Metabolism is largely dependent on adequate levels of thyroid hormone to create the energy needed by the body to carry out vital functions. Insufficient amounts of thyroid hormone can have broad, non-specific but wide-ranging effects. Such common symptoms of fatigue, brain fog, and weight gain are often associated with hypothyroidism, a condition where not enough thyroid hormone is produced to meet the metabolic needs of the body.
Upon suspicion of low thyroid function, a conventional endocrinologist will typically order a laboratory blood test to measure the amount of thyroid stimulating hormone, or TSH, that is present. TSH is a pituitary hormone that signals the thyroid gland to produce additional thyroid hormone. This is part of a signaling cascade that starts with the production of thyroid releasing hormone (TRH) in the hypothalamus, which then stimulates TSH and ultimately the thyroid gland itself.
Hypothalamus (TRH) -> Pituitary (TSH) -> Thyroid gland (T4 +T3) ->Cell
If the TSH number is “normal” by the typical laboratory range, most conventional doctors will stop investigations at this point. This leaves many people frustrated and confused, still suffering with clear symptoms of hypothyroidism, but without a diagnosis or treatment. That is because most conventional doctors only consider one type of hypothyroidism — as a result of insufficient secretion of thyroid hormone from the thyroid gland itself. If the TSH is normal, the reasoning goes, thyroid hormone production must be sufficient, otherwise, the TSH level would rise. Yet this TSH feedback loop is only one of many ways that thyroid problems can occur, and it is not even the most common source of thyroid problems, especially in those with chronic illness.
Functional medicine practitioners go a step further and will often diagnose hypothyroidism after testing the TSH, but also testing the free thyroid hormone levels, free T4and free T3directly in the blood. When these are found to be low or low-normal in the typical laboratory range, subclinical hypothyroidism may be diagnosed, and thyroid hormone prescribed. This (controversial) method typically improves on that used by the conventional endocrinologist, but still leaves many thyroid patients feeling less than optimal and wondering why.
The answer to that question depends on another aspect of thyroid physiology often overlooked during a clinical thyroid assessment. Blood levels of thyroid hormone are used as a proxy for thyroid function, but these are an indirect measure which may not (and often does not) truly reflect what is happening insidethe cell when and where the thyroid hormone binds to the nuclear thyroid receptor and exerts its effects.
Thyroid hormones are not just controlled by the pituitary gland sending TSH to the thyroid gland, but are activated or inactivated locally, at the cell, by a group of enzymes called deiodinases. This local control by deiodinases allows the cell to adjust the amount of thyroid hormone based on the needs of the cell at any given time. The function of deiodinase enzymes varies for every individual based on genetic and environmental factors, which leads to the large variation in treatment response seen clinically to thyroid hormone medication.
To understand how deiodinase enzymes function, it is helpful to have a general understanding of thyroid hormone structure. Thyroxine, or T4, is made up of four iodine atoms attached to a tyrosine backbone. The three different types of deiodinase enzymes, D1, D2 and D3, work by removing iodine atoms selectively, in differing locations, from this backbone to create the active thyroid hormone, T3, or the inactive metabolite, rT3. Further deiodination turns T3 and rT3 into T2 by removal of another iodine atom. The mineral, selenium, is an important component of the deiodinase enzymes.
Thyroid hormone moves through the bloodstream bound to transport proteins. When it reaches the cellular membrane, the transport proteins are cleaved, leaving the free hormone molecule. Deiodinases can then activate or deactivate the hormone at the level of the individual cell by removing specific iodine atoms, as required to meet metabolic demands. The two deiodinase enzymes, D1 and D2, both create the active hormone, T3, through different mechanisms. This redundancy is likely a safety mechanism ensuring the crucial T3 is always available to tissues that need it.
The D1 deiodinase enzyme, found in tissues like the liver, kidney, thyroid and pituitary, converts T4 to T3. D1 is only responsible for activating about 30% of the T4 produced by the thyroid gland to T3, and it is not a significant source of T3 for the pituitary gland. Most of the T3 formed by D1 does not go on to bind to the nuclear thyroid receptor. It either stays in the cell or exits where it contributes to the circulating plasma levels of T3.
Many types of common conditions can suppress the function of the D1 enzyme. Stress of any kind, depression, caloric restriction, leptin or insulin resistance, diabetes, ME/CFS, fibromyalgia, chronic pain and inflammation, autoimmune diseases and exposures to toxins all reduce levels of D1. Without sufficient amounts of D1, insufficient amounts of thyroid hormone are produced overall, leading to lower than expected serum levels of T4 and T3. D1 levels are also lower in women, potentially explaining their higher prevalence of subclinical hypothyroidism.
Conversely, the presence of T3 inducesthe D1 enzyme, keeping conversion from T4 to T3 running smoothly. Someone on T4 only replacement, may find D1 activity slowed as a result of a lack of T3, and conversion improved upon the addition of some T3 to the dose.
Found inside the endoplasmic reticulum of the cells, the D2 deiodinase enzyme also converts T4 to T3 and is responsible for activating the remaining 70% to T3. It is much less susceptible to suppression by medications and toxins as well. As a result, it is the most important regulator of thyroid function both peripherally at the cellular level and in the pituitary gland. Lack of the D2 enzyme results in greatly lowered levels of T3 inside the cell. So, while the T4 level may look sufficient in the blood, without enough D2 enzyme, the cell will always be lacking in T3, rendering it functionally hypothyroid despite a “normal” TSH. Unlike D1, D2 activity is decreased in the presence of high levels of T4 and T3.
Generally, each cell type will only express one kind of deiodinase activity at a time, however some express no activity at all, and the pituitary gland may express all three types at once. The TSH is determined by the level of thyroid hormone in the pituitary gland, which is primarily a reflection of D2 enzyme action. However, the level of thyroid hormone in the pituitary may be vastly different than that at the cellular level.
TSH may not be very useful as a sole measure of thyroid function, but it is not completely useless either, as many online websites like to claim. TSH stimulates the D2 enzyme to convert T4 to T3 and rT3 to T2. Typically, when someone begins thyroid hormone replacement, the TSH will drop, signaling to the brain that thyroid hormone production is sufficient and no more is required. While conventional doctors treat to bring the TSH into the “normal” lab range, typically this leaves patients still functionally hypothyroid, with lower than optimal levels of free T4 and T3.
Functional medicine doctors typically treat to raise the free thyroid hormone levels to an optimal range on standard labs. In this state, the TSH will almost always be suppressed below the bottom of the normal range. This is a normal response, but this lack of TSH will ultimately limit conversion of T4 to T3 by the D2 enzyme at the cellular level. This is another reason why many people on T4 only replacement, like the brand-name thyroid medication,Synthroid, will not have sufficient conversion of the supplemental T4 into T3. In this scenario, replacing T3 along with T4 is necessary to achieve optimal levels of both. This can be achieved by adding a T3 only medication (Cytomel) to the T4 medication or by using some combination of natural desiccated thyroid hormonewhich contains a mixture of both T4 and T3.
While D1 and D2 are activating enzymes, conversely, the deiodinase enzyme, D3, works as an inactivation enzyme. The purpose of D3 is to keep levels of the active thyroid hormone, T3, low during times of metabolic stress. D3 inactivates T4 by turning it into reverse T3 (rT3), the inactive form of T3. rT3 looks a lot like the active form of T3, but a different iodine atom is removed, rendering it unable to activate the nuclear thyroid hormone receptor. D3 can also further go on to inactivate T3 by removing a different iodine atom and turning it into T2.
Under healthy conditions, when T4 crosses the cell membrane through its transporter, it is converted by deiodinase type D2 into the active thyroid hormone, T3, which activates the nuclear thyroid hormone receptor inside the cell. Under these same normal conditions, the cell can either get the active T3 directly from the blood stream or as a result of this cellular conversion from T4. However, when T4 crosses the cell membrane and is acted upon by deiodinase type D3 instead, rT3 is created and sent back out of the cell into the bloodstream. The T3 coming in from the bloodstream can also be acted upon by D3 and converted to T2. In this case, no T3 reaches the nuclear thyroid hormone receptor and the cellular metabolism is stopped.
As a result of increased D3 activity, rT3 levels in the blood are increased, sometimes significantly, which can then be measured on a standard blood test. Some functional medicine practitioners do measure rT3 routinely, however, there is currently no evidence to support the notion that rT3 blocks the nuclear T3 receptor at any point or requires T3-only therapy for some 12 weeks of “clearing” blocked receptors. In fact, the nuclear thyroid receptor has a far greater affinity for the active T3 molecule than rT3. In other words, in the presence of both T3 and rT3 at the thyroid receptor, the T3 will always preferentially bind. Hypothyroidism occurs when there is not enough T3 to bind to the receptor, not due to any rT3 blocking it.
Moreover, a dose of T3 medication that is too high will also cause high rT3 levels by increasing the D3 enzyme. Given that the proportion of T3 to T4 in natural desiccated thyroid hormone is many times higher than in the human thyroid gland naturally, these preparations (Armour thyroid or Naturethroid, for example) may induce D3 activity and increase rT3. This scenario is reversed by lowering the T3 dose to lessen activity of the D3 enzyme, not by increasing it as many online groups suggest. Desiccated thyroid hormone also contains rT3, so when it raises thyroid hormone levels, it also raises rT3 at the same time.
Many chronic health conditions increase the production of the D3 enzyme, causing lower than expected levels of T3. Stress, poor diet, infections, inflammation and gut permeability all can increase D3. The nonthyroidal illness syndrome, or low T3 syndrome, so common in chronic illness, is a result of increased D3 activity which turns the readily available T4 into rT3 instead of the active T3. High rT3 levels should be expected whenever there is illness or tissue damage that needs to be repaired. The more severe the illness, the higher the rT3 level will be. Thus, high levels of rT3 should be considered a symptom of the problem, not the problem itself.
Because the resulting thyroid symptoms are not a result of insufficient precursor hormone amounts, taking more thyroid hormone may not serve to improve the condition. Any additional thyroid hormone will simply also be inactivated by the increased D3 levels. Overriding the body’s natural protective mechanisms by flooding the cell with thyroid hormone, as recommended by some T3-only thyroid supplementation protocols, may ultimately create more problems than it solves. However, if the underlying disease state is resolved, the thyroid system typically reverts to normal function.
Conversely, one can have low serum levels of thyroid hormone, but they can be potentiated by the deiodinase enzymes, D1 and D2, at the cellular level. So those levels that look low, below functional medicine’s optimal ranges, may or may not be indicative of thyroid hormone dysregulation. This is a common scenario in early Hashimoto’s disease. As thyroid cells are destroyed, levels of thyroid hormone secretion are decreased overall. But as a result of upregulating the deiodinase enzymes, D1 and D2, their effects can potentiate the action of the remaining thyroid hormone, making the levels look reasonably normal on a lab test until the very latest stages of thyroid gland destruction. This is known as thyroid hormone reserve and can complicate diagnosis for those who are unaware of the role of deiodinases in thyroid function.
Unfortunately, the activity of deiodinase enzymes is rarely explored or considered in the clinical setting, likely because there is no corresponding lab test, even though the deiodinase enzymes may have the greatest influence on thyroid levels and function overall. Lab tests only reflect systemic D1 conversion and miss entirely D2 conversion at the cellular level (no test measures what is happening inside the cell yet). Chasing after some specific, optimal values using thyroid labs will almost always prove disappointing for this reason. Because the levels of T4 and T3 will determine the activity of the deiodinase enzymes, changes to one will necessarily result in a new equilibrium that may or may not ultimately increase the active thyroid hormone binding to the nuclear receptor where it counts.
While the common lab tests can’t provide much direct information about deiodinase enzyme activity, there are patterns that can be assessed in thyroid labs, however, which may provide some indication of deiodinase function. These patterns are identified in the chart below.
|Free T4||Free T3||Reverse T3|
|D1 activity increased||Normal to Low||Normal to High||Normal to Low|
|D2 activity increased||Normal to Low||Normal to High||Normal to Low|
|D3 activity increased||Normal to Low||Normal to Low||Normal to High|
Ideally, having thyroid labs done during a “healthy” period can provide a baseline from which to compare later values. The absolute values of thyroid hormone can be less important than identifying the patterns or shifts in pattern values over time. Beyond lab testing, assessing the basal metabolic rate through temperature or speed of muscle reflexes may be more useful in assessing overall thyroid sufficiency.
As a result of genetic differences in deiodinase activity, thyroid replacement dosing can never be standardized as a one size fits all solution. Instead, dosing should be thought of as occurring on a continuum with some percentage of people taking T4 only, another percentage taking T3 only, and the majority on some individualized combination of T4 and T3.
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