Metabolism and function of iodine in the thyroid gland

Iodine is an essential element for the synthesis of thyroid hormones (THs) in the human body. Both iodine deficiency and excess can provoke a range of pathological conditions. From conception through adulthood, insufficient iodine intake can lead to functional disorders and developmental abnormalities of various organs, including the brain. On the other hand, excessive iodine intake is also undesirable because it can cause thyroid dysfunction and conditions such as hypothyroidism, hyperthyroidism, goiter, and autoimmune disorders.

The authors of the article “The Iodine Rush: Over- or Under-Iodination Risk in the Prophylactic Use of Iodine for Thyroid Blocking in the Event of a Nuclear Disaster” (Valeria Calcatera et al., 2022) provide data from a summarized analysis published up to 2022 regarding the role of iodine and the risks of excessive and insufficient iodination.

The principal role of iodine relates to thyroid physiology: thyroid hormone synthesis and modulation of thyroid function. In addition, recent studies have identified antioxidant, antimicrobial, and antitumor properties of this element (Sorrenti S, et al. Iodine: Its Role in Thyroid Hormone Biosynthesis and Beyond. Nutrients, 2021).

More relevant information is available via Preventive use of iodine in a nuclear catastrophe

During the first 12 weeks of pregnancy, the fetus is completely dependent on maternal THs. At later stages, the fetus begins to synthesize independently:

• T4 — thyroxine (3,5,3',5'-tetraiodo-L-thyronine);
• T3 — triiodothyronine (3,5,3'-triiodo-L-thyronine).

Production of T3 and T4 is, in turn, regulated by:

• TRH — thyrotropin-releasing hormone (Thyrotropin Releasing Hormone, TRH), produced in the hypothalamus;
• TSH — thyroid-stimulating hormone (Thyroid-Stimulating Hormone, TSH), produced by the anterior pituitary.

TRH and TSH play an important role in fetal development, contributing to development of the neuronal network of the central nervous system (CNS) and somatic development, participating in the mitochondrial respiratory chain, stimulating protein synthesis, and regulating carbohydrate and lipid metabolism. Iodine metabolism is regulated mainly by TRH and TSH and by the iodine concentration itself: iodine deficiency stimulates TSH production, leading to additional iodine uptake, whereas iodine excess suppresses the activity of the enzyme thyroperoxidase (TPO), reducing TH synthesis.

Sources of Iodine

There is considerable variability in the iodine content and bioavailability of soils and, consequently, foods across different geographical regions. Most foods contain small amounts of natural iodine and are not significant dietary sources. It should be noted that iodine content is higher in marine plants than in terrestrial plants.

The main sources of iodine are:

• salt;
• seafood;
• fish;
• seaweed.

Salt is considered the preferred means of enriching the body with iodine because it can contain potassium iodate or potassium iodide.

The World Health Organization recommends the following calculation for adding iodine to salt:

• 14 mg/kg when iodine consumption by the population is high (14 g/day);
• 65 mg/kg when iodine consumption by the population is low (3 g/day).

The iodine concentration in drinking water depends on geographical region, proximity to the sea, groundwater levels, and agricultural runoff. The iodine level in drinking water is usually 1–10 μg/L. (Johnson C. The Geochemistry of Iodine and Its Application to Environmental Strategies for Reducing the Risk from Iodine Deficiency Disorders, 2003). Desalinated water may result in complete loss of iodine.

Iodine content in plant foods is influenced by the proximity of the growing area to seawater and by the amount of iodine in soil, irrigation water, and iodine-containing fertilizers. In general, vegetables and fruits are poor sources of iodine. Eggs and dairy products are major sources of iodine. However, iodine levels are also influenced by feed supplements used in agriculture. In addition, iodine concentration in milk depends on the season: its content is higher in winter because milk yield decreases during the winter season.

In dietary supplements, iodine is present as potassium iodide and sodium iodide. The amount of iodine in vitamin and mineral supplements is usually 150 μg. However, international standards vary between regions and often exceed the tolerable upper intake level. (EFSA. Overview on Tolerable Upper Intake Levels as Derived by the Scientific Committee on Food and the EFSA Panel on Dietetic Products, Nutrition and Allergies, 2017).

It should be noted that many diets lead to a reduction in the required iodine level. These include vegetarian, vegan, low-salt, and lactose-intolerance diets.

Recommended Iodine Intake

Most foods have a low iodine content and do not provide adequate intake. Population iodine sufficiency is achieved mainly through salt iodization. In 2021, mandatory salt iodization was implemented in 124 countries. Voluntary iodization was permitted in 21 countries. As a result of this strategy, 88% of the global population was covered by this program.

The following biomarkers are used to monitor iodine status:

• urinary iodine concentration (UIC);
• thyroglobulin concentration in blood;
• goiter rate.

In 2006, the Institute of Medicine developed Recommended Dietary Allowances (RDA) for all age groups:

• 0–6 months: 100 μg/day;
• 7–12 months: 130 μg/day;
• 1–5 years: 90 μg/day;
• 5–12 years: 120 μg/day;
• 12 years: 150 μg/day.

Salt iodization has been shown to be a sufficient method of preventing iodine deficiency in all population groups. However, situations involving excessive iodine levels in the body should not be overlooked. Iodine excess may result from excessive consumption of iodized salt, drinking water, animal milk, seaweed, and dietary supplements. For this reason, maximum recommended iodine doses have been established.

Iodine plays a key role in thyroid physiology as a principal component of thyroid hormones. Both iodine deficiency and excessive iodine intake can cause thyroid diseases and related complications, including growth retardation and neurological and intellectual developmental disorders.

Additional relevant facts are available via The iodine rush: prophylactic use in the event of a nuclear disaster

Insufficient Iodine Intake and Thyroid Disease

Until the 12th week of pregnancy, the fetus is completely dependent on maternal thyroid hormone levels. If the maternal diet during pregnancy does not provide adequate iodine intake, fetal thyroid dysfunction may develop, which in turn affects development of the fetal neuronal network and ultimately leads to intellectual disability of varying severity. This condition is called cretinism and is accompanied by other somatic and neurological abnormalities, including growth retardation and signs of hypothyroidism. Two forms of cretinism are distinguished: myxedematous and neurological.

Neurological cretinism is associated with maternal hypothyroidism in early pregnancy followed by adequate iodine intake by the newborn and manifests as:

• intellectual disability;
• deaf-mutism;
• gait abnormalities;
• spasticity;
• euthyroidism.

Myxedematous cretinism, in contrast, is caused by maternal iodine deficiency in late pregnancy and manifests as:

• intellectual disability;
• short stature;
• hypothyroidism.

Severe iodine deficiency in the maternal body leads to increased rates of stillbirth, spontaneous abortion, fetal developmental abnormalities, and neonatal infant mortality. These complications can be reduced by 50% with iodine supplementation before conception or during pregnancy. (Mahomed K, et al., “The Cochrane Collaboration, Editor. The Cochrane Database of Systematic Reviews.”, 1997).

Children with mild iodine deficiency demonstrate:

• impaired executive function;
• reduced intelligence scores;
• impaired reading ability;
• reduced cognitive skills;
• reduced language skills.

Reduced iodine intake during childhood leads to reduced thyroid hormone production and, consequently, increased production of thyroid-stimulating hormone by the pituitary gland. TSH, in turn, causes enlargement of the thyroid gland due to cellular hyperplasia. Such hyperplasia of thyroid tissue is called goiter and occurs in two forms:

• diffuse goiter;
• solitary nodular goiter.

Individuals with iodine deficiency and iodine intake below 50 mg per day usually have:

• normal or reduced T3;
• reduced T4;
• increased TSH.

The symptoms of iodine-deficiency hypothyroidism vary widely depending on the patient's age. In a newborn with hypothyroidism during the first weeks of life, the following may be observed:

• lethargy;
• impaired sucking;
• protruding eyes;
• macroglossia;
• prolonged jaundice;
• abdominal distension;
• umbilical hernia;
• thickening of skin folds;
• psychomotor impairment;
• constipation.

During childhood and adolescence, a characteristic clinical picture of myxedema includes:

• slowed growth;
• delayed bone and dental development;
• disproportion between the trunk and extremities;
• lethargy;
• hypotonia;
• hyporeflexia;
• depressive state;
• reduced concentration;
• impaired memory;
• cold intolerance;
• dry and pale skin;
• hair loss;
• constipation;
• bradycardia.

Consequences of Excess Iodine

Excessive regular iodine consumption causes considerably less disability. The main causes of exposure to high iodine doses are related to diet, particularly excessive consumption of iodized salt, milk, and seaweed. Iodine overdose sometimes occurs during radiological examinations using iodine-containing contrast agents. Indeed, acute or regular iodine intake can lead to hypothyroidism, hyperthyroidism, goiter, and autoimmune thyroid disease. When the thyroid gland is exposed to high doses of iodine, thyroid hormone production is temporarily suspended. This effect is known as the Wolff-Chaikoff effect. This response persists for several days, after which normal T4 and T3 synthesis resumes. Thanks to this natural adaptation mechanism, large doses of iodine can be tolerated without clinical manifestations. Excessive iodine consumption has been described as a risk factor for autoimmune thyroid diseases and postpartum thyroiditis. Due to failure of the thyroid adaptation mechanism, goiter may also develop in regions with high iodine intake.

In addition to the effects of iodine excess on the thyroid gland, effects on other systems should also be noted. For example, the salivary glands can accumulate iodide. This leads to damage to their cellular infiltration and sialadenitis—inflammation of the salivary glands. (Southern AP, et al., “Treasure Island (FL): StatPearls Publishing”, 2022). Other complications include skin rash, gastrointestinal disturbance, nausea, vomiting, diarrhea, delirium, and stupor.

Both excessive and insufficient iodine intake should be considered provoking factors affecting the normal functioning of the complex metabolic adaptation mechanism of the thyroid gland. In addition, the effects of radioactive iodine on the human body, a by-product of nuclear fission processes, warrant separate consideration. A review of this topic is available in the article The iodine rush: prophylactic use in the event of a nuclear disaster

References

 Calcaterra V, Mameli C, Rossi V, Massini G, Gambino M, Baldassarre P, Zuccotti G. The Iodine Rush: Over- or Under-Iodination Risk in the Prophylactic Use of Iodine for Thyroid Blocking in the Event of a Nuclear Disaster. Front Endocrinol (Lausanne). 2022;13:901620. doi:10.3389/fendo.2022.901620.

Sorrenti S, Baldini E, Pironi D, Lauro A, D’Orazi V, Tartaglia F, Tripodi D, Lori E, Gagliardi F, Praticò M, Illuminati G, D’Andrea V, Palumbo P, Ulisse S. Iodine: Its Role in Thyroid Hormone Biosynthesis and Beyond. Nutrients. 2021;13(12):4469. doi:10.3390/nu13124469.

Johnson CC. The geochemistry of iodine and its application to environmental strategies for reducing the risk from iodine deficiency disorders (IDD). Nottingham, UK: British Geological Survey; 2003. Report No.: CR/03/057N.

European Food Safety Authority (EFSA). Overview on tolerable upper intake levels as derived by the Scientific Committee on Food (SCF) and the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA). Parma: EFSA; 2017.

Mahomed K, Gülmezoglu AM. Maternal iodine supplements in areas of deficiency. Cochrane Database Syst Rev. 1997;(4):CD000135. doi:10.1002/14651858.CD000135.pub2.

Southern AP, Jwayyed S. Iodine Toxicity. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022.

Author: Olena Vyrva, MD

Questions & Answers

Q1. Why is iodine essential for thyroid function?
Iodine is a principal component required for synthesis of T3 and T4. Both insufficient and excessive iodine intake can disrupt thyroid function and are associated with a range of thyroid-related disorders.

Q2. Which biomarkers are used to assess population iodine status?
The article identifies urinary iodine concentration, blood thyroglobulin concentration, and goiter rate as biomarkers used for monitoring iodine status.