Extrathyroidal tissues

The generic term thyroid hormones refers to the iodinated amino acid derivatives T3 (3,3, 5-triiodo-L-thyronine) and T4 (3,3, 5,5 -tetraiodo-L-thyronine), the only iodinated hormones produced endogenously. T3 is the biologically active hormone and is, for the most part, produced from T4 in extrathyroidal tissues. T4 lacks significant bioactivity and is a hormone precursor however,... 

On average, iodine intake satisfies the normative requirement when the iodine content of intrathyroidal and extrathyroidal tissues exceeds those listed in Table 9-4.10 (Groppel et al. 1988). Normally, the iodine levels in these tissues are higher. 

Thyroid hormones enter the extrathyroidal tissues by the action of specific transporters the organic anion transport protein (OATP) and the monocarboxylic transporter (MCT8) (Ekins et al. 1994 Friesema et al. 1999, 2005). Within some cells, deiodinating enzymes can remove an iodine atom from the T4 or T3 molecules and thereby modify the sensitivity of a cell to the actions of the thyroid hormones. The cellular actions of the thyroid hormones are mediated by nuclear receptor proteins, which bind to DNA and regulate transcription with at least two types of genes that encode these receptors (Barettino, Ruiz, and Stunnenberg 1994) these also provide a negative feedback action on the hypothalamic-pituitary axis. T4 is sometimes... 

In extrathyroidal tissues, the thyroid hormones are catabolized in a series of deiodination, oxidative, or conjugation reactions. Deiodination of circulating T4 occurs mainly in the liver and kidney by type I deiodinases with either 5 -deiodination yielding T3 or 5-deiodination yielding inactive rTj. The production of reverse Tj is thought to be another extrathyroidal control mechanism regulating the delivery of free T3 to the tissues. Type II deiodinases carry out 5 -deiodination in the cerebral cortex and brown adipose tissues. 

The NIS is an intrinsic plasma membrane glycoprotein that mediates active transport of iodide in the thyroid gland and a number of extrathyroidal tissues, in particular the lactating mammary gland. 

T4a invading extrathyroidal tissue T4b invading prevertebral fascia or encasing carotid or mediastinal blood vessels nodes - N1 a level VI metastasis (Delphian, pre/paratracheal, or prelaryngeal nodes) N1 b lateral neck/mediastinum distant metastases - Ml, distant metastasis (TO/NO/MO, clinically absent TX/NX/MX, not assessed). 

TSH. Autoantibodies that react with orbital muscle and fibroblast tissue in the skin are responsible for the extrathyroidal manifestations of Graves disease, and these autoantibodies are encoded by the same germfine genes that encode for other autoantibodies for striated muscle and thyroid peroxidase. The defect leading to abnormal antibody production may be a genomic point mutation in the extracellular domain of the thyrotropin receptor. CfinicaUy, the extrathyroidal disorders may not appear at the same time that hyperthyroidism develops. 

The extrathyroidal effects of iodine are of interest to physicians, due to its possible functions in many other organs. Iodine appears to be a vital trace element that is found in higher concentrations not only in the thyroid, but also in other tissues, such as salivary glands, lacrimal glands, stomach mucous membrane, plexus choroideus, lading mammary gland, pancreas, Langerhans islets and ciliar muscle of the eye. The distribution is not random, but it is related to the action of a specific active transport mechanism, the sodium iodide symporter (NIS). 

In summary, both intra- and extrathyroidal mechanisms are involved in the adaptation of the rat to mild iodine deficiency the former are autoregulatory and very effective in avoiding T3 deficiency in most tissues and the latter occur in tissues in which type 2 iodothyronine deiodinase (D2) plays an important role for the local generation of T3. In mild ID, hypothyroidism, as inferred from the concentrations ofT3, is avoided in all tissues studied. The question remains as to whether or not tissues with elevated T3 concentrations may actually be hyperthyroid. As far as we know, this question cannot yet be answered because tissue-specific thyroid hormone-sensitive biological endpoints have not been measured in mildly iodine-deficient rats with increased circulating T3. 

In summary, in the case of moderate ID, intra- and extrathyroidal responses are still adequate to prevent low T3 levels in plasma and most tissues, despite a reduction in the iodine intake to 25% of that of controls. Some tissues even maintain elevated T3 concentrations, whereas others are markedly (adrenal) or moderately (brain and pituitary) T3 deficient. 

In summary, despite a 100-fold decrease in iodine availability, a combination of intra- and extrathyroidal adaptive mechanism still mitigates T3 deficiency, and presumably hypothyroidism, in most, but not all, tissues. 

In summary, the threshold iodine availabifity below which most tissues are T3 deficient appears to be reached when the intra- and extrathyroidal adaptive mechanisms are no longer capable of ensuring normal circulating T3 levels. But even then, adaptive mechanisms become operative and protect most tissues, and especially the lung, heart, muscle, and ovary, from the degree of T3 deficiency... 

As discussed elsewhere in more detail (Morreale de Escobar et ai, 2004), it is inaccurate to assume, which has been very frequently done, that inhabitants of areas of ID are chnically hypothyroid individuals. The present experimental model supports the epidemiological findings that inhabitants of areas of ID are not clinically hypothyroid individuals, as their normal circulating T3 ensures euthyroidism of most tissues by extrathyroid adaptive mechanisms known to be operative in man when iodine availability decreases. But, as shown experimentally here, this does not avoid selective hypothyroidism of tissues, such as the brain, that depend mostly on T4 for their intracellular T3 supply. This selective hypothyroidism is aheady present in conditions of mildly decreased iodine availability, and may already negatively affect mental functions (Delange, 2001 Vitti et al., 2003 Vermiglio et ai, 2004). Indeed, inhabitants of areas of ID are often described as dull. Whole populations appear to wake up when their ID — and the consequent hypothyroxinemia — are corrected (Dunn, 1992). 

It has been suggested that treatment with supraphysiologic levels of iodine has potential therapeutic uses beyond thyronine function (Miller, 2006). Some clinicians believe that all tissues in the human body should be saturated with iodine (Flechas, 2005). Maintenance of the equilibrium between thyroidal and extrathyroidal iodine is estimated to require about six times the tolerable upper intake level (UL) (Berson and Yalow, 1954). Controlled chronic safety data for daily iodine intake at these levels are difficult to find even though physicians prescribed daily iodine therapy at doses that ranged from 10 to 100 times the UL during the first half of the twentieth century (Kelly, 1961). 

Thyronine—receptor complexes stimulate or inhibit gene expression in almost every tissue in the human body, and therefore necessarily command our focus. The result is a thyroid hormone (TH)-centric perspective of iodine physiology that persuades us to avoid consideration of nonthyronine pharmacologic activity associated with iodine. The role for so-called extrathyroidal iodine has been discussed in the hterature as iodide uptake in the majority of breast cancers has aroused the interest of several researchers (Venturi et at. 

I content remained undetectable until after birth. Thyroidal T4 and T3 increased 250- and 100-fold, respectively, between 18 and 21 dg in the LID+I fetuses. In contrast, there was no increase in LID fetuses, so that by 21 dg the T4 and the T3 contents were 0.43 % and 1.3 % of those of LID+I fetuses. During this period T4 and T3 increased progressively in all fetal tissues of LID+I animals, so that the total fetal extrathyroidal pool of T4 increased from 0.37 ng at 18 dg to 8.35 ng at 21 dg, and that of T3 from 0.18 ng to 2.50 ng. The extrathyroidal T4 and T3 pools of the LID fetuses hardly increased during the same period, so that by 21 dg they were 5 % and 18 %, respectively, of the values for LID+I fetuses. This is illustrated for fetal brain and liver in Figure 4. 

We have indeed studied that situation. When mothers are thyroidectomized without hormonal replacement, the embryos develop with extremely low T4 and T3 serum and tissue concentrations, until their own thyroid function starts. This occurs at day 18. Thereafter, they catch up very rapidly, normalizing their extrathyroidal T4 and T3 pools before birth. Therefore, the pups bom in those conditions have normal hormone levels. This, however, occurs at the expense of the thyroid of the fetus the glands are secreting hormones so actively that they are not able to accumulate intrathyroidal hormones stores before birth. At the time of birth, the small amount of intrathyroidal hormone stores put those pups at a disadvantage for the early postnatal period. 

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