Thyroid Synthesis and Selenium: A Closer Look

David Zava Friday, February 01, 2019

During the cold, rainy month of January, at least where we live in Portland, Oregon, it’s fitting to address thyroid health. As Goldilocks said of her porridge, this one’s too cold, this one’s too hot, and this one’s just right. If your body isn’t making the right amount of the thyroid hormones thyroxine (T4) and triiodothyronine (T3), you’re likely to find yourself on either side of “just right”.

Is It Frank or Functional Hypothyroidism?

Most people who suffer from thyroid issues fall into the “too cold” category of body temperature dysregulation and just don’t make enough thyroid hormones T4 and T3, referred to as hypothyroidism. T3 action in the mitochondria increases metabolism and is responsible for heat production. Mitochondria are the power-houses or furnaces of the cell responsible for creation of energy in the form of ATP. So when T3 is low, your body temperature will be lower than normal, which is why simply taking your body temperature is a good way to determine if the thyroid bellows are adequately stoking the fire.

More often than not, thyroid hormone testing shows adequate amounts of thyroid hormone despite clinical symptoms pointing directly at a thyroid-related issue. Functional hypothyroidism describes a patient who has normal or low-normal levels of T4 and T3, and somewhat normal TSH, but nevertheless suffers from many of the hallmark symptoms that characterize a person as having a “thyroid problem”. Symptoms experienced by such a patient include those that are characteristic of hypothyroidism itself, including:

Feeling cold all the time no matter what the room temperature
Being depressed or having a low mood; apathy; and low libido
Sluggish mental capacity – can’t focus or just can’t get those words out
Low stamina and energy, mostly towards the end of the day
A slow heart rate
Constipation
Brittle or dry hair and nails

This blog focuses on some of the possible causes of functional hypothyroidism, with special reference to the essential element selenium that plays a key role in thyroid hormone synthesis and conversion of the inert thyroid hormone T4 to its bioactive counterpart T3, or reverse T3 (rT3). I will also discuss how heavy metals such as mercury and arsenic can interfere with thyroid hormone synthesis, by inactivating selenium dependent anti-oxidants in the thyroid gland and disrupting cellular conversion of T4 to T3 by selenium-dependent thyroid deiodinases.

Thyroid Hormone Synthesis: The Nuts and Bolts

There’s not enough space here to overview the complex details of how thyroid hormones are manufactured in the thyroid gland, so I’ll elaborate mostly on the indirect role of selenium-dependent enzymes in thyroid hormone synthesis. Thyroid hormone synthesis relies on uptake and concentration of iodine in the thyroid gland by an iodine transport protein located on the outer surface of the cells of the thyroid gland, referred to as the sodium-iodine symporter. This allows the thyroid gland to concentrate iodine, especially important when there is very little of it in the diet. Thyroid-Stimulating Hormone (TSH), produced by the anterior pituitary gland, plays a key role in regulating most aspects of thyroid hormone synthesis and is responsible for stimulating synthesis of: the iodine symporter; thyroid peroxidase (an iron-dependent enzyme necessary for manufacturing thyroid hormones); and thyroglobulin, the protein precursor from which T4 and T3 are manufactured. Thus, TSH is the trigger that signals the thyroid to make T4 and T3.

As TSH-stimulated T4 is synthesized and released into the bloodstream from the thyroid gland, it negatively feeds back to the hypothalamus, slowing the production of TSH releasing hormone (TSH-RH), putting a brake on TSH release from the pituitary, and consequently dampening the entire thyroid-synthesizing machinery in the thyroid gland.

Once the thyroid gland has concentrated enough molecular iodine (I₂), thyroid peroxidase (TPO), an iron-dependent enzyme unique to the thyroid gland, with the help of hydrogen peroxide (H₂0₂), begins the process of ionizing the I₂ to the highly reactive iodide (I^-) molecule. The iodine bonds to the tyrosine residues of thyroglobulin, and when most of the tyrosine residues on the thyroglobulin molecule have been iodinated, 2 iodinated tyrosine molecules then coalesce to form the precursors of the thyroid hormones T4 and T3 in about an 80/20 ratio.

T4 and T3 are stored in the thyroid gland until they are released into the bloodstream where they are tightly bound to thyroid binding globulin (TBG). TBG binding limits the quantity of thyroid hormones that enter cells and protects T4 and T3 from degradation in the bloodstream, which would otherwise occur within minutes. Total or free concentrations of T4 and T3 can be measured in blood. The T4 and T3 available as “free” hormone is about 6000 times lower than total hormone levels, meaning that only about 0.02% of the total T3 and T4 circulating in the bloodstream are released into the cells of tissues and are therefore considered bioavailable. In comparison, steroid hormones like estradiol and testosterone have a bioavailable fraction of approximately 2%, about 100-times more bioavailable than thyroid hormones.

Selenium is Essential to Thyroid Hormone Action

Thyroid hormones, T4 and T3, that are released from the thyroid gland must be able to enter cells in all tissues throughout the body to activate specific genes that are unique to thyroid hormone action. T4 to T3 or rT3 conversion is catalyzed by 3 different selenium-dependent thyroid deiodinases referred to as D1, D2, and D3. D1 converts T4 to T3 in specific tissues such as the liver and kidneys and provides an additional source of T3 for these organs that are highly dependent on thyroid. Some of the T3 produced in these tissues is released back into the bloodstream where it is taken up and utilized by other tissues. However, most other tissues, including the brain and muscles, convert bioinert T4 to active T3 by D2 deiodinase.

T4, which comprises most of the thyroid hormone present in the bloodstream, must be first transported into the cells by an energy-dependent process and then converted to bioactive T3 in order for it to bind the nuclear thyroid receptors. If conditions are not favorable for thyroid hormone activity, such as extreme stressors like hibernation, starvation, and sepsis, then T4 is converted instead to reverse T3 (rT3) by D3, which is induced by the stress condition and localized to the outer plasma membrane of the cell. Activation of D3 in the plasma membrane lowers the level of T4 that enters cells, thus reducing T4 to T3 conversion. rT3 has no affinity for the nuclear thyroid receptor and is therefore unable to activate it like T3. However, rT3 is active in the cytoplasm of neurons and glial cells in the brain where it and T4 bind a cytoplasmic truncated thyroid receptor to trigger actin-cytoskeletal polymerization, which is important for brain development and migration of neurites [1]. Within most cells, iodine is abstracted from T4 by D2 present at the nuclear membrane, converting it to T3 in close proximity to the nuclear thyroid hormone receptors.

It is estimated that D2 deiodinase accounts for 50-80% of the T3 utilized by all cells. T3 taken up directly from the bloodstream or created from D2 deiodination of T4 to T3 is then bound by specific nuclear thyroid receptors where it initiates transcription and activation of thyroid-specific genes. The genes are transcribed and translated into structural proteins and enzymes unique to thyroid hormone actions. Vitamin D and cortisol, through their receptor interactions (dimerization) with nuclear thyroid receptors also play an important role in the actions of T3 on thyroid receptors [2]. This is why T3-bound thyroid receptors are optimally activated and balanced with physiological levels of vitamin D and cortisol.

Selenium-Dependent Anti-Oxidant Enzymes Protect the Thyroid Gland During Thyroid Hormone Synthesis

Thyroid hormone synthesis creates an enormous amount of H₂0₂ that is necessary to activate iodine in the presence of TPO enzyme and bind it to the tyrosine residues of thyroglobulin. H₂0₂ is a Reactive Oxygen Species (ROS) essential to thyroid hormone synthesis, but excess levels created during the chemical reactions need to be contained and rapidly neutralized by antioxidants [3] or it would otherwise eventually oxidize and destroy the tissue/cells of the thyroid gland itself and lead to diseases of the thyroid gland such as Hashimoto’s thyroiditis, Graves’ disease, and thyroid cancer [4].

So, what protects the thyroid gland from destroying itself from this biochemical fire? The principal antioxidant enzymes in play are glutathione peroxidase and thioredoxin reductase, both selenium-dependent enzymes that utilize glutathione to destroy H₂0₂ and convert it to water. Some of the highest tissue levels of these selenium-dependent antioxidants are found in the thyroid gland. Their presence and activity depend on a sufficient supply of selenium from the diet. Insufficient selenium intake in the diet or sequestration of selenium through tight ionic bonding to heavy metals such as mercury, arsenic, cadmium, and lead, can eventually result in lower bioavailability of selenium for synthesis of protective selenium-dependent antioxidant enzymes. Further, direct binding of heavy metals, particularly mercury and arsenic, to seleno-cysteine, the selenium complex found in the active catalytic site of glutathione peroxidase and thioredoxin-reductase, will reduce synthesis of these enzymes as well as inactivate them by forming a tight complex with selenium in the catalytic site [5][6].

It is interesting and relevant that low selenium is closely linked to Hashimoto’s thyroiditis, where the thyroid gland begins to self-destruct from within, releasing excessive amounts of thyroid peroxidase (TPO) as well as the iodide-laden thyroglobulin into the bloodstream. Because these proteins are unique only to the thyroid gland, the immune system recognizes TPO and iodinated thyroglobulin as foreign molecules and mounts an auto-immune reaction to them, which can result in a high level of antibodies to TPO (TPOab) as well as thyroglobulin. High antibody titers to TPO in the blood is characteristic of, and diagnostic for, Hashimoto’s thyroiditis, or autoimmune thyroiditis.

Many individuals with Hashimoto’s thyroiditis may benefit from selenium supplementation [7][8], which increases levels of active selenium-dependent antioxidant enzymes and helps remove excessive levels of toxic heavy metals like mercury and arsenic from the body [9].

Simply measuring T3, T4, and TSH in blood may not explain why patients can often present with “apparently normal” thyroid hormones but suffer from hallmark symptoms of thyroid deficiency.

Comprehensive Testing to Assess Thyroid Deficiency

With all the above in mind, it is easier to see how just simply measuring T3, T4, and TSH in blood may not explain why patients can often present with “apparently normal” thyroid hormones but suffer from hallmark symptoms of thyroid deficiency. If thyroid tests are within normal ranges, but symptoms listed above are problematic, even with thyroid therapy, consider also evaluating the status of essential elements iodine and selenium in combination with heavy metals. Evaluation of the full picture is key to understanding why thyroid hormones may be present in ostensibly “normal” levels but are just not stoking the fire and creating the heat necessary for optimal biological function.

Testing with ZRT

ZRT Laboratory has developed a simple and convenient way to assess both true thyroid dysfunction and functional thyroid deficiency, or hypometabolism. Our Comprehensive Thyroid Profile, including thyroid hormone and heavy metal/essential elements tests, uses patient- and provider-friendly, dried blood spot (DBS) and dried urine collections that provide deeper insight into the causes and treatment opportunities for various types of thyroid dysfunction.