As one follows the thyroid hormone journey through the human body, at a crucial stage inside many of our cells, a beautiful and complex cascade transforms our thyroid hormones.
Three deiodinase enzymes, types 1, 2 and 3 (D1, D2, D3), each regulated by their own separate gene (Dio1, Dio2, and Dio3), are at the core of our thyroid hormone metabolism.
Deiodinases convert T4 hormone into a diverse family tree of T3, RT3, T2, and T1 hormones by strategically removing one iodine atom at a time.
As the continual river of thyroid hormones never stops flowing, these industrious enzymes are hard at work every minute of every day, transforming our hormones. We rarely appreciate their action because it is invisible, hidden inside our cells.
When D1, D2 or D3 enzymes convert a thyroid hormone by changing its shape, the hormone radically changes its function in the body. T3 is not just a “more active” type of T4, but a different hormone with unique signaling capabilities at various receptors. Each type of thyroid hormone has a different part to play in this drama, and deiodinases can make all of them except T4.
Since T3 is the most powerful and essential thyroid hormone, a major function of deiodinases is to fine-tune the level of T3 signaling to local needs in each tissue or organ by co-regulating T3’s local production and clearance rates.
Your cerebral cortex, your muscles, and your colon each require a different customized level of receptor occupancy by T3. One tissue will use deiodinase type 3 to get rid of some excess T3 and/or T4 it does not need, while another uses deiodinase type 1 or 2 to generate a little or a lot more T3 or active T2.
However, the deiodinase trio do not form an entirely “autoregulatory” system that always runs perfectly well on their own no matter what we throw at them. They form, instead, a “co-regulatory system” that can itself become dysregulated.
After deiodination, and sometimes without being de-iodinated, thyroid hormones are transported out of cells and re-enter circulation at various rates. Therefore, the second essential function of all the body’s deiodinases, considered collectively, is to serve as co-regulators of our global T3 supply and FT3:FT4 ratio in bloodstream.
Thirdly, D1, D2, and D3 each respond sensitively and differently to a variety of other hormones, nutrients, endocrine disruptors, foods, health disorders, and medications. Often these influences and deiodinase adjustments are organ- and tissue-specific, not generalized to D2 enzymes everywhere in your body. Each deiodinase may be upregulated or downregulated somewhat independently of the others, yet each “DIO” potentially affects the entire trio by the hormones it permits to signal, and the hormones it sends back into blood.
Many of these influences on deiodinases we can control, and some we can’t control.
The clearest evidence that deiodinases do not fully autoregulate themselves occurs during a severe illness, when powerful signals from the illness itself induce a deiodinase imbalance called “nonthyroidal illness syndrome” (NTIS), also called Low T3 Syndrome. The acute phase is inevitable and can be adaptive, but scientists have discovered that a prolonged chronic state of Low T3 is pathological and increases health risk. Many people’s deiodinases cannot fully recover depleted T3 levels by pulling up their own “bootstraps.”
The deepest deiodinase handicaps tend to be in people with a thyroid gland dysfunction in addition to a genetic and/or acquired deiodinase dysfunction. This is because natural thyroid hormone supply has the most natural, regulated, fine-tuned control over deiodinase response. Human thyroid gland tissue is very rich in both D1 and D2 expression, so a portion of these enzymes is lost when thyroid tissue is lost.
Fortunately, thyroid therapies can potentially compensate for deiodinase handicaps and imbalances if they adapt to individuals’ unique needs for both circulating Free T3 and tissue T3. These therapy targets are synonymous with the deiodinases’ T3-centric targets.
In contrast, it’s not respectful of our deiodinase diversity to dose all uniquely hypothyroid individuals on T4 hormone alone, or to prioritize a normalized TSH over an individual’s T3 supply in blood and the clinical signs and symptoms of T3 signaling. These are outdated, draconian therapy policies instituted prior to most of our scientific advances in understanding the deiodinases.
In this post, as usual, I rely only on scientific journal articles as my data sources. I keep in mind that scientific understanding of thyroid metabolism has radically transformed over the decades and still involves debates and mysteries. I’ll provide a birds-eye view of the full thyroid hormone metabolic system, focusing mainly on the three deiodinases.
I’ll first touch on the following basics of how the metabolic system works:
- The place of the “metabolism” stage in the broader “thyroid hormone journey,”
- The mechanisms by which D1, D2 and D3 transform hormones,
- The basic meaning of scientific language and concepts regarding deiodinases,
- The locations of deiodinases inside our cells,
- The major locations of each deiodinase’s expression in the human body,
- The major factors that upregulate each deiodinase —
Then I move into applications:
- The power of thyroid hormone metabolism over human health,
- Individual variation and shifts in deiodinases throughout life,
- The major causes of deiodinase imbalance and dysfunction
- The flexibility of therapeutic approaches
- 7 major lessons taught by deiodinases
- And finally, a brief visual overview of other pathways of thyroid hormone metabolism beyond the deiodinases.
Whether you’re a beginner or a scientifically-informed thyroid patient or thyroid doctor, there’s something here for you. My aims are to summarize the information in one multi-sectioned mammoth post, to bring people up to date on the science, and to equip us all to keep learning more about deiodinases.
The place of metabolism in the thyroid hormone journey
This is the first detailed post in the “Journey” collection since I began it with an overview post titled “Infographic: Thyroid hormone journey.”
Distinguishing the different phases of the thyroid hormone journey is very practical. It can help one detect mistaken claims about thyroid disorders or challenges in thyroid therapy. A common mistake is to misattribute a dysfunction in one aspect of the thyroid economy to a different aspect altogether.
For example, some people claim that a substance benefits thyroid metabolism just because it often elevates T3. But many aspects of thyroid hormone economy besides metabolism can change the T3 level or the FT3:FT4 ratio.
Here is a simplified infographic showing we’re currently in the “middle” of the thyroid hormones’ journey through the human body.
As you can see, the deiodinase enzymes D1, D2 and D3 act as a highly flexible metabolic engine within our cells. (Below, you’ll see why D1 is placed between D3 and D2.)
- First we need enough hormones and a healthy T3:T4 ratio in our bloodstream.
- Next, a variety of specialized transporters select those thyroid hormones from our blood and carry them into cells (Bernal, 2000/2015).
- Next, our thyroid hormones may make contact with deiodinases and other enzymes of metabolism.
- Next, the transformed and untransformed hormones interact with receptors and send signals.
- Then, thyroid hormones exit cells and re-enter the bloodstream, or are cleared out through waste.
Metabolism is a major filter that stands between bloodstream hormone levels and healthy rates of thyroid hormone signaling.
The basics: What are deiodinases?
Deiodinases are enzymes. Enzymes are specialized proteins that work like machines to construct or deconstruct other substances. In the thyroid hormone economy,
- One enzyme, thyroid peroxidase, puts T4 and T3 thyroid hormones together from their basic building blocks of tyrosine and iodine, and that only happens within thyroid gland tissue.
- The deiodinase enzymes, on the other hand, take thyroid hormones apart, and they work everywhere in your body, including inside the thyroid gland.
The word “iodine” is in “de-iodin-ase” because it is an iodine-removal enzyme (enzymes often end with “-ase”).
Deiodinases are part of the natural recirculation of iodine in the human body. Because of what deiodinases do, dosing thyroid hormone constitutes part of one’s daily iodine intake.
Deiodinases are made largely of selenium — they are “selenoproteins.” Over the years, scientists have noticed that selenium deficiency compromises thyroid hormone conversion. Correcting selenium deficiency can enhance T3:T4 ratios and reduce elevated TSH (Kobayashi et al 2021). However, raising a normal selenium level will not necessarily enhance D1 and D2 further. One must be careful not to overdose selenium.
Another selenoprotein is in the same family as deiodinases: “glutathione peroxidase,” (GPx). This is the enzyme that enables the function of the body’s most powerful antioxidant, glutathione (GSH). Glutathione defends us against the buildup of the byproducts of thyroid hormone synthesis and T3-supported mitochondrial function.
For many decades, scientists have theorized that glutathione is at least one of the “thiol” cofactors that all deiodinases may require to function (Imai et al, 1980; Fliers & Boelen, 2020). Glutathione can become depleted during various illnesses (Polonikov, 2020). This underlies the importance of sufficient selenium and glutathione in thyroid hormone metabolism.
How do deiodinases convert hormones?
In models, thyroid hormones look like two hexagonal rings with a tail. Bonded to the rings and tail are chemical components, including up to four iodine atoms.
- T4 has four iodine atoms (shown below as purple dots)
- T3 has three iodine atoms.
- The structure or backbone of thyroid hormones is made of tyrosine (a common amino acid),
- The two rings are called the “inner” ring (shown in blue) and “outer” ring (shown in pink)
In the image above, deiodinases did their work where the red arrows are located.
- To make T4 into T3, a deiodinase must remove iodine (purple dot) from a location on the outer ring (pink ring). This action is performed by D2 and D1.
- To make T4 into Reverse T3, iodine must be removed from the inner ring (blue). This action is performed by D3 and D1.
Here’s a visual analogy. Imagine the hormone’s shape like that of a horse.
- Making T3 is like removing a bridle from the head of a horse, which would set it free,
- Making RT3 or inactive T2 is like removing a foot of the horse, which would cripple it:
Terminology and concepts for deiodinases
Each deiodinase has a gene that regulates the rate of its own creation. D1 enzyme is regulated by DIO1 gene (Dio1, often capitalized). Sometimes scientists refer to the gene name DIO1, sometimes the enzyme D1.
Upregulation / downregulation. When D1 or DIO1 is “upregulated” it means that the body is instructed to create more D1 enzyme molecules in its cells, sometimes only in a specific type of cell or tissue.
RNA Expression vs. activity. Sometimes a dediodinase’s RNA expression may be high but its activity level may be low, or vice versa. Deiodinases can be genetically “expressed” in a tissue, but the deiodinase “activity” is the efficiency of the enzyme actually at work converting thyroid hormones.
For example, when D2 is inactivated by excess T4, it occurs “post-transcriptionally,” so it loses “activity” but not its “expression” in a tissue. (Werneck de Castro et al, 2015).
“Substrate” — The substrate is the hormone molecule (T4, or RT3, for example) that a deiodinase can break up. Each deiodinase has several thyroid hormone substrates. Scientists discover in lab experiments which hormones are the most “preferred substrates” in a priority list. For example,
- D1’s major substrates are RT3 and T3-Sulfate. T4 is lower on its priority list of molecules to convert, and that’s why D1 is not the major contributor of T4-T3 conversion when thyroid hormone levels are average or normal.
- D2’s primary substrate, T4, can reduce D2’s activity if it is too abundant in cells, much like giving an office worker too much paperwork to process.
Thyroid hormone ring names, iodine positions, and symbols
This section goes over hormone prefixes like “3,5-” mean, and inner-ring vs. outer-ring deiodination.
For advanced technical readers: Click to reveal
The function of each deiodinase
In the following diagram, you can see D1, D2 and D3 located at the arrows between hormone types.
Deiodinase type 1 (D1, DIO1) is a two-faced and multi-purpose enzyme. It converts T4 to either T3 or RT3, and converts T3 and RT3 to all three forms of T2.
However, it has a priority “preferred substrate” system that prevents these roles from canceling each other out. D1 is far more efficient at converting RT3. When upregulated, it creates more T3 and destroys more RT3.
Deiodinase type 2 (D2, DIO2) converts T4 to T3, and can convert T3 into an active form of T2. Far lower on its priority list is to convert RT3 into an 3,3′-T2.
Deiodinase type 3 (D3, DIO3) converts T4 to Reverse T3 (RT3) and T3 into two different inactive forms of T2.
The map above can be turned on its side to be viewed as the waterfall, now with all the details added.
The “Other metabolic pathways” shown with the arrow to the left are briefly discussed at the end of this post, after the review of deiodinases.
The next diagram adds T1 and T0 hormones:
Together, all three deiodinases can convert T3 and RT3 into three forms of T2 hormone, then two forms of T1 hormone, finally leaving thyronine with no iodine, T0.
How deiodinases co-regulate thyroid hormone signaling
Each hormone that deiodinases create or destroy has a different “affinity” to bind with and signal at various thyroid hormone receptors. Thyroid hormones can signal in receptors found in the nucleus of cells, in mitochondria, and in a thyroid hormone receptor found on some cell membranes.
The T3 hormone is the highest priority hormone to regulate:
- T3 signals at all nuclear hormone receptors. Its 100% affinity at this receptor is the standard to which all other hormones’ receptor affinity has been compared.
- T3 also co-regulates mitochondria by signaling in its receptors (Yau et al, 2018)
- T3 signals at the cell membrane integrin receptor, although its affinity is lower than that of T4 at this receptor (Davis et al, 2018).
In contrast, T4 is only known to signal at the integrin receptor on the cell membrane. Scientists have confirmed that T4 has 10-15% affinity with nuclear receptors and that TRa1 can in certain situations “sense T4 as an agonist” (Schroeder, 2014), but as of early 2021, no one has conclusively measured the potency of T4 effects in nuclear receptors.
A brief overview of T2 hormone signaling
Inevitably, showing these hormone maps raises the question “why are there three types of T2?”
Many diagrams only show one or two forms of T2 (diiodothyronine). Three forms have been measured in humans for many decades (Faber et al, 1983). In the history of thyroid science, the most commonly measured T2 has been 3,3′-T2, which is the byproduct of both T3 and RT3.
T2 was once considered to be an inactive metabolite. However, T2 hormones play important roles in our bodies.
3,5-T2 is active in many ways. It mildly functional in nuclear receptors, reduces TSH if dosed over 50 mcg, and feeds and co-regulates our mitochondria (Moreno et al, 2017; Giammanco et al, 2020).
Two of the T2 hormones are considered inactive (the ones with red arrows pointing to them). One can think of these inactive T2 hormones as “Reverse T2,” since both can be made from Reverse T3.
- However, the LAT1 and LAT2 transporters prefer to carry 3,3′-T2 into cells more than other types of thyroid hormones, which makes it possible that there is a function for this hormone (Groeneweg et al, 2020).
The active T2, 3,5-T2, is theorized to arise from T3 hormone.
- However, there has recently been some puzzlement about this deiodination pathway because 3,5-T2’s concentrations are higher in T4 monotherapy than in T3 therapy (Köhrle et al, 2020).
- This form of T2 also builds up in nonthyroidal illness when T3 is low (Dietrich et al, 2015).
- (A plausible answer to this puzzle is that 3,5-T2, like Reverse T3, could be a D1-preferred substrate. The 3,5-T2 may be converted to T1 more quickly in the presence of higher T3 levels. Higher T3 levels upregulate D1. If there is less high-priority RT3 to convert, and less T4 to convert to T3, then D1 could focus more on converting 3,5-T2.)
T2 hormones have far lower concentrations and shorter half-lives than T3, making them difficult to measure in blood tests. It is rare to find a T2 test one can order at a laboratory. Recent years have seen several efforts to develop and test T2 assays and to discover T2 levels in T3-inclusive thyroid therapies (Köhrle et al, 2020).
One DIO enzyme per cell
In the large “thyroid hormone journey” sections image above, one aspect is not true to physiology because there was no room to represent it in the overview graphic.
Inside a single cell, only one type of deiodinase may be expressed (Bianco et al, 2019).
Here’s why this location is important: If both D2 and D3 were present in the same cell, they would in theory be able to cancel out each other’s products. They would compete to influence nuclear receptor binding in that cell, which would contradict their basic function.
Even though one deiodinase dominates per cell, in every type of tissue in the human body, either one, two or all three of these enzymes is present. Working together in neighboring cells in a tissue, and as all tissues in the body, their synergy adds up to a significant overall balance (or imbalance) of thyroid hormone ratios and levels in blood.
Deiodinase locations within the cell
The specific locations of deiodinases within cells shown above — near the cell membrane or near the nucleus in the middle, or both — are meaningful.
Location enables both D1 and D3 to quickly exchange their hormone products with bloodstream through the intracellular transporters, while D2 appears to inject its main product, T3, into the nucleus where it can bind to receptors right away (Bianco et al, 2019).
- Both the D1 and D3 enzyme are usually attached to the cell membrane with their active site facing the inside of the cell (Bernal, 2000/2015) — not facing the outside of the cell as once believed — and as some continue to claim (Louzada & Carvalho, 2018).
- D3 locations can vary. D3 can be found floating unanchored in the cytosol in certain cell types, and in conditions of hypoxia, D3 can even be found in the nucleus (van der Spek et al, 2016; Jo et al, 2012). This diverse location shows that D3 activity may be needed in various locations inside the cell.
- D2 enzyme is anchored to the endoplasmic reticulum, a structure closer to the nucleus of the cell (Arrojo E Drigo et al, 2011). This gives the T3 it produces easy access to the nuclear receptors (Bianco et al, 2019).
It is not a weakness of D1 that it quickly exchanges its T3 product with bloodstream and does not usher T3 into the nucleus. Free T3 entering cells from the bloodstream is still a significant contributor to nuclear receptor binding in cells that do not express D3, as outlined by Bianco and colleagues’ various studies and reviews. (See “How do we get enough T3 into thyroid hormone receptors?“)
What upregulates or activates each deiodinase?
The list of substances and health conditions that upregulate (or downregulate) D1, D2, and D3 is long and complex, deserving separate posts for each deiodinase. Here is a summary only of the most powerful forces that upregulate them.
Thyroid hormone levels of T3 and T4 are the most powerful upregulators of all three deiodinases, followed by illness as an upregulator of D3.
Paradoxically, as T3 levels RISE, they enhance D1 expression and activity, but as T4 levels FALL, they enhance D2 activity.
Deiodinase type 1
- It is upregulated as T3 supply and T3 nuclear signaling rises. This is because the DIO1 gene expresses “thyroid response elements” (TREs) that receive signals sent from T3 when it is bound to thyroid hormone receptors in the nucleus (Maia et al, 2011).
- Therefore, D1 rises in expression and activity when euthyroid, hyperthyroid, and hormone-treated thyroid status is characterized by high-normal or elevated T3.
- Conversely, D1 is downregulated after circulating T3 levels fall.
- In the thyroid gland, D1 is also upregulated by rising TSH levels.
“The type I deiodinase in the thyroid gland … increases in the hypothyroid state under the influence of TSH stimulation.”(St. Germain, 1994)
- TSH-receptor stimulating antibodies (TSAb, Graves’ hyperthyroidism) can enhance the TSH signal more powerfully than TSH hormone itself (McLachlan & Rapoport, 2013).
Deiodinase type 2
- D2 is upregulated when FT4 levels are low or low-normal. This is because D2 is progressively deactivated by higher levels of T4, its primary substrate, through the process of “ubiquitination.” (Bianco et al, 2019)
- D2 is upregulated by TSH, but only in TSH-receptor expressing tissues, and under certain conditions:
- TSH signaling can be blocked by the TSH-receptor-blocking antibody (TBAb). This antibody is found in approximately 11% of patients with hypothyroidism using special assays for blocking antibody detection (Diana et al, 2018).
- According to new research, TSH’s upregulation of DIO2 in the human thyroid gland peaks at around 1 mU/mL and begins to diminish as TSH levels rise above 1 mU/mL, while TSH receptor stimulating antibodies (which cause Graves’ hyperthyroidism) do not decrease DIO2 expression but continue to enhance it (Jang et al, 2020).
- D2 is not upregulated directly by TSH, but by cAMP signaling in cells.
- cAMP is short for “Cyclic adenosine monophosphate.” It is a “second messenger” signal that is produced in the cell after certain types of receptors, such as TSH receptors, are activated on the cell membrane.
- The primary mechanism by which TSH upregulates D2 is through generating cAMP signals inside the cell.
The DIO2 gene has cAMP-responsive elements that make it capable of sensing cAMP (Wang et al, 2010).
- But TSH is not the only hormone that can send this signal to upregulate DIO2. Many other substances and hormones besides TSH can generate cAMP signals.
- This is good news for treated thyroid patients who have a suppressed TSH or a TSH deficiency due to pituitary dysfunction.
For example, norepinephrine signaling at its receptors can generate cAMP signals that significantly upregulate DIO2 in brown adipose tissue (BAT). However, untreated hypothyroidism can dampen this cAMP signal from norepinephrine by decreasing its receptor sensitivity. Fortunately, T3 treatment can elevate cAMP signaling in cells by re-sensitizing norepinephrine’s receptors (Tsibulnikov et al, 2020).
Therefore, TSH levels in blood do not always correspond to TSH receptor signaling or D2 upregulation.
As explained above, in some patients with autoimmune thyroid disease, TSH receptor antibodies (TRAb) interfere with TSH signaling by blocking or stimulating its receptor.
Deiodinase type 3
- It is upregulated as T4 and/or T3 exceed a tissue’s current setpoint, such as hyperthyroidism or thyroid hormone overdose. The main role of this enzyme is to reduce T3 receptor occupancy in the nucleus and mitochondria.
- Unlike D2, the D3 enzyme shows no limit to its upregulation in hyperthyroidism or T4 overdose, since Reverse T3 levels continue to rise as T4 rises (See “Reverse T3 in the context of health status, dosages, and thyroid levels.”)
- It is upregulated by many illnesses, especially those that involve inflammatory cytokines (IL-6), hypoxia (oxygen deprivation in tissues), and tumors. (Vries et al, 2020)
Deiodinase locations in the human body
It is very difficult to quantify the D1, D2, and D3-dominant tissues in the human body due to its variable expression and activity, even during health, as described below.
But a major challenge is that the advancement of deiodinase knowledge is not coordinated, but has been based on limited resources, methods, and scientists’ personal curiosity:
- Scientific study of deiodinases has often focused on laboratory animals, not humans. Rats and mice have a different distribution of deiodinases across tissues in their bodies. For example, mouse/rat thyroid gland tissue does not express very much DIO2, but human thyroid tissue does.
- Scientists have historically studied only selected tissue types, rather than sampling of tissues across the body. Lists are biased by scientific interests.
- Reviews of scientific research going back many decades inevitably combine findings from studies using diverse methods, making it difficult to compare DIO expression across tissues studied by two different scientists.
The best scientists have been able to do is compile diverse findings into tidy tables, such as this subsection copied from Marsili’s table from 2011:
Marsili’s study does not claim such tissue lists are complete, but they are longer lists than those found in most deiodinase tables.
However, the tissue lists above are not arranged in any rational order from highest to lowest deiodinase expression.
Fortunately, in recent years, scientists have gathered RNA expression data from hundreds of human tissue samples per tissue type. Finally we are coming close to being able to compare the ranges and averages of DIO-expression in various human tissues, per unit of volume.
The Human Protein Atlas provides a “consensus data set” of RNA expression in many more tissue types and cell types than those listed above.
According to the Atlas, Which tissues have the richest RNA expression of each deiodinase, per unit of volume?
- DIO1 and DIO2: Richest in samples of thyroid gland tissue.
- DIO3: Richest in samples from a variety of female tissues: Cervix (uterine tissue); Placenta; Ovary; Vagina; Fallopian tube; Breast; Endometrium.
(See more comparative details and discussion in “Tissue RNA expression of DIO1, DIO2, and DIO3“)
Applications of Deiodinase Science
The power of thyroid hormone metabolism
The deiodinases in particular have an effect on, and are influenced by, every other stage in the thyroid hormone journey.
Deiodinases play all of the following regulatory roles:
- Customize signaling at TRa1, TRb1, and TRb2, the three main types of nuclear thyroid receptors, which also have tissue-specific expression throughout the body (Bianco et al, 2019)
- Supply mitochondria with appropriate amounts of T3 and 3,5′-T2 (Wrutniak-Cabello et al, 2018; Giammanco et al, 2020)
- Co-regulate TSH secretion from the pituitary, as local D2 influences thyroid hormone signaling in hypothalamus and pituitary (Paragliola et al, 2020).
- Shift thyroid gland T3:T4 secretion ratios as TSH and/or TSH-receptor antibodies upregulate or downregulate thyroidal D1 and D2 (Jang et al, 2020).
- Protect the developing fetus from high maternal levels of T4 hormone while supplying enough T3 to the developing brain (Gutiérrez-Vega et al, 2020)
- Influence bloodstream thyroid hormone levels, ratios and clearance rates, and even their circadian rhythms, (Sun et al, 2020).
Deiodinases can do all these functions because of their location in cells all over our bodies.
As deiodinases mediate between the bloodstream thyroid hormone environment and local tissue thyroid hormone demands, they also give back to that bloodstream environment. Deiodinases can maintain, shift, or radically transform the bloodstream thyroid hormone environment for the entire human body.
Deiodinase efficiency is individualized and variable throughout life.
The individuality and variability of deiodinase function also makes it difficult to generalize which deiodinases, and which tissues’ DIOs, are the most responsible for a given hormone level or ratio in a given individual human being.
One of the major debates has been about whether D1 or D2 contributes the most to bloodstream T3 levels in an average healthy adult human. Scientists used to think it was D1 that contributed the most, but now they believe D2 contributes the most.
In 2015, a research review summarized deiodinases in a way that made them seem relatively inflexible “in [all] humans”:
In humans, ~70% of the circulating T3 is produced via the extrathyroidal DIO2 pathway, whereas ~15% originates from the DIO1 pathway.(Gereben et al, 2015)
However, the review immediately added information about an exception:
“Given that DIO1 is positively regulated by T3,81 whereas the opposite is seen for DIO2, the contribution of DIO1 to the circulating T3 pool is increased in patients with hyperthyroidism.”(Gereben et al, 2015)
In other words, hyperthyroidism causes a switch to D1 dominance.
In hyperthyroid people, excess T3 upregulates D1, so it contributes significantly more to T4-T3 conversion than normal. They can’t say D1 always contributes more than D2 in hyperthyroidism. The degree of D1 versus D2 activity will depend on the degree to which a patient is hyperthyroid.
Deiodinases are very sensitive to their hormonal environment. They can quickly change their expression and activity in response to the circulating thyroid hormone levels and ratios that are carried into cells on transporters.
Imagine a rugged off-road vehicle navigating a bumpy terrain as we go through life.
The deiodinase system is capable of handling certain types of bumps in the road, but obviously not huge vehicle-sized potholes (a severe lack, like extreme hypothyroidism) or vehicle-sized obstacles (like extreme hyperthyroidism).
In the bumpy terrain between extremes, you can navigate by changing gears, going faster or slower, turning right or left. The vehicle is maneuverable because the steering wheel can move independently of the brake and gas pedal.
- Dio1 is the steering wheel, since it is a multi-functional enzyme. It focuses on Reverse T3 clearance but is also responsible for converting T4 to T3.
- Dio2 is the gas pedal, since it focuses mainly on T4-T3 conversion, more so than D1 does.
- Dio3 enzyme is the “metabolic brake” (not the hormone Reverse T3 as is commonly claimed online), because it not only converts T4 to RT3 but also converts T3 to an inactive form of T2.
Like these parts of the vehicle, each deiodinase can work faster or slower independently of the others.
Upregulating one DIO doesn’t necessarily downregulate the other two DIOs.
Each enzyme is driven up or down by different forces, and each cell expresses only one deiodinase at a time. Some tissues are D1 dominant, and others are D2 dominant.
- Inverse relationship 1: When D2 dominates, D3 tends to be suppressed, and vice versa. This is because D2 dominates over D3 in Low-T4 states (untreated hypothyroidism) and D3 dominates over D2 in High-T4 states (untreated hyperthyroidism) (Bianco et al, 2019). In severe illness, D3 also dominates over D2.
- Inverse relationship 2: D1 will be enhanced by higher-normal or high T3 even if D2 activity is depressed by higher T4. (Untreated hyperthyroidism, LT4 overtreatment.)
- Rising together: D1 and D3 both become more efficient as circulating T3 rises, since their genes are sensitive to signals sent by T3 from the nuclear receptor. The tug-of-war between them can maintain euthyroid balance with a mid-range or high-normal T3 (LT4 monotherapy in a good converter) or mildly high FT3 state (T3-dominant thyroid therapy).
- Falling together: D1 and D2 may both be oppressed in a symptomatically hypothyroid person with “normal” thyroid hormones if they have a low FT3:FT4 ratio with FT4 near top of range and FT3 in the lower half of reference. This is because D2 is increasingly deactivated as FT4 rises above mid-range, and D1 is downregulated as T3 falls below mid-range. (LT4 monotherapy in a poor converter.)
This principle of DIO independence was exemplified in a study of rats with induced subclinical hypothyroidism who were treated with T4 hormone:
“Dio2 mRNA expression was downregulated in the hippocampus and pituitary, and Dio1 was upregulated in the kidney and pituitary of the SCH [subclinically hypothyroid] animals. The changes in Dio3 expression were tissue-specific.”(Oliveira et al, 2020)
Oliveira’s particular way of inducing a disorder and choosing an intervention altered all three deiodinases in various tissues, and the alterations in D2, D1, and D3 went in diverse directions.
- DIO2 expression went down because T4 was excessive in the hippocampus and pituitary.
- DIO1 expression was elevated because T3 was high enough in circulation to render D1 more efficient.
- Finally, the DIO3 gene expression varied by location based on the specific T3 needs of each tissue. D3 would become more active in any tissues with excess T3 or T4.
Deiodinases can fine-tune supply so carefully that even as TSH moves within the normal reference range, it turns up or down specific deiodinases (Jang et al, 2020).
Deiodinases can change their relative activity levels in different health conditions.
Even exercise can affect deiodinases. Studies have focused on the effect of exercise on D2 in brown adipose tissue and D1 in liver and found varying results depending on the exercise duration and intensity as well as other experimental methods (Neto et al, 2013).
Each DIO also responds to a different set of signals from other hormones and substances:
“Many factors are involved in the regulation of deiodinases:(Calvo et al, 2017)
• thyroidal status,
• cAMP and catecholamines (norepinephrine),
• insulin, biliary acids …
Of course, these factors can change throughout life, and your deiodinases will respond.
Because deiodinases are so sensitive and flexible, In every human being, D1, D2, and D3 expression and activity levels will vary throughout life.
- Fetal life. During fetal life, we are D3-dominant in most tissues, but we become D2-dominant shortly after birth (Bianco et al, 2019).
- Pregnancy (Gutiérrez-Vega et al, 2020)
- Losing further thyroid gland tissue while hypothyroid (Ito et al, 2015)
- Taking up high intensity exercise (Neto et al, 2013)
- Ingesting excess iodine (Li et al, 2012),
- Changing one’s diet (Vernia et al, 2013)
Across all these changes and individual differences, the deiodinases have two T3-targets to achieve. They attempt to maintain health via T3 sufficiency 1) in the bloodstream and 2) in our most vital tissues:
“Dramatic changes in deiodinase activity accompany alterations in TH [Thyroid Hormone] status.
From a physiologic viewpoint, these changes appear to be coordinated in such a fashion as to maintain T3 levels as normal as possible in the circulation and selected tissues such as the brain.”(St Germain, 1994)
In perfect human health, the deiodinases don’t work alone. They don’t entirely autoregulate.
Deiodinases work in partnership with a healthy TSH-guided thyroid gland.
The healthy human thyroid gland can often compensate for deiodinase handicaps by supplying an individualized T3:T4 dose ratio to buoy up circulating T3 levels.
The thyroid gland’s deiodinases, not just its ability to synthesize T3 de novo, contribute to a TSH-driven circadian rhythm in thyroidal T3 secretion. This creates the gently undulating FT3 levels that hover at mid-range in approximately 50% of the most thoroughly screened healthy (and thyroid-healthy) populations (Ganslmeier et al, 2014).
Even this gentle fluctuation in naturally-produced FT3 is physiologically meaningful and associates with human longevity. (See “The significance of the TSH-FT3 circadian rhythm“)
With this natural deiodinase variability in mind, it is quite miserly and hypocritical to write policies that withhold T3 dosing from those who lack thyroid function, since every person with a healthy thyroid gland takes an extra “dose” of T3 while they sleep, thanks to the far wider variation in TSH over each 24 hour period in health. And that T3 “dose” upregulates deiodinase type 1 not just in the thyroid, but everywhere Dio1 is expressed.
What can go wrong with deiodinases?
Since three deiodinases are each regulated by different genes and different stimuli, they can become imbalanced: For example, one or two of them may be underactive, while another is hyperactive, causing an overall T3 deficiency (tissue hypothyroidism), or overall T3 excess (tissue thyrotoxicosis).
Three situations can cause dysfunction:
- Acquired deiodinase dysfunctions, and
- Thyroid gland loss/dysfunction in combination with genetic or acquired deiodinase handicaps.
Genetic polymorphisms in DIO1 and DIO2 can limit function of these two deiodinases.
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2. Acquired deiodinase dysfunctions
Various substances can cause dysfunction, but so can any type of severe illness.
The “nonthyroidal illness syndrome” (NTIS) or “Low T3 Syndrome” is the most severe type of deiodinase imbalance.
Experts in the area acknowledge that while the acute phase may be benign, chronic NTIS is pathological (van den Berghe, 2014). Low T3 can put life at risk if one cannot recover from it (Rhee et al, 2015).
Many scientific reviews and studies have failed to distinguish the acute and chronic phases of NTIS. This has led to the incorrect conclusions that Low T3 is always benign and adaptive, and that a low T3 is always the result, never the cause, of illness and death. Misunderstanding can cost many people’s lives.
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3. Thyroid gland loss/dysfunction in combination with genetic or acquired deiodinase handicaps.
As T3-secreting and D1- and D2-rich thyroid tissue is lost, it forces the body to depend on the remaining “peripheral” D1 and D2 enzymes outside the thyroid.
If deiodinases beyond the thyroid are weak, then after losing thyroidal deiodinases, the person is doubly disabled.
The thyroid’s variable T3 secretion rate can no longer compensate for losses in peripheral T4-T3 conversion. (See “Thyroid T3 secretion compensates for T4-T3 conversion” )
Overall, thyroid gland function disorders can do the following things to deiodinases:
- Reveal our genetic or acquired deiodinase handicaps after thyroidal deiodinases are lost, and/or
- Actively handicap or distort deiodinases within the thyroid gland and beyond, as seen in untreated hypo- or hyperthyroidism, and/or
- Worsen the deiodinase imbalance of chronic disease and acute “nonthyroidal illness” (NTIS) by lowering T3 more significantly or failing to aid T3 recovery, increasing health risk in ways that scientists have yet to explore.
Example: Thyroid function loss can worsen T3 loss the brain
The brain’s thyroid hormone economy is uniquely vulnerable to D2 and/or D3 deiodinase dysfunction together with thyroid dysfunction. Standard T4 therapy can be rendered ineffective, and T4 dose increases can be counterproductive.
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The flexibility of therapeutic approaches
Fortunately, it’s possible for individualized thyroid hormone therapy to compensate not only for thyroid tissue loss but also for genetic or acquired deiodinase inefficiencies.
Of course, T3-inclusive thyroid therapy can’t stop the Low T3 Syndrome of acute illness. Nor can it fully cure a chronic disease like cancer or liver failure that drives chronic NTIS. But it can:
- compensate for the net loss of tissue T3 due to genetic handicaps
- top up T3 supply that is lowered by chronic illness.
Since deiodinases themselves are flexible, and individuals have varying degrees of metabolic disability, a flexible approach to therapy is necessary.
Biochemical overcompensation: Abnormal blood levels of T3, T4, and/or TSH
Ensuring the bloodstream has a FT3 above the mid-range population mean (Larisch et al, 2018) can supply the T3 that is missing from cells due to a severely handicapped thyroid gland.
Adding deiodinase dysfunction to thyroid failure may require a compensation involving much higher-than-mean FT3 with a lower FT4 to counterbalance it.
Therapeutic compensation will also affect the hypothalamus and pituitary by moving the TSH lower, due to the “TSH-T3 disjoint” seen in thyroid therapy.
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Therapeutic adaptability over a lifetime
As thyroid therapy is life-long, therapeutic demands may change as health status changes during chronic disease. Homeostatic equilibrium is relative to tissue demands and deiodinase function.
Above, I’ve already mentioned how chronic illness and acute NTIS can create challenges for deiodinase function. Therapy may need to adapt when a person has a car accident or stroke, or acquires a new health disorder.
Handicapped deiodinases can hinder the adaptation to seasonal change and exposure to cold in thyroid-disabled populations. Healthy D2 enzyme activity and/or a T3-secreting thyroid is needed for adequate response to cold stress, as shown by studies of adipose tissue metabolism (Tsibulnikov et al, 2020). Levels of FT3 rise significantly during winter even in healthy populations, even while their TSH and FT4 remain steady. However, T4-treated thyroid patients without thyroid glands lose significant amounts of T3 in winter — even in the balmy winters of Sicily where a large-scale comparative study was done. (See “In Winter, everyone gains T3 except thyroidless patients on T4.”)
The nature of the seasonal response would likely differ in T3-treated populations, but the presence of a seasonal shift would likely remain. Therefore, thyroid-disabled patients living in climates with warm summers and cold winters may require more T3 in winter to compensate for changes in T4 and T3 metabolism in winter.
In fragile, metabolically-disabled thyroid patients, customization of T3-inclusive therapy to the individual is a process of trial and error that can take months or years.
Two types of challenges may be overcome.
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7 major lessons taught by deiodinases:
- T3 is the highest priority hormone for deiodinases to defend and manage because T3 signals so powerfully in so many receptors compared to all other thyroid hormones.
- Low T3 will downregulate D1 enzyme, hindering T4-T3 conversion rate in D1-rich tissues like thyroid, liver and kidney, while higher T3 will do the opposite.
- Normal FT3 blood levels can sometimes conceal low-normal or low levels of T3 signaling in D2-rich tissues such as brain, if there is D2 inefficiency and/or upregulation of D3.
- Deiodinases co-regulate TSH concentrations. T3 signaling in the hypothalamus and pituitary is affected locally by the tissue-specific behavior of D2. TSH does not represent deiodinase activity and T3 signaling levels elsewhere in the body, especially during illness.
- TSH is not a significant regulator of D1 or D2 outside the thyroid gland, except in extrathyroidal tissues that express both TSH receptors and D2. TSH-receptor antibodies can block TSH signaling in a minority of hypothyroid patients.
- T3’s adequacy in bloodstream and in cells must be interpreted in the context of concurrent FT3, FT4, TSH, thyroid gland status, and overall health status, because these are the most powerful factors that regulate deiodinases.
- T3-inclusive thyroid therapy can compensate for deiodinase dysfunction and imbalance, but it must be flexibly adapted to the individual’s disability to be effective. Deiodinase disabilities may make a higher T3, lower T4 and/or lower TSH necessary to achieve euthyroid thyroid hormone signaling levels.
Final big picture: Other pathways of thyroid hormone metabolism
Metabolic pathways for thyroid hormone include not just the removal of iodine (deiodination), but also the addition and/or substitution of several other components to the thyroid hormone molecule, such as:
- acetic acid (oxidative deamination), yeilding Tetrac (TA4) and Triac (TA3),
- glucoronide (glucoronidation) occurring mainly in kidneys, creating T4G, T3G, and
- sulfate (sulfation) occurring mainly in liver, yielding T4S, T3S.
(See Van der Spek et al, 2017)