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Cristina Eller-Vainicher, Elisa Cairoli, Volha V Zhukouskaya, Valentina Morelli, Serena Palmieri, Alfredo Scillitani, Paolo Beck-Peccoz and Iacopo Chiodini

Objective

The prevalence of subclinical contributors to low bone mineral density (BMD) and/or fragility fracture is debated. We evaluated the prevalence of subclinical contributors to low BMD and/or fragility fracture in the presence of normal 25-hydroxyvitamin D (25OHVitD) levels.

Design

Prospective observational study.

Methods

Among 1095 consecutive outpatients evaluated for low BMD and/or fragility fractures, 602 (563 females, age 65.4±10.0 years) with apparent primary osteoporosis were enrolled. A general chemistry profile, phosphate, 25OHVitD, cortisol after 1-mg overnight dexamethasone suppression test, antitissue transglutaminase and endomysial antibodies and testosterone (in males) were performed. Serum and urinary calcium and parathyroid hormone levels were also evaluated after 25OHVitD levels normalization. Vertebral deformities were assessed by radiograph.

Results

In total, 70.8% of patients had low 25OHVitD levels. Additional subclinical contributors to low BMD and/or fragility fracture were diagnosed in 45% of patients, with idiopathic hypercalciuria (IH, 34.1%) and primary hyperparathyroidism (PHPT, 4.5%) being the most frequent contributors, apart from hypovitaminosis D. Furthermore, 33.2% of IH and 18.5% of PHPT patients were diagnosed only after 25OHVitD levels normalization. The subclinical contributors to low BMD and/or fragility fracture besides hypovitaminosis D were associated inversely with age (odds ratio (OR) 1.02, 95% CI 1–1.04, P=0.04) and BMI (OR 1.1, 95% CI 1.05–1.17, P=0.0001) and directly with fragility fractures (OR 1.89, 95% CI 1.31–2.73, P=0.001), regardless of BMD.

Conclusions

Subclinical contributors to low BMD and/or fragility fracture besides hypovitaminosis D are present in more than 40% of the subjects with apparent primary osteoporosis. Hypovitaminosis D masks a substantial proportion of IH and PHPT patients.

Free access

Antonio Stefano Salcuni, Valentina Morelli, Cristina Eller Vainicher, Serena Palmieri, Elisa Cairoli, Anna Spada, Alfredo Scillitani and Iacopo Chiodini

Objective

Subclinical hypercortisolism (SH) is associated with increased risk of vertebral fractures (VFx). The effect on bone following recovery from SH is unknown.

Design

Of the 605 subjects consecutively referred for monolateral adrenal incidentalomas (AIs) to our outpatient clinics, 55 SH patients (recruited on the basis of the exclusion criteria) were enrolled. We suggested to all patients to undergo adrenalectomy, which was accepted by 32 patients (surgical group, age 61.3±8.1 years) and refused by 23 patients, who were followed with a conservative management (non-surgical group, age 65.4±7.1 years).

Methods

We diagnosed SH in patients with serum cortisol after 1 mg dexamethasone suppression test (1 mg-DST) >5.0 μg/dl or with greater than or equal to two criteria among 1 mg-DST >3.0 μg/dl, urinary free cortisol >70 μg/24 h and ACTH <10 pg/ml. We assessed: bone mineral density (BMD) at lumbar spine (LS) and femoral neck (as Z-score) by dual-energy X-ray absorptiometry and the VFx presence by X-ray at baseline and at the end of follow up (surgical group 39.9±20.9 months and non-surgical group 27.7±11.1 months).

Results

The LS Z-score (ΔZ-score/year) tended to increase in the surgical group (0.10±0.20) compared with the non-surgical group (−0.01±0.27, P=0.08) and in the former, the percentage of patients with new VFx was lower (9.4%) than in the latter (52.2%, P<0.0001). Surgery in AI patients with SH was associated with a 30% VFx risk reduction (odds ratio 0.7, 95% CI 0.01–0.05, P=0.008) regardless of age, gender, follow up duration, 1 mg-DST, LS BMD, and presence of VFx at baseline.

Conclusion

In patients with monolateral AI and SH, adrenalectomy reduces the risk of VFx.

Free access

Benedetta Masserini, Valentina Morelli, Silvia Bergamaschi, Federica Ermetici, Cristina Eller-Vainicher, Anna Maria Barbieri, Maria Antonia Maffini, Alfredo Scillitani, Bruno Ambrosi, Paolo Beck-Peccoz and Iacopo Chiodini

Objective

The criteria for defining subclinical hypercortisolism (SH) are debated and a real gold standard test or combination of tests is lacking. Recently, late-night salivary cortisol (MSC) has been described as a sensitive and easy-to-perform marker for diagnosing overt hypercortisolism. No data are available on the role of MSC in the diagnosis of SH. The aim of this study was to evaluate the sensitivity and specificity of MSC levels in the diagnosis of SH in patients with adrenal incidentalomas (AI).

Methods

In 103 (females/males, 69/34) patients with AI, MSC levels were studied. One milligram overnight dexamethasone suppression test (DST), urinary-free cortisol (UFC), and ACTH plasma levels were also evaluated. Patients were defined as affected by SH if they showed two of the following criteria: DST>83 nmol/l, ACTH <2.2 pmol/l, and UFC >193 nmol/24 h.

Results

No difference in MSC levels in patients with SH (3.1±3.1 nmol/l) compared with patients without SH (2.2±2.8 nmol/l) was observed. In patients with SH, MSC levels were significantly correlated with DST (r=0.4, P<0.05). Using the cut-off of 5.1 nmol/l, the sensitivity and specificity of MSC levels for diagnosis of SH is 22.7 and 87.7% respectively.

Conclusion

In patients with AI, normal levels of MSC do not exclude SH, whereas high levels may suggest the presence of SH identified by conventional tests. Thus, MSC is not suitable as a screening test, although it may be used in conjunction with other tests as the confirming test in selected patients.

Free access

Valentina Morelli, Serena Palmieri, Andrea Lania, Alberto Tresoldi, Sabrina Corbetta, Elisa Cairoli, Cristina Eller-Vainicher, Maura Arosio, Massimiliano Copetti, Enzo Grossi and Iacopo Chiodini

Background

The independent role of mild autonomous cortisol secretion (ACS) in influencing the cardiovascular event (CVE) occurrence is a topic of interest. We investigated the role of mild ACS in the CVE occurrence in patients with adrenal incidentaloma (AI) by standard statistics and artificial neural networks (ANNs).

Methods

We analyzed a retrospective record of 518 AI patients. Data regarding cortisol levels after 1 mg dexamethasone suppression (1 mg DST) and the presence of obesity (OB), hypertension (AH), type-2 diabetes (T2DM), dyslipidemia (DL), familial CVE history, smoking habit and CVE were collected.

Results

The receiver-operating characteristic curve analysis suggested that 1 mg DST, at a cut-off of 1.8 µg/dL, had the best accuracy for detecting patients with increased CVE risk. In patients with 1 mg-DST ≥1.8 µg/dL (DST+, n = 223), age and prevalence of AH, T2DM, DL and CVE (66 years, 74.5, 25.9, 41.4 and 26.8% respectively) were higher than that of patients with 1 mg-DST ≤1.8 µg/dL (61.9 years, 60.7, 18.5, 32.9 and 10%, respectively, P < 0.05 for all). The CVE were associated with DST+ (OR: 2.46, 95% CI: 1.5–4.1, P = 0.01), regardless of T2DM, AH, DL, smoking habit, gender, observation period and age. The presence of at least two among AH, T2DM, DL and OB plus DST+ had 61.1% sensitivity in detecting patients with CVE. By using the variables selected by ANNs (familial CVE history, age, T2DM, AH, DL and DST+) 78.7% sensitivity was reached.

Conclusions

Cortisol after 1 mg-DST is independently associated with the CVE occurrence. The ANNs might help for assessing the CVE risk in AI patients.

Free access

Cristina Eller-Vainicher, Marcello Filopanti, Serena Palmieri, Fabio Massimo Ulivieri, Valentina Morelli, Volha V Zhukouskaya, Elisa Cairoli, Rosa Pino, Antonella Naccarato, Uberta Verga, Alfredo Scillitani, Paolo Beck-Peccoz and Iacopo Chiodini

Objective

In primary hyperparathyroidism (PHPT), vertebral fractures (VFx) occur regardless of bone mineral density (BMD) and may depend on decreased bone quality. Trabecular bone score (TBS) is a texture measurement acquired during a spinal dual-energy X-ray absorptiometry (DXA). Recently, TBS has been proposed as an index of bone micro-architecture.

Design

We studied 92 PHPT patients (74 females, age 62.1±9.7 years) and 98 control subjects. In all patients at baseline, in 20 surgically treated patients and in 10 conservatively treated patients after 24 months, TBS, spinal (lumbar spine (LS)) and femoral (total hip (TH) and femoral neck (FN)) BMD were assessed by DXA and VFx by spinal radiograph.

Results

PHPT patients had lower TBS (−2.39±1.8) and higher VFx prevalence (43.5%) than controls (−0.98±1.07 and 8.2% respectively, both P<0.0001). TBS was associated with VFx (odds ratio 1.4, 95% CI 1.1–1.9, P=0.02), regardless of LS-BMD, age, BMI and gender, and showed a better compromise between sensitivity (75%) and specificity (61.5%) for detecting VFx than LS-BMD, TH-BMD and FN-BMD (31 and 75%, 72 and 44.2%, and 64 and 65% respectively). In surgically treated patients, TBS, LS-BMD, TH-BMD and FN-BMD increased (+47±44.8,+29.2±34.1,+49.4±48.7 and +30.2±39.3% respectively, all P<0.0001). Among patients treated conservatively, TBS decreased significantly in those (n=3) with incident VFx (−1.3±0.3) compared with those without (−0.01±0.9, P=0.048), while BMD changes were not statistically different (LS 0.3±1.2 vs −0.8±0.9 respectively, P=0.19; TH 0.4±0.8 vs −0.8±1.4 respectively, P=0.13 and FN 0.4±0.9 vs −0.8±1.4 respectively, P=0.14).

Conclusions

In PHPT, bone quality, as measured by TBS, is reduced and associated with VFx and improves after surgery.

Free access

Cristina Eller-Vainicher, Valentina Morelli, Antonio Stefano Salcuni, Claudia Battista, Massimo Torlontano, Francesca Coletti, Laura Iorio, Elisa Cairoli, Paolo Beck-Peccoz, Maura Arosio, Bruno Ambrosi, Alfredo Scillitani and Iacopo Chiodini

Context

It is unknown whether the metabolic effects of the removal of an adrenal incidentaloma (AI) can be predicted by the assessment of cortisol hypersecretion before surgery.

Objective

To evaluate the accuracy of several criteria of hypothalamic–pituitary–adrenal axis activity in predicting the metabolic outcome after adrenalectomy.

Design

Retrospective longitudinal study.

Patients

In 55 surgically treated AI patients (Group 1) before surgery and in 53 nontreated AI patients (Group 2) at the baseline, urinary free cortisol (UFC), cortisol after 1 mg overnight dexamethasone-suppression test (1 mg-DST), ACTH, and midnight serum cortisol (MSC) were measured. In Groups 1 and 2, metabolic parameters were evaluated before and 29.6±13.8 months after surgery and at the baseline and after 35.2±10.9 months respectively.

Main outcome measures

The improvement/worsening of weight, blood pressure, glucose, and cholesterol levels (endpoints) was defined by the presence of a >5% weight decrease/increase and following the European Society of Cardiology or the ATP III criteria respectively. The accuracy of UFC, 1 mg-DST, ACTH, and MSC, singularly taken or in combination, in predicting the improvement/worsening of ≥2 endpoints was calculated.

Results

The presence of ≥2 among UFC>70 μg/24 h (193 nmol/l), ACTH<10 pg/ml (2.2 pmol/l), 1 mg-DST>3.0 μg/dl (83 nmol/l) (UFC–ACTH–DST criterion) had the best accuracy in predicting the endpoints' improvement (sensitivity (SN) 65.2%, specificity (SP) 68.8%) after surgery. In the nontreated AI patients, this criterion predicted the worsening of ≥2 endpoints (SN 55.6%, SP 82.9%).

Conclusions

The UFC–ACTH–DST criterion seems to be the best for predicting the metabolic outcome in surgically treated AI patients.

Free access

Cristina Eller-Vainicher, Valentina Morelli, Antonio Stefano Salcuni, Massimo Torlontano, Francesca Coletti, Laura Iorio, Antonello Cuttitta, Angelo Ambrosio, Leonardo Vicentini, Vincenzo Carnevale, Paolo Beck-Peccoz, Maura Arosio, Bruno Ambrosi, Alfredo Scillitani and Iacopo Chiodini

Objective

Few data are available regarding the need of steroid substitutive therapy after unilateral adrenalectomy for adrenal incidentaloma (AI). It is unknown whether, before surgery, the hypothalamic–pituitary–adrenal (HPA) axis secretion parameters can predict post-surgical hypocortisolism.

Aim

This study aimed to evaluate whether, in AI patients undergoing unilateral adrenalectomy, post-surgical hypocortisolism could be predicted by the parameters of HPA axis function.

Design

Prospective, multicenter.

Methods

A total of 60 patients underwent surgical removal of AI (surgical indication: 29 subclinical hypercortisolism (SH); 31 AI dimension). Before surgery, SH was diagnosed in patients presenting at least three criteria out of urinary free cortisol (UFC) levels>60 μg/24 h, cortisol after 1-mg dexamethasone suppression test (1 mg-DST)>3.0 μg/dl, ACTH levels<10 pg/ml, midnight serum cortisol (MSC)>5.4 μg/dl.

Two months after surgery, HPA axis function was assessed by low dose ACTH stimulation test or insulin tolerance test when needed: 39 patients were affected (Group B) and 21 were not affected (Group A) with hypocortisolism. The accuracy in predicting hypocortisolism of pre-surgical HPA axis parameters or their combinations was evaluated.

Results

The presence of >2 alterations among 1 mg-DST>5.0 μg/dl, ACTH<10 pg/ml, elevated UFC and MSC has the highest odds ratio (OR) for predicting post-surgical hypocortisolism (OR 10.45, 95% confidence interval, CI 2.54–42.95, P=0.001). Post-surgical hypocortisolism was predicted with 100% probability by elevated UFC plus MSC levels, but not ruled out even in the presence of the normality of all HPA axis parameters.

Conclusion

Post-surgical hypocortisolism cannot be pre-surgically ruled out. A steroid substitutive therapy is indicated after unilateral adrenalectomy for SH or size of the adenoma.