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Initial treatment for differentiated thyroid carcinoma (DTC) often consists of surgery and the administration of radioiodine. In this context, post-treatment Whole-Body Scans (ptWBS) are currently recommended, but data on its diagnostic accuracy are rare. The aim of the study was to evaluate the performance of ptWBS for distant metastasis in DTC patients. We included DTC patients who received radioiodine and underwent ptWBS between 2009–2015. The medical data were independently reviewed by two specialists to evaluate the concordance of positive distant ptWBS uptake and distant metastasis documented by imaging exams (gold standard). We studied 268 DTC patients. The mean age was 46±16 years (82% women), and papillary thyroid carcinoma was diagnosed in 87% of the patients. The median tumor size was 2.7 cm, 40% had lymph node involvement, and 11% had distant metastasis. Twenty-eight patients (10%) had distant ptWBS uptake, and nine of them (32%) were false-positives. In addition, nine false-negative ptWBS uptakes were identified. The overall performance of ptWBS showed 68% sensitivity and 96% specificity with significantly different performance according to the American Thyroid Association (ATA) risk groups. While the ptWBS performance for ATA low-intermediate-risk showed 29% sensitivity, 97% specificity, and Kappa of 0.19, the ATA high-risk group ptWBS displayed high sensitivity (82%), specificity (100%), and good agreement (Kappa 0.74). ptWBS is useful for a subgroup of ATA high-risk DTC patients. The overall poor performance of ptWBS suggests that it should be reconsidered for routine use in ATA at low to intermediate risk: the exam has little value to this subgroup.

Objective: Although the prognostic role of BRAFV600E mutation in papillary thyroid carcinoma (PTC) is controversial, the American Thyroid Association (ATA) includes the mutational status in their risk stratification system. To evaluate the impact of the BRAFV600E mutation status on PTC risk stratification. Subjects and methods: PTC patients attending a university-based hospital who had the analysis of the BRAFV600E mutation were included. Persistent disease was defined as the presence of biochemical or structural disease. The performance of the ATA risk stratification system on predicting persistent disease with or without the BRAFV600E mutation status information was evaluated. Results: Of the 134 patients evaluated, 44 (32.8%) carried BRAFV600E mutation. The median tumor size was 1.7 cm (P25-75 1.0-3.0), 64 (47.8%) patients had lymph node, and 11 (8.2%) distant metastases. According to the ATA risk stratification system, patients were classified as low, intermediate, and high risk in 55 (41%), 59 (44%), and 20 (14%) patients, respectively.The data on BRAFV600E mutation reclassified 12 (8.9%) patients from low to intermediate risk. After a median follow-up of 8.5 years, the prevalence of persistent disease was similar in patients with and without BRAFV600E mutation (P = 0.42). Multivariate analysis failed to demonstrate an association between the BRAFV600E mutation and persistent disease status (RR 0.96; 95%CI 0.47-1.94). Notably, none of the patients reclassified from low to intermediate risk showed persistent disease on follow-up. Conclusion: Inclusion of BRAFV600E mutational status has a limited impact on risk stratification and does not add to the prediction of outcomes in PTC patients. Arch Endocrinol Metab. 2020;64(6):751-7., SCOPUS: ar.j, info:eu-repo/semantics/published

Genetic variability in humans is influenced by many factors, such as natural selection, mutations, genetic drift, and migrations. Molecular epidemiology evaluates the contribution of genetic risk factors in the etiology, diagnosis, and prevention of a particular disease. Few areas of medicine have been so clearly affected by genetic diagnosis and management as multiple neoplasia type 2 (MEN2), in which activating pathogenic variants in the RET gene results in the development of medullary thyroid carcinoma (MTC), pheochromocytoma, and hyperparathyroidism in nearly 98, 50, and 25% of gene carriers, respectively. Here, we aimed to collect RET genotyping data worldwide to analyze the distribution and frequency of RET variants from a global perspective. We show that the mutational spectrum of RET is observed worldwide. The codon 634 variants seem to be the most prevalent, but there are differences in the type of amino acid exchanges among countries and in the frequencies of the other RET codon variants. Most interestingly, studies using haplotype analysis or pedigree linkage have demonstrated that some pathogenic RET variants have been transmitted to offspring for centuries, explaining some local prevalence due to a founder effect. Unfortunately, after almost three decades after the causative role of the germline RET variants has been reported in hereditary MTC, comprehensive genotyping data remain limited to a few countries. The heterogeneity of RET variants justifies the need for a global effort to describe epidemiological data of families with MEN2 to further understand the genetic background and environmental circumstances that affect disease presentation.

Made available in DSpace on 2021-06-25T10:29:49Z (GMT). No. of bitstreams: 0 Previous issue date: 2021-03-01 Objective: Choosing Wisely (CW) is an initiative that aims to advance the dialogue between physicians and patients about low-value health interventions. Given that thyroid conditions are frequent in clinical practice, we aimed to develop an evidence-based list of thyroid CW recommendations. Materials and methods: The Thyroid Department of the Brazilian Society of Endocrinology and Metabolism (SBEM) named a Task Force to conduct the initiative. The Task Force work was based on an electronic Delphi approach. The 10 recommendations that received the highest scores by the Task Force were submitted for voting by all SBEM associates. The 5 recommendations that received the highest scores by SBEM associates are presented herein. Results: The Task Force was composed of 14 thyroidologists from 10 tertiary-care, teaching-based Brazilian institutions. The brainstorming/ideation phase resulted in 69 recommendations. After the removal of duplicates and recommendations that did not adhere to the initiative’s scope, 35 remained. Then the Task Force voted to attribute a grade (0 [lowest agreement] to 10 [highest agreement]) for each recommendation. The 10 recommendations that received the highest scores by the Task Force were submitted to all SBEM associates. A total of 683 associates voted electronically, attributing a grade (0 to 10) for each recommendation. The 5 recommendations that received the highest scores by the SBEM associates compose our final list. Conclusion: A set of recommendations to avoid unnecessary medical tests, treatments, or procedures for thyroid conditions are offered with a transparent methodology. This initiative aims to foster productive interactions between physicians and patients, stimulating shared decision-making. Unidade de Tireoide do Hospital de Clínicas de Porto Alegre Faculdade de Medicina da Universidade Federal do Rio Grande do Sul (UFRGS) Universidade Federal de São Paulo (Unifesp) Faculdade de Medicina da Universidade Federal de Pernambuco (UFPE) Faculdade de Medicina da Universidade Federal do Paraná (UFPR) Instituto do Câncer do Estado de São Paulo (ICESP) Faculdade de Medicina da Universidade Estadual Paulista (Unesp) Universidade de São Paulo (USP) Universidade Federal do Rio de Janeiro (UFRJ) Instituto Nacional de Câncer (INCA) Faculdade de Medicina da Pontifícia Universidade Católica de Campinas Faculdade de Medicina da Universidade Estadual Paulista (Unesp)

Imbalances in redox status modulate type 3 deiodinase induction in nonthyroidal illness syndrome. However, the underlying mechanisms that lead to D3 dysfunction under redox imbalance are still poorly understood. Here we evaluated D3 induction, redox homeostasis, and their interrelationships in the liver, muscle, and brain in an animal model of NTIS. Male Wistar rats were subjected to left anterior coronary artery occlusion and randomly separated into two groups and treated or not (placebo) with the antioxidant N-acetylcysteine. Sham animals were used as controls. Animals were killed 10 or 28 days post-MI induction and tissues were immediately frozen for biochemical analysis. D3 activity, protein oxidation and antioxidant defenses were measured in liver, muscle, and brain. Compared to those of the sham group, the levels of D3 expression and activity were increased in the liver (P = 0.002), muscle (P = 0.03) and brain (P = 0.01) in the placebo group. All tissues from the placebo animals showed increased carbonyl groups (P P P = 0.001). NAC prevented all the alterations described previously. D3 dysfunction in all tissues correlates with post-MI-induced protein oxidative damage and altered antioxidant defenses. NAC treatment prevents D3 dysfunction, indicating that reversible redox-related remote D3 activation explains, at least in part, the thyroid hormone derangements of NTIS.

Risk stratification for persistent disease is an important step in pediatric differentiated thyroid cancer (DTC) management. The dynamic risk stratification (DRS) is a well validated system for adults, but not yet for children and adolescents. This study evaluated the DRS as well as other prognostic factors in pediatric DTC.Patients aged ≤18 years from four DTC tertiary teaching hospitals in Southern Brazil were included. Clinical characteristics were systematically retrieved, and all patients were classified according to the risk-stratification system of the 2015 American Thyroid Association pediatric DTC guidelines (ATA risk) and according to DRS (excellent, indeterminate, biochemical, or structural incomplete responses). Disease status was evaluated after initial therapy and at last follow-up visit.Sixty-six patients aged 14.5 ± 3.0 years were studied of whom 54 (81.8%) were girls and 62 (93.9%) had papillary thyroid carcinomas. Tumor size was 2.3 cm (P25-75 1.6-3.5); 41 (63.1%) had cervical and 18 (27.7%) distant metastasis at diagnosis. All patients underwent total thyroidectomy, and 63 (95.5%) received radioiodine. Patients were classified according to DRS after initial therapy (n = 63) as follows: 21 (33%) excellent, 13 (21%) indeterminate, 6 (9%) biochemical, and 23 (37%) structural incomplete responses. Notably, after six years (P25-75 2.7-10.0), most patients remained in the same category. Interestingly, the cutoff analysis of stimulated postoperative thyroglobulin (sPOTg) through receiver operating characteristic curve showed that the value of 37.8 ng/mL showed 81% sensitivity and 100% specificity to predict an excellent response. Prognostic factors associated with persistent disease in the univariate analysis were TNM, ATA risk, DRS, and sPOTg.DRS after initial therapy and sPOTg are strong predictors of disease outcome and might be helpful for defining follow-up strategies in pediatric DTC.

Background Changes in global DNA methylation have been suggested to cause genomic instability leading to increased risk of cancer. The accumulation of epigenetic changes is believed to contribute to tumorigenesis and dedifferentiation, but the effects of such changes in thyroid cancer are still yet defined. Objective To evaluate the global DNA methylation levels in thyroid cancer patients. Methods Total DNA was extracted from peripheral blood leukocytes of the medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC) patients and the methylation pattern was evaluated using the Imprint Methylated DNA Quantification kit (Sigma-Aldrich). Results A total of 42 patients were analyzed (24 MTC, 12 PTC, and 6 controls). For MTC, the mean age was 41 ± 20 years, 54% were women and 12 cases were sporadic. The median calcitonin level at diagnosis was 1692 (637–8865), 65% of the MTC patients had local metastases and 23% distant metastases. For PTC, the median age was 43 ± 15 years, 58% were women and 50% had local metastases. The percentage of overall methylation differed according to the tumor subtype. Patients with MTC had a higher level of DNA methylation when compared to individuals with PTC (35 (24–48) vs. 17 (6.5–20.5); P = 0.002, respectively). Interestingly, among patients with MTC, individuals with the sporadic form of the disease had a higher level of methylation when compared to the hereditary form (25 (16–37) vs. 43 (33–52); P = 0.025, respectively). No association was observed between global methylation levels and clinical and/or oncological characteristics of the disease. Conclusion Global methylation levels were higher in MTC as compared to PTC patients. These results suggest the overall DNA methylation profile may be influenced by the histological subtype of thyroid cancer.

Thyroid hormones (TH) are critical regulators of several physiological processes, which include development, differentiation and growth in virtually all tissues. In past decades, several studies have shown that changes in TH levels caused by thyroid dysfunction, disruption of deiodinases and/or thyroid hormone receptor (TR) expression in tumor cells, influence cell proliferation, differentiation, survival and invasion in a variety of neoplasms in a cell type-specific manner. The function of THs and TRs in neoplastic cell proliferation involves complex mechanisms that seem to be cell specific, exerting effects via genomic and nongenomic pathways, repressing or stimulating transcription factors, influencing angiogenesis and promoting invasiveness. Taken together, these observations indicate an important role of TH status in the pathogenesis and/or development of human neoplasia. Here, we aim to present an updated and comprehensive picture of the accumulated knowledge and the current understanding of the potential role of TH status on the different hallmarks of the neoplastic process.

Prognostic factors are essential for risk stratification in patients with differentiated thyroid carcinoma (DTC). The role of stimulated postoperative thyroglobulin (sPOTg) has been well established in adult DTC population, but it remains unclear in children and adolescents. This study aimed to evaluate potential prognostic factors in children and adolescents with DTC, with special emphasis on sPOTg analysis.Individuals aged ≤18 years at diagnosis were selected from a cohort of DTC patients attending the thyroid clinic of a tertiary university-based hospital. Baseline clinical and oncological characteristics, interventions, disease status, and outcomes were obtained from medical records. Clinical variables included in the univariate analysis were sex, age at diagnosis, tumor size, the presence of lymph node and distant metastasis, and sPOTg. Additionally, sPOTg was evaluated using the area under the receiver operating characteristic curve analysis.Thirty-two children and adolescents with DTC (28 girls, 87.5%; the mean age at diagnosis = 14.7 ± 3.2 years) were included in this study. Thirty-one (96.9%) patients had papillary thyroid carcinoma. The median tumor size was 2.0 cm (P25-75 = 1.6-3.5), 22 patients (68.8%) had lymph node disease, and 5 (15.6%) had distant metastasis at diagnosis. All patients underwent total thyroidectomy, and 29 (90.6%) received radioactive iodine therapy. After a median follow-up of 5.0 years (P25-75 = 2.0-10.0), disease status was available for 27 patients: 15 (55.6%) patients were disease free, six (22.5%) had biochemical disease, and six (22.2%) had persistent structural disease (two cervical and four distant metastasis). Prognostic factors associated with persistent disease in the univariate analysis were lymph node and distant metastasis at diagnosis and sPOTg. According to the receiver operating curve analysis (n = 17 patients), the best sPOTg cutoff to predict disease-free status was 31.5 ng/mL, with a sensitivity and specificity of 100%.The data demonstrate that sPOTg displayed high accuracy in predicting the risk of persistent disease in young patients with DTC.

Nonthyroidal illness syndrome (NTIS) affects patients with myocardial infarction (MI). Oxidative stress has been implicated as a causative factor of NTIS, and reversed via N-acetylcysteine (NAC). Male Wistar rats submitted to left anterior coronary artery occlusion received NAC or placebo. Decreases in triiodothyronine (T3) levels were noted in MI-placebo at 10 and 28 days post-MI, but not in MI-NAC. Groups exhibited similar infarct areas whereas MI-NAC exhibited higher ejection fraction than did MI-placebo. Left ventricular systolic and diastolic diameters were also preserved in MI-NAC, but not in MI-placebo. Ejection fraction was positively correlated with T3 levels. Oxidative balance was deranged only in MI-placebo animals. Increased type 3 iodothyronine deiodinase expression was detected in the cardiomyocytes of MI-placebo compared with normal heart tissue. NAC was shown to diminish type 3 iodothyronine deiodinase expression and activity in MI-NAC. These results show that restoring redox balance by NAC treatment prevents NTIS- related thyroid hormone derangement and preserves heart function in rats subjected to MI.

Selective serotonin reuptake inhibitors (SSRI) have been claimed to negatively affect the thyroid function, albeit the evidence is controversial. We searched for studies that measured parameters of thyroid function (TSH, T4, Free T4, or T3) before and after a course of SSRI treatment in euthyroid patients with major depressive disorder. Electronic searches were conducted on MEDLINE, Embase and Web of Science databases from inception through April 4th, 2018. We performed random-effects meta-analyses to estimate the effect of SSRIs on each hormone. A total 1791 records were identified in the electronic search, and 14 observational clinical studies were included in the analyses. All studies had at least moderate risk of bias and were considered of low quality. A course of SSRI treatment was associated with a decrease in T4 of –6.58 nmol/L (95% Confidence Interval [CI], –12.17 to –.99, p = .005, I2=97%; Cohen's d = .50), a decrease in Free T4 of –.91 pmol/L (95% CI, –1.65 to –.16, p = .017, I2=96%; Cohen's d = .66), and a decrease in T3 of –.10 nmol/L (95% CI, –.18 to –.03, p = .007, I2=96%; Cohen's d = .45), and no effect on TSH (0.06 microIU/L, 95% CI, –.05 to .17, p = .285, I2=98%; Cohen's d = .17). We did not detect publication bias in any of the four meta-analyses. We conclude that there is preliminary evidence that SSRIs slightly decrease thyroid function, but quality of evidence is low. Clinical magnitude of such effect is yet unclear.

The principle underlying personalized medicine is that using specific information about a person’s disease will help in establishing a diagnostic, a therapeutic strategy or defining a prognosis. Nevertheless, the underlying assumptions of the precision-medicine model may not be obvious, since it includes the existence of meaningful subgroups of patients and the ability to identify them with this approach. Perhaps the most successful area of personalized medicine is cancer treatment. Tumors arise as a result of an accumulative series of events [...]

Imbalances in the redox status are involved in type 3 deiodinase (D3) induction in the non-thyroidal illness syndrome (NTIS). The mechanisms responsible for D3 dysfunction under systemic redox alterations in disease are poorly understood. Recently, the resemblance of D3 with peroxiredoxin-like proteins has been suggested. Objective: Evaluate the paths of redox alterations leading to D3 induction in liver, muscle, and brain in an animal model of NTIS. Methods: Male Wistar rats submitted to left anterior coronary artery occlusion (MI) were treated or not with N-acetylcysteine (NAC), an antioxidant that replenishes cysteine levels. Ten days post-MI animals were sacrificed and tissues collected. D3 activity was measured in liver, muscle, and brain. Total carbonyl and sulphydryl contents, as well as enzymatic and nonenzymatic oxidative parameters, were determined. Results: Compared to sham, D3 activity was increased in liver (P=0.002), muscle (P=0.03) and brain (P=0.01) in MI-placebo animals. All tissues from placebo group showed increased carbonyls, marker of oxidative damage to protein, and diminished sulphydryl levels, indicating cysteine and thiol consumption (all P=0.001). GSH/GSSG ratio was altered in all tissues (P=0.001). GSH is a critical antioxidant that depends on sulphydryl groups as a ready source of reducing equivalents. Liver and muscle had augmented glutathione peroxidase (GPx), glutathione reductase (GR) and thioredoxin reductase (TRx) levels (P=0.001). NAC prevented all the alterations described above. Conclusion: D3 induction in tissues correlates to MI-induced redox changes. NAC preventing D3 dysfunction indicates a role for altered cysteine/thiol in this process. The enzymatic profile suggests a functional regenerating GSH system. The set of these results adds to the present knowledge of NTIS physiopathology since they indicate a reversible oxidative post-transcriptional modification of D3 probably through a putative formation of mixed disulfides with cysteine and glutathione (glutathionylation process) that could be reduced by TRx as one of the causes for D3 induction in disease. The possibility that the thiols are being consumed to form disulphide bonds from augmented GSSG could also be considered. Antioxidant treatment prevents D3 dysfunction in multiple tissues, which probably contribute to avoiding NTIS.

Purpose of review Medullary thyroid carcinoma (MTC) comprises approximately 4% of all malignant thyroid neoplasms. Although the majority of patients have a good prognosis, a subgroup of patients develops progressive disease and requires systemic therapy. Here, we focused on the current MTC therapeutic approaches and discussed the advantages and disadvantages of molecular targeted therapies. Recent findings Targeted molecular therapies that inhibit RET and other tyrosine kinase receptors involved in angiogenesis have been shown to improve progression-free survival in patients with advanced MTC. Two drugs, vandetanib and cabozantinib, have been approved for the treatment of progressive or symptomatic MTC, and several others have exhibited variable efficacy. No tyrosine kinase inhibitor has been shown to improve survival. Although no definitive recommendation can currently be made, cumulative data indicate that knowledge of the tumor mutational profile may facilitate improvements in targeted therapy for MTC. Summary Tyrosine kinase inhibitors are effective therapeutic agents for the treatment of progressive MTC. Nevertheless, it is not clear who will benefit the most from therapy, and the decision regarding when and how to initiate the treatment should be made based on the patient's medical history and tumor behavior. Hopefully, in the near future, molecular profiling of MTC can be used to determine the most effective molecular therapeutic target.

Type 3 deiodinase (DIO3, D3) is reactivated in human neoplasias. Increased D3 levels in papillary thyroid carcinoma (PTC) have been associated with tumor size and metastatic disease. The objective of this study is to investigate the signaling pathways involved inDIO3upregulation in PTC. Experiments were performed in human PTC cell lines (K1 and TPC-1 cells) or tumor samples.DIO3mRNA and activity were evaluated by real-time PCR and ion-exchange column chromatography respectively. Western blot analysis was used to determine the levels of D3 protein.DIO3gene silencing was performed via siRNA transfection.DIO3mRNA levels and activity were readily detected in K1 (BRAFV600E) and, at lower levels, in TPC-1 (RET/PTC1) cells (PP=0.02 respectively). Similarly,DIO3mRNA levels were higher in PTC samples harboring theBRAFV600Emutation as compared with those with RET/PTC1 rearrangement or negative for these mutations (PBRAFoncogene (PLX4032, 3 μM), MEK (U0126, 10–20 μM) or p38 (SB203580, 10–20 μM) signaling was associated with decreases inDIO3expression in K1 and TPC-1 cells. Additionally, the blockage of the sonic hedgehog (SHH) pathway by cyclopamine (10 μM) resulted in markedly decreases inDIO3mRNA levels. Interestingly, siRNA-mediatedDIO3silencing induced decreases on cyclin D1 expression and partial G1 phase cell cycle arrest, thereby downregulating cell proliferation. In conclusion, sustained activation of the MAPK and SHH pathways modulate the levels ofDIO3expression in PTC. Importantly,DIO3silencing was associated with decreases in cell proliferation, thus suggesting a D3 role in tumor growth and aggressiveness.

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant genetic disease caused by RET gene germline mutations that is characterized by medullary thyroid carcinoma (MTC) associated with other endocrine tumors. Several reports have demonstrated that the RET mutation profile may vary according to the geographical area. In this study, we collected clinical and molecular data from 554 patients with surgically confirmed MTC from 176 families with MEN2 in 18 different Brazilian centers to compare the type and prevalence of RET mutations with those from other countries. The most frequent mutations, classified by the number of families affected, occur in codon 634, exon 11 (76 families), followed by codon 918, exon 16 (34 families: 26 with M918T and 8 with M918V) and codon 804, exon 14 (22 families: 15 with V804M and 7 with V804L). When compared with other major published series from Europe, there are several similarities and some differences. While the mutations in codons C618, C620, C630, E768 and S891 present a similar prevalence, some mutations have a lower prevalence in Brazil, and others are found mainly in Brazil (G533C and M918V). These results reflect the singular proportion of European, Amerindian and African ancestries in the Brazilian mosaic genome.

Objective: The 8th TNM system edition (TNM-8) released in 2018 presents significant changes when compared to the 7th edition (TNM-7). The aim of this study was to assess the impact of changing the TNM staging criteria on the outcomes in a Brazilian cohort of differentiated thyroid carcinoma (DTC). Subjects and methods: DTC patients, attending a tertiary, University-based hospital, were classified by TNM-7 and TNM-8. Prediction of disease outcomes status of the two systems was compared in a retrospective cohort study design. Results: Four hundred and nineteen DTC patients were evaluated, comprised by 82% (345/419) women, with mean age at diagnosis of 46.4 ± 15.6 years, 89% (372/419) papillary thyroid carcinoma, with a median tumor size of 2.3 cm (P25-P75, 1.3-3.5). One hundred and sixty patients (38%) had lymph node metastases and 47 (11%) distant metastases at diagnosis. Using the TNM-7 criteria, 236 (56%) patients were classified as Stage I, 50 (12%) as Stage II, 75 (18%) as Stage III and 58 (14%) as Stage IV. When evaluated by the TNM-8, 339 (81%) patients were classified as Stage I, 64 (15%) as Stage II, 2 (0.5%) as Stage III and 14(3%) as Stage IV. After a median follow-up of 4.4years (P25-P75 2.6-6.6), the rate of incomplete biochemical and/or structural response was 54% vs. 92% (P = 0.004) and incomplete structural response was 42% vs. 86% (P = 0.009) for patients classified as stage IV by TNM-7 vs TNM-8, respectively. Only 4 (1%) disease-related deaths were recorded. Conclusions: In our cohort, 37% of DTC patients were down staged with the application of TNM-8 (vs. TNM-7). Additionally, TNM-8 seems to better stratify the risk of structural incomplete response at follow-up.

Polycystic ovary syndrome (PCOS) is the most prevalent endocrine disorder affecting women of reproductive age. PCOS has been associated with distinct metabolic and cardiovascular diseases and with autoimmune conditions, predominantly autoimmune thyroid disease (AITD). AITD has been reported in 18-40% of PCOS women, depending on PCOS diagnostic criteria and ethnicity. The aim of this systematic review and meta-analysis was to summarize the available evidence regarding the likelihood of women with PCOS also having AITD in comparison to a reference group of non-PCOS women. We systematically searched EMBASE and MEDLINE for non-interventional case control, cross-sectional, or cohort studies published until August 2017. The Ottawa-Newcastle Scale was used to assess the methodological quality of studies. Statistical meta-analysis was performed with R. Thirteen studies were selected for the present analysis, including 1,210 women diagnosed with PCOS and 987 healthy controls. AITD was observed in 26.03% and 9.72% of PCOS and control groups respectively. A significant association was detected between PCOS and chance of AITD (OR= 3.27, 95%CI 2.32-4.63). Notably, after geographical stratification, the higher risk of AITD in PCOS women persisted for Asians (OR= 4.56, 95%CI 2.47-8.43), Europeans (OR= 3.27, 95%CI 2.07-5.15), and South Americans (OR= 1.86, 95 %CI 1.05-3.29). AIDT is a frequent condition in PCOS patients, and might affect thyroid function. Thus, screening for thyroid function and thyroid-specific autoantibodies should be considered in patients with PCOS even in the absence of overt symptoms. This systematic review and meta-analysis is registered in PROSPERO under number CRD42017079676., info:eu-repo/semantics/published

Nonthyroidal illness syndrome (NTIS) is marked by low T3 and high reverse T3 levels. The physiopathology is poorly understood but involves oxidative stress-induced disruption of the iodothyronine deiodinases, which activate or inactivate thyroid hormones. Selenium, an essential trace element, exerts antioxidant function mainly through the thioredoxin reductase (TRx) and glutathione peroxidase (GPx) redox-regulating systems. We evaluated the effect of sodium selenite on IL6-induced disruption on deiodinase function. Cell lines expressing endogenous deiodinases type 1(D1), 2(D2) or 3(D3) (HepG2, MSTO, and MCF-7 cells, respectively) were used in an intact cell model that mimics the deiodination process under physiological conditions of substrate and cofactor, in the presence or not of IL6, with or without selenite. Deiodinase activity was quantified by the amount of iodine-125 in the medium (D1 and D2) or by ion-exchange chromatography (D3). Oxidative stress was evaluated by measuring reactive species (RS), carbonyl content as well as enzymatic and non-enzymatic antioxidant defenses. Results: IL6 induced ROS and carbonyl content in all 3 cell lines (all P, Graphical abstract fx1, Highlights • IL6 induced oxidative stress impairs deiodinase function in critically ill patients. • Selenite induces the antioxidant defense through the enzymatic TRx and GPx pathways. • Selenite attenuates redox imbalance but it does not restore deiodinase activities. • Intracellular cysteine levels are critical to proper deiodinases function.

Trends in the epidemiological profiles of differentiated thyroid cancer (DTC) have shifted the disease spectrum. This study aimed to evaluate the recurrence rates and identify factors related to persistent disease in a contemporary cohort of patients with DTC.A cohort of DTC patients submitted to total thyroidectomy followed in a referral center were included in the study. "Disease free" was defined as no clinical, imaging, or biochemical evidence of tumors. "Recurrence" was defined as evidence of disease in a patient who had been previously classified as disease free.A total of 786 patients were included. The mean age at diagnosis was 45.8±15.1 years, 81.6% were female, and papillary thyroid cancer accounted for 86.6% of cases. The median tumor size was 2.0 cm, 28.5% had lymph node involvement, and 6.1% had distant metastases. Disease status after the initial therapy was available for 548 patients: 357 (65.1%) were disease free, and 191 (34.9%) had persistent disease (90 biochemical and 101 structural disease). In multivariate model analyses, the variables male sex, lateral lymph nodal involvement, distant metastasis, and 2009 ATA high-risk classification were independent prognostic factors for persist disease. After a four-year follow-up (two to eight years), 97.2% of the patients who had been classified as disease free remained in disease remission status. Of the 10 (2.8%) patients with recurrent disease, eight presented biochemical and two cervical structural disease.The majority of the DTC patients who were considered to be disease free after the initial treatment remained with this status at long-term follow-up. These data suggest that less intensive follow-up may apply for these patients.

Background: Thyroglobulin measurements in the washout of fine needle aspiration (FNA-Tg) are an excellent tool to detect lymph node (LN) metastases of differentiated thyroid carcinoma (DTC). Nevertheless, how to define the best cutoffs and the influence of potential confounders are still being discussed. Objective: To evaluate the accuracy of FNA-Tg measurement to detect DTC metastases and the influence of thyroid status and anti-thyroglobulin antibodies (TgAb). Methods: One hundred thirty-eight patients with DTC and suspicious cervical LN were included. Patients underwent ultrasound (US)-guided FNA for cytological examination and FNA-Tg measurements. Final diagnoses were confirmed by histological examination or clinical and US follow-up for at least 1 year. Results: Data from 119 subjects with suspicious LN were evaluated. The median value of FNA-Tg in patients with metastatic LN (n = 65) was 3,263.0 ng/mL (838.55–12,507.5), while patients without LN metastasis (n = 54) showed levels of 0.2 ng/mL (0.2–0.2). According to the ROC curve analysis, the best cutoff value to predict metastasis was 4.41 ng/mL for FNA-Tg, with a sensitivity of 98% and specificity of 96%. There were no differences in the median of FNA-Tg measurements between those on (TSH 0.16 mUI/mL) and those off levothyroxine (TSH 99.41 mUI/mL) therapy (47.94 vs. 581.15 ng/mL, respectively; p = 0.79). Interestingly, the values of FNA-Tg in patients with LN metastasis (n = 65) did not differ between patients with positive and those with negative TgAb (88.8 vs. 3,263.0 ng/mL, respectively; p = 0.57). Conclusion: US-guided FNA-Tg proved to be a useful examination in the follow-up of patients with DTC, independently of TSH status and the presence of TgAb.

The acute phase of the nonthyroidal illness syndrome (NTIS) is characterized by low T3 and high rT3 levels, affecting up to 75% of critically ill patients. Oxidative stress has been implicated as a causative factor of the disturbed peripheral thyroid hormone metabolism.The objective of the study was to investigate whether N-acetylcysteine (NAC), a potent intracellular antioxidant, can prevent NTIS in patients with acute myocardial infarction.This was a randomized, multicenter clinical trial.Consecutive patients admitted to the emergency and intensive care units of two tertiary hospitals in southern Brazil were recruited. Patients and intervention included 67 patients were randomized to receive NAC or placebo during 48 hours. Baseline characteristics and blood samples for thyroid hormones and oxidative parameters were collected.Variation of serum T3 and rT3 levels was measured.Baseline characteristics were similar between groups (all P.05). T3 levels decreased in the placebo group at 12 hours of follow-up (P = .002) but not in NAC-treated patients (P = .10). Baseline rT3 levels were elevated in both groups and decreased over the initial 48 hours in the NAC-treated patients (P = .003) but not in the control group (P = .75). The free T4 and TSH levels were virtually identical between the groups throughout the study period (P.05). Measurement of total antioxidant status and total carbonyl content demonstrated that oxidative balance was deranged in acute myocardial infarction patients, whereas NAC corrected these alterations (P.001).NAC administration prevents the derangement in thyroid hormone concentrations commonly occurring in the acute phase of acute myocardial infarction, indicating that oxidative stress is involved in the NTIS pathophysiology.

We reported thyroid hormone (TH) receptor expression in murine dendritic cells (DCs) and 3,5,3'-triiodothyronine (T3)-dependent stimulation of DC maturation and ability to develop a Th1-type adaptive response. Moreover, an increased DC capacity to promote antigen-specific cytotoxic T-cell activity, exploited in a DC-based antitumor vaccination protocol, was revealed. However, putative effects of the main circulating TH, l-thyroxine (T4) and the mechanisms of TH transport and metabolism at DC level, crucial events for TH action at target cell level, were not known. Herein, we show that T4 did not reproduce those registered T3-dependent effects, finding that may reflect a homoeostatic control to prevent unspecific systemic activation of DCs. Besides, DCs express MCT10 and LAT2 TH transporters, and these cells mainly transport T3 with a favored involvement of MCT10 as its inhibition almost prevented T3 saturable uptake mechanism and reduced T3-induced IL-12 production. In turn, DCs express iodothyronine deiodonases type 2 and 3 (D2, D3) and exhibit both enzymatic activities with a prevalence towards TH inactivation. Moreover, T3 increased MCT10 and LAT2 expression and T3 efflux from DCs but not T3 uptake, whereas it induced a robust induction of D3 with a parallel slight reduction in D2. These findings disclose pivotal events involved in the mechanism of action of THs on DCs, providing valuable tools for manipulating the immunogenic potential of these cells. Furthermore, they broaden the knowledge of the TH mechanism of action at the immune system network. Fil: Gigena, Nicolás. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina Fil: Alamino, Vanina Alejandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina Fil: Montesinos, Maria del Mar. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina Fil: Nazar, Magalí. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina Fil: Louzada, Ruy A.. Universidade Federal do Rio de Janeiro; Brasil Fil: Wajner, Simone M.. Universidade Federal do Rio Grande do Sul; Brasil Fil: Maia, Ana L.. Universidade Federal do Rio Grande do Sul; Brasil Fil: Masini, Ana María. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina Fil: Carvalho, Denise P.. Universidade Federal do Rio de Janeiro; Brasil Fil: Cremaschi, Graciela Alicia. Pontificia Universidad Católica Argentina "Santa María de los Buenos Aires". Instituto de Investigaciones Biomédicas. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Biomédicas; Argentina Fil: Pellizas, Claudia Gabriela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; Argentina

Radioactive iodine (RAI) is widely used in the management of differentiated thyroid cancer (DTC). The impact of the time interval between total thyroidectomy (TT) and RAI administration on disease outcome remains controversial. The objective of the present study was to evaluate the impact of the time interval between TT and RAI.This study evaluated a cohort of DTC patients who received RAI therapy for whom data on disease status were available. Patients were allocated to one of two groups, according to the time interval between TT and RAI. "Disease-free" was defined as no clinical, imaging, or biochemical evidence of thyroid cancer.The study included 545 individuals. The TNM stages were: 322 (59.1%) patients in Stage I, 62 (11.4%) in Stage II, 65 (11.9%) in Stage III, and 82 (15.0%) in Stage IV. The median time interval between TT and RAI was six months (P25-75: 3-10 months). Patients were allocated to one of two groups according to RAI timing administration: group A ≤6 months after TT (median 3 months; n = 295), or group B6 months after TT (median 10.5 months; n = 250). There were no differences for sex, histological type, tumor size, distant metastasis, or RAI dose between the groups (p 0.1). Patients in group B were older (47.1 vs. 43.1 years; p = 0.02), had less cervical metastasis (73.6% vs. 59.3%; p = 0.002), and were more commonly classified as low ATA risk (48.0% vs. 36.6%; p = 0.027). One year after initial therapy, 59.3% and 65.6% of patients in groups A and B, respectively, were considered disease-free (p = 0.15). Remarkably, the percentage of patients classified as disease-free was similar, even when analyzing a subgroup of high-risk patients (n = 72; 9.5% vs. 10.0%; p = 1.0). These findings did not change after a median of six years of follow-up. Accordingly, further analysis by multiple logistic regression showed that timing of RAI was not associated with persistent disease (relative risk 0.97 [confidence interval 0.80-1.19]).Timing of RAI does not seem to interfere with the disease outcomes in DTC and can therefore be safely planned while taking into account the health system logistics.

Objective: RET single nucleotide polymorphisms (SNPs) have been implicated in the pathogenesis and progression of medullary thyroid carcinoma (MTC). Here, we investigated the influence of multiple RET variants (G691S, L769L, S836S, and S904S) on the risk of MTC and tumor behavior. Design and methods: One hundred and seven MTC patients and 308 cancer-unaffected control individuals were included. SNPs were analyzed using Custom TaqMan Genotyping Assays. Haplotypes based on the combination of allelic variants were inferred using a Bayesian statistical method. Results: The minor allele frequencies in MTC patients were as follows: L769L: 28.0%, S836S: 8.9%, and G691S/S904S: 22.2%. The RET L769L and S836S SNPs were associated with increased risk of MTC (odds ratio (OR)Z1.95, 95% CI: 1.2–3.1, PZ0.005 and ORZ2.29, 95% CI: 1.2–4.5, PZ0.017 respectively). The adjusted OR for individuals harboring haplotypes with three or more polymorphic alleles was 3.79 (95% CI: 1.5–9.5; PZ0.004), indicating an additive effect of these variants on the risk for MTC. Among MTC patients, no significant associations were observed between RET variants and age of diagnosis or tumor size but serum calcitonin levels increased according to the number of risk alleles (PZ0.003). Remarkably, patients carrying haplotypes with three or four risk alleles had increased risk for lymph node and distant metastases at diagnosis (ORZ5.84, 95% CI: 1.1–31.2, PZ0.039). Further analysis using Kaplan–Meier model demonstrated that metastatic disease occurred earlier in individuals harboring multiple risk alleles. Conclusion: Our results demonstrated an additive effect of RET polymorphic alleles on the estimated risk of developing aggressive MTC.

Resistance to thyroid hormone (RTH) is a rare autosomal dominant inherited disorder characterized by end-organ reduced sensitivity to thyroid hormone. This syndrome is caused by mutations of the thyroid hormone receptor (TR) β gene, and its clinical presentation is quite variable. Goiter is reported to be the most common finding. A close association of TRβ mutations with human cancers has become apparent, but the role of TRβ mutants in the carcinogenesis is still undefined. Moreover, higher TSH levels, described in RTH syndrome, are correlated with increased risk of thyroid malignancy, whereas TSH receptor stimulation is likely to be involved in tumor progression. We report here an illustrative case of a 29 year-old patient with RTH caused by a mutation in exon 9 (A317T) of TRβ gene, who presented multicentric papillary thyroid cancer. We review the literature on this uncommon feature, and discuss the potential role of this mutation on human tumorigenesis, as well as the challenges in patient follow-up.

Type 2 deiodinase (D2) converts T4 into its active metabolite T3, an essential step in thyroid metabolism. A Thr92Ala polymorphism in the gene encoding D2 has been inconsistently associated with insulin resistance (IR). Recently, it was reported that the D2 Thr92Ala (rs225014) and the peroxisome proliferator-activated receptor (PPAR) γ2 Pro12Ala (rs1801282) polymorphisms interact in the modulation of metabolic syndrome in nondiabetic subjects. Here, we investigated the effect of both polymorphisms, isolated or in combination, on IR in patients with type 2 diabetes mellitus (DM2). The D2 Thr92Ala and PPARγ2 Pro12Ala polymorphisms were genotyped in 721 DM2 patients. IR was evaluated using the homeostasis model assessment-IR (HOMA(IR)) index in a subgroup of 246 DM2 subjects. The frequencies of D2 Ala92 and PPARγ2 Ala12 variants were 0.390 and 0.074, respectively. Patients carrying D2 Ala/Ala genotype had a higher fasting plasma insulin and HOMA(IR) index as compared to patients carrying Thr/Ala or Thr/Thr genotypes (P = 0.022 and P = 0.001, respectively). A significant synergistic effect was observed between D2 Thr92Ala and PPARγ2 Pro12Ala polymorphisms on HOMA(IR) index, with carriers of both D2 Ala/Ala genotype and PPARγ2 Ala12 allele showing the highest HOMA(IR) values, after adjusting for age, gender, BMI, and use of medication for DM2 (P = 0.010). In conclusion, DM2 patients harboring both D2 Ala/Ala genotype and PPARγ2 Ala12 allele seem to present more severe IR than those with other D2/PPARγ2 genotype combinations. These findings suggest that these polymorphisms interact in the IR modulation, which may constitute a potential therapeutic target.

Thyroid hormone is essential for the normal function of virtually all tissues. The iodothyronine deiodinases catalyze the removal of an iodine residue from the pro-hormone thyroxine (T4) molecule, thus producing either the active form triiodothyronine (T3; activation) or inactive metabolites (reverse T3; inactivation). Type I deiodinase (D1) catalyzes both reactions. Over the last years, several studies have attempted to understand the mechanisms of D1 function, underlying its effects on normal thyroid hormone metabolism and pathological processes. Although peripheral D1-generated T3 production contributes to a portion of plasma T3 in euthyroid state, pathologically increased thyroidal D1 activity seems to be the main cause of the elevated T3 concentrations observed in hyperthyroid patients. On the other hand, D1-deficient mouse models show that, in the absence of D1, inactive and lesser iodothyronines are excreted in feces with the loss of associated iodine, demonstrating the scavenging function for D1 that might be particularly important in an iodine deficiency setting. Polymorphisms in the DIO1 gene have been associated with changes in serum thyroid hormone levels, whereas decreased D1 activity has been reported in the nonthyroid illness syndrome and in several human neoplasias. The current review aims at presenting an updated picture of the recent advances made in the biochemical and molecular properties of D1 as well as its role in human physiology.

The possible role of RET variants in modifying the natural course of medullary thyroid carcinoma (MTC) is still a matter of debate. Here, we investigate whether the RET variants L769L, S836S, and G691S/S904S influence disease presentation in hereditary or sporadic MTC patients. One hundred and two patients with hereditary MTC and 81 patients with sporadic MTC attending our institution were evaluated. The frequencies of RET polymorphisms in hereditary MTC were as follows: L769L, 17.3%; S836S, 7.95%; and S904S/G691S, 18.2%. No associations were observed between these polymorphisms and pheochromocytoma, hyperparathyroidism, lymph node, or distant metastasis. However, patients harboring the S836S variant were younger than those without this allele (17±8.2 vs 28.6±14.4 years, P=0.01), suggesting that these patients had metastases at a young age. Accordingly, the cumulative frequency of local and/or distant metastases as estimated by Kaplan–Meier curves showed that lymph node and distant metastases occurred earlier in patients harboring the S836S variant (P=0.003 and P=0.026 respectively). The S836S allele frequency was higher in sporadic MTC patients than in controls (10.5 vs 3.1%, P=0.01). Individuals harboring the S836S variant were younger (38.6±13.3 vs 48.5±16.7 years, P=0.02) and showed a higher percentage of lymph node and distant metastases (P=0.02 and P=0.04 respectively). Kaplan–Meier estimates of lymph node and distant metastases yielded distinct curves for patients with or without the S836S allele (P=0.002 and P=0.001 respectively). Additional analyses using a COX regression model showed that the S836S variant was independently associated with metastatic disease (hazard ratio 2.82 (95% confidence interval 1.51–5.26), P=0.001). In conclusion, the RET S836S variant is associated with early onset and increased risk for metastatic disease in patients with hereditary or sporadic MTC.

ObjectiveThe type 2 deiodinase (D2) is a key enzyme for intracellular triiodothyronine (T3) generation. A single-nucleotide polymorphism in D2 (Thr92Ala) has been associated with increased insulin resistance in nondiabetic and type 2 diabetes (DM2) subjects. Our aim was to evaluate whether the D2 Thr92Ala polymorphism is associated with increased risk for DM2.Design and methodsA case–control study with 1057 DM2 and 516 nondiabetic subjects was performed. All participants underwent genotyping of the D2 Thr92Ala polymorphism. Additionally, systematic review and meta-analysis of the literature for genetic association studies of D2 Thr92Ala polymorphism and DM2 were performed in Medline, Embase, LiLacs, and SciELO, and major meeting databases using the terms ‘rs225014’ odds ratio (OR) ‘thr92ala’ OR ‘T92A’ OR ‘dio2 a/g’.ResultsIn the case–control study, the frequencies of D2 Ala92Ala homozygous were 16.4% (n=173) versus 12.0% (n=62) in DM2 versus controls respectively resulting in an adjusted OR of 1.41 (95% confidence intervals (CI) 1.03–1.94, P=0.03). The literature search identified three studies that analyzed the association of the D2 Thr92Ala polymorphism with DM2, with the following effect estimates: Mentuccia (OR 1.40 (95% CI 0.78–2.51)), Grarup (OR 1.09 (95% CI 0.92–1.29)), and Maia (OR 1.22 (95% CI 0.78–1.92)). The pooled effect of the four studies resulted in an OR 1.18 (95% CI 1.03–1.36, P=0.02).ConclusionsOur results indicate that in a case–control study, the homozygosity for D2 Thr92Ala polymorphism is associated with increased risk for DM2. These results were confirmed by a meta-analysis including 11 033 individuals, and support a role for intracellular T3 concentration in skeletal muscle on DM2 pathogenesis.

Multiple endocrine neoplasia type 2A (MEN2A) is an autosomal dominant inherited condition that predisposes to the triad of medullary thyroid cancer (MTC), pheochromocytoma (Pheo), and primary hyperparathyroidism (PHT). Nearly 100% of MEN2A are associated with germ line mutation of the RET proto-oncogene (RET), and DNA-based RET genotype analysis is now considered essential for earlier diagnosis. The first manifestation of MEN2A is most often due to MTC, and less frequently to Pheo. Rarely, MEN2A is recognized during the search for PHT associated conditions. Most patients with primary hyperparathyroidism are asymptomatic, and the focus of the presentation may be the side effects of chronic hypercalcemia, osteoporosis, renal lithiasis, peptic ulcer disease, and hypertension. Hypercalcemic pancreatitis is rare, being an uncommon first manifestation of PHT. Here, we report on a patient who presented recurrent pancreatitis as the first manifestation of MEN2A. In the present case, prompt sequential dosage of calcium, diagnosis of PHT, and genetic analysis would have resulted in pancreatitis prevention and early MEN2A management. Neoplasia endócrina múltipla do tipo 2 (NEM2A) é uma síndrome genética com herança autossômica dominante, que predispõe à tríade de carcinoma medular de tireóide (CMT), feocromocitoma (Feo) e hiperparatireoidismo primário (HPP). Aproximadamente 100% dos casos de NEM2A estão associados a mutações germinativas do protooncogene RET (RET), e a análise molecular do RET é atualmente considerada essencial para diagnóstico precoce. A primeira manifestação da NEM2A é geralmente em decorrência de CMT, e menos freqüentemente devido ao Feo. Raramente, a NEM2A é descoberta durante investigação para condições associadas ao HPP. A maioria dos pacientes com HPP é oligossintomática e a apresentação ocorre devido a sintomas relacionados à hipercalcemia, à osteoporose, à dispepsia, à hipertensão ou à litíase renal. A pancreatite hipercalcêmica é rara, sendo uma manifestação incomum do HPP. Este artigo relata um caso de paciente que apresentou pancreatite recorrente como primeira manifestação de NEM2A. Neste caso, abordagem seqüencial com determinação do cálcio sérico, diagnóstico de HPP e análise genética poderiam ter resultado prevenção de pancreatite e manejo precoce da NEM2A.

As iodotironinas desiodases formam uma família de selenoenzimas com propriedades catalíticas distintas que ativam ou inativam os hormônios tireoidianos via desiodação do anel fenólico ou tirosínico da molécula do T4. As desiodases tipo I e II (D1 e D2) são as enzimas responsáveis pela geração do T3 e são amplamente expressas na tireóide normal. A transformação neoplásica benigna ou maligna da glândula tireóide está associada a alterações na expressão dessas isoenzimas, sugerindo um possível papel da D1 e da D2 como marcadores de diferenciação celular. Anormalidades na expressão de ambas enzimas e da desiodase tipo III (D3), inativadora do hormônios tireoidianos, são também encontradas em outras neoplasias humanas. Os mecanismos ou implicações do aumento ou diminuição das desiodases na patogênese neoplásica são pouco compreendidas. No entanto, é importante observar que a expressão anormal da D2 pode ser responsável por um quadro de tireotoxicose em pacientes com metástases de carcinoma folicular de tireóide, enquanto que o aumento da D3 em hemangiomas pode causar hipotireoidismo de difícil tratamento.

O câncer de tireóide é responsável por cerca de 1% dos novos casos de doença maligna diagnosticados. A maioria destes tumores são carcinomas papilares e foliculares, também denominados de carcinomas diferenciados de tireóide (CDT). Estes carcinomas têm uma taxa de cura de aproximadamente 80%, enquanto 20% apresentarão recorrência local e 5 a 10% desenvolverão metástases à distância. Porém, alguns pacientes apresentam uma doença mais agressiva. A identificação de tais pacientes tem grande impacto no manejo clínico do CDT. Várias classificações de estádio clínico e fatores prognósticos são apresentados, bem como os principais exames para seguimento dos pacientes com CDT. Thyroid carcinoma accounts for roughly 1% of all new malignant diseases. Of these, at least 94% are differentiated thyroid carcinoma (DTC), either papillary thyroid carcinoma or follicular thyroid carcinoma. Patients with DTC are usually considered as having a good prognosis, 80% of patients are cured, 20% will develop loco-regional recurrence and 5- 10% distant metastasis. However, the disease may have an aggressive course in some patients. The identification of these patients has a major impact in the clinical management of DTC. Several prognostic factors and classification will be addressed, as well the most useful tests for patient’s follow-up.

Summary Objective Type I iodothyronine deiodinase (D1) catalyses the 5′ monodeiodination of T4 and is highly expressed in normal human thyroid gland. We have investigated D1 expression in a series of benign and malignant differentiated thyroid neoplasias. Design Surgically isolated thyroid tumour fragments were used. D1 expression was determined by reverse transcription polymerase chain reaction (RT-PCR) and enzymatic assay. Patients Tumours and adjacent normal tissues were obtained from 28 unselected patients (papillary carcinoma, n = 14; follicular adenoma, n = 7; follicular carcinoma, n = 6; anaplastic carcinoma, n = 1). Measurements D1 mRNA levels were determined using specific primers for the human D1 gene and enzymatic assays were performed using T4 as substrate. Results In papillary thyroid carcinoma (PTC), D1 mRNA and activity levels were decreased compared with the surrounding tissue (0·25 ± 0·24 vs. 1·09 ± 0·54 arbitrary units (AU), P

Objective: Radioiodine therapy ( 131 I) in hyperthyroid Craves' disease is generally followed by a transitory increase in levels of thyrotropin receptors antibodies (TRAb). Immunosuppressive effects of antithyroid drugs are still a matter of debate. In this study we evaluated the effect of methimazole pretreatment on the TRAb boost induced by 131 I. Design: A randomized, prospective clinical trial. Methods: 61 patients were randomly assigned to receive 131 I alone (32 patients) or 131 I plus pretreatment with methimazole (30 mg/day; 29 patients). Serum TRAb levels were measured on the day of 131 I dosing (DO), and at 1, 3, 6 and 12 months after 131 I administration. Results: The mean serum TRAb levels decreased significantly from baseline to DO in patients treated with methimazole (80.8 vs 48.8 U/l; P < 0.05). After 131 I treatment, TRAb levels increased at 3 months (48.8 to 60 U/l; 19%) and they were still elevated at 6 months compared with D0 values (99.9 U/l; 105%). Thereafter, TRAb levels decreased to baseline values (47.8 U/l) at 12 months. In hyperthyroid patients, TRAb levels increased significantly from DO to 1 month (45.0 to 78 U/l; 73%) reaching their highest levels at 3 months (225 U/l; 400%). After this, we observed a progressive decrease to the baseline levels at 12 months (40.0 U/l). The course of TRAb levels after 131 I treatment was significantly different between the two groups (P < 0.05). Multiple regression analysis identified serum TRAb levels on DO as independent predictors of TRAb increment after 131 I therapy (r 2 = 0.34; P = 0.001). A higher increment in serum TRAb levels was associated with hypothyroidism after 1 year of follow-up. Conclusion: Methimazole pretreatment attenuates the 131 I-induced rise in serum TRAb levels. The effects of methimazole could be attributed to a direct immunomodulatory action or may be due to its effects on the control of hyperthyroidism, which is a known cause of immune dysregulation.

In the present study we show the expression profiles of both type 1 and type 2 iodothyronine deiodinases (D1 and D2) in a wide spectrum of mouse tIssues, and D2 regulation by thyroid status. A characteristic tIssue-specific expression for each isoform was observed. D2 transcripts were detected in most tIssues with variable levels of expression. The observed D2 mRNA tIssue distribution was similar to that described in rats and is in agreement with the view of different patterns of expression between rodents and humans. However, it is interesting to note that despite the low levels of D2 transcripts in mouse heart and testis in the euthyroid state, the induction of hypothyroidism caused a significant increase in D2 activity in these tIssues. Similar results were also obtained in adult rats. These results suggest a previously unrecognized role for type 2 deiodinase in controlling intracellular triiodothyronine levels in rodent heart and testis during states of thyroid hormone deficiency.

OBJECTIVE—To determine the fatty acid composition of serum phospholipid, triglyceride, and cholesterol ester fractions and to analyze the lipid profile of microalbuminuric type 2 diabetic patients. RESEARCH DESIGN AND METHODS—A case-control study was conducted with 72 patients: 37 were normoalbuminuric (urinary albumin excretion rate [UAER] RESULTS—Microalbuminuric patients showed a lower proportion of polyunsaturated fatty acids (24.8 ± 11.0%), especially of the n-6 family (21.7 ± 10.5%), in triglyceride fraction than normoalbuminuric patients (34.1 ± 11.3%, P = 0.001 and 31.4 ± 11.5%, P < 0.001, respectively). Patients with microalbuminuria also presented higher levels of saturated fatty acids in triglyceride fraction (43.4 ± 18.0% vs. 34.7 ± 13.1%, P = 0.022). In the logistic regression analysis, only the proportion of polyunsaturated fatty acids in triglyceride fraction remained significantly associated with microalbuminuria (odds ratio [OR] 0.92, 95% CI 0.85–0.98, P = 0.019). Total cholesterol, HDL cholesterol, triglyceride, and apolipoprotein B levels were similar in normo- and microalbuminuric patients. CONCLUSION—Microalbuminuria in type 2 diabetic patients is associated with low polyunsaturated fatty acid contents in serum triglyceride fraction. This association may represent a risk factor for cardiovascular disease and may contribute to the progression of renal disease.

The aim of this study was to analyze the role of ACE gene insertion/deletion (I/D) and PC-1 gene K121Q polymorphisms in the changes of glomerular filtration rate (GFR), urinary albumin excretion rate (UAER), and blood pressure (BP) levels in a cohort of normoalbuminuric Type 1 diabetic patients. This is a 10.2±2.0-year prospective study of 30 normotensive normoalbuminuric Type 1 diabetic patients. UAER (immunoturbidimetry), GFR ( 51 Cr-EDTA single injection technique), GHb (ion exchange chromatography), and BP levels were measured at baseline and at 1.7±0.6-year intervals. The presence of ACE gene I/D and PC-1 gene K121Q polymorphisms was determined by polymerase chain reaction (PCR) and restriction enzyme techniques. Three patients developed diabetic nephropathy (DN), all carriers of allele D. The presence of allele D was the only predictor ( R 2 =.15, F =4.92, P =.035) of the observed GFR decline (−0.29±0.34 ml/min/month, P P =.002) and was associated with baseline UAER levels only ( R 2 =.17, F =5.72, P =.024). A significant increase ( P n =19) and not in II patients ( n =11). Patients with the KQ/QQ genotype ( n =8) presented a significant increase ( P =.045) in new cases of retinopathy. In conclusion, the presence of the ACE gene D allele in this sample of normoalbuminuric normotensive Type 1 diabetic patients was associated with a higher proportion of microvascular complications and hypertension.

Radioiodine (131I) is the preferred definitive treatment for Graves' hyperthyroidism. Pretreatment with antithyroid drugs is often used to avoid thyroid hormone discharge after 131I ablation. However, this may represent an unnecessary increase in risk and costs. Fifty-one patients with Graves' disease were randomly assigned to receive 131I alone (28 patients) or 131I plus pretreatment with methimazole (30 mg/day; 23 patients). Methimazole was interrupted 4 days before 131I therapy. Serum T4, free T4 (FT4), and T3 were measured on days -4 and -1, on the day of treatment, and on days 2, 5, 7, 14, 20, and 30. In patients receiving 131I alone, mean serum T4 levels did not change after therapy. Mean serum FT4 and T3 levels decreased significantly 5 days after 131I administration (15% and 18%, respectively). Serum T3 reached its lowest level on day 30 (38%). With pretreatment, mean serum T4, FT4, and T3 levels increased (38%, 39%, and 70%, respectively) after methimazole discontinuation and before 131I administration. After 131I, serum T4 levels peaked on day 7 (23% vs. treatment day; 70% vs. baseline); FT4 levels peaked on day 14 (53% vs. treatment day; 107% vs. baseline). The serum T3 concentration increased 9% on day 2 (85% vs. baseline) and decreased from day 14 (15%) to day 30 (21%). We conclude that interruption of antithyroid drugs causes a short term increase in serum thyroid hormone levels in patients with Graves' hyperthyroidism receiving 131I. Thyroid hormone levels stabilize or decrease during the first 30 days after 131I therapy.

Objective: To evaluate the influence of the menstrual cycle and the effects of medroxyprogesterone acetate (MPA) on the expression of the protooncogene c- fos and of prolactin (PRL) in the human endometrium in vivo. Design: Double-blind, placebo-controlled trial. Setting: Healthy volunteers in an academic research environment. Patient(s): Regularly cycling women who were not taking hormonal medication. Intervention(s): Medroxyprogesterone acetate (10 mg/d) or placebo was given for 10 days. Endometrial and blood samples were collected 8–12 hours after the last dose. Main Outcome Measure(s): Immunohistochemical localization of PRL and c- fos in the endometrium, PRL and c- fos messenger RNA levels in the endometrium, and E 2 and progesterone levels in the serum. Result(s): Immunoreactive c- fos was concentrated in the nucleus of stromal cells and was observed in a higher proportion of proliferative endometrial specimens compared with secretory specimens from placebo- or MPA-treated patients. The levels of c- fos messenger RNA were greatly reduced in the secretory endometrium regardless of treatment with placebo or MPA, compared with the proliferative endometrium. The c- fos gene expression correlated positively with the serum E 2 levels ( r = 0.56) and inversely with the progesterone/E 2 ratio ( r = −0.56). The endometrial PRL gene expression (messenger RNA and protein) was rare in the proliferative samples, increased from the early to the mid and late secretory samples, and was increased markedly after treatment with MPA compared with placebo. Conclusion(s): The differentiation of secretory endometrium is accompanied by decreased c- fos and increased PRL gene expression. The inhibition of c- fos gene expression may contribute to the antiproliferative effect of progestins on the endometrium.

Background: RET polymorphisms have been involved in the clinical presentation and prognosis of multiple endocrine neoplasia type 2 (MEN2)-associated medullary thyroid carcinoma.ObjectiveTo investigate the effect of RET variants on the penetrance of pheochromocytoma (PHEO) in MEN2 patients. Methods: The RET variants L769L, S836S, and G691S/S904S were evaluated in a cohort of 153 MEN2 patients attending a tertiary teaching hospital. A comparison of RET variant frequencies between patients with and without PHEO was performed. Kaplan–Meier curves and Cox regression analysis were used to estimate the effect of RET variants on the age-dependent penetrance.ResultsA total of 48 (31.4%) patients presented with MEN2-associated PHEOs. The mean age at diagnosis was 35.5±13.4 years, 60.4% of patients were women, and 92.8% had RET mutations at codon 634. The frequencies of RET polymorphisms were as follows: 20.1% L769L, 4.75% S836S, and 17.3% S904S/G691S. We did not observe any association between the frequencies of L769L, S836S, or S904S/G691S variants and PHEO development (all P>0.05). However, individuals carrying two RET polymorphic alleles had an increased estimated risk of PHEO (2.63; 95% CI, 1.4–5.0; P=0.004) and were younger at diagnosis when compared with those with one or no polymorphism (29.6±6.3 and 39.3±14.4 years respectively; P=0.006). Accordingly, additional analysis using Cox proportional hazard models demonstrated that the presence of two RET variants was associated with an increased risk for early PHEO development (hazard ratio, 5.99 (95% CI, 2.24–16.03); PConclusionsRET polymorphic alleles have an additive effect on the estimated risk of age-related PHEO penetrance in MEN2 patients.

ContextMedullary thyroid carcinoma (MTC) accounts for 3–4% of all malignant thyroid neoplasias. Vandetanib, a tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor 2, epidermal growth factor receptor, and RET, has been approved by the FDA for the treatment of locally advanced or metastatic MTC. The heart seems to be particularly susceptible to adverse effects associated with TKI therapy, and virtually all TKIs have been associated with cardiovascular events.Clinical presentationWe report the case of a patient with metastatic MTC who was enrolled in the Phase III clinical study (NCT00410761) and presented a favorable response to vandetanib therapy, displaying marked decrease in the level of serologic tumor markers and shrinkage of metastatic lesions. After 14 months of therapy, the patient developed a fatal cardiac failure. Myocardial infarction was excluded by serial measurements of specific cardiac markers (serial troponin-T measurements varied from 0.037 to 0.042 ng/ml) and serologic tests for Chaga's disease were negative. Postmortem examination of the heart revealed cardiomyocyte hypertrophy and marked myocyte degeneration in the subendocardial zones and papillary muscles of the myocardium. These pathological changes are similar to those observed in TKI-treated rats and are suggestive of drug-induced cardiotoxicity.ConclusionThis case illustrates a previously unreported serious vandetanib-related adverse effect and highlights the need for close monitoring of patients under TKI therapy in order to identify early signs of congestive heart failure or myocardium damage.

Type 1 iodothyronine deiodinase (D1) converts T4 to T3, the active thyroid hormone, by removal of the outer ring iodine. Previous studies in liver and thyroid cells have shown that T3 regulates Type 1 deiodinase (dio1) gene expression by a mechanism not requiring ongoing protein synthesis. For certain T3-regulated genes, such as rat GH, T3-induced transcription is blocked by protein synthesis inhibitors. Because the somatotrope tumor cell lines express both dio1 and GH, we compared these two positively T3-regulated genes to establish whether cycloheximide blockade of T3 effects is cell-type or gene specific. In these cells, the T3 stimulation of dio1 messenger RNA (mRNA) is not blocked by cycloheximide, whereas the T3 effect on GH mRNA synthesis is eliminated. Other differences between these two genes were also noted. Retinoic acid does not alter dio1 gene expression or the response to T3 but increases GH and synergizes with T3. Dexamethasone alone had no effect on dio1 mRNA but did enhance the effect of T3 on both dio1 and GH. These results point to distinct pathways for T3 induction of mRNA synthesis from different genes within the same cell.

Thyroid carcinoma is the most common malignant endocrine neoplasia. Differentiated thyroid carcinomas (DTCs) represent more than 90% of all thyroid carcinomas and comprise the papillary and follicular thyroid carcinoma subtypes. Anaplastic thyroid carcinomas correspond to less than 1% of all thyroid tumors and can arise de novo or by dedifferentiation of a differentiated tumor. The etiology of DTCs is not fully understood. Several genetic events have been implicated in thyroid tumorigenesis. Point mutations in the BRAF or RAS genes or rearranged in transformation (RET)/papillary thyroid carcinoma (PTC) gene rearrangements are observed in approximately 70% of papillary cancer cases. Follicular carcinomas commonly harbor RAS mutations and paired box gene 8 (PAX8)-peroxisome proliferator-activated receptor γ (PPARγ) rearrangements. Anaplastic carcinomas may have a wide set of genetic alterations, that include gene effectors in the mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K) and/or β-catenin signaling pathways. These distinct genetic alterations constitutively activate the MAPK, PI3K and β-catenin signaling pathways, which have been implicated in thyroid cancer development and progression. In this context, the evaluation of specific genes, as well as the knowledge of their effects on thyroid carcinogenesis may provide important information on disease presentation, prognosis and therapy, through the development of specific tyrosine kinase targets. In this review, we aimed to present an updated and comprehensive review of the recent advances in the understanding of the genetic basis of follicular cell-derived thyroid carcinomas, as well as the molecular mechanisms involved in tumor development and progression.

The non-thyroidal illness syndrome (NTIS) refers to changes in serum thyroid hormone levels observed in critically-ill patients in the absence of hypothalamic-pituitary-thyroid primary dysfunction. Affected individuals have low T3, elevated rT3 and inappropriately normal TSH levels. The pathophysiological mechanisms are poorly understood but the acute and chronic changes in pituitary–thyroid function are probably the consequence of the action of multiple factors. The early phase seems to reflect changes occurring primarily in the peripheral thyroid hormone metabolism, best seen in humans since 80-90% of the circulating T3 are derived from the pro-hormone T4. The conversion of T4-to-T3 is catalyzed by type 1 (D1) and type 2 (D2) deiodinases via outer-ring deiodination. In contrast, type 3 deiodinase (D3) catalyzes the inactivation of both T4 and T3. Over the last decades, several studies have attempted to elucidate the mechanisms underlying the changes on circulating thyroid hormones in NTIS. Increased inflammatory cytokines, which occurs in response to virtually any illness, has long been speculated to play a role in derangements of deiodinase expression. On the other hand, oxidative stress due to augmented reactive oxygen species (ROS) generation is characteristic of many diseases that are associated with NTIS. Changes in the intracellular redox state may disrupt deiodinase function by independent mechanisms, which might include depletion of the as yet unidentified endogenous thiol cofactor. Here we aim to present an updated picture of the advances in understanding the mechanisms that result in the fall of thyroid hormone levels in the acute phase of NTIS.

In patients with Graves disease, unilateral or markedly asymmetric ocular manifestations should raise suspicion of other ocular disorders. In the present report, we describe a patient with Graves disease who presented with a 24-hour history of severe left-sided headache and fever. Cranial computed tomography revealed pansinusitis, and the patient was treated with antibiotics and discharged. He returned 24 hours later with worsening of the headache and left eye proptosis with retrobulbar pain, periorbital swelling, conjunctival redness, and chemosis. There was also external ophthalmoplegia on lateral, upward and downward gaze of the left eye. A diagnosis of Graves ophthalmopathy was made. Later, based on computed tomography of the orbit, which revealed frontal sinusitis and thrombosis of the left cavernous sinus, and on clinical and laboratory data, a diagnosis of thyroid storm with septic thrombosis of the cavernous sinus was made. To our knowledge, this is the first report of an association between a benign condition, sinusitis, and potentially lethal septic thrombosis of the cavernous sinus and thyroid storm. The presence of sinusitis in patients with Graves disease should alert physicians to the possibility of cavernous sinus thrombosis.

Review on DIO2 (deiodinase, iodothyronine, type II), with data on DNA, on the protein encoded, and where the gene is implicated.

Nonthyroidal illness syndrome (NTIS) is a state of low serum 3,5,3′ triiodothyronine (T3) that occurs in chronically ill patients; the degree of reduction in T3 is associated with overall prognosis and survival. Iodothyronine deiodinases are enzymes that catalyze iodine removal from thyroid hormones; type I and II deiodinase (D1 and D2, respectively) convert the prohormone thyroxine T4 to active T3, whereas the type III enzyme (D3) inactivates T4 and T3. Increased production of cytokines, including IL-6, is a hallmark of the acute phase of NTIS, but the role of cytokines in altered thyroid hormone metabolism is poorly understood. Here, we measured the effect of IL-6 on both endogenous cofactor–mediated and dithiothreitol-stimulated (DTT-stimulated) cell sonicate deiodinase activities in human cell lines. Active T3 generation by D1 and D2 in intact cells was suppressed by IL-6, despite an increase in sonicate deiodinases (and mRNAs). N-acetyl-cysteine (NAC), an antioxidant that restores intracellular glutathione (GSH) concentrations, prevented the IL-6–induced inhibitory effect on D1- and D2-mediated T3 production, which suggests that IL-6 might function by depleting an intracellular thiol cofactor, perhaps GSH. In contrast, IL-6 stimulated endogenous D3–mediated inactivation of T3. Taken together, these results identify a single pathway by which IL-6–induced oxidative stress can reduce D1- and D2-mediated T4-to-T3 conversion as well as increasing D3-mediated T3 (and T4) inactivation, thus mimicking events during illness.