Carla Scaroni

Prevalence of AIP mutations in a large series of sporadic Italian acromegalic patients and evaluation of CDKN1B status in acromegalic patients with multiple endocrine neoplasia

BACKGROUNDnGermline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene and the p27(KIP1) encoding gene CDKN1B have been associated with two well-defined hereditary conditions, familial isolated pituitary adenoma (FIPA) and multiple endocrine neoplasia type 4 (MEN4). Somatotropinomas are present in most AIP mutated FIPA kindreds, as well as in two-thirds of MEN4 patients who carry pituitary tumors.nnnMETHODSnGermline DNA samples of 131 Italian sporadic acromegalic patients including 38 individuals with multiple tumors, and of six FIPA families (four homogeneous for prolactinomas and two heterogeneous with prolactin/nonfunctioning pituitary adenomas) were collected in a multicentric collaborative study. The prevalence of AIP and CDKN1B gene point mutations and copy number variations were evaluated.nnnRESULTSnTwo novel (IVS3+1G>A and c.871G>A) and one previously described (c.911G>A) AIP mutations were detected in four apparently sporadic cases (3.1%) with relatively high age at diagnosis (49+/-18, range 30-67). No mutations/rearrangements were detected in FIPA families. The highly conserved c.871G>A substitution was detected in a patient who also carried a MEN1 mutation suggesting that she is a double heterozygote. The possible pathogenic effect on AIP splicing of the silent substitution c.144G>A found in another patient was ruled out using a minigene-based approach. CDKN1B mutations/rearrangements were neither identified in patients with multiple neoplasia nor in FIPA families.nnnCONCLUSIONnAIP is mutated in about 3% of apparently sporadic acromegalic patients. The relatively high age at diagnosis, as well as its sporadic presentation, suggests that these patients are carriers of mutations with reduced pathogenicity. p27(KIP1) is unlikely to represent the common unifying nonendocrine etiology for acromegaly and cancer.

AHR Over-Expression in Papillary Thyroid Carcinoma: Clinical and Molecular Assessments in a Series of Italian Acromegalic Patients with a Long-Term Follow-Up

Aim Acromegaly reportedly carries an increased risk of malignant and benign thyroid tumors, with a prevalence of thyroid cancer of around 3–7%. Germline mutations in the aryl-hydrocarbon receptor (AHR) interacting protein (AIP) have been identified in familial forms of acromegaly. The molecular and endocrine relationships between follicular thyroid growth and GH-secreting pituitary adenoma have yet to be fully established. Our aim was to study the prevalence of differentiated thyroid cancer (DTC) in acromegaly, focusing on the role of genetic events responsible for the onset of thyroid cancer. Methods Germline mutations in the AIP gene were assessed in all patients; BRAF and H-N-K RAS status was analyzed by direct sequencing in thyroid specimens, while immunohistochemistry was used to analyze the protein expression of AIP and AHR. A set of PTCs unrelated to acromegaly was also studied. Results 12 DTCs (10 papillary and 2 follicular carcinomas) were identified in a cohort of 113 acromegalic patients. No differences in GH/IGF-1 levels or disease activity emerged between patients with and without DTC, but the former were older and more often female. BRAF V600E was found in 70% of the papillary thyroid cancers; there were no RAS mutations. AIP protein expression was similar in neoplastic and normal cells, while AHR protein was expressed more in PTCs carrying BRAF mutations than in normal tissue, irrespective of acromegaly status. Conclusions The prevalence of DTC in acromegaly is around 11% and endocrinologists should bear this in mind, especially when examining elderly female patients with uninodular goiter. The DTC risk does not seem to correlate with GH/IGF-1 levels, while it may be associated with BRAF mutations and AHR over-expression. Genetic or epigenetic events probably play a part in promoting thyroid carcinoma.

The role of an acute pasireotide suppression test in predicting response to treatment in patients with Cushing's disease: findings from a pilot study

Pasireotide is a multireceptor-targeted somatostatin analog effective in the treatment of Cushing’s disease (CD). We evaluate the value of an acute pasireotide suppression test (PST) in predicting response to medium/long-term treatment in CD. Nineteen patients with active CD were prospectively investigated at two referral centers from May 2013 to August 2014. Follow-up data (median 6xa0months; range 1–9xa0months) were available for sixteen patients. All patients received at 09:00xa0h a single subcutaneous (sc) injection of 600xa0μg pasireotide. Serum cortisol and plasma ACTH were assessed before, and every 2xa0h for 8xa0h after, drug administration. Late-night salivary cortisol (LNSC) was assessed before and after pasireotide administration. After acute PST, all patients were continued on pasireotide 600xa0μg sc twice a day. During PST, cortisol and ACTH levels quickly decreased in all patients except one with a mean percentage fall, respectively, of 48.9xa0±xa024.3 and 48.1xa0±xa025.4xa0% compared to baseline. LNSC decreased in about 82xa0% of patients (14/17) achieving a normalization in five of them. Pasireotide treatment was associated with a normalization of 24-h urinary-free cortisol at last follow-up in about 68xa0% of patients. A fall >27xa0% of LNSC during PST calculated by ROC curve was the best parameter in predicting a positive response to treatment with pasireotide (sensitivity 91xa0%; specificity 100xa0%; positive predictive value 100xa0%; negative predictive value 75xa0%). Acute PST may be useful to identify CD patients who will benefit from pasireotide treatment. A LNSC fall >27xa0% as well as a LNSC normalization during PST is associated with a probability of 100xa0% of achieving a favorable response to pasireotide treatment in the medium/long term.

First-line screening tests for Cushing's syndrome in patients with adrenal incidentaloma: the role of urinary free cortisol measured by LC-MS/MS.

Introduction and aimPatients with adrenal incidentaloma present a wide range of cortisol secretion, which is not always properly defined by first-line screening tests recommended to rule out Cushing’s syndrome (CS), such as 1-mg dexamethasone suppression test (1-mg DST), late night salivary cortisol (LNSC), or 24-h urinary free cortisol (UFC). Therefore, we examined the diagnostic performance of each screening test in patients with adrenal incidentaloma.Materials and methodsIn a series of 164 consecutive patients with adrenal incidentaloma, we measured serum cortisol after 1-mg DST, LNSC, and UFC (with LC-MS/MS). Medical history was investigated for cardiovascular events (CVE) in a subgroup of 93 patients with at least 2 years of follow-up.ResultsSerum cortisol <50xa0nmol/L after 1-mg DST presented the highest sensitivity (100%) to rule out CS, despite a low specificity (62%). UFCu2009>u2009170xa0nmol/24xa0h achieved the highest diagnostic accuracy (sensitivity 98%, specificity 91%, and negative/positive likelihood ratios of 0.02/10.83, respectively). The prevalence of CVE was higher in patients with non-suppressed cortisol after 1-mg DST and high UFC levels (pu2009=u20090.018). Traditional cardiovascular risk factors (hypertension, diabetes mellitus, dyslipidemia, BMIu2009>u200930xa0kg/m2, smoke or high gender-based waist circumference) were not associated with CVE.ConclusionsThe 1-mg DST at its lowest threshold presented high sensitivity in identifying CS, but its low specificity encourages us to consider UFC levels, measured with LC-MS/MS, to reduce false-positive test results. High UFC levels could also be considered as markers to stratify cardiovascular risk in patients with adrenal incidentaloma.

Sleep apnea syndrome in endocrine clinics.

Obstructive sleep apnea syndrome (OSAS) is a chronic condition with a high prevalence (up to 7xa0% of the general population) characterized by frequent episodes of upper airway collapse while sleeping. Left untreated, OSAS can cause severe complications, including systemic hypertension, cardiovascular disease, stroke, and abnormal glucose metabolism. This review aims to summarize the close links between OSAS, endocrinology, and metabolism. In patients with metabolic syndrome, OSAS is an independent risk factor for the onset of type 2 diabetes and a worsening glycemic control. The accumulation of adipose tissue in the neck and limited chest wall dynamics, hypoxia, and local micro-inflammation link visceral obesity closely with OSAS. There is now an abundance of convincing data indicating that promoting lifestyle changes, improving sleep hygiene, and adjusting diet can ameliorate both metabolic syndrome and OSAS, especially in obese patients. The incidence of OSAS in acromegaly is high, though GH treatments seem to be unrelated to the onset of apnea in GH-deficient individuals. Prospective studies have suggested an association between hypertension and OSAS because intermittent nocturnal hypoxia prompts an increase in sympathetic tone, endothelial dysfunction, and vascular inflammation: aldosterone excess may have a pathophysiological role, and some authors have reported that treating OSAS leads to a modest, but significant, reduction in blood pressure.

Medical Treatment for Acromegaly does not Increase the Risk of Central Adrenal Insufficiency: A Long-Term Follow-Up Study

Central adrenal insufficiency (CAI) in acromegaly may be related to pituitary adenoma or induced by various medical treatments, transsphenoidal neurosurgery (TNS) or radiotherapy (RT), alone or combined. We assessed the role of all available treatments for acromegaly in inducing CAI. We retrospectively studied 97 patients. CAI was diagnosed if morning serum cortisol was <138u2009nmol/l, or if its response was inadequate in the low-dose short synacthen test. Seventy-four subjects underwent TNS (and 17 of whom also underwent RT), and 23 were on primary medical therapy: overall we diagnosed 21 cases of CAI. Duration of acromegaly, invasion of cavernous sinus, disease control, and type of medical treatment were much the same for patients with and without CAI, which was identified in 18% of patients (10/57) after one TNS, and in 53% (9/17) after RT (p=0.01); repeat surgery increased the risk of CAI (p=0.02). The risk of CAI onset during the follow-up was lower among patients treated with TNS or medical therapy than after RT (p=0.035). Medical treatment did not raise the risk of CAI, whereas a 5- and 4-fold higher risk of CAI was associated with repeat TNS and RT, respectively. Basal or stimulated cortisol levels were similar among acromegalic patients without CAI and matched controls with nonsecreting pituitary lesions. A significant proportion of patients with acromegaly developed CAI over time. While primary or secondary medical treatment did not contribute to the risk of CAI, repeat TNS and RT correlated with pituitary-adrenal axis impairment.

Sindromi cliniche surrenaliche riferibili a recettori illeciti

SommarioLa regolazione della produzione di cortisolo o di aldosterone quando l’ACTH o il sistema renina angiotensina sono soppressi, è stato motivo di numerosi studi negli ultimi anni. Questo ha permesso d’identificare la presenza di recettori accoppiati alla proteina G (GPCRs) che, espressi in modo aberrante o illecito sul tessuto tumorale, mimano gli eventi cellulari che sono normalmente innescati dagli stimoli fisiologici. Inoltre, è stata un’opportunità d’identificare nuove opzioni terapeutiche mediante l’utilizzo di antagonisti dei recettori o l’inibizione del peptide coinvolto.

Pasireotide treatment reduces cardiometabolic risk in Cushing’s disease patients: an Italian, multicenter study

PurposePatients with Cushing’s disease (CD) experience metabolic alterations leading to increased cardiovascular mortality. Recently, the visceral adiposity index (VAI) has been proposed as a marker of visceral adipose tissue dysfunction (ATD) and of the related cardiometabolic risk. We aimed to evaluate the impact of 12-month pasireotide treatment on cardiometabolic risk in CD patients.MethodsThis is a multicentre, prospective, and observational study. Sixteen CD patients, referred to the Endocrine Units of the University Hospitals of Messina, Napoli, Padova, and Palermo (Italy), successfully treated with pasireotide for 12 month have been enrolled. In all patients, we assessed anthropometric, clinical, and biochemical parameters and calculated VAI, ATD severity, Framingham, and atherosclerotic cardiovascular disease (ASCVD) risk scores, before and after 6 and 12 months of treatment with pasireotide (1200–1800 mcg/daily).ResultsBefore starting pasireotide treatment, ATD was present in 7/16 patients (mild in 2/16, moderate in 3/16, and severe 2/16). After 12 months of treatment: (i) 24h-urinary free cortisol levels (pu2009=u20090.003), BMI (pu2009<u20090.001), waist circumference (pu2009=u20090.001), LDL-cholesterol (pu2009=u20090.033), total-cholesterol (pu2009=u20090.032), triglycerides (pu2009=u20090.030), VAI (pu2009=u20090.015), and ATD severity (pu2009=u20090.026) were significantly decreased as compared to baseline; (ii) ATD was present in only 1/16 patients; (iii) prevalence of diabetes mellitus (pu2009=u20090.015) and HbA1c levels (pu2009=u20090.001) were significantly increased as compared to baseline; (iv) Framingham and ASCVD risk scores were not significantly different from pre-treatment values.ConclusionsTwelve-month pasireotide treatment significantly reduces VAI and ATD in CD patients. These positive effects on cardiometabolic risk occur despite no change in Framingham and ASCVD risk scores and the increase in the prevalence of diabetes mellitus.

Il trauma cranico e l’emorragia subaracnoidea sono condizioni ad alto rischio di ipopituitarismo: valutazione a 3 mesi dopo danno cerebrale

RiassuntoL’ipopituitarismo acquisito nei soggetti adulti è ovviamente sospettato in pazienti con patologia primitiva della regione ipotalamo-ipofisaria, particolarmente dopo neurochirurgia e/o radioterapia. Il trauma cranio-encefalico è inserito tra le cause di ipopituitarismo. Tuttavia la valutazione neuroendocrina non è inclusa di routine nel monitoraggio di questi pazienti. Scopo di questo studio è quello di chiarire la prevalenza di ipopituitarismo dopo trauma cranico (TBI) o emorragia subaracnoidea (SAH) a 3 mesi dall’evento acuto. A tale scopo sono stati arruolati in uno studio multicentrico 140 soggetti a 3 mesi dall’evento acuto [TBI, n=100, 31 donne, 69 uomini; età: 37,1±1,8 anni; indice di massa corporea (BMI) 23,7±0,4 kg/m2; Glasgow Coma Scale (GCS) 3–15;SAH, n=40, 14 uomini, 26 donne, età: 51,0±2,0 anni; BMI: 25,0±0,6 kg/m2; Fisher’s scale 1–4]. Tutti i pazienti sono stati sottoposti ad un’ampia valutazione ormonale basale; l’asse GH/IGF-I è stato valutato mediante test al GHRH+Arginina e dosaggio dell’IGF-I. Il 25–30% dei pazienti traumatizzati in età adulta presentava gradi diversi di ipopituitarismo. In particolare il 4, 6 ed il 25% dei pazienti presentava un deficit totale, multiplo ed isolato, rispettivamente. Il diabete insipido era presente nel 4%. Ipocorticosolismo, ipotiroidismo ed ipogonadismo secondari erano presenti nell’ 8,5 e 17%, rispettivamente. Il deficit di GH grave (GHD) era il più frequente dei deficit ipofisari (25%). Nel 37,5% dei pazienti con SAH erano presenti gradi diversi di ipopituitarismo. Benché nessun caso di ipopituitarismo totale era presente in questa popolazione, deficit multipli ed isolati erano presenti nel 10 e 27,5%, rispettivamente. Il diabete insipido era presente nel 7,5%. Ipocorticosolismo, ipotiroidismo ed ipogonadismo secondari erano presenti nel 2,5, 7,5 e 12,5%, rispettivamente. Anche in questa popolazione il deficit di GH grave era il più frequente (25%). Il TBI e la SAH sono condizioni associate ad un alto rischio di ipopituitarismo acquisito. L’ipopituitarismo è spesso multiplo ed il deficit di GH grave è quello più frequente. Pertanto una valutazione neuroendocrina è sempre necessaria in pazienti dopo danno cerebrale.