The thyroid gland is a compact, butterfly‑shaped organ that exerts a disproportionate influence on whole‑body physiology. Its primary function—synthesizing the iodinated hormones thyroxine (T₄) and triiodothyronine (T₃)—relies on two trace elements that are often mentioned together: iodine and selenium. While both are required in minute quantities, their biochemical roles are distinct and interdependent. Understanding how iodine and selenium participate in thyroid hormone synthesis provides a foundation for appreciating the gland’s exquisite regulation and the consequences when either element is lacking or in excess.
Iodine: Essential Element for Thyroid Hormone Production
1. Chemical properties that make iodine indispensable
Iodine (I) is a halogen with a large atomic radius and a relatively low ionization energy compared to other halogens. These characteristics enable the thyroid follicular cells to concentrate iodide (I⁻) from plasma up to 30‑fold higher than extracellular levels, a process that would be energetically prohibitive for most other anions.
2. Dietary sources and systemic handling
Inorganic iodide is absorbed almost completely (≈90 %) from the small intestine. Once in the bloodstream, it circulates bound loosely to plasma proteins (primarily albumin) and is filtered by the glomeruli. The kidney reabsorbs the majority of filtered iodide, preserving systemic stores. The body’s total iodine pool is roughly 15–20 mg in a healthy adult, with the thyroid containing about 70 % of that reserve.
3. The sodium‑iodide symporter (NIS)
The entry point for iodide into the thyroid follicular cell is the sodium‑iodide symporter, an electrogenic transporter located on the basolateral membrane. NIS couples the inward movement of two Na⁺ ions to the transport of one I⁻ ion, exploiting the Na⁺ gradient maintained by Na⁺/K⁺‑ATPase. NIS expression is up‑regulated by thyroid‑stimulating hormone (TSH) and down‑regulated by excess intracellular iodide (the Wolff‑Chaikoff effect).
4. Intracellular iodide trafficking
After entry, iodide traverses the cytoplasm to the apical membrane, where it is oxidized by thyroid peroxidase (TPO) in the presence of hydrogen peroxide (H₂O₂). The oxidized form, iodine (I₂), is then covalently attached to tyrosine residues on thyroglobulin (Tg), a large glycoprotein that serves as the scaffold for hormone assembly.
5. Organification and coupling
TPO catalyzes two sequential reactions: (a) monoiodination of tyrosine residues to form monoiodotyrosine (MIT) and (b) diiodination to generate diiodotyrosine (DIT). Subsequent coupling of MIT and DIT yields T₃, while coupling of two DIT molecules produces T₄. These reactions occur within the colloid, a lumen‑filled space between follicular cells where Tg is stored in a highly concentrated form.
6. Release of hormone
When TSH stimulates the follicular cell, Tg is endocytosed, proteolytically cleaved in lysosomes, and the liberated T₃ and T₄ are secreted into the bloodstream. The efficiency of this process hinges on the availability of iodide for organification; insufficient iodide leads to reduced hormone output and accumulation of uniodinated Tg.
Selenium: The Critical Cofactor for Thyroid Enzyme Function
1. Selenium as a component of selenoproteins
Selenium (Se) is incorporated into proteins as the 21st amino acid, selenocysteine (Sec). The insertion of Sec occurs co‑translationally at UGA codons, which are recoded from stop signals to Sec insertion sites by a specialized SECIS (Selenocysteine Insertion Sequence) element in the mRNA. This unique biosynthetic pathway underscores selenium’s specialized biological role.
2. Principal selenoproteins in the thyroid
Two families dominate thyroid physiology:
- Iodothyronine deiodinases (DIO1, DIO2, DIO3) – enzymes that activate or deactivate thyroid hormones by removing iodine atoms from the aromatic ring. DIO1 and DIO2 convert T₄ to the biologically active T₃, while DIO3 catalyzes the inactivation of T₄ and T₃ to reverse T₃ (rT₃) and T₂, respectively.
- Glutathione peroxidases (GPx) and thioredoxin reductases (TrxR) – antioxidant enzymes that protect the thyroid from oxidative damage generated during hormone synthesis, particularly the H₂O₂ required for TPO activity.
3. Selenium metabolism and tissue distribution
Dietary selenium is absorbed as selenomethionine or selenocysteine, both of which are incorporated into body proteins non‑specifically or specifically, respectively. The liver stores a modest selenium pool and distributes it via selenoprotein P (SelP), the primary selenium transport protein, to peripheral tissues including the thyroid. The thyroid’s selenium content is relatively high, reflecting its reliance on selenoproteins.
4. Redox balance and H₂O₂ detoxification
Thyroid hormone synthesis is a redox‑intensive process. The generation of H₂O₂ by dual oxidases (DUOX1/2) at the apical membrane is essential for TPO‑mediated iodination, yet excess H₂O₂ can cause lipid peroxidation, DNA damage, and protein oxidation. GPx and TrxR, both selenium‑dependent, reduce H₂O₂ to water, thereby safeguarding follicular cells from oxidative injury.
Molecular Mechanisms of Iodide Uptake and Organification
1. Coupling of NIS activity to TSH signaling
TSH binds to the G protein‑coupled TSH receptor (TSHR) on the basolateral membrane, activating adenylate cyclase and raising intracellular cAMP. cAMP‑dependent protein kinase A (PKA) phosphorylates transcription factors (e.g., CREB) that enhance NIS gene transcription. Parallelly, TSH stimulates the expression of TPO, Tg, and DUOX enzymes, synchronizing iodide influx with the machinery needed for organification.
2. Role of pendrin and other anion exchangers
After cytoplasmic transport, iodide reaches the apical membrane where it is exported into the colloid primarily via pendrin (SLC26A4), an anion exchanger that swaps iodide for chloride. Mutations in pendrin cause Pendred syndrome, characterized by defective iodide transport and consequent hypothyroidism.
3. Oxidation of iodide by TPO
TPO, a heme‑containing peroxidase, utilizes H₂O₂ to oxidize I⁻ to I₂. The enzyme’s active site contains a tyrosyl radical that facilitates the electrophilic attack on the phenolic ring of tyrosine residues in Tg. The precise orientation of Tg within the colloid ensures that iodination occurs at the 3‑ and 5‑positions of the phenol ring, generating MIT and DIT.
4. Regulation by the Wolff‑Chaikoff effect
When intracellular iodide concentrations become excessively high, a temporary inhibition of organification occurs (the acute Wolff‑Chaikoff effect). This autoregulatory mechanism prevents overproduction of thyroid hormones. With continued exposure, the gland “escapes” this inhibition by down‑regulating NIS, restoring normal hormone synthesis.
Selenoproteins in Thyroid Hormone Biosynthesis
1. Deiodinases: fine‑tuning hormone activity
- DIO1 – expressed in liver, kidney, and thyroid; contributes to peripheral conversion of T₄ to T₃ and clearance of rT₃.
- DIO2 – located in the brain, pituitary, brown adipose tissue, and thyroid; provides local T₃ for autocrine/paracrine actions, especially important for maintaining intracellular T₃ levels in the hypothalamic‑pituitary‑thyroid axis.
- DIO3 – expressed in placenta, fetal tissues, and the brain; inactivates excess T₄/T₃, protecting developing tissues from hyperthyroidism.
All three deiodinases contain a selenocysteine residue at the active site, which acts as a nucleophile to cleave the carbon‑iodine bond. The catalytic cycle involves reduction of the selenenyl‑iodide intermediate by thioredoxin, linking deiodination directly to the cellular redox system.
2. Antioxidant selenoproteins and hormone synthesis
GPx reduces H₂O₂ and lipid hydroperoxides using glutathione (GSH) as an electron donor, while TrxR reduces oxidized thioredoxin, which in turn can regenerate GPx and other peroxidases. By limiting oxidative stress, these enzymes preserve the structural integrity of TPO, Tg, and the follicular cell membrane, ensuring uninterrupted hormone production.
3. Interdependence of deiodination and organification
The balance between T₄ synthesis (organification) and T₃ generation (deiodination) is a dynamic equilibrium. Selenium deficiency impairs deiodinase activity, leading to reduced conversion of T₄ to T₃ and accumulation of T₄. Simultaneously, insufficient GPx activity heightens oxidative stress, which can inhibit TPO function and diminish iodination efficiency. Thus, optimal thyroid hormone output requires both adequate iodine for hormone backbone construction and sufficient selenium for hormone activation and protection.
Interplay Between Iodine and Selenium: Balancing Redox State
1. The “iodine‑selenium antagonism” hypothesis
Epidemiological observations in regions of high iodine intake but low selenium status have reported increased incidence of autoimmune thyroiditis. The proposed mechanism involves excess iodide generating reactive iodine species that, in the absence of adequate selenium‑dependent antioxidant defenses, provoke oxidative damage to thyrocyte membranes and expose hidden antigens, triggering autoimmunity.
2. Selenium’s role in mitigating iodine‑induced oxidative stress
When iodide is organified, transient iodine radicals are formed. GPx and TrxR rapidly neutralize these radicals, preventing lipid peroxidation and DNA oxidation. Experimental models demonstrate that selenium supplementation restores GPx activity, reduces iodide‑induced lipid peroxidation, and attenuates inflammatory cytokine release from thyroid cells.
3. Coordinated regulation of gene expression
Both iodine and selenium influence the transcription of thyroid‑specific genes. Iodide, via the iodide‑responsive element (IRE) in the NIS promoter, can modulate NIS expression, while selenium, through selenoprotein‑mediated redox signaling, affects the activity of transcription factors such as NF‑κB and AP‑1, which in turn regulate inflammatory and antioxidant gene networks within the thyroid.
Pathophysiological Consequences of Deficiency
1. Iodine deficiency disorders (IDD)
- Goiter – compensatory hypertrophy of follicular cells due to chronic TSH stimulation.
- Hypothyroidism – reduced synthesis of T₄/T₃ leading to metabolic slowdown, neurocognitive impairment, and, in severe cases, cretinism in children.
- Pregnancy complications – maternal hypothyroidism increases the risk of miscarriage, preterm delivery, and neurodevelopmental deficits in the offspring.
2. Selenium deficiency manifestations
- Keshan disease – a cardiomyopathy linked to low selenium, illustrating systemic consequences beyond the thyroid.
- Hashimoto’s thyroiditis – selenium deficiency correlates with higher titers of anti‑thyroperoxidase antibodies and more rapid progression of glandular destruction.
- Impaired deiodination – reduced conversion of T₄ to T₃, resulting in a functional hypothyroid state despite normal circulating T₄ levels.
3. Combined deficiency synergy
When both iodine and selenium are insufficient, the thyroid experiences a “double hit”: limited substrate for hormone synthesis and compromised activation/antioxidant capacity. Clinical studies in endemic regions have shown that simultaneous supplementation yields greater reductions in goiter size and antibody titers than correcting either deficiency alone.
Genetic and Environmental Factors Influencing Iodine and Selenium Status
1. Polymorphisms affecting NIS and deiodinases
Single‑nucleotide polymorphisms (SNPs) in the SLC5A5 gene (encoding NIS) can reduce iodide transport efficiency, predisposing individuals to subclinical hypothyroidism even with adequate dietary iodine. Likewise, variants in the DIO2 gene (e.g., Thr92Ala) alter enzyme stability and have been linked to altered basal metabolic rate and susceptibility to thyroid disease.
2. Soil composition and agricultural practices
Iodine content in crops mirrors the iodine concentration of the soil, which is heavily influenced by geography, rainfall, and use of iodine‑deficient fertilizers. Selenium availability is similarly dependent on soil pH and organic matter; alkaline, low‑organic soils often contain low selenium, leading to regional “selenium deserts.”
3. Environmental pollutants
Perchlorate, thiocyanate, and nitrate act as competitive inhibitors of NIS, reducing iodide uptake. These anions are prevalent in agricultural runoff and industrial waste, potentially exacerbating iodine deficiency in exposed populations. Heavy metals such as cadmium can interfere with selenoprotein synthesis by displacing selenium from its biological binding sites.
Clinical Implications and Diagnostic Considerations
1. Assessing iodine status
- Urinary iodine concentration (UIC) – the most practical population‑level biomarker; median UIC of 100–199 µg/L indicates adequate intake.
- Thyroglobulin (Tg) measurement – elevated serum Tg can reflect recent iodine deficiency or excess, serving as a sensitive early marker before overt goiter develops.
2. Evaluating selenium status
- Serum selenium concentration – reflects recent intake but may not correlate directly with tissue selenium.
- Selenoprotein P (SelP) levels – a more functional indicator of selenium transport capacity.
- Glutathione peroxidase activity – enzymatic assays provide insight into the functional selenium pool.
3. Interpreting hormone panels in the context of trace element status
A patient presenting with normal TSH but low T₃ and high rT₃ may have impaired deiodinase activity, prompting evaluation of selenium status. Conversely, elevated TSH with low urinary iodine suggests insufficient substrate for hormone synthesis. Recognizing these patterns helps clinicians target the underlying micronutrient deficiency rather than defaulting to hormone replacement alone.
Future Directions in Research
1. Precision nutrition for thyroid health
Advances in genomics and metabolomics are enabling individualized assessment of NIS and deiodinase polymorphisms, paving the way for tailored iodine and selenium supplementation strategies that account for genetic susceptibility.
2. Novel imaging of iodide kinetics
Positron emission tomography (PET) using radio‑labeled iodide analogs offers real‑time visualization of NIS activity, allowing researchers to quantify the impact of environmental inhibitors and therapeutic agents on iodide uptake.
3. Engineering selenoprotein mimetics
Synthetic organoselenium compounds that mimic GPx activity are under investigation as potential therapeutics to bolster antioxidant defenses in the thyroid, especially in settings where selenium bioavailability is limited.
4. Interdisciplinary approaches to endemic deficiencies
Integrating agronomy, public health policy, and endocrine research is essential for sustainable solutions—such as biofortified crops and targeted soil amendment programs—that address both iodine and selenium insufficiency at the community level.
In sum, iodine provides the essential halogen atoms that become the functional core of thyroid hormones, while selenium equips the thyroid with the enzymatic tools required for hormone activation, regulation, and protection against oxidative stress. Their interwoven biochemistry underscores why both trace elements must be present in appropriate amounts for the thyroid to fulfill its central role in metabolic homeostasis. Understanding the molecular choreography of iodine and selenium not only clarifies the pathogenesis of thyroid disorders but also informs more nuanced clinical assessment and future therapeutic innovation.
