Antonio Stefano Salcuni

Beneficial Metabolic Effects of Prompt Surgical Treatment in Patients with an Adrenal Incidentaloma Causing Biochemical Hypercortisolism

CONTEXT In patients with adrenal incidentalomas, subclinical hypercortisolism (SH) is associated with an increased prevalence of the metabolic syndrome. The effect of surgical/conservative approach is debated. OBJECTIVE The objective of the study was to determine the effect of the surgical and conservative approaches on the metabolic syndrome in patients with adrenal incidentalomas. DESIGN This was a retrospective longitudinal study (18-48 months follow-up). SETTING The study was conducted on an in- and outpatient basis. PATIENTS One hundred eight patients with adrenal incidentalomas were studied for the presence of SH, which was diagnosed in the presence of more than two of the following: urinary free cortisol greater than 70 microg per 24 h (193 nmol per 24 h), cortisol after 1 mg dexamethasone suppression test greater than 3.0 microg/dl (83 nmol/liter), ACTH less than 10 pg/ml (2.2 pmol/liter). INTERVENTIONS Surgery was performed in 25 patients with SH (group TrSH+) and 30 without SH (group TrSH-), whereas the conservative approach was chosen by 16 patients with SH (group UntrSH+) and 37 without SH (group UntrSH-). MAIN OUTCOME MEASURES During the follow-up, the improvement/worsening of body weight, blood pressure, or glucose and cholesterol levels was defined in the presence of a greater than 5% weight decrease/increase and following the European Society of Cardiology or the Adult Treatment Panel III criteria, respectively. RESULTS In group TrSH+, weight, blood pressure, and glucose levels improved (32, 56, and 48%, respectively) more frequently than in group UntrSH+ (12.5%, P = 0.05; 0.0%, P < 0.0001; 0.0%, P = 0.001; and 0.0%, P = 0.0014, respectively). In group UntrSH+, blood pressure, glucose, and low-density lipoprotein levels worsened more frequently (50.0, 37.5, and 50.0%, respectively) than in group TrSH+ (0.0%, P < 0.0001; 0.0%, P = 0.001; and 20.0%, P = 0.05, respectively). CONCLUSIONS Regarding the various components of the metabolic syndrome, in patients with adrenal incidentalomas and SH, surgery is beneficial.

Long-term follow-up in adrenal incidentalomas: an Italian multicenter study

CONTEXT The long-term consequences of subclinical hypercortisolism (SH) in patients with adrenal incidentalomas (AIs) are unknown. SETTING AND PATIENTS In this retrospective multicentric study, 206 AI patients with a ≥5-year follow-up (median, 72.3 mo; range, 60-186 mo) were enrolled. INTERVENTION AND MAIN OUTCOME MEASURES Adrenocortical function, adenoma size, metabolic changes, and incident cardiovascular events (CVEs) were assessed. We diagnosed SH in 11.6% of patients in the presence of cortisol after a 1 mg-dexamethasone suppression test >5 μg/dL (138 nmol/L) or at least two of the following: low ACTH, increased urinary free cortisol, and 1 mg-dexamethasone suppression test >3 μg/dL (83 nmol/L). RESULTS At baseline, age and the prevalence of CVEs and type 2 diabetes mellitus were higher in patients with SH than in patients without SH (62.2 ± 11 y vs 58.5 ± 10 y; 20.5 vs 6%; and 33.3 vs 16.8%, respectively; P < .05). SH and type 2 diabetes mellitus were associated with prevalent CVEs (odds ratio [OR], 3.1; 95% confidence interval [CI], 1.1-9.0; and OR, 2.0; 95% CI, 1.2-3.3, respectively), regardless of age. At the end of the follow-up, SH was diagnosed in 15 patients who were without SH at baseline. An adenoma size >2.4 cm was associated with the risk of developing SH (sensitivity, 73.3%; specificity, 60.5%; P = .014). Weight, glycemic, lipidic, and blood pressure control worsened in 26, 25, 13, and 34% of patients, respectively. A new CVE occurred in 22 patients. SH was associated with the worsening of at least two metabolic parameters (OR, 3.32; 95% CI, 1.6-6.9) and with incident CVEs (OR, 2.7; 95% CI, 1.0-7.1), regardless of age and follow-up. CONCLUSION SH is associated with the risk of incident CVEs. Besides the clinical follow-up, in patients with an AI >2.4 cm, a long-term biochemical follow-up is also required because of the risk of SH development.

Bone involvement in aldosteronism

In rats with aldosteronism, a reduction of bone mineral density (BMD) and cortical bone strength has been reported. Our study was aimed to evaluate bone involvement in patients with primary aldosteronism (PA). A total of 188 consecutive subjects with adrenal incidentaloma, observed between November 2009 and October 2011, were screened for PA with aldosterone‐to‐renin ratio. After confirmatory tests, in those who screened positive, 11 patients were diagnosed as PA and 15 patients were not (nPA). A serum/urinary biochemical profile, parathyroid hormone (PTH), BMD measured at lumbar spine (LS) and total and femoral neck (TN and FN) by dual X‐ray absorptiometry, and conventional spinal radiographs (T4–L4) were obtained in all subjects. PA patients had a significantly higher 24‐hour urinary calcium (6.28 ± 1.85 versus 4.28 ± 1.18 mmol/d; p < 0.01), and PTH (9.8 [5.8‐14.6], median [range] versus 5.3 [2.5‐10.8] pmol/L; p < 0.01) than nPA patients. BMD expressed as Z‐value at LS (−1.18 ± 0.99 versus 0.22 ± 1.12), FN (−0.85 ± 0.73 versus 0.01 ± 0.82), and TN (−0.49 ± 0.61 versus 0.39 ± 0.93) was lower in PA than in nPA (p = 0.003, p = 0.011, and p = 0.012, respectively). The prevalence of osteoporosis was higher in PA than in nPA (8/11, 72.7% versus 3/15, 20.0%; Fishers exact test: p = 0.015). Vertebral fractures tended to be more prevalent in PA than in nPA (5/11, 45.5% versus 2/15, 13.3%; Fishers exact test: p = 0.095). Logistic regression analysis showed that osteoporosis and morphometric vertebral fractures were associated with PA (odds ratio [OR], 15.4; 95% confidence interval [CI] = 1.83–130, p = 0.012; and OR, 30.4; 95%CI, 1.07–862, p = 0.045, respectively) regardless of age, body mass index (BMI), and LS‐BMD. In 9 of 11 PA patients, 6 months after beginning of treatment (surgery or spironolactone) there was a significant reduction of urinary calcium excretion (p < 0.01) and PTH (p < 0.01), whereas in 5 of 11 PA patients, 1 year after beginning of treatment, BMD was significantly increased at LS, p < 0.01). In conclusion, PA is associated with osteoporosis, vertebral fractures, and increased urinary calcium excretion.

Factors associated with vertebral fracture risk in patients with primary hyperparathyroidism

OBJECTIVE To examine factors, in addition to bone mineral density (BMD), such as the common calcium-sensing receptor (CASR) gene polymorphisms, associated with vertebral fracture (VFx) risk in primary hyperparathyroidism (PHPT). DESIGN AND METHODS A cross-sectional analysis of 266 Caucasian PHPT seen as outpatients. Serum calcium (sCa) phosphate metabolism parameters were measured. BMD was assessed by dual-energy X-ray absorptiometry (expressed as Z-score) at lumbar spine (Z-LS) and femoral neck, morphometric VFx by radiograph, and CASR A986S/R990G genotypes by PCR amplification and genomic DNA sequencing. RESULTS Fractured patients (n=100, 37.6%) had lower sCa (10.8±0.7 mg/dl) and Z-LS BMD (-1.0±1.44), higher age (61±10 years), and prevalence (51%) of ≥1 S alleles of the CASR A986S single-nucleotide polymorphism (SNP; AS/SS), than those not fractured (n=166, 11.2±1.0 mg/dl, -0.57±0.97, 58±13 years, and 38% AS/SS, respectively, P<0.05 for all comparisons). Logistic regression, with VFx as dependent variable, showed independent risks associated with increased age (OR 1.03, 95% CI 1.01-1.06, P=0.006), decreased sCa (OR 1.86, 95% CI 1.28-2.7, P=0.001), and Z-LS BMD (OR 1.4, 95% CI 1.12-1.7, P=0.002) and presence of AS/SS (OR 1.8, 95% CI 1.1-2.9, P=0.05). The presence of two out of three factors (age ≥58 years, sCa <10.8 and Z-LS BMD≤-1.0, and AS/SS genotype) gave an overall OR of 4.2 (95% CI 2.25-7.85, P<0.0001). CONCLUSIONS In PHPT, VFx is associated positively with age, negatively with sCa and spinal BMD, and presence of at least one copy of the CASR A986S SNP.

Increased Prevalence of the GCM2 Polymorphism, Y282D, in Primary Hyperparathyroidism: Analysis of Three Italian Cohorts

CONTEXT Glial cells missing-2 (GCM2) is key for parathyroid gland organogenesis. Its persistent expression in the adult parathyroid raises the possibility that overactive forms play a role in the evolution of parathyroid hyperactivity or tumorigenesis. A GCM2 c.844T → G; p.Y282D missense variant has been described within a transactivation inhibitory domain (amino acids 263-352). OBJECTIVE The aims of the study were to 1) assess the frequency of Y282D in Italian primary hyperparathyroidism (PHPT) and control (C) populations, 2) test for association of 282D with PHPT and its phenotypic features, and 3) compare the transactivation potency of GCM2 282D relative to wild-type Y282. SUBJECTS AND METHODS Subjects included a large southern Italian cohort (310 PHPT and 433 C) and 2 replication cohorts from northern Italy. Association of 282D with PHPT was tested in all cohorts and with phenotypic features in the larger PHPT cohort. An in vitro GCM promoter-luciferase reporter assay was conducted in HEK293 cells. RESULTS 282D was significantly increased in the PHPT group, with a minor allele frequency of 0.066 compared with 0.029 in the C group (P = .0008), in the discovery cohort and was more prevalent in the replication cohorts. Combined analysis (510 PHPT and 665 C) yielded a likelihood ratio of 2.27 (95% confidence interval = 1.50-3.42; P < .0001). The 282D variant was not associated with serum calcium, phosphate, creatinine, or PTH levels or with bone mineral density, fractures, or renal stones in the PHPT group. The 282D variant had significantly greater transcriptional activity than the wild-type Y282 (17× basal vs 12× basal; P < 0.05). CONCLUSION The higher frequency of GCM2 282D in PHPT and enhanced transcriptional activity of this variant supports the notion that it could contribute causally to parathyroid tumorigenesis.

Primary aldosteronism as a cause of secondary osteoporosis

OBJECTIVE Patients with primary aldosteronism (PA) have a high prevalence of osteoporosis (OP) and fractures (Fx). We evaluated the presence of PA in patients admitted to our metabolic bone disease outpatient clinic. DESIGN Study conducted on an in- and outpatient basis in a referral Italian endocrinology unit. METHODS A total of 2632 patients were evaluated. 2310 were excluded because they were taking drugs known to affect bone or mineralocorticoids metabolism or were diagnosed to have a secondary cause of osteoporosis. The remaining 322 subjects (304 females, 18 males) took part in the study. Bone mineral density (BMD) and thoracic and lumbar spine vertebral morphometry were performed by dual X-ray absorptiometry. All patients were screened for PA with aldosterone-to-renin ratio. In those who had positive results, confirmatory tests were performed. RESULTS Among 322 subjects, 213 were osteoporotics and 109 were not. PA was diagnosed in eleven out of 213 osteoporotic patients (5.2%) and one out of 109 non-osteoporotic subjects (0.9%, P = 0.066). PA was observed in the 26.1% of patients with the concomitant presence of osteoporosis, hypertension and hypercalciuria. Compared with patients without PA, patients with PA had mean values of urinary calcium excretion, 4.8 ± 2.5 mmol/day vs 7.6 ± 3.2 mmol/day, P < 0.001 and serum PTH levels, 5.4 pmol/L vs 7.3 pmol/L, P < 0.01, significantly higher. CONCLUSIONS PA should be considered among the causes of secondary OP.

MEN1 gene mutation with parathyroid carcinoma: first report of a familial case

Background The occurrence of parathyroid carcinoma in multiple endocrine neoplasia type I (MENI) is rare and the 15 cases of malignant parathyroid tumor reported so far have been associated with MENI in individuals and not with multiple members within a family. Methods We report on a 61-year-old male, operated for a 7.3 cm parathyroid carcinoma infiltrating the esophagus. In his brother, a 4.6 cm parathyroid carcinoma was diagnosed histologically, while in the daughter, neck ultrasonography revealed 2 extrathyroidal nodules, yet to be excised. Results Screening of the MEN1 gene identified a known germline heterozygous missense mutation (c.1252G>A; p.D418N) in exon 9, in all affected subjects. Conclusions The occurrence of parathyroid carcinoma in more than one affected member of a single MEN1 family represents the first reported familial case. This suggests that additional constitutional genetic mutations may contribute to the variation in malignant potential and clinical behavior of parathyroid tumors in MEN1.

Il carcinoma delle paratiroidi

SommarioIl carcinoma (K) delle paratiroidi è una patologia maligna rara che può presentarsi in modo sporadico o essere parte di una sindrome genetica. Il quadro clinico è generalmente caratterizzato dai segni e sintomi dell’ipercalcemia e, più raramente, dall’effetto massa della lesione. In genere è funzionante, anche se sono state descritte forme non secernenti. Distinguere in base alle caratteristiche cliniche e biochimiche tra lesione maligna e lesione benigna non è possibile, per cui quando viene posto il sospetto, il trattamento deve essere l’intervento chirurgico di asportazione en bloc della lesione e dell’emitiroide ipsilaterale con consensuale linfoadenectomia del comparto centrale. Questo tipo di intervento, infatti, se effettuato alla diagnosi, dà la più alta probabilità di guarigione. I controlli biochimici e strumentali devono essere effettuati con regolarità e protratti nel tempo per l’elevato rischio, anche dopo molti anni, di recidiva locale e di metastasi a distanza. Questo articolo si focalizzerà su alcuni aspetti clinici e patogenetici della malattia; inoltre, ci darà delle informazioni sul suo trattamento e follow-up.

Long-term follow-up in adrenal incidentalomas: an Italian Multicentre Study

Department of Clinical Sciences and Community Health (V.M., S.P., A.D., M.A., P.B.-P., I.C.), University of Milan, 20122 Milan, Italy; Unit of Endocrinology and Diabetology (V.M., S.P., P.B.-P., I.C.), Fondazione IRCCS Ca Granda-Ospedale Maggiore Policlinico, 20122 Milan, Italy; Division of Internal Medicine I (G.R., M.T.), Ospedale San Luigi, 10043 Orbassano, Italy; Department of Biological and Clinical Sciences (G.R., R.G., M.T.), University of Turin, 10124 Turin, Italy; Catholic University (S.D.C., C.P.), Unit of Endocrinology and Metabolism, 00168 Rome, Italy; Unit of Endocrinology (A.S.S., A.S.), Ospedale “Casa Sollievo della Sofferenza,” IRCCS, 71013 San Giovanni Rotondo, Foggia, Italy; Unit of Endocrine Diseases and Diabetology (A.D., M.A.), Ospedale San Giuseppe, Gruppo Multimedica, 20123 Milan, Italy; Department of Biomedical Sciences for Health (M.M., B.A.), University of Milan, Unit of Endocrinology and Diabetology, IRCCS Policlinico San Donato, 20097 San Donato Milanese, Milan, Italy; and Division of Endocrinology, Diabetology, and Metabolism (E.G.), Department of Medical Sciences, University of Turin, 10124 Turin, Italy