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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 T3production contributes to a portion of plasma T3in euthyroid state, pathologically increased thyroidal D1 activity seems to be the main cause of the elevated T3concentrations 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. [ABSTRACT FROM AUTHOR]

Background:Vascular endothelial growth factor (VEGF-A) expression is upregulated in the majority of human tumors, where it stimulates proliferation, migration, and survival of endothelial cells. Studies have suggested that VEGF inhibitors can be used as an alternative therapy in medullary thyroid carcinoma (MTC), but data about expression of VEGF-A and its receptor in this tumor are scarce. The aims of this study were to evaluate VEGF-A, VEGF receptor (VEGFR)-1, VEGFR-2, and microvessel density (MVD) expression in MTC samples and correlate it with clinical parameters.Methods:Paraffin-embedded samples from 38 MTC patients were evaluated for VEGF-A, VEGFR-1, VEGFR-2, and MVD expression by immunohistochemistry. Clinical data were retrospectively reviewed in medical records.Results:Thirty-eight patients aged 31.8 ± 17.1 years were enrolled. Twenty-seven patients had hereditary disease (71.1%). Twenty-five of them were found to have multiple endocrine neoplasia (MEN) 2A and two were found to have MEN 2B. VEGF-A immunohistochemical staining was detected in 95% (36/38), VEGFR-1 in 96% (36/37), and VEGFR-2 in 91% (31/34) of MTC samples. Age at surgery was positively correlated with VEGFR-2 (p= 0.003). There was no correlation between VEGF-A, VEGFR-2, and tumor stage (tumor node metastasis). Nevertheless, VEGFR-1 was found to be inversely correlated with tumor node metastasis (p= 0.034). We also observed a trend toward an association between VEGFR-1 signal intensity and cure of disease, although this did not reach statistical significance (p= 0.054). Neither VEGF-A nor VEGFR-2 was associated with disease outcome after a median follow-up period of 5 years (p= 0.882 and p= 0.236, respectively). As expected, MVD was correlated with age at surgery (p= 0.005) and tumor size (p= 0.03). Patients with the hereditary form of the disease had a stronger intensity for VEGFR-1 (p= 0.039), whereas patients with sporadic disease displayed higher MVD counts (44 [27–63] vs. 21 [9–49], p= 0.018).Conclusion:The VEGF-A, VEGFR-1, and VEGFR-2 immunoreactive proteins are overexpressed in MTC lesions and might be implicated in tumor progression. It is not clear, however, if expression of these molecules provides prognostic information regarding the spread or outcome of MTC. [ABSTRACT FROM AUTHOR]

Background:RETgenotype analysis allows identification of asymptomatic carriers at risk of developing medullary thyroid carcinoma (MTC). However, there is still controversy regarding the ideal timing and extent of prophylactic thyroidectomy due to the wide spectrum of clinical presentation. Surveillance of a large number of young patients is crucial to advance our understanding of the natural course of the disease. This study aimed to describe the clinical presentation, oncological features, and treatment outcome of children and young adults harboring RETmutations followed at our institution from 1997 to 2007.Methods:Forty-one individuals aged ≤25 years from 17 independent multiple endocrine neoplasia type 2A kindred were studied. Twenty-one individuals presented with thyroid nodules at diagnosis, and 20 were disease free at physical examination.Results:Preoperative basal calcitonin levels were elevated in 85.7% of patients with clinical disease and in 54.5% of asymptomatic carriers. Thyroid ultrasonography (US) showed one or more nodules in 69.0% of the patients. A positive correlation between age at surgery and tumor-node-metastasis (TNM) stages was observed (p< 0.001). None of the patients under 15 years of age presented lymph node or distant metastasis. After a follow-up of 4.4 ± 1.4 years all asymptomatic patients were disease free based on physical examination, cervical US, and undetectable serum calcitonin levels. In the group of patients with clinical disease, 47.6% have persistent disease (follow-up of 12.0 ± 5.9 years). Indeed, palpable thyroid nodule at diagnosis was significantly associated with persistent disease (p< 0.001, odds ratio [OR] 1.9, 95% confidence interval [CI 95%] 1.27–2.87). Of note, none of the patients who presented lymph node metastasis at diagnosis were cured by surgical intervention (p< 0.001, OR 5.0, CI 95% 1.45–17.0).Conclusion:Our data show a time-dependent MTC progression. The presence of a palpable thyroid nodule and lymph node metastasis at diagnosis was associated with persistent or recurrent disease after surgical procedure. [ABSTRACT FROM AUTHOR]

Context:Medullary thyroid carcinoma (MTC), a tumor of the parafollicular C cells of the gland, comprises 3–5 of all malignant thyroid neoplasms. Calcitonin, a polypeptidic hormone secreted by the neoplastic cells, is considered a very sensitive and specific MTC tumor marker. Patients with MTC usually present elevated serum calcitonin levels, which correlate with tumor burden and prognosis.Objectives:To describe a case of advanced MTC with normal serum calcitonin and review the literature on this subject.Design:A case study was performed.Intervention:There were no interventions.Patients:A case of advanced MTC with normal serum calcitonin was studied.Results:Serum calcitonin was measured by two distinct assays, a chemiluminescent immunometric and an in-house two-site monoclonal antibody–based immunofluorometric assay. To rule out a “hook effect,” or posttranslational modifications of calcitonin molecule, serum dilutions and tumor immunohistochemistry for calcitonin with the same antibodies used for serum calcitonin measurements were performed. Serum calcitonin levels were within the normal range in both assays, whereas the tumor stained strongly positive for calcitonin. These findings suggest that the tumor was able to produce but not to secrete the calcitonin protein. Five other cases of advanced MTC with normal serum calcitonin levels had been previously reported.Conclusions:We present an unusual case of advanced MTC with normal serum calcitonin levels. Awareness of MTC cases presenting with normal serum calcitonin levels is important in clinical practice and is particularly relevant to centers that use this test for screening. [ABSTRACT FROM AUTHOR]

Background:Type 2 deiodinase plays a critical role in thyroid hormone homeostasis. A single nucleotide polymorphism in DIO2gene (A/G) in humans has been associated with a ∼20% lower glucose disposal rate and greater insulin resistance in type 2 diabetes (DM2) patients. Objective:This study was designed to test whether homozygosity for the DIO2A/G polymorphism would be associated with risk of DM2 or elevated levels of diabetes intermediate traits. Design and setting:Community-based, longitudinal study. Participants were withdrawn from a subset of unrelated individuals from the Offspring Cohort of the Framingham Heart Study who had DNA collected between 1995 and 1998. Methods:DNA samples from 1633 participants (mean age, 62 years) underwent genotyping of the DIO2A/G polymorphism. Incident DM2 and diabetes-related traits (fasting plasma glucose, mean fasting plasma glucose, 2-hour glucose, hemoglobin A1c, fasting insulin, insulin resistance) were measured. Results:The minor allele (G) frequency was 0.37. Using multivariable regression for intermediate traits and Cox proportional hazards regression for DM2, pvalues were calculated for two models: Model 1: age, age-squared, sex, and smoking; Model 2: Model 1 body mass index. There were no significant associations (all p> 0.20) for any trait examined. For DM2 risk, the hazard ratios associated with A/G or G/G relative to the A/A genotype were 1.0 (95% confidence interval CI 0.7–1.3) and 1.2 (95% CI 0.7–1.9), respectively. Conclusions:Our results indicate that in this community-based sample, there is no association of the DIO2A/G polymorphism with diabetes intermediate trait levels or DM2 risk. [ABSTRACT FROM AUTHOR]