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Background

Iodine is a chemical element. It is found in trace amounts in the human body, in which its only known function is in the synthesis of thyroid hormones. Severe iodine deficiency results in impaired thyroid hormone synthesis and/or thyroid enlargement (goiter). Population effects of severe iodine deficiency, termed iodine deficiency disorders (IDDs), include endemic goiter, hypothyroidism, cretinism, decreased fertility rate, increased infant mortality, and mental retardation.[1] Iodine is obtained primarily through the diet but is also a component of some medications, such as radiology contrast agents, iodophor cleansers, and amiodarone. Worldwide, the soil in large geographic areas is deficient in iodine. Twenty-nine percent of the worlds population, living in approximately 130 countries, is estimated to live in areas of deficiency (see Table).[2] This occurs primarily in mountainous regions such as the Himalayas, the European Alps, and the Andes, where iodine has been washed away by glaciation and flooding. Iodine deficiency also occurs in lowland regions far from the oceans, such as central Africa and Eastern Europe. Those who consume only locally produced foods in these areas are at risk for IDD. See the distribution in the image below.

Distribution of iodine deficiency in developing countries. Table. Iodine Deficiency Characteristics (Open Table in a new window) Iodine Deficiency Median urine iodine, mcg/L Goiter prevalence Neonatal thyroid stimulating hormone (TSH), >5 IU/mL whole blood Cretinism 0 0 + + Adapted from the World Health Organization (WHO)/United Nations Children's Fund (UNICEF)/International Council for Control of Iodine Deficiency Disorders (ICCIDD). Normal dietary iodine intake is 100-150 mcg/d. The US Institute of Medicine (IOM) recommended dietary allowance (RDA) is 150 mcg/d of iodine for adults and adolescents, 220 mcg/d for pregnant women, 290 mcg/d for lactating women, and 90-120 mcg/d for children aged 1-11 years. The adequate intake for infants is 110-130 mcg/d. In areas where iodine is not added None Mild >100 50-99 < 5% 5-20% < 3% 3-20% Moderate 20-49 20-30% 20-40% Severe < 20 >30% >40%

to the water supply or food products meant for humans or domesticated animals, the primary sources of dietary iodine are saltwater fish, seaweed, and trace amounts in grains. The upper limit of safe daily iodine intake is 1100 mcg/d for adults, and it is lower for children.[3, 4, 5, 6] In the United States, iodine has been voluntarily supplemented in table salt (70 mcg/g). Salt was selected as the medium for iodine supplementation because intake is uniform across all socioeconomic strata, intake is uniform across seasons of the year, supplementation is achieved using simple technology, and the program is inexpensive. The estimated annual cost of iodine supplementation of salt in the United States is $0.04 per person. Other major sources of dietary iodine in the United States are egg yolks, milk, and milk products because of iodine supplementation in chicken feed, the treatment of milk cows and cattle with supplemental dietary iodine to prevent hoof rot and increase fertility, and the use of iodophor cleaners by the dairy industry. In the early 1900s, the Great Lakes, Appalachian, and northwestern regions of the United States were endemic regions for IDD, but since the iodization of salt and other foods in the 1920s, dietary iodine levels generally have been adequate. However, sustaining these iodization programs has become a new concern. The National Health and Nutrition Examination Survey (NHANES), NHANES III, demonstrated that the median US urinary iodine excretion fell from 320 mcg/d to 145 mcg/d between the early 1970s and the early 1990s and that some subsets of the population may be at increased risk for moderate IDD.[7] This reduction in US dietary iodine intake likely was a result of the removal of iodate conditioners in store-bought breads, widely publicized recommendations for reduced salt and egg intake for blood pressure and cholesterol control, and the increasing use of noniodized salt in manufactured or premade convenience foods. The NHANES surveys of 2005-2006 and 2007-2008 showed that US dietary iodine intake has stabilized.[8, 9] Although the most recent NHANES survey reveals adequate iodine intake in the general US population, certain groups have an insufficient intake of iodine, such as pregnant women who had a median urinary iodine concentration of 125 g/L).[10]

Pathophysiology
Dietary iodine is taken up readily through the gut in the form of iodide. From the circulation, it is concentrated in the thyroid gland by means of an energy-dependent sodium-iodate symporter. In the follicle cells of the thyroid gland, 4 atoms of iodine are incorporated into each molecule of thyroxine (T4) and 3 atoms into each molecule of triiodothyronine (T3). These hormones are essential for neuronal development, sexual development, and growth and for regulating the metabolic rate, body heat, and energy. When dietary iodine intake is inadequate for thyroid hormone synthesis, the serum T4 level initially falls and a number of processes ensue to restore adequate thyroid hormone production. The pituitary gland senses low levels of circulating T4 and releases more TSH. TSH stimulates the growth and metabolic activity of thyroid follicular cells. TSH stimulates each cell to increase iodine uptake and thyroid hormone synthesis and secretion. Increased TSH levels and reduction

of iodine stores within the thyroid result in increased T3 production relative to T4 production. T3 is 20-100 times more biologically active than T4 and requires fewer atoms of iodine for biosynthesis. These processes tend to conserve iodine stores and help maintain normal thyroid function. In addition, thyroid hormones are deiodinated in the liver, and the iodine is released back into the circulation for reuptake and reuse by the thyroid gland. Even under these circumstances, iodine is passively lost in the urine, with additional small (10%) losses from biliary secretion into the gut. Therefore, enlargement of the thyroid gland begins as an adaptive process to low iodine intake. Iodine deficiency is the most common cause of goiter in the world. The goiter initially is diffuse but eventually becomes nodular. Some nodules may become autonomous and secrete thyroid hormone regardless of the TSH level. These autonomous nodules have been demonstrated to frequently contain TSH-activating mutations. Initially, thyroid hormone output by the normal thyroid surrounding the autonomous nodules is reduced to maintain euthyroidism. Autonomous nodules may cause hyperthyroidism. High levels of iodine, such as those found in radiographic contrast dyes or amiodarone, may cause hyperthyroidism in the setting of nodular goiter with hot or autonomous nodules or hypothyroidism in the setting of autoimmune thyroid disease. If the total output of thyroid hormone by the autonomous nodules exceeds that of the normal thyroid gland, the patient becomes biochemically hyperthyroid. This condition is known as a toxic multinodular goiter. When iodine deficiency is more severe, thyroid hormone production falls and the patient experiences a hypothyroid condition. Adults have the usual signs and symptoms of hypothyroidism, while hypothyroidism in the fetus and in young children prevents central nervous system development and maturation, with permanent mental retardation, neurologic defects, and growth abnormalities known as cretinism.[3, 11]

Epidemiology
Frequency
United States Early in the 20th century, the Great Lakes, Appalachian, and northwestern regions of the United States were endemic for iodine deficiency disorder, but since the iodization of salt and other foods in the 1920s, dietary iodine levels generally have been adequate. National survey data suggest that average US dietary iodine intake fell dramatically from 1971-1990 and then stabilized. Urinary iodine values of less than 50 mcg/L are found in 11.1% of the total population, 7.3% of pregnant women, and 16.8% of reproductive-aged women.[8, 7] International Internationally, 2.2 billion people worldwide are at risk for iodine deficiency disorder. Of these persons, 30-70% have goiter and 1-10% have cretinism.

Mortality/Morbidity
Mild-to-moderate iodine deficiency disorder (IDD) can cause thyroid function abnormalities and endemic goiter.

In areas with severe endemic IDD, rates of miscarriage and infant mortality are increased. Cretinism is rare, but populations in which severe iodine deficiency is prevalent are at risk for reduced intelligence and mental retardation. In fact, iodine deficiency is the leading cause of preventable mental retardation worldwide. Whether iodine deficiency causes an increased risk for thyroid cancer is unclear, but a higher proportion of more aggressive thyroid cancers (ie, follicular thyroid carcinoma) and an increased thyroid cancer mortality rate are found in areas where iodine deficiency is endemic. The clinical disorders of iodine deficiency tend to be more profound in geographic areas associated with coexisting selenium and vitamin A deficiencies and in regions where goitrogens, such as cassava or millet, are major staples of the diet.

Race
No race predilection exists for iodine deficiency disorder; prevalence is affected only by geographic area and diet.

Sex
After age 10 years, the prevalence of goiter is higher in girls than in boys in areas of iodine deficiency. No sex-based difference is observed in the incidence of cretinism.

Age
Patients of any age can be affected by iodine deficiency. The most devastating complications of iodine deficiency disorder occur when iodine is deficient during fetal and neonatal growth.