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Alessandro Brancatella and Claudio Marcocci

Thyroid hormones stimulate bone turnover in adults by increasing osteoclastic bone resorption. TSH suppressive therapy is usually applied in patients with differentiated thyroid cancer (DTC) to improve the disease outcome. Over the last decades several authors have closely monitored the potential harm suffered by the skeletal system. Several studies and meta-analyses have shown that chronic TSH suppressive therapy is safe in premenopausal women and men. Conversely, in postmenopausal women TSH suppressive therapy is associated with a decrease of bone mineral density, deterioration of bone architecture (quantitative CT, QCT; trabecular bone score, TBS), and, possibly, an increased risk of fractures. The TSH receptor is expressed in bone cells and the results of experimental studies in TSH receptor knockout mice and humans on whether low TSH levels, as opposed to solely high thyroid hormone levels, might contribute to bone loss in endogenous or exogenous thyrotoxicosis remain controversial. Recent guidelines on the use of TSH suppressive therapy in patients with DTC give value not only to its benefit on the outcome of the disease, but also to the risks associated with exogenous thyrotoxicosis, namely menopause, osteopenia or osteoporosis, age >60 years, and history of atrial fibrillation. Bone health (BMD and/or preferably TBS) should be evaluated in postmenopausal women under chronic TSH suppressive therapy or in those patients planning to be treated for several years. Antiresorptive therapy could also be considered in selected cases (increased risk of fracture or significant decline of BMD/TBS during therapy) to prevent bone loss.

Open access

Elena Pardi, Stefano Mariotti, Natalia S Pellegata, Katiuscia Benfini, Simona Borsari, Federica Saponaro, Liborio Torregrossa, Antonello Cappai, Chiara Satta, Marco Mastinu, Claudio Marcocci and Filomena Cetani

Inactivating germline mutations of the CDKN1B gene encoding the nuclear cyclin-dependent kinase inhibitor P27kip1 protein have been reported in patients with multiple endocrine neoplasia type 4 (MEN4), a MEN1-like phenotype without MEN1 mutations. The aim of this study was to characterize in vitro the germline CDKN1B mutation c.374_375delCT (S125X) we detected in a patient with MEN4. The proband was affected by primary hyperparathyroidism due to multiglandular parathyroid involvement and gastro–entero–pancreatic tumors. We carried out subcellular localization experiments by transfection with plasmid vectors expressing the WT or mutant CDKN1B cDNA into the eukaryotic human cervix adenocarcinoma (HeLa) and GH3 cell lines. Results from western blotting studies indicated that fusion proteins were expressed at equal levels. The mutated protein was shorter compared with the WT protein and lacked the highly conserved C-terminal domain, which includes the bipartite nuclear localization signal at amino acids 152/153 and 166/168. In HeLa and GH3 cells, WT P27 localized in the nucleus, whereas the P27_S125X protein was retained in the cytoplasm, predicting the loss of tumor-suppressive function. The proband's tumoral parathyroid tissue did not show allelic loss, because both WT and mutant alleles were determined to be present by sequencing the somatic DNA. Immunohistochemistry revealed a complete loss of nuclear expression of P27 in a parathyroid adenoma, which had been removed by the second surgery in the patient. In conclusion, our results confirm the pathogenic role of the c.374_375delCT CDKN1B germline mutation in a patient with MEN4.

Open access

Federica Saponaro, Alessandro Saba, Sabina Frascarelli, Concetta Prontera, Aldo Clerico, Marco Scalese, Maria Rita Sessa, Filomena Cetani, Simona Borsari, Elena Pardi, Antonella Marvelli, Claudio Marcocci, Claudio Passino and Riccardo Zucchi

Objectives

The aims of this paper were to evaluate the levels of Vitamin D (VitD) in patients with heart failure (HF), compared to a control group, to assess the effects of VitD on HF outcome and to compare VitD measurement between LIAISON immunoassay and HPLC-MS-MS methods in this population.

Design and Methods

We collected clinical, biochemical and outcome data from 247 patients with HF and in a subgroup of 151 patients, we measured VitD both with LIAISON and HPLC-MS-MS.

Results

HF patients had statistically lower 25OHD levels (45.2 ± 23.7 nmol/L vs 58.2 ± 24.0 nmol/L, P < 0.001) and a statistically higher prevalence of VitD insufficiency (61.1% vs 39.5%, P < 0.001) and deficiency (24.7% vs 6.6%, P < 0.001), compared to healthy controls. There was a significant inverse relationship between baseline 25OHD and risk of HF-related death, with a HR of 0.59 (95% CI 0.37–0.92, P = 0.02), confirmed in a multivariate adjusted analysis. Kaplan–Meier survival analyses showed that VitD insufficiency was associated with reduced survival in HF patients (log rank P = 0.017). There was a good agreement between LIAISON and HPLC-MS-MS (Cohen’s kappa coefficient 0.70), but the prevalence of VitD insufficiency was significantly higher with the former compared to the latter method (58.3%, n = 88 vs 55.6%, n = 84, P < 0.001). LIAISON underestimated the 25OHD levels and showed a mean relative bias of −0.739% with 95% of limits of agreement (−9.00 to +7.52%), when compared to HPLC-MS-MS.

Conclusions

25OHD levels adequately measured by HPLC-MS-MS showed to be low in HF population and to be correlated with HF-related risk of death.

Open access

Filomena Cetani, Chiara Banti, Elena Pardi, Simona Borsari, Paolo Viacava, Paolo Miccoli, Liborio Torregrossa, Fulvio Basolo, Maria Rosa Pelizzo, Massimo Rugge, Gianmaria Pennelli, Guido Gasparri, Mauro Papotti, Marco Volante, Edda Vignali, Federica Saponaro and Claudio Marcocci

Inactivating mutations of the CDC73 tumor suppressor gene have been reported in parathyroid carcinomas (PC), in association with the loss of nuclear expression of the encoded protein, parafibromin. The aim of this study was to further investigate the role of the CDC73 gene in PC and evaluate whether gene carrier status and/or the loss of parafibromin staining might have an effect on the outcome of the disease. We performed genetic and immunohistochemical studies in parathyroid tumor samples from 35 patients with sporadic PC. Nonsense or frameshift CDC73 mutations were detected in 13 samples suitable for DNA sequencing. Six of these mutations were germline. Loss of parafibromin expression was found in 17 samples. The presence of the CDC73 mutation as well as the loss of parafibromin predicted a high likelihood of subsequent recurrence and/or metastasis (92.3%, P=0.049 and 94.1%, P=0.0017 respectively), but only the latter was associated with a decreased overall 5- and 10-year survival rates (59%, P=0.107, and 23%, P=0.0026 respectively). The presence of both the CDC73 mutation and loss of parafibromin staining compared with their absence predicted a lower overall survival at 10- (18 vs 84%, P=0.016) but not at 5-year follow-up. In conclusion, loss of parafibromin staining, better than CDC73 mutation, predicts the clinical outcome and mortality rate. The added value of CDC73 mutational analysis is the possibility of identifying germline mutations, which will prompt the screening of other family members.