Iodine: Its Role in Thyroid Hormone Biosynthesis and Beyond

The present review deals with the functional roles of iodine and its metabolism. The main biological function of iodine concerns its role in the biosynthesis of thyroid hormones (THs) by the thyroid gland. In addition, however, further biological roles of iodine have emerged. Precisely, due to its significant action as scavenger of reactive oxygen species (ROS), iodine is thought to represent one of the oldest antioxidants in living organisms. Moreover, iodine oxidation to hypoiodite (IO−) has been shown to possess strong bactericidal as well as antiviral and antifungal activity. Finally, and importantly, iodine has been demonstrated to exert antineoplastic effects in human cancer cell lines. Thus, iodine, through the action of different tissue-specific peroxidases, may serve different evolutionarily conserved physiological functions that, beyond TH biosynthesis, encompass antioxidant activity and defense against pathogens and cancer progression.

NADPH oxidases in GtoPdb v.2021.3

The two DUOX enzymes were originally identified as participating in the production of hydrogen peroxide as a pre-requisite for thyroid hormone biosynthesis in the thyroid gland [9].NOX enzymes function to catalyse the reduction of molecular oxygen to superoxide and various other reactive oxygen species (ROS). They are subunits of the NADPH oxidase complex.

Case Report: Expanding the Digenic Variants Involved in Thyroid Hormone Synthesis−10 New Cases of Congenital Hypothyroidism and a Literature Review

Congenital hypothyroidism (CH) is the most common neonatal metabolic disorder. Although it has been understood to be a monogenic disease, some CH patients are reported to carry two or more variants at different genes. Here, ten permanent congenital hypothyroidism (PCH) patients were retrospectively reviewed, with elevated levels of serum thyroid-stimulating hormone and levothyroxine dependence during follow-up between 2015 and 2019. Each affected individual carried digenic variants, which were heterozygous at two of pathogenic genes. In total, five pathogenic genes, TSHR, TG, TPO, DUOX2 and DUOXA2, were simultaneously identified in subjects that were involved in the same metabolic pathway: thyroid hormone biosynthesis. There were digenic variants at TSHR and DUOX2 combined in three patients, DUOX2 and TG combined in two patients, DUOX2 and DUOXA2 combined in two patients, TG and DUOXA2 combined in two patients, and TG and TPO combined in one patient. Additionally, seven novel variants, TSHR c.679G>A, DUOX2 c.127A>T, c.608-619del, c.959T>C, TG c.2307G>A, and c.6759_6765del, and DUOXA2 c.93T>G, were identified in these PCH patients. Along with a literature review on digenic variants in patients with CH, our findings illustrated the complexity of genetic etiology in CH.

Effects of iodine excess on serum thyrotropin-releasing hormone levels and type 2 deiodinase in the hypothalamus of Wistar rats

Iodine is an important element in thyroid hormone biosynthesis. Thyroid function is regulated by the hypothalamic-pituitary-thyroid axis (HPT). Excessive iodine leads to elevated thyroid stimulating hormone (TSH) levels, but the mechanism is not yet clear. Type 2 deiodinase (Dio2) is a selenium-containing protease that plays a vital role in thyroid function. The purpose of this study was to explore the role of hypothalamus Dio2 in regulating TSH increase caused by excessive iodine and to determine the effects of iodine excess on thyrotropin-releasing hormone (TRH) levels. Male Wistar rats were randomized into five groups and administered different iodine dosages (folds of physiological dose): normal iodine (NI), 3-fold iodine (3HI), 6-fold iodine (6HI), 10-fold iodine (10HI), and 50-fold iodine (50HI). Rats were euthanized at 4, 8, 12, or 24 weeks after iodine administration. Serum TRH, TSH, total thyroxine (TT4), and total triiodothyronine (TT3) were determined. Hypothalamus tissues were frozen and sectioned to evaluate expression of Dio2, Dio2 activity, and monocarboxylate transporter 8 (MCT8). Prolonged high iodine intake significantly increased TSH expression (p < 0.05), but did not affect TT3 and TT4 levels. Prolonged high iodine intake decreased serum TRH levels in the hypothalamus (p < 0.05). Dio2 expression and activity in the hypothalamus exhibited an increasing trend compared at each time point with increasing iodine intake (p < 0.05). Hypothalamic MCT8 expression was increased in rats with prolonged high iodine intake(p < 0.05). These results indicate that iodine excess affects the levels of Dio2, TRH, and MCT8 in the hypothalamus.

A study to estimate similarities or dissimilarities of thyroid parameters of cord blood and new-born venous blood amongst new-borns

Background: Hypothyroidism may be congenital or may be acquired which might or may not have a delayed onset. Incomplete thyroid development and decreased thyroid hormone biosynthesis is a result of congenital hypothyroidism. Screening is usually missed in areas where testing is not done and being the reason for new cases of hypothyroid cases. The aim was to assess/evaluate whether cord blood can be used as a primary screening method for congenital hypothyroidism.Methods: The study was taken up in the department of pediatrics of a tertiary teaching hospital. A total of 200 babies were taken for the study during the whole study period. The cord blood at the time of delivery and 48 hour serum blood was collected and sent to the lab for thyroid profile estimation.Results: The study consisted of 109 males and 91 female infants. Among the 200 subjects, 156 were term babies and 44 preterm. The mean birth weight was 2.44 kgs. The mean cord TSH was 6.89±4.56, the mean T3 level was 81.03±38.84 and mean T4 level among the subjects was 11.17±3.33. The capillary venous blood was collected after 48 hours for thyroid profiling. The mean TSH was 5.15±3.13, mean T3 level was 111.53±36.49 and mean T4 level was 14.65±6.07. On comparison of cord blood and venous blood association was noted between them.Conclusions: From the present study findings it can be suggested cord blood can be used as a marker for early detection of congenital hypothyroidism.

Co-inhibition of SMAD and MAPK signaling enhances 124I update in BRAF-mutant thyroid cancers

Constitutive MAPK activation silences genes required for iodide uptake and thyroid hormone biosynthesis in thyroid follicular cells. Accordingly, most BRAFV600E papillary thyroid cancers (PTC) are refractory to radioiodide (RAI) therapy. MAPK pathway inhibitors rescue thyroid differentiated properties and RAI responsiveness in mice and patient subsets with BRAFV600E-mutant PTC. TGFβ also impairs thyroid differentiation and has been proposed to mediate the effects of mutant BRAF. We generated a mouse model of Braf-PTC with thyroid-specific knockout of the TgfβR1 gene to investigate the role of TGFβ on thyroid differentiated gene expression and RAI uptake in vivo. Despite appropriate loss of TgfβR1, pSmad levels remained high, indicating that ligands other than TGFβ1 were engaging this pathway. The activin ligand subunits Inhba and Inhbb were found to be overexpressed in BrafV600E mutant thyroid cancers. Treatment with follistatin, a potent inhibitor of activin, or vactosertib, which inhibits both TGFβR1 and the activin type I receptor ALK4, induced a profound inhibition of pSMAD in BrafV600E-PTCs. Blocking SMAD signaling alone was insufficient to enhance iodide uptake in the setting of constitutive MAPK activation. However, combination treatment with either follistatin or vactosertib and the MEK inhibitor CKI increased 124I uptake compared to CKI alone. In summary, activin family ligands converge to induce pSMAD in Braf-mutant PTCs. Dedifferentiation of BrafV600E-PTCs cannot be ascribed primarily to activation of SMAD. However, targeting Tgfβ/activin-induced pSMAD augmented MAPK inhibitor effects on iodine incorporation into BRAF tumor cells, indicating that these two pathways exert interdependent effects on the differentiation state of thyroid cancer cells.

Bone Maturnity Delay in Congenital Hypothyroid

Congenital hypothyroid (CH) is a Hormonal disorder that can be caused by thyroid gland dysfunction and if not treated early on, will cause serious mental and physical growth disorders. CH is divided into permanent and transient forms which etiologically can be divided into primary, secondary or peripheral. Thyroid dysgenesis is the primary cause and 85% of permanent CH is with abnormalities of thyroid hormone biosynthesis from birth (dishormongeneses). The incidence of dysgenesis accounts for 10-15% of cases. Transient congenital thyroid occurs mostly in infants with preterm birth in low-iodine endemic areas. A study showed a permanent incidence of CH 1: 1500 and transient CH 1: 300 in one of the areas with iodine deficiency in Central Java.Survival analysis showed that the risk of developing mental retardation and delayed physical growth was greater at the age of diagnosis over 1 year.

Re-visiting autoimmunity to sodium-iodide symporter and pendrin in thyroid disease

Objective Iodide transport across thyrocytes constitutes a critical step for thyroid hormone biosynthesis, mediated mainly by the basolateral sodium-iodide-symporter (NIS (SLC5A5)) and the apical anion exchanger pendrin (PDS (SLC26A4)). Both transmembrane proteins have been described as autoantigens in thyroid disease, yet the reports on autoantibody (aAb) prevalence and diagnostic usefulness are conflicting. Reasons for the inconclusive findings may be small study groups and principle differences in the technologies used. Design We decided to re-evaluate this important issue by establishing novel non-radioactive tests using full-length antigens and comparable protocols, and analyzing a large cohort of thyroid patients (n = 323) and control samples (n = 400). Methods NIS and PDS were recombinantly expressed as fusion protein with firefly luciferase (Luc). Stably transfected HEK293 cells were used as reproducible source of the autoantigens. Results Recombinant NIS-Luc showed iodide transport activity, indicating successful expression and correct processing. Commercial antibodies yielded dose-dependent responses in the newly established assays. Reproducibility of assay signals from patient sera was verified with respect to linearity, stability and absence of matrix effects. Prevalence of PDS-aAb was similar in thyroid patients and controls (7.7% vs 5.0%). NIS-aAb were more prevalent in patients than controls (7.7% vs 1.8%), especially in Graves’ Disease (12.3%). Neither NIS-aAb nor PDS-aAb concentrations were related to TPO-aAb or TSH-receptor-aAb concentrations, or to serum zinc or selenium status. Conclusions Our data highlight a potential relevance of autoimmunity against NIS for thyroid disease, whereas an assessment of PDS-aAb in thyroid patients seems not to be of diagnostic value (yet).

Thyroglobulin interactome profiling defines altered proteostasis topology associated with thyroid dyshormonogenesis

Thyroglobulin (Tg) is a secreted iodoglycoprotein serving as the precursor for T3 and T4 hormones. Many characterized Tg gene mutations produce secretion-defective variants resulting in congenital hypothyroidism (CH). Tg processing and secretion is controlled by extensive interactions with chaperone, trafficking, and degradation factors comprising the secretory proteostasis network. While dependencies on individual proteostasis network components are known, the integration of proteostasis pathways mediating Tg protein quality control and the molecular basis of mutant Tg misprocessing remain poorly understood. We employ a multiplexed quantitative affinity purification–mass spectrometry approach to define the Tg proteostasis interactome and changes between WT and several CH-variants. Mutant Tg processing is associated with common imbalances in proteostasis engagement including increased chaperoning, oxidative folding, and engagement by targeting factors for ER-associated degradation (ERAD). Furthermore, we reveal mutation-specific changes in engagement with N-glycosylation components, suggesting distinct requirements for one Tg variant on dual engagement of both oligosaccharyltransferase complex isoforms for degradation. Modulating dysregulated proteostasis components and pathways may serve as a therapeutic strategy to restore Tg secretion and thyroid hormone biosynthesis.