HypoparaNet: A Database of Chronic Hypoparathyroidism Based on Expert Medical-Surgical Centers in Italy.

Hypoparathyroidism is a rare disease characterized by low serum calcium levels and absent or deficient parathyroid hormone level. Regarding the epidemiology of chronic hypoparathyroidism, there are limited data in Italy and worldwide. Therefore, the purpose of this study was to build a unique database of patients with chronic hypoparathyroidism, derived from the databases of 16 referral centers for endocrinological diseases, affiliated with the Italian Society of Endocrinology, and four centers for endocrine surgery with expertise in hypoparathyroidism, to conduct an epidemiological analysis of chronic hypoparathyroidism in Italy. The study was approved by the Institutional Review Board. A total of 537 patients with chronic hypoparathyroidism were identified. The leading etiology was represented by postsurgical hypoparathyroidism (67.6%), followed by idiopathic hypoparathyroidism (14.6%), syndromic forms of genetic hypoparathyroidism (11%), forms of defective PTH action (5.2%), non-syndromic forms of genetic hypoparathyroidism (0.9%), and, finally, other forms of acquired hypoparathyroidism, due to infiltrative diseases, copper or iron overload, or ionizing radiation exposure (0.7%). This study represents one of the first large-scale epidemiological assessments of chronic hypoparathyroidism based on data collected at medical and/or surgical centers with expertise in hypoparathyroidism in Italy. Although the study presents some limitations, it introduces the possibility of a large-scale national survey, with the final aim of defining not only the prevalence of chronic hypoparathyroidism in Italy, but also standards for clinical and therapeutic approaches.

Pulmonary hypertension in thyroid diseases.

The influence of thyroid hormones on cardiovascular system is well established. Thyroid diseases can effectively enhance the alteration on cardiovascular system by influencing chronotropic and inotropic actions of the heart; altering the strength and the speed of contraction, the speed of relaxation, the duration of the potential of action, and the duration of the refractory period and atrio-ventricular conduction time; modulating circulation and peripheral vascular beds. One of the more intriguing insights in the connection between thyroid diseases and cardiovascular alterations is related to the evaluation of the influence of thyroid hormones on pulmonary vascular beds. Literature reported several studies regarding the association between both hypothyroidism and hyperthyroidism and the occurrence of increased vascular pulmonary arterial pressure. Nevertheless, the pathogenetic mechanisms able to explain such relationship are not fully understood. Many doubts still persist in the comprehension of the mechanisms of pulmonary hypertension in thyroid diseases. The aim of this review was to provide possible explanation about the possible interaction between pulmonary vascular beds and thyroid function in order to evaluate the possibility of novel perspectives in the general management of patients suffering from thyroid and cardiovascular diseases.

RAS/BRAF mutational status in familial non-medullary thyroid carcinomas: A retrospective study.

There are contrasting views on whether familial non-medullary thyroid carcinomas (FNMTCs) are characterized by aggressive behavior, and limited evidence exists on the prognostic value of BRAF and RAS mutations in these tumors. Thus, in the present study, clinicopathological features were analyzed in 386 non-medullary thyroid carcinomas (NMTCs), subdivided in 82 familial and 304 sporadic cases. Furthermore, the RAS and BRAF mutational statuses were investigated in a subgroup of 34 FNMTCs to address their clinical and biological significance. The results demonstrated that, compared with sporadic NMTCs, FNMTCs are characterized by significantly higher rates of multicentricity and bilaterality and are more frequently associated with chronic autoimmune thyroiditis. Notably, a statistically significant difference in the rates of multicentricity was observed by subgrouping familial tumors according to the number of relatives involved; those with ≥3 affected relatives were more likely to be multicentric. Furthermore, the FNMTC cohort exhibited higher rates of tumors >4 cm in size with extrathyroidal or lymph node involvement. However, no significant difference was observed. Similarly, no differences were observed with respect to the age of onset or the patient outcome. The mutational profiling exhibited a rate of 58.8% for BRAF V600E mutations in familial tumors, which is at the upper limit of the mutational frequency observed in historical series of sporadic thyroid cancer. A high rate of NRAS mutations (17.6%) was also observed, mostly in the follicular variant histotype. Notably, compared with BRAF/RAS-wild type FNMTCs, the familial carcinomas bearing BRAF or NRAS mutations exhibited slightly higher rates of bilaterality and multicentricity, in addition to increased frequency of locally advanced stage or lymph node involvement. The present data support the theory that FNMTCs are characterized by clinicopathological features that resemble a more aggressive phenotype and suggest that RAS/BRAF mutational analysis deserves to be further evaluated as a tool for the identification of FNMTCs with a potentially unfavorable prognosis.

Clusterin transcript variants expression in thyroid tumor: a potential marker of malignancy?

BACKGROUND: Clusterin (CLU) is a ubiquitous multifunctional factor involved in neoplastic transformation. The CLU transcript variants and protein forms play a crucial role in balancing cells proliferation and death. METHODS: We investigated the regulation of CLU transcript variants expression in an in vivo model system consisting of both neoplastic tissues and fine needle aspiration biopsy (FNAB) samples isolated from patients undergoing thyroidectomy. RESULTS: The immunohistochemical analyses showed an overall CLU up-regulation in papillary carcinoma. A specific CLU2 transcript variant increase was registered using qPCR in papillary carcinomas while CLU1 decreased. In addition, the analysis of CLU transcripts expression level showed an increase of the CLU2 transcript in the TIR 3 patients with histologically confirmed thyroid cancer. CONCLUSIONS: Our results suggest the existence of a specific alteration of CLU2:CLU1 ratio towards CLU2, thus providing the first circumstantial evidence for the potential use of CLU transcript variants as effective biomarkers for a more accurate assessment of the so called "indeterminate" thyroid nodules.

Pulmonary hypertension and Hashimoto's thyroiditis: does a relationship exist?

Several studies examined the possibility that idiopathic pulmonary hypertension is related to thyroid autoimmune diseases. The aim of our study was to highlight the possible correlations between the pulmonary hypertension and Hashimoto's thyroiditis (HT). A total of 93 patients were enrolled, 70 suffering from HT in euthyroidism state and 23 controls. All underwent anthropometric [weight (Kg); height (m); Body Mass Index (Kg/m(2)): waist circumference (cm)] and biochemical [fasting blood glucose (mg/dl), TSH (µUI/mL), FT3 (pg/ml), FT4 (pg/ml), total, HDL and LDL-cholesterol (mg/dl), triglycerides (mg/dl)] evaluations. All patients underwent two-dimensional trans-thoracic echocardiographic evaluations in order to measure systolic (sPAP) and the end-diastolic pressure of the pulmonary artery (dPAP). There were no differences between the two populations regarding anthropometric and biochemical parameters. Patients with HT had higher sPAP values than controls (Hashimoto: 20.06 ± 6.56 mmHg vs controls: 19.96 ± 8.58 mmHg, p = 0.044). Patients with HT had lower dPAP values than controls (2.51 ± 0.90 mmHg vs. controls 3.17 ± 1.58 mmHg, p < 0.0001), and there was a statistically significant difference in the left ventricle ejection fraction between the two groups (60.57 ± 1.60 % in patients with HT vs. 61.04 ± 2.03 % in controls, p = 0.037). The multivariate regression analysis did not confirm such results. We demonstrated that patients with HT did not show relevant pulmonary hypertension when compared to healthy controls.

Incidental carcinoma of the thyroid.

The diagnosis of incidental thyroid carcinoma in patients submitted to thyroidectomy for a benign disease is quite frequent. A retrospective analysis was performed on 455 patients submitted to surgical intervention in order to establish the incidence of this kind of carcinoma. Two hundred fifty-six patients (56%) were affected by benign disease (176 multinodular goiter, 12 uninodular goiter, 1 Plummer disease and 67 Basedow disease) and 202 (44%) by carcinoma. In 28 of 256 patients (11%), affected by benign disease, occurred a histological diagnosis of thyroid carcinoma, (10 papillary carcinoma, 1 follicular carcinoma, 29 papillary carcinoma follicular variant). In this study it's considered incidental thyroid carcinoma the one occurred in patients who never underwent Fine Needle Aspiration (FNA) and there were no suspicious features in all exams that may suggest the presence of carcinoma. Twenty-three of the 40 incidental carcinoma (57.5%) were microcarcinomas. Ten patients had a sincronous carcinoma. Actually, these patients are still in a follow up program and no recurrency of disease is occasionally observed. This study shows that the only way to put doubts on the real benignity of the disease is the fine needle aspiration; there are no other instruments that could identify the occurrence of the carcinoma. Moreover in the majority of cases the incidental carcinoma is a microcarcinoma, it doesn't reach significant volume, may be not centered by a FNA, but in most cases it's not really biologically aggressive.

[Incidental carcinoma in thyroid pathology: our experience and review of the literature]. / Il carcinoma incidentale nella patologia tiroidea. La nostra esperienza e revisione della letteratura.

The diagnosis of incidental thyroid carcinoma in patients submitted to thyroidectomy for a benign disease is quite frequent. A retrospective analysis was performed on 240 patients submitted to surgical intervention in order to establish the incidence of the carcinoma. One hundred sixty five patients (68.75%) were affected by benign disease (132 multinodular goiter, 30 uninodular goiter, 2 Plummer and 1 Basedow) and 75 (31.25%) by carcinoma. In 30 of 165 patients (18.2 %), affected by benign disease, occurred a histological diagnosis of thyroid carcinoma, (18 papillary carcinoma, 6 follicular carcinoma, 5 papillary carcinoma follicular variant and 1 oncocytic carcinoma). In this study it's considered incidental thyroid carcinoma the one occurred in patients who never underwent FNA and there were no suspicious features in all exams that may suggest the presence of carcinoma. Fifteen of the 30 incidental carcinoma (50%) were microcarcinomas; in the other 13, dimensions were more than 1 cm, but less than 2 cm in 9 cases. Two patients had a synchronous carcinoma. Actually these patients are still in a follow up program and no recurrency of disease is occasionally observed. This study shows that the only way to put doubts on the real benignity of the disease is the fine needle aspiration; there are no other instruments that could let think about the occurrence of the carcinoma. Moreover in the majority of cases the incidental carcinoma is a microcarcinoma, it doesn't reach significant volume, may be not centered by a FNAB, but in must cases it's not really biologically aggressive.

[Incidental thyroid carcinoma: a multicentric experience]. / Il carcinoma incidentale della tiroide: esperienza multicentrica.

BACKGROUND: In recent years it has seen an increase of incidental thyroid carcinomas (ICs), most of the ICs are any microcarcinoma (MC). The term refers to a CT, predominantly papillary, and smaller than or equal to 1 cm. The MC is characterized by a papillary heterogeneous clinical behavior ranging from small outbreak discovered accidentally after surgery than the cancer that manifests clinically with lymph node metastases in the neck or rarely systemic. METHODS: From January 2007 to June 2009, 1507 patients for benign disease were subjected to surgery. RESULTS: Histological examination confirmed the diagnosis of benignity in 1339 cases. In 168, however, we detected unexpected, incidental carcinoma (CI). In patients with CI receiving total surgery (TT), the next iteration we agree with the endocrinologist. In cases of lobectomia, was run TT and was heading endocrinology. Of the 168 patients with incidental CT, 147 had papillary carcinomas, 12 follicular carcinomas, 5 follicular variant papillary carcinomas, 2 oncocytic carcinomas, 1 uncertain malignancy. CONCLUSION: In our study has highlighted the lack of data (medical history, ultrasound, scintigraphic), they may portend the presence of a tumor in the specimen CI. In all patients with CI, the surgical indication was given for symptomatic disease, for impairment of thyroid function, for failure to respond to medical therapy or unable to continue. The IC is almost always a microcarcinoma, predominantly papillary, and smaller than or equal to 1 cm, has little biological aggressiveness and is susceptible to metabolic radioiodine therapy. On the basis of these data we feel reasonably acceptable to a close follow-up endocrine surgery, particularly in patients with multinodular disease and stress the need for a multi-specialized team.

Abnormalities of insulin-like growth factor-I signaling and impaired cell proliferation in osteoblasts from subjects with osteoporosis.

IGF-I regulates bone acquisition and maintenance, even though the cellular targets and signaling pathways responsible for its action in human bone cells are poorly understood. Whether abnormalities in IGF-I action and signaling occur in human osteoblasts under conditions of net bone loss has not been determined. Herein we carried out a comparative analysis of IGF-I signaling in primary cultures of human osteoblasts from osteoporotic and control donors. In comparison with control cells, osteoporotic osteoblasts showed increased tyrosine phosphorylation of the IGF-I receptor in the basal state and blunted stimulation of receptor phosphorylation by IGF-I. Augmentation of basal IGF-I receptor phosphorylation was associated with coordinate increases in basal tyrosine phosphorylation of insulin receptor substrate (IRS)-2 and activation of Erk, which were also minimally responsive to IGF-I stimulation. By contrast, phosphorylation levels of IRS-1, Akt, and glycogen synthase kinase-3 were similar in the basal state in control and osteoporotic osteoblasts and showed marked increases after IGF-I stimulation in both cell populations, even though these responses were significantly lower in the osteoporotic osteoblasts. The IGF-I signaling abnormalities in osteoporotic osteoblasts were associated with reduced DNA synthesis both under basal conditions and after stimulation with IGF-I. Interestingly, treatment of the osteoporotic osteoblasts with the MAPK kinase inhibitor PD098059 reduced the elevated levels of Erk phosphorylation and increased basal DNA synthesis. Collectively, our data show that altered osteoblast proliferation in human osteoporosis may result from dysregulation of IGF-I receptor signaling, including constitutive activation of the IRS-2/Erk signaling pathway, which becomes unresponsive to IGF-I, and defective induction of the IRS-1/Akt signaling pathway.

Prevalence of thyroid nodules in an occupationally radiation exposed group: a cross sectional study in an area with mild iodine deficiency.

BACKGROUND: Thyroid nodules and thyroid cancer occur more frequently in people exposed to radiation for therapeutic purposes, and to nuclear fallout. Furthermore, it is known that a moderate degree of iodine deficiency may be responsible for an increased prevalence of thyroid nodules, while it is suspected that radiation exposure could induce changes in thyroid autoimmunity. The iodine intake of people resident in Bari, S. Italy, is mildly deficient, which could be presumed to cause a higher prevalence of thyroid pathology. This study was conducted to evaluate the prevalence of thyroid nodules in a population occupationally exposed to radiation, in an area of mild iodine deficiency. METHODS: A cross-sectional study was designed to evaluate the prevalence of thyroid nodules in radiation exposed workers, compared with a stratified sample of non exposed workers. After giving written consent to participate in the study, all the recruited subjects (304 exposed and 419 non exposed volunteers) were interviewed to fill in an anamnestic questionnaire, and underwent a physical examination, ultrasound thyroid scan, serum determinations of fT3, fT4 and TSH, fine needle aspiration biopsy. The sample was subdivided into one group exposed to a determined quantity of radiation (detected by counter), one group exposed to an undetectable quantity of radiation, and the non exposed control group. RESULTS: The prevalence of thyroid nodules < 1 cm in diameter, defined as incidentalomas, in the exposed group with detected doses, was 11.28% in males and 9.68% in females, while in the exposed group with undetectable dose the prevalence was 10.39% in males and 16.67% in females. In the non exposed group the prevalence of incidentalomas was 9.34% in males and 13.20% in females. These prevalences were not statistically different when analysed by a multiple test comparison with the bootstrap method and stratification for sex. Instead, the prevalence of thyroid nodules > 1 cm in diameter resulted statistically different in exposed and non exposed health staff: 18.68% in non exposed males vs exposed: 3.76% (determined dose) and 9.09% (undetectable dose) in males, and 20.30% in non exposed females versus 3.23% (detected dose) and 9.52% (undetectable dose) in exposed females. There was a higher proportion of healthy staff in the exposed group than in the non exposed: (80.45% vs 68.68% in males; 80.65% vs 57.87% in females). CONCLUSION: In our study, occupational exposure to radiation combined with mild iodine deficiency did not increase the risk of developing thyroid nodules. The statistically significant higher prevalence of thyroid nodules in the non exposed group could be explained by the high percentage (22%) of people with a familial history of, and hence a greater predisposition to, thyroid disease. The endemic condition of mild iodine deficiency, demonstrated in other studies, played a major role in determining the thyroid pathology in our study groups.

Prospective study of post-partum thyroid immune dysfunctions in type 1 diabetic women and in a healthy control group living in a mild iodine deficient area.

Second to diabetes mellitus, thyroid diseases are the most common endocrinopathies seen in pregnancy. The incidence of post-partum thyroid dysfunction (PPTD) in women with type 1 diabetes mellitus is three-fold increased. We determined the incidence of thyroid abnormalities in a well-defined group of young subjects with type 1 diabetes and in an age-matched healthy controls during and six months after pregnancy in an area of mild iodine deficiency. Twenty-five out of twenty-eight pregnant women completed the study. Fifteen were affected by type 1 diabetes and ten were controls. Our protocol of study consisted of four evaluations of each subject: in the first, in the second trimester, at delivery and six months after. At each control the patients were submitted to physical examination, thyroid ultrasonography, and determination of fT3, fT4, TSH, Antithyroglobulin antibodies (TgAbs), Antithyroperoxidase antibodies (TPOAbs). The variation of thyroid volume is statistically significant in both the diabetics and in the controls during the different times of observations. Four out of the fifteen diabetic pregnant patients (27%) developed a thyroid disease: two cases of post-partum thyroiditis (PPT) and two cases of euthyroid benign nodular goiter, as confirmed by cytological examination. Two out ten controls (20%) developed positive antibodies (TPO Abs and TgAbs) since the first observation and showed an autoimmune thyroiditis six months after delivery. Both of them showed a familial history of thyroid disease. Our study suggests that in an area of mild iodine deficiency the incidence of thyroid autoimmunity in pregnant women is similar, whether diabetic or not; moreover, thyroid volume is increasing in the diabetics as much as in the non diabetics during pregnancy.