Treatment of Obesity with Thyroid hormones in Europe. Data from the THESIS* Collaboration.

PURPOSE: The use of thyroid hormones (TH) to treat obesity is unsupported by evidence as reflected in international guidelines. We explored views about this practice, and associations with respondent characteristics among European thyroid specialists. METHODS: Specialists from 28 countries were invited to a survey via professional organisations. The relevant question was whether "Thyroid hormones may be indicated in biochemically euthyroid patients with obesity resistant to lifestyle interventions". RESULTS: Of 17,232 invitations 5695 responses were received (33% valid response rate; 65% women; 90% endocrinologists). Of these, 290 (5.1%) stated that TH may be indicated as treatment for obesity in euthyroid patients. This view was commoner among non-endocrinologists (8.7% vs. 4.7%, p < 0.01), private practice (6.5% vs. 4.5%, p < 0.01), and varied geographically (Eastern Europe, 7.3%; Southern Europe, 4.8%; Western Europe, 2.7%; and Northern Europe, 2.5%). Respondents from Northern and Western Europe were less likely to use TH than those from Eastern Europe (p < 0.01). Gross national income (GNI) correlated inversely with this view (OR 0.97, CI: 0.96-0.97; p < 0.001). Having national guidelines on hypothyroidism correlated negatively with treating obesity with TH (OR 0.71, CI: 0.55-0.91). CONCLUSIONS: Despite the lack of evidence, and contrary to guidelines' recommendations, about 5% of respondents stated that TH may be indicated as a treatment for obesity in euthyroid patients resistant to life-style interventions. This opinion was associated with (i) respondent characteristics: being non-endocrinologist, working in private practice, treating a small number of hypothyroid patients annually and (ii) national characteristics: prevalence of obesity, Eastern Europe, low GNI and lack of national hypothyroidism guidelines.

Results of a nationwide survey on multidisciplinary teams on thyroid cancer in Spain.

AIM: There is an important lack of knowledge as to the functioning of multidisciplinary teams on thyroid cancer in current clinical practice. We aimed to retrieve data on the composition, structure, and procedures developed by the multidisciplinary units of thyroid cancer in Spain. METHODS: A nationwide survey consisting of questions about composition, structure, and functioning of multidisciplinary teams was designed. It was available online from November 15, 2017 to February 15, 2018. RESULTS: Seventy-two multidisciplinary units responded to our survey. Of these, 15 (20.8%) focused only in thyroid cancer, while 57 (79.2%) included other endocrine disorders or non-endocrine tumors. The median (interquartile range) of members of the teams was 11 (9-14). The most frequent medical specialties in the units were endocrinology (100%), surgery (94.4%), pathology (80.6%), radiology (75.0%), nuclear medicine (73.6%), and medical oncology (55.6%). The annual number of patients reviewed by the teams was 40 (20-74). 56.9% of the multidisciplinary teams have elaborated clinical protocols for local use. Apart from clinical case discussions in the meetings, 45.8% of the units included educational activities and 36.1% research subjects. Quality indicators were developed by 22% of the teams. CONCLUSIONS: These results suggest that there are some hopeful signs that international recommendations of having multidisciplinary approach to patients with thyroid cancer are being followed in Spain. This gives us the opportunity to proceed with further studies to analyze the real impact of this high standard of care on patient outcomes.

Spanish consensus for the management of patients with anaplastic cell thyroid carcinoma.

Anaplastic thyroid cancer (ATC) is the most aggressive solid tumor and almost uniformly lethal in humans. The Boards of the Thyroid Cancer Group of the Spanish Society of Endocrinology and Nutrition and the Grupo Español de Enfermedades Huérfanas e Infrecuentes of the Spanish Society of Oncology requested that an independent task force draft a more comprehensive consensus statement regarding ATC. All relevant literature was reviewed, including serial PubMed searches together with additional articles. This is the first, comprehensive Spanish consensus statement for ATC and includes the characteristics, diagnosis, initial evaluation, treatment goals, recommendations and modalities for locoregional and advanced disease, palliative care options, surveillance, and long-term monitoring. Newer systemic therapies are being investigated, but more effective combinations are needed to improve patient outcomes. Though more aggressive radiotherapy has reduced locoregional recurrences, median overall survival has not improved in more than 50 years.

Consensus on the management of advanced radioactive iodine-refractory differentiated thyroid cancer on behalf of the Spanish Society of Endocrinology Thyroid Cancer Working Group (GTSEEN) and Spanish Rare Cancer Working Group (GETHI).

Thyroid cancer is the single most prevalent endocrine malignancy; differentiated thyroid cancer (DTC) accounts for more than 90 % of all malignancies and its incidence has been rising steadily. For more patients, surgical treatment, radioactive iodine (RAI) ablation, and thyroid-stimulating hormone (TSH) suppressive therapy achieve an overall survival (OS) rate of 97.7 % at 5 years. Nevertheless, locoregional recurrence occurs in up to 20 % and distant metastases in approximately 10 % at 10 years. Two-thirds of these patients will never be cured with radioactive iodine therapy and will become RAI-refractory, with a 3-year OS rate of less than 50 %. Over the last decade, substantial progress has been made in the management of RAI-refractory DTC. Given the controversy in some areas, the Spanish Task Force for Thyroid Cancer on behalf of Spanish Society of Endocrinology Thyroid Cancer Working Group (GTSEEN) and the Spanish Rare Cancer Working Group (GETHI) have created a national joint task force to reach a consensus addressing the most challenging aspects of management in these patients. In this way, multidisciplinary management should be mandatory and nuclear medicine targeted therapy, novel molecular targeted agents, and combinations are currently changing the natural history of RAI-refractory DTC.

Consensus on management of advanced medullary thyroid carcinoma on behalf of the Working Group of Thyroid Cancer of the Spanish Society of Endocrinology (SEEN) and the Spanish Task Force Group for Orphan and Infrequent Tumors (GETHI).

BACKGROUND: Of all thyroid cancers, <5 % are medullary (MTC). It is a well-characterized neuroendocrine tumor arising from calcitonin-secreting C cells, and RET gene plays a central role on its pathogeny. METHODS: The electronic search was conducted using MEDLINE (PubMed), EMBASE and Cochrane Central Register of Controlled Trials. Quality assessments of selected current articles, guidelines and reviews of MTC were performed. RESULTS: This consensus updates and summarizes biology, treatment and prognostic considerations of MTC. CONCLUSIONS: Multidisciplinary teams and specialized centers are recommended for the management of MTC patients. In the metastatic setting, those patients with large volume of disease are candidates to start systemic treatment mainly if they are symptomatic and the tumor has progressed in the last 12-14 months. Wait and see strategy should be offered to patients with: disseminated disease with only high levels of calcitonin and no macroscopic structural disease, low burden and absence of progression.

Body mass index classification misses subjects with increased cardiometabolic risk factors related to elevated adiposity.

CONTEXT: Body mass index (BMI) is widely used as a measure of overweight and obesity, but underestimates the prevalence of both conditions, defined as an excess of body fat. OBJECTIVE: We assessed the degree of misclassification on the diagnosis of obesity using BMI as compared with direct body fat percentage (BF%) determination and compared the cardiovascular and metabolic risk of non-obese and obese BMI-classified subjects with similar BF%. DESIGN: We performed a cross-sectional study. SUBJECTS: A total of 6123 (924 lean, 1637 overweight and 3562 obese classified according to BMI) Caucasian subjects (69% females), aged 18-80 years. METHODS: BMI, BF% determined by air displacement plethysmography and well-established blood markers of insulin sensitivity, lipid profile and cardiovascular risk were measured. RESULTS: We found that 29% of subjects classified as lean and 80% of individuals classified as overweight according to BMI had a BF% within the obesity range. Importantly, the levels of cardiometabolic risk factors, such as C-reactive protein, were higher in lean and overweight BMI-classified subjects with BF% within the obesity range (men 4.3 ± 9.2, women 4.9 ± 19.5 mg l(-1)) as well as in obese BMI-classified individuals (men 4.2 ± 5.5, women 5.1 ± 13.2 mg l(-1)) compared with lean volunteers with normal body fat amounts (men 0.9 ± 0.5, women 2.1 ± 2.6 mg l(-1); P<0.001 for both genders). CONCLUSION: Given the elevated concentrations of cardiometabolic risk factors reported herein in non-obese individuals according to BMI but obese based on body fat, the inclusion of body composition measurements together with morbidity evaluation in the routine medical practice both for the diagnosis and the decision-making for instauration of the most appropriate treatment of obesity is desirable.

Relationship between thyroid-stimulating hormone and insulin in euthyroid obese men.

BACKGROUND/AIMS: Obesity has been associated with hypothyroidism and impaired insulin sensitivity. However, few studies have specifically addressed the association between insulin sensitivity and thyroid function. Our aim was to look for a relation between these 2 factors in a sample of obese males. METHODS: One hundred and forty-four euthyroid male obese patients--mean age 42.6 years, mean body mass index (BMI) 41.8--were enrolled in this cross-sectional study. The hospital study protocol at entrance included baseline serum thyroid-stimulating hormone (TSH), insulin and glucose concentrations. Data were studied using an age-adjusted simple and multivariate linear regression analysis with TSH as the dependent and insulin and BMI as the independent variables. RESULTS: Mean TSH and insulin were 1.6 and 21.2 mU/l, respectively. It was found that their relationship follows a regression model: TSH=1.725-0.019 (age) + 0.003 (insulin) + 0.017 (BMI). Further data showed a positive correlation between BMI and TSH (r= 0.22; p<0.05), as well as between serum baseline insulin (>10 mU/l) and TSH concentration (r=0.27; p<0.05). This association was stronger in patients with higher insulin values (>21.2 mU/l; r=0.40; p<0.01). However, negative correlations between age and insulin (r= -0.14; not significant) and age and TSH (r= -0.35; p<0.05) were observed. CONCLUSIONS: In obese males, insulin resistance is significantly related with impairment of thyroid function, and this situation seems to be attenuated with age.

Advantage of salivary cortisol measurements in the diagnosis of glucocorticoid related disorders.

OBJECTIVE: Salivary cortisol in the assessment of glucocorticoid related disorders. DESIGN-METHODS: Serum and salivary cortisol were measured in 189 patients (22 Cushing's syndrome, 67 pseudo-Cushing, 11 Addison's disease, 89 controls) at 8:00 and 24:00 h. RESULTS: Serum and salivary cortisol correlated in the whole study population (r=0.62, p=0.000). Morning serum and saliva cortisol in Addison's disease were lower than in controls (6.74+/-1.69 vs 22.58+/-1.78 microg/dL, and 0.15+/-0.25 vs 0.67+/-0.12 microg/dL) (p<0.001). Morning serum cortisol was similar in controls and patients with Cushing's syndrome or pseudo-Cushing (22.58+/-1.78 vs 13.96+/-6.02 vs 16.13+/-1.69 microg/dL). Morning serum and salivary cortisol at 8:00 had the same sensitivity to distinguish patients with Addison's disease from healthy controls. 24:00 am serum cortisol in controls (2.61+/-0.20 microg/dL) was lower than in the pseudo-Cushing group (6.53+/-0.77 microg/dL, p<0.001) and in Cushing's syndrome (10.90+/-2.36 microg/dL, p=0.003). 24:00 am salivary cortisol in controls (0.0025+/-0.001 microg/dL) was lower than in patients with Cushing's syndrome (0.58+/-0.11 microg/dL, p<0.001) and those higher than in patient with pseudo-Cushing (0.10+/-0.06 microg/dL, p=0.001). Both salivary cortisol and serum cortisol presented high specificity (82% and 100%) to detect Cushing's syndrome but salivary cortisol higher sensitivity (saliva 88% and serum 50%). CONCLUSION: Morning salivary cortisol is as good as serum as screening test for patients with Addison's disease and nighttime salivary cortisol is more adequate than serum in the screening of Cushing's syndrome.

[Markers of thyroid function (I). Assessment of glandular activity]. / Marcadores de función tiroidea (I). Evaluación de la actividad glandular.

Thyroid hormones have a fundamental role in the metabolism, and are active in all organs and systems. Thyroid dysfunction (TD) is an important public health problem that concerns 10% of the general population. Diagnosis of TD is currently carried out on the basis of serum hormone levels determined by laboratory analysis. The results are classified into clinical (TSH and thyroid hormones out of normal range) and subclinical (isolated TSH disorder) dysfunction. The development of third generation assays in the TSH test represents a great step forward in the diagnosis of TD. However, the debate about the pathological significance of subclinical TD has intensified. There is as yet no agreement on the best approach for diagnosis and treatment of this common condition. It is currently impossible to know which subjects with subclinical TD will develop the typical complications of clinical dysfunction. In this setting, it is feasible that a number of subclinical hypothyroid subjects may in some cases be overtreated with thyroxin, while others remain undertreated with increased iatrogenic morbidity as a consequence.

[Markers of thyroid function (II). Assessment of tissue action]. / Marcadores de función tiroidea (II). Evaluación de la acción tisular.

Advances in molecular medicine have increased our knowledge of the consequences of hormone action in target cells. We are currently able to determine to some extent the molecular thyroid hormone activity in different organs. The effects are related with a variety of factors, but their association with plasmatic hormone levels is only partially correlated. Recent advances indicate that there are several intermediate factors in thyroid tissue activity. The iodothyronine selenodeiodinases have a relevant role in this context. The clinical and biochemical methods currently available for thyroid function assessment do not permit us to explore many of these new elements. However, it is well known that thyroid hormones enhance the expression of a number of proteins, and some of these can be measured by simple methods. Accordingly, the plasmatic value of these proteins may be related with the effect of thyroid hormones in the target tissues, which is the result of thyroid function. The ability to determine the tissue activity of thyroid hormones will enable us to administrate the treatment dose more accurately, only to patients who require it, avoiding iatrogenism.

[Molecular biology of follicular thyroid carcinoma (II). Clinical applications]. / Biología molecular del carcinoma de tiroides de estirpe folicular (II). Aplicaciones clínicas.

The great advance of molecular medicine over the last few years gives us an attractive vision of the new possibilities in diagnosis and therapeutics of thyroid cancer and helps us to understand its biological behaviour. The clinical application of the growing understanding of gene alterations involved in thyroidal oncogenesis is becoming a reality. Such knowledge might contribute to greater diagnostic accuracy, by helping us characterise malignant or benign cells, predict tumour outcome or state its origin. Likewise it might be useful to know the response to conventional therapies or the future implications of pharmacogenetics. In addition molecular medicine applications ought to be considered in determining the prognosis of spontaneous and familiar carcinomas. Such information can significantly improve current clinical-pathologic prognostic methods.

Pancreatic cancer escape variants that evade immunogene therapy through loss of sensitivity to IFNgamma-induced apoptosis.

Combined injections into experimental tumor nodules of adenovirus encoding IL-12 and certain chemokines are capable to induce immune-mediated complete regressions. In this study, we found that the combination of two adenoviruses, one encoding IL-12 and other MIP3alpha (AdCMVIL-12+AdCMVMIP3alpha) was very successful in treating CT-26-derived colon carcinomas. However, in experimental tumors generated from the pancreatic carcinoma cell line Panc02 such combined treatment induces 50% of macroscopic complete regressions, although local relapses within 1 week are almost constant. We derived cell lines from such relapsing tumors and found that experimental malignancies derived from their inoculum were not amenable to treatment in any case with AdCMVIL-12+AdCMVMIP-3alpha. Importantly, relapsing cell lines were insensitive to in vitro induction of apoptosis by IFNgamma, in clear contrast with the original Panc02 cells. Comparative analyses by cDNA arrays of relapsing cell lines versus wild-type Panc02 were performed revealing an important number of genes (383) whose expression levels were modified more than two-fold. These changes grouped in certain gene ontology categories should harbor the mechanistic explanations of the acquired selective resistance to IFNgamma.

Cidofovir inhibits growth of B16 melanoma cells in vivo.

BACKGROUND: Cidofovir [(S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl) cytosine] is a commercially available nucleotide analogue that has antiviral activity against a broad range of DNA viruses and is effective against human cytomegalovirus infection. OBJECTIVES: We aimed to study the effect of cidofovir on growth of the highly aggressive melanoma tumour arising from mouse melanoma B16 cells grafted subcutaneously in C57B16/J mice. METHODS: Mice were treated daily with systemic cidofovir at several doses. In treated and control groups, tumour growth was measured using a calliper, and histological studies were performed. RESULTS: In untreated mice, massive invasive melanoma tumours were observed on day 5 after tumour cell grafting. Cidofovir treatment gave a dose-dependent reduction in tumour size. Tumour growth was inhibited by 62% at a dose of 37.5 mg kg(-1) three times weekly, as compared with control mice treated with saline alone. At 67 mg kg(-1) three times weekly, tumour growth was inhibited by 90%. Increasing the cidofovir dose to 50 or 100 mg kg(-1) daily resulted in a gradual increase in the antitumoral effect of the compound. In one experiment, cidofovir was administered at 100 mg kg(-1) five times weekly from the eighth day after the injection of tumour cells, when the tumour already had a volume of approximately 100 mm(3). In the treatment group, on the 14th day the tumour volume was approximately 200 mm(3), while in the control group it had increased to 750 mm(3). CONCLUSIONS: Although the mechanism is unknown, an antitumoral or antiangiogenic effect may be the reason for the activity of cidofovir in this model. In view of our findings, use of cidofovir should be further explored in the treatment of neoplastic diseases.

Incidence of different forms of thyroid dysfunction and its degrees in an iodine sufficient area.

STUDY OBJECTIVE: The aim of the study was to determine the incidence of thyroid dysfunction in an iodine sufficient area (Vigo city, Galicia, North-West of Spain). DESIGN: Case-finding study during a 3-year (1990-1992) period. SUBJECTS: Subjects from a random sample of the population with abnormal results on FT4, sensitive-TSH or antithyroid autoantibodies. MEASUREMENTS: Thyroid size by ultrasound study. FT4 by RIA; TSA Ab by radio receptor assays; TSH, Tg Ab and TMS Ab by IRMA. MAJOR RESULTS: Overall incidence of thyroid dysfunction was 97.96 per 100,000 per year (CI 95% 78.86-117.06); female 162.45, male 17.44. Incidence rate of hyperthyroidism was 52.37 per 100,000 per year (CI 95% 38.41-66.36); 24.24 for Graves' disease, 11.63 for nodular hyperthyroidism, 13.57 for iatrogenic hyperthyroidism and 2.90 for others causes. Incidence rate of hypothyroidism was 45.58 per 100,000 per year (CI 95% 32.55-58.620 27.15 for hypothyroid autoimmune thyroiditis, 8.72 for postoperative hypothyroidism, 4.89 for miscellaneous hypothyroidism, 1.93 for amiodarone induced hypothyroidism and 2.90 for secondary hypothyroidism. CONCLUSIONS: This investigation provides extensive data on incidence of clinical and subclinical thyroid dysfunction and its different forms in an iodine sufficient area.

Increased incidence of thyrotoxicosis after iodine supplementation in an iodine sufficient area.

UNLABELLED: The aim of this study was to determine the incidence rate of thyrotoxicosis (TT) before and during dietary-iodine supplementation in an iodine-sufficient area. POPULATION: the study was carried out in Vigo, South Galicia (northwest of Spain), from January 1977 to December 1989. The mean population throughout the study period was 267,330 inhabitants (47% males and 53% females). From January 1985, a mandatory consumption of iodinized salt on the whole population started in Galicia. This region was considered as an iodine-deficient area but Vigo is an iodine-sufficient area. MEASUREMENTS: all newly diagnosed TT cases in Vigo city within the study period were included in this study. Diagnosis of TT was based on the clinical manifestations, an elevated level of T4 and suppressed TSH values. The difference between diffuse and nodular forms of goiter was assessed by scintigraphy. The average incidence rate (AIR) was determined in two periods, before (period A, 1977-1984) and during (period B, 1985-1989) iodine supplementation. RESULTS: the AIR throughout the whole study period was 4.89 new cases per 100,000 population, 95% confidence limits 4.16 to 5.63; AIR was 1.34 for males and 8.03 for females. AIR in period B was significantly higher with respect to period A, 7.68 and 3.10 per 100,000 respectively. The confidence interval for the difference was from -20.4 to 30.1, p < 0.05. The increase of the incidence of TT was comprised of both nodular and diffuse goiters. CONCLUSIONS: dietary iodinesupplementation in iodine-sufficient areas may induce an increase of the incidence of TT.(ABSTRACT TRUNCATED AT 250 WORDS)

Antithyroid drug and Graves' hyperthyroidism. Significance of treatment duration and TRAb determination on lasting remission.

OBJECTIVE: To investigate the significance of treatment with antithyroid drugs longer than 12 months on lasting remission in Graves' hyperthyroid patients, and to study clinical and laboratory parameters of prognostic value. PATIENTS: Fifty-two untreated Graves' hyperthyroid patients were assigned at random to two therapeutic groups. They were treated with carbimazole during 12 and 24 months in Group I (n = 28) and Group II (n = 24), respectively. MEASUREMENTS: Serum levels of FT4, T3, sTSH and TSH receptor antibody (TRAb) were measured before starting treatment and at regular intervals during treatment and follow-up after drug withdrawal. We compared the relapse rate in both groups of patients, at short (2-yr) and long-term (5-yr) periods after drug withdrawal. Also, we compared clinical and biochemical parameters between patients who stayed in remission and who had relapse. RESULTS: At the end of the short-term period, relapse had occurred in 13 (46.4%) Group I patients and in 13 (54.1%) Group II patients, p = 0.36. At the end of the long-term period, relapse had occurred in 24 (85.7%) Group I and 20 (83.3%) Group II patients, p = 0.78. No difference could be observed between patients who had stayed in remission and who had suffered relapse, within the 5-yr follow-up period regarding to goiter size, frequency of ophthalmopathy, TSH and TRAb levels. CONCLUSIONS: The high relapse rate observed could be due to high iodine intake in our country. In this study and in a review of the available data, we have been unable to find any rational basis for courses of antithyroid drugs longer than twelve months for the treatment of Graves' hyperthyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)

[Association between post-initial remission and HLA phenotype in Type I diabetics]. / Asociación entre remisión postinicial y fenotipo HLA en diabéticos tipo I.

Our goal was to estimate the occurrence rate of the post-initial remission and its relation with HLA phenotype in type I diabetics (DMI). We studied 50 type I diabetics, 22 women and 28 men, with an average age at the onset of the disease to 15.8 +/- years (range 3-30 years). All patients were conventionally treated with insulin therapy, diet and regular exercise. Six (12%) of the diabetics presented a complete remission during 57.3 +/- 46 weeks, whereas fifteen (30%) patients presented partial remission during 20.1 +/- weeks. No significant differences were observed with regard to age at the onset of the disease, sex, BMI, initial ketoacidosis and stage of gonadal development between those diabetics presenting remission and those who did not presented so. We observed a higher incidence of the HLA-DR4 antigen among diabetics with remission (complete and partial, 61.9%), compared with patients without remission (20%, p less than 0.5). In conclusion, our results support the findings suggesting the presence of a clinical-immunological heterogenicity in DMI, genetically determined and linked to the HLA system.