoid‐excess model as well as in in vitro studies using primary human adipose and primary rat hypothalamic cell cultures, and a human hepatoma cell line treated with dexamethasone and metformin. Glucocorticoid treatment inhibited AMPK activity in rat adipose tissue and heart, while stimulating it in the liver and hypothalamus. Similar data were observed in vitro in the primary adipose and hypothalamic cells and in the liver cell line. Metformin, a known AMPK regulator, prevented the corticosteroidinduced effects on AMPK in human adipocytes and rat hypothalamic neurons. Our data suggest that glucocorticoid‐induced changes in AMPK constitute a novel mechanism that could explain the increase in appetite, the deposition of lipids in visceral adipose and hepatic tissue, as well as the cardiac changes that are all characteristic of glucocorticoid excess. Our data suggest that metformin treatment could be effective in preventing the metabolic complications of chronic glucocorticoid excess.— Christ‐Crain M., Kola, B., Lolli F., Fekete, C., Seboek, D., Wittmann, G., Feltrin, D., Igreja, S. C., Ajodha, S., Harvey‐White, J., Kunos, G., Müller B., Pralong, F., Aubert, G., Arnaldi, G., Giacchetti, G., Boscaro, M., Grossman, A. B., Korbonits M. AMP‐activated protein kinase mediates glucocorticoidinduced metabolic changes: a novel mechanism in Cushings syndrome. FASEB J. 22, 1672–1683 (2008)

Adrenal Incidentaloma: An Overview of Hormonal Data from the National Italian Study Group

Adrenal masses are more and more frequently detected by adrenal ultrasound, computed tomography or nuclear magnetic resonance carried out for a reason other than the suspicion of adrenal disease (incidentalomas). The findings of an incidentaloma still leaves many diagnostic and therapeutic questions open. We report the results of a multicentric retrospective evaluation of patients with adrenal incidentalomas, performed by a Study Group of the Italian Society of Endocrinology. According to the definition of incidentaloma, exclusion criteria a priori were: severe or paroxysmal hypertension, frank hypokalemia and clinical signs of hypercortisolism or hyperandrogenism. 29 centers participated in the study and the data obtained by questionnaire were collected in 2 centers for final elaboration. Center 1 carried out the epidemiological and clinical evaluation. Basal and dynamic hormonal evaluation of 786 among the 1013 cases recruited were performed in our center (center 2). Functional studies included: diurnal rhythm of cortisol, urinary free cortisol (UFC), ACTH, DHEAS, 17-OH progesterone, testosterone, androstenedione, supine and upright plasma renin activity (PRA) and aldosterone, urinary aldosterone, urinary catecholamines and VMA. The hormonal dynamic evaluation included the overnight dexamethasone suppression test (1 mg), CRH test and ACTH test. In our study, 89% (702 patients) of adrenal incidentalomas were non-hypersecretory masses; 6.2% (49 patients) showed a preclinical Cushings syndrome (PCS) (at least two altered parameters of pituitary-adrenal axis); 3.4% (27 patients) were pheochromocytomas; 0.89% (7 patients) were aldosteronomas. One tumor was a masculinizing adrenocortical carcinoma. Two hundred sixty patients underwent surgical exploration and the histological diagnosis showed: 138 adenomas (53%), 32 carcinomas (12%), 26 pheochromocytomas (10%). 16 myelolipomas (8%), 13 cystic lesions (5.5%), 7 tumors of neuronal lineage (3%). 12 metastases (4%), 13 others (5%). The 138 patients with adenomas had the following hormonal diagnosis: 103 nonfunctional adenomas (74%), 31 PCS (23%) and 4 cases of hyperaldosteronism (3%). In the patients with PCS an abnormal dexamethasone suppression test was found in 86% of cases (37/41 patients). Values for ACTH were low in 78% (32/41 patients). UFC was elevated in 64% of patients, the diurnal rhythm of cortisol evaluated in 14 patients was absent in 7. Only in 50% of cases DHEAS values (12/24 patients) were decreased, whereas they were normal in the other 50%. Interestingly, 8 patients with normal DHEAS and normal UFC showed nonsuppressible cortisol by dexamethasone test (1 mg). Blunted ACTH response to CRH was detected in 9 of 14 patients (64%). Thus our data suggest that the best parameter for evaluating subclinical hypercortisolism seems to be the overnight dexamethasone suppression test. In 27 patients with pheochromocytoma 24-hour urinary catecholamine and VMA levels were elevated in 86 and 46% of cases respectively. In 7 patients with hyperaldosteronism upright PRA was suppressed in 100% of cases and aldosterone plasma levels were elevated in 6 patients (86%); serum potassium level was slightly decreased in 60% of cases. In 86 of 138 histologically proven adenomas, DHEAS levels were: normal in 59% of patients, decreased in 36% and elevated in 4.6%, whereas in 22 of 32 cortical carcinomas evaluated. DHEAS levels were normal in 63% of cases, decreased in 18% and elevated 18%. Post-ACTH 17-OH progesterone levels were elevated in 52% (62/118 patients) of non-functioning adenomas and in 2 of 4 carcinomas. Not enough data are yet available postoperatively. In summary, endocrine evaluation can lead to the identification of a nonnegligible number of cases of clinically unsuspected pheochromocytomas and subtle hypercortisolism (about 3.4 and 6.2%, respectively of all adrenal incidentalomas), while cases of primary subclinical aldosteronism are rarely found. (ABSTRACT TRUNCATED)

Cardiovascular Risk In Cushing's Syndrome

Chronic cortisol hypersecretion causes central obesity, hypertension, insulin resistance, dyslipidemia, protrombotic state, manifestations which form a metabolic syndrome in all patients with Cushings syndrome. These associated abnormalities determine an increased cardiovascular risk not only during the active phase of the disease but also long after the “biomedical remission”. Clinical management of these patients should be particularly careful in identifyin global cardiovascular risk. Considering that remission from hypercortisolism is often difficult to achieve care and controlof all cardiovascular risk factors should be one of the primary goals during the follow up of these patients. Extending theindications of the recent consensus on Cushings syndrome, we suggest to carry out an OGTT to avoid underestimation of diabetes mellitus, an echocardiography and Doppler ultrasonography of the epiaortic vessels in all patients at diagnosisand during follow-up.

Pathophysiology of dyslipidemia in Cushing's syndrome.

Dyslipidemia seems to be less frequent than other metabolic comorbidities in human Cushing’s syndrome. Nevertheless, it plays an important role in determining the global cardiovascular risk in overt and subclinical Cushing’s syndrome. In Cushing’s syndrome, there is an increase of triglyceride and total cholesterol levels whereas HDL can be at variable levels. Overt and subclinical Cushing’s syndrome share many features with metabolic syndrome including insulin resistance, abnormal fasting glucose levels, hypertension, obesity and dyslipidemia. The pathogenetic mechanisms are multifactorial, including direct and indirect cortisol action on lipolysis, free fatty acid production and turnover, very-low-density lipoprotein synthesis and fatty accumulation in the liver. AMP-activated protein kinase mediates many of glucocorticoid-induced metabolic changes. Insulin resistance plays a key role in determining lipid abnormalities. Other hormonal changes are involved including growth hormone, testosterone in men and estrogen in women, catecholamines and cytokines. In vitro, cortisol increases lipoprotein lipase in adipose tissues and particularly in visceral fat where lipolysis is activated, resulting in the release of free fatty acids into the circulation. The increase of free fatty acids may enhance the accumulation of hepatic lipids reducing glucose uptake and activating various serine kinases which results in decreased insulin signaling. Moreover, mice with a liver-specific disruption of the glucocorticoid receptor had diminished hepatic triglycerides levels. In humans, a high prevalence (up to 20%) of hepatic steatosis was also reported in patients with Cushing’s syndrome. Genetic variations in the glucocorticoid receptors may also affect the activity of cortisol, lipid metabolism and cardiovascular risk.

Changes in Adenosine 5-Monophosphate-Activated Protein Kinase as a Mechanism of Visceral Obesity in Cushing's Syndrome

OBJECTIVE Features of the metabolic syndrome such as central obesity with insulin resistance and dyslipidemia are typical signs of Cushings syndrome and common side effects of prolonged glucocorticoid treatment. AMP-activated protein kinase (AMPK), a key regulatory enzyme of lipid and carbohydrate metabolism as well as appetite, is involved in the development of the deleterious metabolic effects of excess glucocorticoids, but no data are available in humans. In the current study, we demonstrate the effect of high glucocorticoid levels on AMPK activity of human adipose tissue samples from patients with Cushings syndrome. METHODS AMPK activity and mRNA expression of genes involved in lipid metabolism were assessed in visceral adipose tissue removed at abdominal surgery of 11 patients with Cushings syndrome, nine sex-, age-, and weight-matched patients with adrenal incidentalomas, and in visceral adipose tissue from four patients with non-endocrine-related abdominal surgery. RESULTS The patients with Cushings syndrome exhibited a 70% lower AMPK activity in visceral adipose tissue as compared with both incidentalomas and control patients (P = 0.007 and P < 0.001, respectively). Downstream targets of AMPK fatty acid synthase and phosphoenol-pyruvate carboxykinase were up-regulated in patients with Cushings syndrome. AMPK activity was inversely correlated with 0900 h serum cortisol and with urinary free cortisol. CONCLUSIONS Our data suggest that glucocorticoids inhibit AMPK activity in adipose tissue, suggesting a novel mechanism to explain the deposition of visceral adipose tissue and the consequent central obesity observed in patients with iatrogenic or endogenous Cushings syndrome.

Bone mineral density in acromegaly: the effect of gender, disease activity and gonadal status

objective Data on bone mineral density (BMD) in acromegaly are conflicting as most previous studies collectively evaluated eugonadal and hypogonadal patients of both sexes, with or without active disease. We have evaluated BMD in 152 acromegalic patients of both sexes with varying disease activity and gonadal status.