Key Event Overview
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AOPs Including This Key Event
Level of Biological Organization
How this Key Event works
Iodine (I2) is a non-metallic chemical element which is required for the normal cellular metabolism. It is one of the essential components of the TH, comprising 65% and 58% of T4's and T3's weight, respectively and therefore it is crucial for the normal thyroid function. It is a trace element and a healthy human body contains 15-20 mg of iodine, most of which is concentrated in the thyroid gland (Dunn, 1998). Iodide (I-) that enters the thyroid gland remains in the free state only briefly and subsequently it bounds to the tyrosine residues of thyroglobulin to form the precursors of the thyroid hormones mono-iodinated tyrosine (MIT) or di-iodinated tyrosine (DIT) (Berson and Yalow, 1955). The bounding rate of iodide is 50-100% of the intrathyroidal iodide pool, meaning that only a very small proportion of this element is free in the thyroid and this comes mainly by the deiodination of MIT and DIT.
The body is not able to produce or make iodine, thus the diet is the only source of this element. Iodine is found in nature in various forms, such as inorganic sodium and potassium salts (iodides and iodates), inorganic diatomic iodine and organic monoatomic iodine (Patrick, 2008). Thus, it is widely distributed in the earth's environment but in many regions of the world the soil's iodine has been depleted due to different environmental phenomena. In these regions, the incidence of iodine deficiency is greatly increased (Ahad and Ganie, 2010).
The daily iodine intake of adult humans varies greatly due to the different dietary habits between the different regions on earth (Dunn, 1993). In any case, the ingested iodine is absorbed through the intestine and transported into the plasma to reach the thyroid gland. However, thyroid is not the only organ of the body that concentrates iodide. It has been shown that other tissues have also the ability of iodide concentration, such as the salivary glands, the gastric mucosa, the mammary glands and the choroid plexus, all of which express NIS, the well-known iodine transporter protein (Jhiang et al., 1998; Cho et al., 2000). The thyroid, salivary glands and the gastric mucosa have a common embryologic origin, from the primitive alimentary tract, which may explain the reason of the NIS expression in these tissues. Furthermore, in regards to the gastric mucosa and the breast, there is an obvious value of concentrating iodide, as it is the route for its derivation to the bloodstream and to the breast milk, respectively. The iodide from the circulation will eventually reach the thyroid in order to participate in its most important function, namely the production of thyroid hormones. In contrast, the biological role of iodide in the salivary glands and the choroid plexus is not yet specified, but it is a research area of high interest, as it is believed that it may be involved in important pathways but yet undiscovered.
The most important role of iodine is the formation of the thyroid hormones (T4 and T3). The thyroid actively concentrates the circulating iodide through the basolateral membrane of the thyrocytes by the sodium/iodide symporter protein (NIS). The concentrated thyroid-iodine is oxidized in the follicular cells of the gland and consequently binds to tyrosines to form mono- or di-iodotyrosines (MIT and DIT respectively), being incorporated into thyroglobulin. This newly formed iodothyroglobulin forms one of the most important constituents of the colloid material, present in the follicle of the thyroid unit. If two di-iodotyrosine molecules couple together, the result is the formation of thyroxin (T4). If a di-iodotyrosine and a mono-iodotyrosine are coupled together, the result is the formation of tri-iodothyronine (T3). From the perspective of the formation of thyroid hormone, the major coupling reaction is the di-iodotyrosine coupling to produce T4. Although T3 is more biologically active than T4, the major production of T3 actually occurs outside of the thyroid gland. The majority of T3 is produced by peripheral conversion from T4 in a deiodination reaction involving a specific enzyme which removes one iodine from the outer ring of T4.
A sodium-iodide (Na/I) symporter pumps iodide (I−) actively into the cell, which previously has crossed the endothelium by largely unknown mechanisms. This iodide enters the follicular lumen from the cytoplasm by the transporter pendrin, in a purportedly passive manner. In the colloid, iodide (I−) is oxidized to iodine (I0) by an enzyme called thyroid peroxidase (TPO). Iodine (I0) is very reactive and iodinates the thyroglobulin at tyrosyl residues in its protein chain. In conjugation, adjacent tyrosyl residues are paired together. Thyroglobulin binds the megalin receptor for endocytosis back into the follicular cell. Proteolysis by various proteases liberates thyroxine (T4) and triiodothyronine molecules (T3), which enter the bloodstream where they are bound to thyroid hormone binding proteins. The major thyroid hormone binding protein is thyroxin binding globulin (TBG) which accounts for about 75% of the bound hormone. In order to attain normal levels of thyroid hormone synthesis, an adequate supply of iodine is essential. In iodine sufficient areas, the adult thyroid absorbs 60-80 μg of iodide per day to maintain the thyroid homeostasis (Degroot, 1966). Inadequate amount of iodide results to deficient production of thyroid hormones, which consequently leads to an increase of TSH secretion and goiter, as compensating effect (Delange, 2000). On the other hand, excess iodide could also inhibit TH synthesis (Wolff and Chaikoff, 1948). The proposed mechanism for this latter effect is the possible formation of 2-iodohexadecanal that inhibits the generation of H2O2 and the subsequent oxidation of iodide in the thyroid follicular cells. The lack of oxidized free radicals of iodide affects the reaction with the tyrosine residues of Thyroglobulin (Tg) and the subsequent formation of MIT and DIT (Panneels et al., 1994). During pregnancy, the organism of the mother is also supporting the needs of the foetus and therefore the iodide requirements are greatly increased (Glinoer, 1997). Additionally, small iodine concentrations have been found to have significant antioxidant effects that resembles to ascorbic acid (Smyth, 2003).
How it is Measured or Detected
The radioactive iodine uptake test, or RAIU test, is a type of scan used in the diagnosis of thyroid gland dysfunction. The patient swallows radioactive iodine in the form of capsule or fluid, and its absorption by the thyroid is studied after 4–6 hours and after 24 hours with the aid of a gamma scintillation counter. The percentage of RAIU 24 hours after the administration of radioiodide is the most useful, since this is the time when the thyroid gland has reached the plateau of isotope accumulation, and because it has been shown that at this time, the best separation between high, normal, and low uptake is obtained. The test does not measure hormone production and release but merely the avidity of the thyroid gland for iodide and its rate of clearance relative to the kidney.
Evidence Supporting Taxonomic Applicability
Animal studies have proven that iodine normalizes elevated adrenal corticosteroid hormone secretion and has the ability to reverse the effects of hypothyroidism in the ovaries, testicles and thymus in thyroidectomized rats (Nolan et al., 2000).
Ahad F, Ganie SA. (2010). Iodine, iodine metabolism and iodine deficiency disorders revisited. Indian J Endocrinol Metab. 14: 13-17.
Berson SA, Yalow RS. (1955). The iodide trapping and binding functions of the thyroid. J Clin Invest. 34: 186-204.
Cho JY, Leveille R, Kao R, Rousset B, Parlow AF, Burak WE Jr, Mazzaferri EL, Jhiang SM.(2000). Hormonal regulation of radioiodide uptake activity and Na+/I- symporter expression in mammary glands. J Clin Endocrinol Metab. 85:2936-2943.
Degroot LJ.(1966). Kinetic analysis of iodine metabolism. J Clin Endocrinol Metab. 26: 149-173.
Delange F. (2000). Iodine deficiency. In: Braverman L, Utiger R, editors. Werner and Ingbar's the thyroid: a fundamental and clinical text. Philadelphia: JD Lippincott. pp 295-316.
Dunn JT. (1993). Sources of dietary iodine in industrialized countries. In: Delange F, Dunn JT, Glinoer D, editors. Iodine deficiency in Europe. A continuing concern. New York: Plenum press. pp 17-21.
Dunn JT. (1998). What's happening to our iodine? J Clin Endocrinol Metab. 83: 3398-3400. Glinoer D. (1997). The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocr Rev. 18: 404-433.
Jhiang SM, Cho JY, Ryu KY, DeYoung BR, Smanik PA, McGaughy VR, Fischer AH, Mazzaferri EL.(1998). An immunohistochemical study of Na+/I- symporter in human thyroid tissues and salivary gland tissues. Endocrinology. 139:4416-4419.
Nolan LA, Windle RJ, Wood SA, Kershaw YM, Lunness HR, Lightman SL, Ingram CD, Levy A. (2000). Chronic iodine deprivation attenuates stress-induced and diurnal variation in corticosterone secretion in female Wistar rats. J Neuroendocrinol. 12:1149-1159.
Panneels V, Van den Bergen H, Jacoby C, Braekman JC, Van Sande J, Dumont JE, Boeynaems JM. (1994). Inhibition of H2O2 production by iodoaldehydes in cultured dog thyroid cells. Mol Cell Endocrinol. 102:167-176.
Patrick L. (2008).Iodine:Deficiency and therapeutic considerations. Altern MedRev. 13:166-127.
Smyth PA. (2003). Role of iodine in antioxidant defense in thyroid and breast disease. Biofactors. 19:121-130.
Wolff J, Chaikoff IL. (1948). Plasma inorganic iodide as a homeostatic regulator of thyroid function. J Biol Chem. 174: 555-564.