INTRODUCTIONThe term "iodine deficiency disorders" (IDD) refers to the several consequences that iodine deficiency imposes on individuals. The most important are goiter, hypothyroidism, mental retardation, cretinism, and increased neonatal and infant mortality.

Iodine is an essential component of thyroxine (T4) and triiodothyronine (T3), and it must be provided in the diet. Inadequate iodine intake leads to inadequate thyroid hormone production, and all the consequences of iodine deficiency stem from the associated hypothyroidism. However, iodide excess can also cause thyroid dysfunction.

In developing countries, iodine deficiency has been identified as one of the modifiable factors that have an adverse effect of child development [1] . It is a global public health problem and, in combating it, emphasis should be placed on diagnosis and correction at the level of the community rather than the individual. The International Council for the Control of Iodine Deficiency Disorders (ICCIDD) maintains a website (http://www.iccidd.org) with databases of information about iodine nutrition in different countries and an information reference desk.

This topic will review the consequences of iodine deficiency, its geographical distribution, diagnostic measures, prophylaxis, and treatment. Other aspects of iodine and the thyroid are discussed separately. (See "Iodide and thyroid function" and see "Thyroid hormone synthesis and physiology").

CONSEQUENCES OF IODINE DEFICIENCY

Diffuse and nodular goiterGoiter is the most obvious manifestation of iodine deficiency. Low iodine intake leads to reduced T4 and T3 production, which results in increased thyrotropin (TSH) secretion in an attempt to restore T4 and T3 production to normal. TSH also stimulates thyroid growth; thus, goiter occurs as part of the compensatory response to iodine deficiency.

The goiter is initially diffuse, but eventually becomes nodular, because the cells in some thyroid follicles proliferate more than others. In some instances, the nodules have mutations in the TSH-receptor gene that lead to constitutive activation of the receptor and TSH-independent growth and function [2,3] . Therefore, in regions of iodine deficiency, children and adolescents generally have diffuse goiters and adults nodular goiters.

With continued growth of one or more TSH-independent nodules, hyperthyroidism may ensue if iodine deficiency is not extremely severe. Hyperthyroidism is more likely to develop if iodine intake is supplemented, just as it can occur in patients with nontoxic nodular goiters living in iodine-replete regions who are given large doses of iodine. (See "Iodide and thyroid function").

Goiter has traditionally been assessed by palpation, particularly in field studies. In the last decade, ultrasonography, which allows precise estimation of thyroid volume, has become the preferred method of assessment. In regions of iodine deficiency, the median thyroid volume at any age is considerably larger than that in regions of iodine sufficiency. For subjects living in iodine-sufficient regions, thyroid volume measurements standardized for age, sex and body size are now available [4] . The volume in subjects living in the United States is smaller than that in Europe, many regions of which have a lower iodine intake than in the United States.

Iodine-deficiency goiter is only a cosmetic problem for many subjects. In some, however, particularly older adults, the goiter may be large enough to cause compression of the trachea or esophagus, or delay recognition of coexisting thyroid cancer. (See "Clinical manifestations and evaluation of obstructive or substernal goiter").

HypothyroidismHypothyroidism occurs when iodine intake is very low. Adults have the usual clinical manifestations of hypothyroidism and usually a goiter. (See "Clinical manifestations of hypothyroidism"). For the developing fetus or infant, hypothyroidism is a catastrophe, because thyroid hormone is essential for normal maturation of the central nervous system, particularly its myelination. Hypothyroidism during these critical periods of development leads to permanent mental retardation which, in its most severe form, is known as cretinism. (See "Clinical features and detection of congenital hypothyroidism").

CretinismIn addition to mental retardation, cretinism is accompanied by other neurologic and somatic defects. This has led to cretinism being subdivided into neurologic and myxedematous types: Neurological cretinism is characterized by mental retardation, deaf mutism, gait disturbances, and spasticity, but not hypothyroidism. It is thought to result from hypothyroidism in the mother during early pregnancy. Myxedematous cretinism is characterized by mental retardation, short stature, and hypothyroidism. It is thought to result from iodine deficiency and thyroid injury predominantly late in pregnancy and after birth.

These two syndromes overlap considerably [5] , and attributing them to specific developmental periods is undoubtedly overly simplistic. Both can be prevented by adequate maternal and infant iodine intake.

Mental retardationWhile classic cretinism is uncommon, all fetuses and infants in regions of iodine deficiency are at risk for some degree of mental retardation. A meta-analysis of studies relating iodine deficiency to cognitive development suggested that iodine deficiency alone caused an average loss of 13.5 IQ points in affected subjects [6] . Developmental studies in iodine-deficient regions have many limitations, but they do indicate roughly the magnitude of the risk.

Even in developed countries marginal iodine sufficiency may lead to intellectual compromise. In Jaen province, Spain, schoolchildren with urinary iodine concentrations below 100 mcg/L had lower IQ scores: 96.4 versus 99.0 in schoolchildren with urinary iodine concentrations greater than 100 mcg/L [7] .

Mental retardation resulting from the effects of iodine deficiency on central nervous system development is not reversible. However, in comparison, the additional impairment caused by postnatal hypothyroidism may improve with appropriate thyroid hormone replacement. Additional factors can exacerbate the effects of iodine deficiency, including coexistent deficiencies of selenium and vitamin A [8] and the ingestion of foods such as cassava or millet that contain goitrogenic substances. Iodine supplementation appeared to improve cognition in a survey of children in Albania [9] . (See "Treatment and prognosis of congenital hypothyroidism").

Subclinical neurological defectsOptimal iodine nutrition in the pregnant woman is required for a full development of the fetus [10] .

Minor neuropsychological defects are present in children born to mothers exposed to mild to moderate iodine deficiency during pregnancy. These defects may be detected by appropriate neuropsychological tests [11] .

An increased auditory threshold may be another clinical manifestation of iodine deficiency. As an example, in a study of 150 school-age children in Spain, 38 percent had a goiter [12] . In this subset, there was an inverse relationship between auditory threshold and urinary iodine excretion (ie, the more iodine deficient, the higher the auditory threshold). Thus, iodine repletion in children may be important not only to prevent goiter, but to prevent changes in auditory threshold. (See "Evaluation of hearing impairment in children").

Neonatal and infant mortalityIodine deficiency increases neonatal and infant mortality, an effect that can be reduced by up to 50 percent with correction of severe iodine deficiency [13] . The mechanism of this benefit is not known, but multiple factors are probably involved. Hypothyroid or retarded infants may suffer more birth trauma and be more prone to infectious diseases and nutritional deficiencies typical of the poor rural communities in which iodine deficiency is so prominent.

Socioeconomic effectsPeople in iodine deficient communities are typically less educable and less economically productive. Correction of the deficiency has resulted in dramatic improvement in school performance, agricultural output, and per capita income.

GEOGRAPHIC DISTRIBUTIONA summary compiled by the World Health Organization in 2005 showed that, worldwide, approximately 2 billion individuals (35 percent of the world), including 285 million children, were iodine deficient (defined by a daily iodine intake