See: Chapter from Towards The Global Elimination of Brain Damage Due to Iodine Deficiency
Excerpt from
Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium and Zinc
2000, Food and Nutrition Board, Institute of Medicine, National Academy of Sciences (US)
2000, Food and Nutrition Board, Institute of Medicine, National Academy of Sciences (US)
Iodine is an essential component of the thyroid hormones that are involved in the regulation of various enzymes and metabolic processes. Thyroid iodine accumulation and turnover were used to set the Estimated Average Requirement. The Recommended Dietary Allowance (RDA) for adult men and women is 150 μg/day. The median intake of iodine from food in the United States is approximately 240 to 300 μg/day for men and 190 to 210 μg/day for women. The Tolerable Upper Intake Level (UL) for adults is 1,100 μg/day (1.1 mg/day), a value based on serum thyroptropin concentration in response to varying levels of ingested iodine.
Function
Iodine is an essential component of the thyroid hormones, thyroxine (T4) and triiodothyronine (T3), comprising 65 and 59 percent of their respective weights. Thyroid hormones, and therefore iodine, are essential for mammalian life. They regulate many key biochemical reactions, especially protein synthesis and enzymatic activity. Major target organs are the developing brain, muscle, heart, pituitary, and kidney.
Observations in several areas have suggested possible additional roles for iodine. Iodine may have beneficial roles in mammary dys-plasia and fibrocystic breast disease (Eskin, 1977; Ghent et al., 1993). In vitro studies show that iodine can work with myeloperoxidase from white cells to inactivate bacteria (Klebanoff, 1967). Other brief reports have suggested that inadequate iodine nutrition impairs immune response and may be associated with an increased incidence of gastric cancer (Venturi et al., 1993). While these other possibilities deserve further investigation, the overwhelming importance of nutritional iodine is as a component of the thyroid hormones.
Physiology of Absorption, Metabolism, and Excretion
Iodine is ingested in a variety of chemical forms. Most ingested iodine is reduced in the gut and absorbed almost completely (Nath et al., 1992). Some iodine-containing compounds (e.g., thyroid hormones and amiodarone) are absorbed intact. The metabolic pathway of iodinated radiocontrast media, such as Lipiodol, is not entirely clear. The oral administration of Lipiodol increases the iodine stores of the organism and has been successfully used in the correction of iodine deficiency (Benmiloud et al., 1994). Iodate, widely used in many countries as an additive to salt, is rapidly reduced to iodide and completely absorbed.
Once in the circulation, iodide is removed principally by the thyroid gland and the kidney. The thyroid selectively concentrates iodide in amounts required for adequate thyroid hormone synthesis, and most of the remaining iodine is excreted in urine. Several other tissues can also concentrate iodine, including salivary glands, breast, choroid plexus, and gastric mucosa. Other than the lactating breast, these are minor pathways of uncertain significance.
A sodium/iodide transporter in the thyroidal basal membrane is responsible for iodine concentration. It transfers iodide from the circulation into the thyroid gland at a concentration gradient of about 20 to 50 times that of the plasma to ensure that the thyroid gland obtains adequate amounts of iodine for hormone synthesis. During iodine deficiency, the thyroid gland concentrates a majority of the iodine available from the plasma (Wayne et al., 1964).
Iodide in the thyroid gland participates in a complex series of reactions to produce thyroid hormones. Thyroglobulin, a large glycoprotein of molecular weight 660,000, is synthesized within the thyroid cell and serves as a vehicle for iodination. Iodide and thyroglobulin meet at the apical surface of the thyroid cell. There thyroperoxidase and hydrogen peroxide promote the oxidation of the iodide and its simultaneous attachment to tyrosyl residues within the thyroglobulin molecule to produce the hormone precursors diiodotyrosine and monoiodotyrosine. Thyroperoxidase further catalyzes the intramolecular coupling of two molecules of diiodotyrosine to produce tetraiodothyronine (T4). A similar coupling of one monoiodotyrosine and one diiodotyrosine molecule produces triiodothyronine (T3). Mature iodinated thyroglobulin is stored extra-cellularly in the lumen of thyroid follicles, each consisting of a central space rimmed by the apical membranes of thyrocytes. Typically, thyroglobulin contains from 0.1 to 1.0 percent of its weight as iodine. About one-third of its iodine is in the form of thyroid hormone, the rest as the precursors. An average adult thyroid in an iodine-sufficient geographic region contains about 15 mg iodine (Fisher and Oddie, 1969b).
Thyroglobulin, which contains the thyroid hormones, is stored in the follicular lumen until needed. Then endosomal and lysosomal proteases digest thyroglobulin and release the hormones into the circulation. About two-thirds of thyroglobulin’s iodine is in the form of the inactive precursors, monoiodotyrosine and diiodotyrosine. This iodine is not released into the circulation, but instead is removed from the tyrosine moiety by a specific deiodinase and then recycled within the thyroid gland. This process is an important mechanism for iodine conservation, and individuals with impaired or genetically absent deiodinase activity risk iodine deficiency.
Once in the circulation, T4 and T3 rapidly attach to several binding proteins synthesized in the liver, including thyroxine-binding globulin, transthyretin, and albumin. The bound hormone then migrates to target tissues where T4 is deiodinated to T3, the metabolically active form. The responsible deiodinase contains selenium, and selenium deficiency may impair T4 conversion and hormone action. The iodine of T4 returns to the serum iodine pool and follows again the cycle of iodine or is excreted in the urine.
Thyrotropin (TSH) is the major regulator of thyroid function. The pituitary secretes this protein hormone (molecular weight about 28,000) in response to circulating concentrations of thyroid hormone, with TSH secretion increasing when circulating thyroid hormone decreases. TSH affects several sites within the thyrocyte, the principal actions being to increase thyroidal uptake of iodine and to break down thyroglobulin in order to release thyroid hormone into the circulation. An elevated serum TSH concentration indicates primary hypothyroidism, and a decreased TSH concentration shows hyperthyroidism.
The urine contains the fraction of the serum iodine pool that is not concentrated by the thyroid gland. Typically, urine contains more than 90 percent of all ingested iodine (Nath et al., 1992). Most of the remainder is excreted in feces. A small amount may be in sweat.
Clinical Effects of Inadequate Intake
The so-called iodine deficiency disorders (IDD) include mental retardation, hypothyroidism, goiter, cretinism, and varying degrees of other growth and developmental abnormalities. These result from inadequate thyroid hormone production from lack of sufficient iodine. Most countries in the world currently have some degree of iodine deficiency, including some industrialized countries in Western Europe (Stanbury et al., 1998). Iodine deficiency was a significant problem in the United States and Canada, particularly in the interior, the Great Lakes region, and the Pacific Northwest, during the early part of the 20th century (Trowbridge et al., 1975). The Third National Nutrition and Health Examination Survey study of samples collected from 1988 to 1994 showed a median urinary iodine excretion of 145 μg/L, well above the lower level considered to reflect adequate intake (100 μg/L) (WHO Nutrition Unit, 1994), but this is a decrease from the value of 321 μg/L found in a similar survey in the 1970s (Hollowell et al., 1998). Estimated iodine intakes for Canadians are in excess of 1 mg/day (Fischer and Giroux, 1987). Both countries iodize salt with potassium iodide at 100 ppm (76 mg iodine/kg salt). Iodized salt is mandatory in Canada and used optionally by about 50 percent of the U.S. population.
The most damaging effect of iodine deficiency is on the developing brain. Thyroid hormone is particularly important for myelination of the central nervous system, which is most active in the perinatal period and during fetal and early postnatal development. Numerous population studies have correlated an iodine-deficient diet with increased incidence of mental retardation. A meta-analysis of 18 studies concluded that iodine deficiency alone lowered mean IQ scores by 13.5 points (Bleichrodt and Born, 1994).
The effects of iodine deficiency on brain development are similar to those of hypothyroidism from any other cause. The United States, Canada, and most developed countries have routine screening of all neonates by blood spot for TSH or T4 to detect among iodine-sufficient children the approximately one in 4,000 who will be hypothyroid, usually from thyroid aplasia. Iodine treatment can reverse cretinism especially when the treatment is begun early (Klein et al., 1972).
Cretinism is an extreme form of neurological damage from fetal hypothyroidism. It occurs in severe iodine deficiency and is characterized by gross mental retardation along with varying degrees of short stature, deaf mutism, and spasticity. As many as one in ten of some populations with very severe iodine deficiency may be cretins. Correction of iodine deficiency in Switzerland completely eliminated the appearance of new cases of cretinism, and a similar experience has occurred in other countries (Stanbury et al., 1998).
Thyroid enlargement (goiter) is usually the earliest clinical feature of iodine deficiency. It reflects an attempt to adapt the thyroid to the increased need, brought on by iodine deficiency, to produce thyroid hormones. Initially, goiters are diffuse but become nodular over time. In later stages they may be associated with hyperthyroidism from autonomous nodules or with thyroid follicular cancer. Goiter can be assessed approximately by palpation and more precisely by field ultrasonography. The International Council for the Control of Iodine Deficiency Disorders (WHO/UNICEF/ICCIDD, 1993) and the World Health Organization (WHO Nutrition Unit, 1994) have recommended surveying schoolchildren for thyroid size as one of the most practical indicators of iodine deficiency, and many reports on iodine nutrition are based primarily on such goiter surveys.
Other consequences of iodine deficiency are impaired reproductive outcome, increased childhood mortality, decreased educability, and economic stagnation. Major international efforts have produced dramatic improvements in the correction of iodine deficiency in the 1990s, mainly through use of iodized salt in iodine-deficient countries.
