Thyroid hormone journey: Metabolism

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.)

  1. First we need enough hormones and a healthy T3:T4 ratio in our bloodstream.
  2. Next, a variety of specialized transporters select those thyroid hormones from our blood and carry them into cells (Bernal, 2000/2015).
  3. Next, our thyroid hormones may make contact with deiodinases and other enzymes of metabolism.
  4. Next, the transformed and untransformed hormones interact with receptors and send signals.
  5. 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

Each thyroid hormone has a technical name using numbers and symbols that describe its unique shape.

The “prime” symbol ( ‘ ) designates positions on the outer ring, and the lack of a prime symbol means the inner ring.

  • Outer-ring deiodination (ORD), 5′-deiodination, tyrosine ring: Sometimes called “activation.” Removing the 5′-iodine makes T4 into T3.
  • Inner-ring deiodination (IRD), 5-deiodination, phenolic ring: Sometimes called “inactivation.” The removal of an iodine atom from the inner ring makes T4 to RT3, or T3 to 3,3′-T2.

3- and/or 5- prefixes identify specific positions on rings.

  • 3,5,3′-triiodothyronine is the official chemical name of T3 hormone. Removal of the 3′ outer-ring iodine makes it into 3,5-T2.
    • The 3,5-T2 hormone, derived only from T3, is active in mitochondria. Both iodine atoms are on the inner ring. (Shown in the diagram.)
    • The 3,3′-T2 form of T2 can be derived from both T3 and RT3. It has an iodine atom located at position 3 of the inner ring and position 3 of the outer ring. It’s missing the 5-iodine in the inner ring, so it’s inactive at the nucleus receptor. (Shown in the diagram.)
  • The 3′,5′-T2 hormone is derived only from RT3. Like 3,3′-T2, it is inactive at the nuclear receptor. Both iodine atoms are on the outer ring. (Not shown.)

Hormones that lack iodine at position 5 on the inner tyrosyl ring are inactive in the nuclear hormone receptor where T3’s “genomic” activity occurs.

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.
  • 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:

[*CNS = Central nervous system. ]

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:
• thyroidal status,
• cAMP and catecholamines (norepinephrine),
• insulin, biliary acids …

(Calvo et al, 2017)

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:

  1. Genetics,
  2. Acquired deiodinase dysfunctions, and
  3. Thyroid gland loss/dysfunction in combination with genetic or acquired deiodinase handicaps.

1. Genetics

Genetic polymorphisms in DIO1 and DIO2 can limit function of these two deiodinases.

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Deiodinase genetic polymorphisms with health implications have been identified for DIO1 and DIO2, but not yet for DIO3. The DIO1 polymorphisms tend to have an influence on average circulating FT3:FT4 ratios (See “REVIEW: DIO1 gene affects T3:T4 ratio“).

One of the DIO1 polymorphisms enhances the deiodinase, while the other risk allele limits its function. Paragliola and colleagues (2020) provide an excellent updated review of the research in section 4 of their article, which is fully available online.

One DIO2 polymorphism, the topic of many studies (T92A or Thr92Ala), has been associated with significant health problems despite not causing as significant a change in circulating hormone ratios. A study by Carlé and team in 2017 found that

“the combination of polymorphisms in DIO2 (rs225014) and MCT10 (rs17606253) enhances hypothyroid patients’ preference for L-T4 + L-T3 replacement therapy.”

(Carle et al, 2017)

However, the study was weakened by common biases found in T4-T3 combination therapy studies, as well as subjective criteria for “preference” rather than measurable biomarkers associated with health outcomes.

A more definitive but smaller two-case study looked at the combination of TSHR and DIO2 genetic polymorphisms and found significant abnormalities in blood work over time (Park et al, 2018). The TSH-receptor gene can worsen a DIO2 polymorphism because the TSH receptor blocking antibody and/or TSH receptor dysfunction may reduce cAMP signaling that is needed to upregulate DIO2:

“lack of cAMP production caused by loss-of-function mutation of TSHR and DIO2 T92A SNP cooperatively causes decreased DIO2 enzymatic activity”

(Park et al, 2018)

The two case studies in Park’s report reveal that a longitudinal study of laboratory history and response to T4 monotherapy vs. T4-T3 combination therapy may be more effective at identifying signs of genetic deiodinase dysfunction and its correction during thyroid therapy, compared to studies based on a single random blood test per person.

Genetic deiodinase handicaps in DIO1 and DIO2 are not usually deletions that cause the enzymes to fail. However, this is still a frontier of discovery, and new variants are being found. A new “missense DIO1 pathogenic variant” was recently identified by Franca et al, 2020 in two families. The signs were:

“abnormal TH metabolism with elevated serum reverse triiodothyronine (rT3) levels and rT3/T3 ratios. … Kinetic studies of the resulting mutant D1 proteins demonstrate two- to threefold higher Km indicating lower substrate affinity and slower enzyme velocity.”

(França et al, 2020)

Instead of disabling a deiodinase completely, the common polymorphisms usually function as limitations on the degree that deiodinase can be upregulated by the usual stimuli. Genetically lower-functioning D1 and D2 are associated with various health conditions, including autoimmune hypothyroidism (Pargliola et al, 2020)

All deiodinases — D1, D2, D3 — require SECISBP2 gene (formerly named SBP2) in their creation, so a genetic handicap in this gene can cause deiodinase dysfunction. A syndrome of “partial SBP2 deficiency” in humans can present even as late as 35 years of age with “high total and free T4, low T3, high rT3 and slightly elevated serum TSH” (Dumitrescu et al, 2013). It is not curable by selenium supplementation (Schomburg et al, 2009), but responds well to T3 therapy (Dumitrescu et al, 2010).

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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Sometimes temporary deiodinase imbalances can be acquired or induced by medications, nutrient deficiencies, and substances considered endocrine disruptors. (The medications, nutrients, and substances that may affect deiodinases are so numerous and complex that they ought to be covered in separate posts.)

During any severe illness, deiodinases can become very dysregulated, resulting in low T3, often despite a normal TSH and normal T4 in bloodstream. This is the process of nonthyroidal illness syndrome (NTIS) or Low T3 syndrome.

NTIS can happen to anyone, whether or not they have a healthy thyroid gland. A swift and acute phase of T3 loss and Reverse T3 gain is the deiodinase response to a major health crisis like a heart attack or stroke. Deiodination is also theorized to suddenly release blood iodide to help the body manage systemic stress and inflammation during the acute phase (Morrison et al, 2020)

But “recovery” does not always occur. Many studies show that Low T3 is independently predictive of mortality and morbidity rates (Rhee et al, 2015).

If the patient does not die from acute NTIS, the syndrome may enter a chronic phase, as it often does in chronic diseases like heart failure, dementia, and cancer. A chronic NTIS deiodinase imbalance can then become pathological (van den Berghe, 2014). A low or low-normal T3 may be sustained in chronic illness outside the hospital setting (Pappa et al, 2011).

During NTIS, circulating T3 entering the damaged or diseased tissues is being depleted locally at a higher rate than normal by Deiodinase type 3 (D3).

“In NTIS, the decrease in T3-dependent gene expression is independent of circulating T3 concentration, demonstrating that after an ischemic event, there is potent and stable induction of D3 activity in cardiomyocytes, resulting in subsequent local cardiac hypothyroidism.” 

(von Hafe et al, 2019)

Sometimes local deiodinase imbalances can make suffering organs and tissues more hypothyroid than the T3 levels in blood reveal (Von Hafe et al, 2019; Paragoglia et al, 2020).

Buildup of RT3 in blood during NTIS is the outcome of simultaneous D3 dominance and D1 suppression. High D3 activity boosts T4-RT3 conversion rates. The D1 enzyme is suppressed by the low T3 as well as by illness and cannot perform its main role of RT3 clearance.

Therefore, RT3 testing is useful when a differential diagnostic is needed. Diagnosis may be needed if chronic NTIS is suspected as a cause of T3 loss. The RT3:T4 ratio (not the T3:RT3 ratio) can confirm the presence or severity of both acute and chronic NTIS. If the RT3:T4 ratio is similar to the ratio found in healthy controls, it rules out “systemic illness” (NTIS) as a cause of a low T3 or a low FT3:FT4 ratio (Ingbar & Braverman, 1982). The main exceptions are in cases of kidney failure, which can prevent RT3 elevation (Kaptein et al, 1983), and in hyperthyroidism.

Total T3 and Total T4 are measured in NTIS, not free thyroid hormones. This is because free thyroid hormone blood tests can become deceptive in this condition. Lower levels of binding proteins like TBG can occur both because of severe illness and the use of blood thinners. (Baloch et al, 2003; Fliers & Boelen, 2020)

TSH is not a valid index of euthyroid tissue status during illness. This is because hypothalamus and pituitary deiodinases are distorted.

“In the hypothalamus, DIO2 is expressed in glial cells and tanycytes and DIO3 is expressed in neurons…

Illness results in increased DIO2 mRNA expression and activity while hypothalamic DIO3 decreases.”

(Fliers & Boelen, 2020)

In NTIS, neither the TSH level and T4 level are correlated with death or poor recovery, unless they also fall low while T3 is low, worsening the prognosis.

The loss of “central” hypothalamus and pituitary stimulus of TSH secretion and thyroid hormone secretion is seen also in the images below.

(NOTE: The arrows in the chart represent increases and decreases found in untreated patients with healthy thyroid glands. They would not necessarily apply to people dosing T3 and/or T4 thyroid hormones. They also vary across different diseases.)

Fliers and Boelen’s 2020 review of nonthyroidal illness confirms that acute NTIS differs from chronic NTIS.

A major health risk in NTIS is the failure to recover from T3 depletion in a timely manner.

In recent years, thyroid scientists such as Fliers have suggested that people with healthy thyroids could be treated with TRH-TSH-stimulating agents, since it is known that the swift rise of TSH stimulation is the first stage of natural recovery in people with healthy thyroids.

Scientists and physicians are wary of using T3 to treat NTIS partly because there are very few studies. There are few studies because so many are fearful of T3 dosing side effects. Many fear cardiovascular harm and are unaware of T3’s cardiovascular benefits (von Hafe et al, 2019).

Unfortunately, policy writers continue to imply that thyroid-disabled people treated with T4 hormone alone will be fully capable of deiodinase recovery and T3 supply recovery. These assumptions lack sufficient evidence to support them. One study reassuring doctors of LT4-treated patients’ safety was performed on only 6 men dosing Synthroid who appeared to have TSH-responsive thyroid remnants supporting their recovery. (See “Low T3 syndrome in thyroid therapy: THREE studies” and “Thyroid patients are routinely excluded from low T3 syndrome (NTIS) research“).

It is already known that T4 supplementation in thyroid-healthy subjects can be counterproductive during NTIS (Brent & Hershman, 1986), and that high-normal levels of T4 during therapy can downregulate D2 (Werneck de Castro et al, 2015). Some treated patients are already identifiable as chronic “poor converters” of T4 before injury or illness, as revealed by their low FT3:FT4 ratios (Midgley et al, 2015). Yet the standard recommendation, in spite of these facts, is to maintain T4 dosing in all the thyroid-disabled during NTIS.

It is more rational to suspect that without partial thyroid function, deiodinase-handicapped patients on T4 monotherapy will be at higher risk of non-recovery from NTIS. There is not enough research to dismiss such a reasonable hypothesis.

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:

  1. Reveal our genetic or acquired deiodinase handicaps after thyroidal deiodinases are lost, and/or
  2. Actively handicap or distort deiodinases within the thyroid gland and beyond, as seen in untreated hypo- or hyperthyroidism, and/or
  3. 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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A recent study concluded that hypothyroidism treated by T4 monotherapy can finally bring to light underlying DIO2 deiodinase dysfunctions:

“it is conceivable that, once carriers of the Thr92Ala-DIO2 polymorphism become hypothyroid and are treated with LT4, … adaptive mechanisms are exhausted, bringing out a phenotype that is similar to the Ala92-Dio2 mice [mice bred with genetic Dio2 handicaps].

For example, the approximately 10% lower serum T3 levels observed in adequately LT4-treated hypothyroid patients could be the key element that tips the balance toward behavioral and cognitive dysfunction.

(Jo et al, 2018)

It is refreshing to find scientists admit that even an approximate 10% deficit could be harmful and “tip the balance” toward cognitive dysfunction. Yet their words “adequately … treated” are highly doubtful, since truly adequate treatment supports adequate T3 supply and signaling.

The issue of behavioral and cognitive dysfunction is an important one. We can’t measure T3 levels in tissues behind the blood-brain-barrier (BBB) in living humans, but we can use science to understand how circulating FT3 and FT4 blood levels and ratios are likely to affect deiodinases in the brain, which expresses mostly D2 and D3.

  • Compared to most other tissues, brain tissue must maintain a very high level of T3 receptor occupancy to function — receptors are “almost fully occupied” with T3 at all times. Compare this with brown adipose tissue T3 receptors, which varies from “~75% to >95%” occupied (Bianco et al, 2019).
  • In health, most brain tissues are largely dependent for their T3 supply on local T4-T3 conversion via D2, but they also require a “top up” from circulating T3 crossing the blood-brain-barrier (BBB) into the brain (Bianco et al, 2019).
  • Very little D1 is expressed in brain tissue compared to D2, so elevated circulating T3 in brain will not boost its local tissue T4-T3 conversion rates.

There’s not much wiggle room; the brain will become less functional if T3 receptor occupancy drops.

Bianco and team reason that merely having a DIO2 genetic handicap is not enough to severely handicap the brain. They’re right, because transporters carry “top-up” T3 supply into the brain from peripheral circulation. Fortunately, circulating T3 crosses the BBB primarily via MCT8 transporter, which prefers to carry T3 slightly more so than T4 (Bernal et al, 2015).

If you have a healthy, TSH-guided thyroid gland secreting T3, in addition to functional D1 activity in thyroid, liver, and kidney, there will be enough T3 in peripheral circulation coming into the brain to compensate for a DIO2 polymorphism.

But if a person has both a DIO2 polymorphism affecting the brain AND a low-normal or lower level of T3 supply in peripheral blood due to illness, thyroid dysfunction or T3-insufficient therapy, that’s another story.

It is well known that low T4 supply causes hypothyroidism in the brain, but few people acknowledge the brain’s dependence circulating T3. There is little to no tolerance for a D2 dysfunction producing a local T3 deficiency in brain if there is not enough compensatory T3 in peripheral blood being transported into the brain.

During chronic illnesses that affect various parts of the brain and central nervous system, D3 enzyme may become chronically elevated, making the brain’s T3 loss from a D2 dysfunction even more severe.

Adding more T4 to the blood will not necessarily make more T3 appear in the deiodinase-handicapped brain or the bloodstream. To upregulate D2 even at low-normal T4 levels, one needs elevated TSH-receptor signaling in the thyroid and/or cAMP signaling in extrathyroidal tissues. The D1 enzyme in thyroid, liver, and kidney is dependent on higher-normal T3 levels for its upregulation.

As a result, a T4 dose increase will not always make FT3 levels rise above the mid-range population mean, in people without any thyroid function:

“Dose escalation had a stronger effect on suppressing TSH than raising FT3 concentrations, leaving 31 % of the presentations with FT3 concentrations still in the lower half of the reference range despite a suppressed TSH.

(Larisch et al, 2018)

Larisch’s graphs show that some thyroid-disabled people with low and suppressed TSH can even have LOW FT3 levels in blood. This is logical because:

  • Adding more T4 will downregulate the “poor converter’s” D2 enzyme.
  • Adding T4 and does nothing to upregulate their D1 enzyme, which is T3-sensitive, not T4 sensitive. One’s DIO1 may also be genetically handicapped.
  • As T4 rises beyond one’s setpoint, it can also elevate D3 enzyme activity, which has a net effect of intracellular T3 loss.
  • T4-toxicosis is a concern, since T4 is also a signaling hormone. Excess T4 signaling in the “integrin” receptor can drive pathological signaling from that receptor, with significant implications for cancers and cardiovascular diseases (Davis et al, 2018).
  • Even if a poor converter had a partially functioning thyroid, TSH stimulation levels would be inevitably lowered by adding T4.
  • Overall, it is counterproductive to elevate FT4 in such patients.

No compensatory mechanisms exist in the brain to handle a double T3 deficit — 1) a lower net T3 production via deiodinases in brain and peripheral tissues, and 2) the loss of flexible, adaptive thyroidal T3 secretion rates to compensate for deiodinase dysfunction.

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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One of the main challenges for therapies that compensate for deiodinases is what I’ve called “biochemical bigotry.” This is the standard medical belief that the thyroid biochemistry of the healthy population prescribes thyroid hormone targets for the thyroid-disabled, thyroid-dosed population. Reference ranges provide less reliable guidance the farther the patient is from the characteristics of the reference population.

The thyroid-disabled, deiodinase-disabled, thyroid-hormone-treated person may need to have an abnormal biochemical profile in one or more of the following ways:

  • A physiological demand for a high-normal or mildly elevated FT3. This can support D1 activity that may partly compensate for handicaps in D2. It can also compensate for metabolic T3 losses in tissues caused by illness. FT3 tests should be taken 12+ hours after a T3 dose due to the predictable T3 peaks and valleys during T3-inclusive therapy.
  • A lower or suppressed TSH that is not representative of T3 signaling in deiodinase-handicapped tissues beyond the pituitary. It is well known that illness can cause a falsely normal or low TSH due to altered deiodinase function in the hypothalamus and pituitary (van den Berghe, 2014).

    TSH secretion rate is co-regulated by tissue-specific T3 signaling based on its unique local deiodinase expression & response, plus a unique T3 receptor type (TRb2) only found in a few tissues such as the pituitary and retina.

    The “TSH-T3 disjoint” found in T4 thyroid therapy also exists in T3-inclusive therapy. The research on Low-TSH health risk associations has never studied where TSH naturally falls when T3-inclusive treatments are dosed to target health outcomes (See “Fear of Low TSH causing osteoporosis“).
  • Some may require low or low-normal FT4 levels. Lowering T4 can prevent thyrotoxicosis when FT3 is concurrently high-normal or mildly elevated due during T3-inclusive therapy. A lower T4 can support efficient D2 function, since it enhances DIO2 activity. D2 enzyme becomes less active when FT4 is high-normal, but D2 activity may be enhanced at lower T4 levels.

Regardless of the wide range of therapeutic approaches available, whether T4 monotherapy, desiccated thyroid (DTE/NDT), or flexible synthetic dose ratios, the primary therapeutic target ought to be the same as it is for our trio of deiodinases: enable tissue and bloodstream T3 sufficiency that meets individual needs and local tissue demands.

To respect our adaptable deiodinases, a rigid policy of biochemical mimicry ought to be set aside. Healthy levels of thyroid hormone signaling are what protects health in the individual. Laboratory results still matter, but reference ranges provide a context for interpretation, not a prison.

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.

Therapeutic challenges

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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In flexible T3-T4 dose combinations that optimize handicapped deiodinases, it helps to monitor FT3 and interpret it in light of concurrent FT4 levels. Measuring both hormones enables the physician and patient to interpret symptoms and signs and to manage the two key challenges:

1. FT3 may rise too high while FT4 is not low enough to counterbalance its elevation.

Excess of T3 and/or T4 above one’s individual setpoint inevitably triggers D3, causing a higher rate of loss of both T4 and T3 within cells. Sometimes the mild overdose can paradoxically induce some symptoms of hypothyroidism in spite of high-normal or high circulating FT3. (The loss of T4 to RT3 may not be observable in RT3 levels, since T3-upregulated D1 activity converts RT3 to T2 at a higher rate.)

2. As T4 dose reduces to counterbalance a higher T3 level, the stable T4-T3 conversion rate will fall lower as well.

As the baseline level of T3 supplied by T4-T3 conversion drops, the body requires a higher direct T3 supply from T3 dosing. The T4-T3 conversion rate will likely already be lower in a deiodinase-disabled person anyway, but less T4 will become T3 when there is less T4 supply.

Managing the fluctuations of fast-release T3 often requires the patient to manage two or more T3 and/or NDT doses per day. Doses of various sizes must be placed at times that work with their body and lifestyle.

A daily schedule of doses may need to be micro-managed by a competent, well-informed patient herself. Just as Physicians must place faith in patient responsibility in cases of insulin-dependent Type 1 Diabetes, so physicians must learn to trust the educated, competent patient to micro-manage their own T3-dependent hypothyroidism within a prescription that supplies a sufficient daily dose.

Armed with a simple pill cutter and knowledge of predictable post-dose peaks, T3 can be dosed to create a daily peak and valley with a circadian rhythm. Peer guidance can offer support (See “Q&A. Dosing T3 in light of circadian rhythm“)

The most extreme example of the need to respect human metabolic flexibility is T3 monotherapy — the therapeutic dosing of T3 hormone alone while T4 is low or undetectable.

  • It is best seen as a last-resort therapy for rare thyroid patients with poor outcomes even on T4-T3 combinations. It is the most challenging form of therapy, but it has a good long-term safety profile in research, when approached with due caution (See “Finkler, 1959: Liothyronine as a replacement for thyroid therapy“).
  • To maintain euthyroid status, FT3 / Total T3 in monotherapy will often need to be up to twice as high in blood to fully replace a T4-T3 conversion rate. The necessary doubling of T3 levels was noted by early thyroid scientists (Larsen, 1981; Busnardo et al, 1980). Yavuz and team confirmed via TRH-TSH testing and many biochemical indicators that during T3 monotherapy, TSH levels are only indicative of “pituitary euthyroidism” and are not indicative of “generalized euthyroidism” (Yavuz et al, 2013).
  • More than just the deiodinases will adapt over time. The daily dose in adults on long-term maintenance LT3 usually ranges from 50 to 100 mcg per day with 75 mcg as an average (See the tables in “No, 25 mcg of L-T3 Liothyronine isn’t equivalent to 100 mcg L-T4“). An euthyroid, safe maintenance dose may be discovered after a few months in some, or after a year or two in others.
  • With far less T4, RT3, and T2 to convert, faster T3-T2-T1 conversion rates ought to be expected via upregulation of D1 and a potential upregulation of D3 during transient post-dose peaks. See “Thyroid therapies: What my life is like in the T3-monotherapy wheelchair.”

In any pharmaceutical approach to deiodinase-compensatory thyroid therapy, the individual’s health outcomes ought to improve as their individually optimal FT3 and FT4 ratios and levels are discovered.

7 major lessons taught by deiodinases:

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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.
  6. 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.
  7. 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)

Click to reveal 2 scientific diagrams and statistics

In early works of thyroid science, it was calculated that deiodination accounts for approximately 81% of all transformations of T4 hormone, while the other 19% of T4 hormone is either metabolized through other pathways or excreted in waste (Wiersinga, 1979).

The mathematical estimate was confirmed and updated in 1989 by Faber and team:

deiodination: 79.5%;
deamination: 1.1%;
ether link cleavage: 0%;
urinary excretion: 2.5%;
and fecal excretion: 14%.

Thus a conservative estimate of the metabolic pathways seems to explain 97% of the daily production and disposal of T4.”

(Faber et al, 1989)

The effects of these different thyroid hormones are complex and rarely explored by scientists.

Further details on what we currently know of non-deiodination metabolites are subjects for separate posts, such as “When dosing T3, you get higher levels of Triac.”


Click to view reference list

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Categories: Deiodinases, Thyroid hormone conversion

11 replies

  1. This epic, monumental article by Tania Sona Smith is amazing. Everyone should read it, immediately!

    • I did …. and i agree.
      I will have to read it again… and again. to find what’s in all the ‘Advanced’ bits and ‘extra’ bits.
      But for starters , at least i now know what a ‘substrate’ is.
      Thankyou Tania … Epic indeed .

  2. Just wanted to say thanks for your articles on this blog. I have recently managed to start on T3 after 4 years on T4 Monotherapy after Thyroidectomy. Your writing was hugely explanatory and helpful for me to work out that T4 was what my body needed and push for it as a treatment. I feel so much better now with T3 added so just wanted to say thanks for all this research and writing xx

    • Thanks, Helen, for sharing your experience and appreciation!

    • Dear Helen, a belated thank you for your comment back in early February. I’m glad you’ve benefited from my writing. It’s my goal to synthesize multiple scientific sources that would otherwise be ignored or be too advanced for most to read, and to bring their implications to the attention of patients and physicians. Best wishes for your continued journey toward optimal treatment – Tania S. Smith

  3. every endocrinologist should read your articles.


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