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.

Mitotane enhances doxorubicin cytotoxic activity by inhibiting P-gp in human adrenocortical carcinoma cells.

Mitotane is currently employed as adjuvant therapy as well as in the medical treatment of adrenocortical carcinoma (ACC), alone or in combination with chemotherapeutic agents. It was previously demonstrated that mitotane potentiates chemotherapeutic drugs cytotoxicity in cancer cells displaying chemoresistance due to P-glycoprotein (P-gp), an efflux pump involved in cancer multidrug resistance. The majority of ACC expresses high levels of P-gp and is highly chemoresistent. The aim of our study was to explore in vitro whether mitotane, at concentrations lower than those currently reached in vivo, may sensitize ACC cells to the cytotoxic effects of doxorubicin and whether this effect is due to a direct action on P-gp. NCI-H295 and SW13 cell lines as well as 4 adrenocortical neoplasia primary cultures were treated with mitotane and doxorubicin, and cell viability was measured by MTT assay. P-gp activity was measured by calcein and P-gp-Glo assays. P-gp expression was evaluated by Western blot. We found that very low mitotane concentrations sensitize ACC cells to the cytotoxic effects of doxorubicin, depending on P-gp expression. In addition, mitotane directly inhibits P-gp detoxifying function, allowing doxorubicin cytotoxic activity. These data provide the basis for the greater efficacy of combination therapy (mitotane plus chemotherapeutic drugs) on ACC patients. Shedding light on mitotane mechanisms of action could result in an improved design of drug therapy for patients with ACC.

Growth hormone values after an oral glucose load do not add clinically useful information in patients with acromegaly on long-term somatostatin receptor ligand treatment.

The optimal method of assessing GH status in acromegalic patients receiving medical therapy with somatostatin analogs (SSA) has been matter of debate. The aim of the study has been to investigate whether OGTT may add information in patients with discordant random GH (GHr) and IGF values. Moreover, we evaluated the association of GH nadir with the prevalence of co-morbidities observed in acromegalic patients on SSA therapy. We evaluated 130 patients with proven diagnosis of acromegaly on SSA. The patients were subdivided in three groups: patients with controlled disease (both safe random GH and normal IGF-I, group A, 20.0 %), patients with uncontrolled disease (both high random GH and IGF-I, group B, 34.6 %), and patients with discordant random GH and IGF-I values (group C, 35.4 %). A high concordance rate for GH nadir with random GH and IGF-I was observed in group B, while a significant reduced concordance rate has been observed in group A (100 % sensitivity, 64.5 % specificity). By contrast, in group C, we observed concordant results between GH nadir and IGF-I only in 14/59 patients. In group A, the prevalence of diabetes was lower than in group B or C. Safe random GH was the only single criteria associated with a lower prevalence of diabetes. Discrepant IGF-I and either GH nadir or random GH values are frequently observed in acromegalic patients treated with SSA. Concordant IGF-I and random GH may influence the prevalence of metabolic complications. GH nadir measurement may help to interpret discrepancies between random GH and IGF-I data only in few cases.

BRAF mutation positive papillary thyroid carcinoma is less advanced when Hashimoto's thyroiditis lymphocytic infiltration is present.

BACKGROUND: Concomitant papillary thyroid cancer (PTC) and Hashimoto's thyroiditis (HT) is a frequent occurrence. Whether these two conditions are linked and whether PTC with concurrent HT has distinct clinicopathological characteristics are still debated issues. Lymphocytic infiltration is abundant in HT and might be relevant in the pathogenesis and progression of PTC. BRAF(V600E) mutation is associated with a more advanced PTC at diagnosis; however, its role in the clinicopathological characteristics of PTC with concurrent HT is unknown. DESIGN AND PATIENTS: We enrolled 146 patients with histological diagnosis of PTC. Microscopic assessment of histology samples was performed to identify the presence of lymphocytic infiltration. Detection of BRAF(V600E) was performed on cytology samples by both direct sequencing and pyrosequencing, and results were correlated with clinical parameters. RESULTS: Concurrent HT lymphocytic infiltration was associated with the female gender, smaller tumour size, a less frequent extracapsular extension and a lower grade of TNM staging. BRAF(V600E) was more frequent in PTC with concomitant lymphocytic infiltration. In PTC harbouring BRAF(V600E) , concurrent lymphocytic infiltration was still associated with the female gender, a less frequent extracapsular extension and a lower TNM staging. CONCLUSIONS: These results suggest that lymphocytic infiltration of HT is a protective factor against PTC progression, and it is independent of BRAF mutational status.

Subclinical hypothyroidism.

PURPOSE OF REVIEW: Mild or subclinical hypothyroidism is characterized by normal serum free thyroxine concentrations with elevated serum thyroid-stimulating hormone concentrations. Subclinical hypothyroidism is relatively prevalent in the general population, especially among women and the elderly. The main cause of subclinical hypothyroidism is autoimmune chronic thyroiditis. The present report reviews the most important and recent studies on subclinical hypothyroidism, and discusses the most controversial aspects of this topic. RECENT FINDINGS: Several studies have demonstrated that subclinical hypothyroidism may affect both diastolic and systolic cardiac function. It may also worsen many risk factors for cardiovascular disease, including hypertension, abnormal endothelial function, and elevated low-density lipoprotein cholesterol concentrations. Furthermore, a growing body of evidence suggests that subclinical hypothyroidism may cause symptoms or progress to symptomatic overt hypothyroidism. SUMMARY: Prompt treatment of subclinical hypothyroidism in pregnant women is mandatory to decrease risks for pregnancy complications and impaired cognitive development in offspring. Children with subclinical hypothyroidism should be treated to prevent growth retardation. Whether nonpregnant adult patients with subclinical hypothyroidism should be treated, and at what thyroid-stimulating hormone values, is debatable.

Solitary fibrous tumor of the thyroid gland.

Solitary fibrous tumor (SFT) is a rare spindle-cell neoplasm more commonly involving the pleura, but recognized also in other tissues. Nineteen patients with SFT arising from the thyroid gland have been reported in the literature. The present report reviews these cases and discusses epidemiology, etio-pathogenesis, clinical-pathologic characteristics, differential diagnosis, therapy, and prognosis of thyroid SFT.

Post-partum thyroiditis--a clinical update.

Since the late 1960s, many studies have focused on post-partum thyroiditis (PPT) and 295 papers whose titles mention PPT were recorded on MEDLINE as of August 2001. We refer briefly to some excellent reviews and some original articles in order to update our knowledge on PPT.

Cortisol and ACTH response to oral dexamethasone in obesity and effects of sex, body fat distribution, and dexamethasone concentrations: a dose-response study.

There is increasing evidence that the abdominal obesity phenotype may be associated with multiple alterations of the hypothalamic-pituitary-adrenocortical (HPA) axis activity in both sexes. Our hypothesis is that the lack of adequate cortisol suppression after the dexamethasone test may constitute an indirect marker of HPA axis hyperactivity in the presence of the abdominal obesity phenotype. A total of 34 normal-weight (13 men and 21 women) and 87 obese (36 men and 51 women), healthy, nondepressed subjects therefore underwent four different dexamethasone suppression tests randomly performed at varying intervals of at least 1 wk between each test. After a standard overnight 1-mg dexamethasone test, which served as a reference, three other tests were randomly performed at 1-wk intervals by administering 0.0035, 0.0070, and 0.015 mg oral dexamethasone per kilogram of body weight overnight. Blood samples were obtained for cortisol, ACTH, and dexamethasone. Results were analyzed separately in men and women as well as in normal-weight [body mass index (BMI) < or = 25 kg/m(2)] and overweight or obese (BMI > 25 kg/m(2)) subjects. The waist circumference and the waist to hip ratio (WHR) were used as markers of body fat distribution. After the standard 1-mg test, cortisol suppression was greater than 90% in all subjects. However, after each test, obese women had significantly higher values of percent cortisol and percent ACTH suppression than normal-weight women without any difference between obese and normal-weight men. Considering the response to the three variable-dose tests, a clear dose- response pattern (P < 0.001 for trend analysis) in percent cortisol and percent ACTH suppression was found in all subjects. After each test men had significantly higher dexamethasone levels than women, regardless of BMI. However, obese women, but not men, had significantly higher dexamethasone levels after each test than their normal-weight counterpart. Plasma dexamethasone concentrations were dose related (P < 0.001 for trend analysis) in all subjects, but the dose-related increase was significantly higher in normal-weight men than normal-weight women, whereas it was similar in obese subjects of both sexes. Stepwise multiple regression analysis revealed that both percent cortisol and percent ACTH variations were significantly and negatively influenced by dexamethasone levels, as well as by waist circumference values in men, and independently by BMI and waist circumference in women. However, in contrast to what has been found in men, a divergent contribution of BMI and waist circumference was found in women indicating that, with increasing waist values, a smaller suppression of the HPA axis was found with respect to that expected on the basis of BMI values. In conclusion, this study provides data of both physiological and physiopathological relevance. Overall, our data indicated that adjustment of the dexamethasone dose to body weight does not seem to substantially improve the sensitivity of the test, even in obese individuals, particularly when near-maximal doses are administered. However, this study demonstrated a highly significant effect of dexamethasone blood level concentrations on cortisol and ACTH suppression to low-dose dexamethasone tests. In addition, a significant effect of gender on postdexamethasone cortisol concentrations, suppression of the HPA axis, and dexamethasone levels were found, which may be dependent on related differences in both cortisol and dexamethasone metabolism. We showed that pituitary sensitivity to feedback inhibition by dexamethasone is preserved in obesity in both sexes even at low dosages. On the other hand, our data suggest that, at least in women, abdominal fat distribution may partially counteract the progressively greater suppressibility of the HPA axis that would be expected according to increasing BMI.