Extrathyroidal iodine

Extrathyroidal iodine includes the measurable iodide and thyroid hormones in the plasma and in their peripheral... 

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. 

Venturi, 2001). The question of extrathyroidal iodine is worthy of consideration as the path to understanding the relationship between dietary iodine intake and conditions, such as autoimmune thyroid disease, may he outside TH biochemistry. 

In the most simplistic physiological model, inadequate intake of iodine results in a reduction in thyroid hormone production, which stimulates increased TSH production. TSH acts directly on thyroid cells, and without the ability to increase hormone production, the gland becomes hyperplastic. In addition, iodine trapping becomes more efficient, as demonstrated by increased radioactive iodine uptake in deficient individuals. However, this simplistic model is complicated by complex adaptive mechanisms which vary depending on the age of the individual affected. In adults with mild deficiency, reduced intake causes a decrease in extrathyroidal iodine and reduced clearance, demonstrated by decreased urinary iodine excretion, but iodine concentration in the gland may remain within normal limits. With further reduction in intake, this adaptive mechanism is overwhelmed, and the iodine content of the thyroid decreases with alterations in iodination of thyroglobulin, in the ratio of DIT to MIT, and reduction in efficient thyroid hormone production. The ability to adapt appears to decrease with decreasing age, and in children the iodine pool in the thyroid is smaller, and the dynamics of iodine metabolism and peripheral use more rapid. In neonates, the effects of iodine deficiency are more directly reflected in increased TSH. Diminished thyroid iodine content and increased turnover make neonates the most vulnerable to the effects of iodine deficiency and decreased hormone production, even with mild deficiency. 

Ascophyllum nodosum, Fucus vesiculosus, Fucus serra-tus. Laminaria species, and Macrocystis pyrifera). As kelp contains iodine, it occasionally produces hyperthyroidism (1), hypothyroidism, or extrathyroidal reactions, such as skin eruptions. It can also contain contaminants such as arsenic, and bone marrow depression and autoimmune thrombocjdopenia have been described in consequence (2). 

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,... 

Inherited decreases in TBG have been reported (R5, Tl). The serum of these patients was characterized by a low protein-bound iodine in the absence of demonstrable hypothyroidism. Tracer studies revealed decreased extrathyroidal thyroxine pools and normal absolute thyroxine turnover (C3, T2). The condition is probably transmitted as a dominant X chromosome-linked trait (N3, R5). No abnormalities in TBPA have been reported in these conditions. 

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... 

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 is obvious that T4 by RIA and T4 by CPBA are unaffected by contaminating iodine. However, it should be stressed that both total T4 and PBI are uniformly affected by abnormalities in the T4-binding serum proteins, namely TBG, TBPA, and albumin as referred to in Section 2.2. In summary, where drugs or any other extrathyroidal factor increases any of the binding proteins (usually TBG) there is a concomitant increase in PBI or total T4 levels in the serum, and a decrease in the T3 resin uptake. Conversely, decreases in TBP are associated with decreases in PBI and in total T4, and increases in T3 resin uptake. 

The kinetic study of Stanbury et al. was based on a three compartment model which included intrathyroidal iodine and extrathyroidal pools of organic and inorganic icxline (1). This model was investigated after the administration of a tracer dose of Ij From Ij distribution and freon the sequential modifications of the spedfic aeftivies, it was possible, through this model to deduce the iodine content of these cximpartments and their transfer rate exmstants. (1)... 

In patieitt FL elevated I thytxMd uptake is followed by a fast release of the 3 1 thyroid content which is associated with a concomitant marked increase in the extrathyroidal organic pool. These observations are in agreement with a marked acceleration of the turnover rate of the thyroidal iodine pool. 

Distribution of radioiodine in two goitrous subjects (FL and DD) from a severe iodine deficient area in Zaire. 3 I thyroid content, extrathyroidal 31i pool (PB 1311 x distribution volume of thyroxine) and urine (cumulative excretion) are expressed in % of 1311 administered. Adapted from Ermans et al. (2) with the permission of the publisher... 

The multiple mechanisms which permit compensatory adaptation of the thyroid gland to severe and chronic iodine deficiency (ID) are known since many years. As a result there is a shift in the synthesis of T4 in favour of T3 and a preferential secretion of T3 over T4, so that with very little iodine normal circulating T3 is maintained despite very low T4. Overt clinical hypothyroidism is not apparent and is attributed to the normal serum T3. Here we will summarize information regarding extrathyroidal responses to ID in the rat, with special attention to the fetus and newborn and its brain during early development, as studied in our laboratory. 

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