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.

In this post, I use many visuals and analogies — waterfall, professions, leaky buckets — to help conceptualize for laypeople the science found in original research articles and scientific reviews, including some of the most recent insights from the past decade.

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.

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.

Transport comes before metabolism.

There are two stages of transport:

  1. Binding proteins within bloodstream distribute T4 and T3 everywhere in the body. Only 0.3% of T3 is free, and only 0.02 to 0.04% of T4 is free. The rest is bound, mainly to:
    • Thyroxine binding globulin (TBG) — about 75% of bound T4 and T3,
    • Albumin — binds more of the remaining T3 than T4
    • Transthyretin — binds more of the remaining T4 than T3.
  2. Transmembrane transporters (the blue buses in the model) embedded in cell membranes actively pick and choose which hormones to carry into cells and out of cells. As explained by Groeneweg et al, 2020:
    1. MCT8 is dedicated to thyroid hormones and transports nothing else. It prefers to transport T3, and secondarily T4 and other thyroid hormones.
    2. MCT10 is just as efficient as MCT8 at transporting T3, but is not as efficient at T4 transport. It also transports tryptophan and L-dopa.
    3. OATP transporters of many types assist in carrying T3, T4, and other thyroid hormones and substances into various tissues and organs.
    4. LAT1 carries T3, 3,3′-T2, T4, and RT3 (in that order of preference) and amino acids such as L-leucine, L-isoleucine, L-tyrosine and L-tryptophan, and they can compete for transport.
    5. LAT2 carries 3,3′-T2 and T3, but not RT3 or T4.

There are two basic lessons of transport.

First, the “free hormone hypothesis,” which is held by most endocrinologists today, is that only the free (unbound) fraction of thyroid hormones is capable of being carried into cells by transmembrane transporters. Therefore,

  • Only Free T3 and Free T4 can be carried into cells. That’s why it’s important to measure the free fraction of both hormones. It demonstrates concern about how much is getting into cells, not just departing from a cell or a thyroid gland and joining the large pool of bound hormones.
  • Measuring Total T3 and Total T4 includes the >99% bound fraction. It can be deceptive because TBG levels vary with estrogen and kidney health, and albumin levels vary with liver and kidney health.

Second, when T3 desires entry into a cell, the cell will open its doors. Hardly any transporters prefer RT3 over T3.

But after entering the cell, T4 and T3 hormones still have an uncertain fate before T3 can bind to receptors in the nucleus in the heart of the cell.

Therefore, once there is enough T3 in blood, the major barrier to T3 getting into receptors in the nucleus are enzymes located within cells:

  • Downregulated D1 and D2 enzymes that transform T4 into T3
  • Upregulated enzymes that transform T3 and T4 into non-T3 metabolites.

After deiodination, and sometimes without being de-iodinated, thyroid hormones are transported out of cells and re-enter circulation at various rates.

Therefore, an 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.

The basics: What are deiodinases?

The most important engines of thyroid hormone metabolism are called deiodinases, so I’ll focus mainly on them here. At the end I’ll give a bigger picture of thyroid hormone metabolism beyond the 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”).

Participating elements and substances

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 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?

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.

When D1, D2 or D3 enzymes convert a thyroid hormone by changing its shape, the hormone radically changes its function in the body.

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 and “outer” ring.

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:

And here is a more scientific model showing the conversion pathway from T4 to either T3 or RT3.

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.

Terminology and concepts for deiodinases

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. enzyme activity. RNA functions like an instruction set for building proteins like deiodinases, and scientists look for RNA to see how many D1 enzymes are being built in a cell. Sometimes a dediodinase’s

  • RNA expression may be high (like having many light bulbs)
  • Enzyme activity level may be low (like having only 40-watt light bulbs, not 100-watt bulbs)
  • or vice versa,
  • or both their expression and activity may be high.

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 entering a D2-expressing cells, this dimming of D2’s efficiency occurs “post-transcriptionally” (after the enzymes have been transcribed or built). D2 can lose “activity” but may still be highly “expressed” in a cell or 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

D1, like a philanthropist, cleans up the excess RT3 from the “streets” of our bloodstream. Meanwhile, it donates most of its converted T3 hormones back to bloodstream so they can enter other cells in other tissues. Secondarily, it adds to the FT3 entering cells by donating some freshly-converted T3 to its own cell’s nucleus.

Read a post about D1: Meet deiodinase type 1 (D1): The philanthropist enzyme

D2, like a personal chef, focuses on converting T4 into T3 and feeding its freshly made T3 hormone to its own cell’s nucleus. It ushers it in and keeps it there for a while before it leaves the cell. Secondarily, it donates its T3 to the bloodstream.

D3, like an emergency first responder, defends cells and their nuclei from being flooded with excess T4 and T3. When a second line of defense is needed, T3 can translocate itself closer to the nucleus. D3’s byproducts can’t bind to the receptor, so inactive 3,3′-T2 and RT3 exit the cell without signaling.

Now let’s put the deiodinases side by side using another analogy.

The deiodinase waterfall analogy

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.

In the post’s title image, you saw a waterfall infographic:

Now let’s look at the waterfall with all the details added.

In the following diagram derived from a scientific publication, you can see D1, D2 and D3 enzymes located at the arrows between hormone types.

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.

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 next diagram by Jongejan et al, 2020, adds T1 and T0 hormones at the bottom:

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.

Deiodinase locations in the human 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.

It is very difficult to quantify the D1, D2, and D3-dominant tissues in the human body due to their variable expression and activity, even during health, as described below. We can’t measure them in laboratory blood tests.

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.

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“)

One enzyme type 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.

Scientists believe only one type of deiodinase may be expressed per cell (Bianco et al, 2019).

The location of D1 near the cell membrane, and D2 near the nucleus, and D3 near the membrane or by the nucleus, is significant for their functions.

Deiodinase locations within the cell

Just as each family has its own home, giving each enzyme its own cell prevents intracellular conflicts when two enzymes have contradictory roles.

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?“)

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.

Indirectly, each “DIO” potentially affects the other two by the amount of T3 hormone it permits to signal in its cell’s receptors, and the hormones it sends back out of the cell into blood.

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.

Because a given cell usually expresses only ONE deiodinase at a time, they work in parallel as T4 and T3 enter neighboring cells expressing different enzymes. In your brain, your glial cells express D2, but your neurons only express D3. Each deiodinase may be upregulated or downregulated somewhat independently of the others.

The D1-expressing cell

Bianco’s publications provided the basis of these images:

The D2-expressing cell

The D3-expressing cell

How deiodinases co-regulate thyroid hormone signaling

Each hormone has a different “affinity” (imagine strength of attraction or preference) to 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 and another hormone only derived from T3 (3,5-T2) also co-regulates mitochondria by signaling in its truncated 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.

What can go wrong with deiodinases?

Overall, the independence and synergy of these enzymes are like three unique singers or dancers, working in harmony, counterbalancing each other, or fighting each other.

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).

D1, D2, and D3 each respond sensitively and differently to a variety of other hormones, nutrients, endocrine disruptors, foods, health disorders, and medications. Often the influences and adjustments to D2 are organ- and tissue-specific, not generalized to D2 enzymes everywhere in your body.

This means the deiodinase trio do not form an entirely “autoregulatory” system that always runs perfectly well.

They form, instead, a “co-regulatory system” that can itself become dysregulated.

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

As mentioned above, D1, D2, D3 are each regulated by their own separate gene (Dio1, Dio2, and Dio3).

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

Deiodinase genetic polymorphisms with health implications have been identified for DIO1 and DIO2, but not yet for DIO3.

Genetically lower-functioning D1 and D2 are associated with various health conditions, including autoimmune hypothyroidism (Pargliola et al, 2020)

You can still convert T4 to T3, just not as efficiently

Technically it is incorrect to say “you can’t convert T4” due to a polymorphism.

Instead of disabling a deiodinase completely, the common DIO1 and DIO2 polymorphisms usually function as limitations on the degree that deiodinase can be upregulated by the usual stimuli.

DIO1 polymorphisms

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.

DIO2 polymorphisms

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.

TSHR + DIO2 polymorphisms

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 an effective way to identify signs of genetic deiodinase dysfunction and its correction during thyroid therapy is to perform longitudinal case studies of laboratory history and response to T4 monotherapy vs. T4-T3 combination therapy.

New DIO1 variant 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)

The rare partial SBP2 deficiency

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. Illness causes deiodinase imbalance: NTIS

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. The common presumption is that a low T3 is always the result, never the cause, of illness and death, as if the low T3 is just a biochemical side effect, like the high RT3.

However, T3 is the most powerful hormone. While some people can thrive without T4 if they dose T3, no one can live without enough T3 in blood for very long. Blind faith in the importance of TSH and T4 and the denigration of circulating T3 can cost many people’s lives.

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 because levels of T4, T3, and cAMP signals will upregulate or downregulate deiodinases, 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.

Final big picture: Beyond the deiodinases

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)

The Leaky Buckets visual analogy

This diagram is designed for intermediate learners and laypeople.

It brings together the activity of deiodinases and other enzymes, showing the complete system from appearance to clearance — including urinary clearance:

Read a step by step walkthrough of the visual: The leaky buckets analogy of thyroid hormone metabolism

Scientific thyroid pathway maps

I developed this more complicated pathway map from visuals in scientific research articles. It has been designed so that it all fits in one compact image.

An accompanying pathway map zooms in and illustrates the system of T3 metabolism alone. This is very useful for physicians and scientists to understand the T3 losses in people treated with T3 monotherapy:

Read the rationale behind these pathway maps and view some of the original visuals published by scientists: A complete pathway map of T4 and T3 metabolism and clearance.


Click to view reference list

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11 thoughts on “Thyroid hormone journey: Metabolism

    1. 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 .

  1. 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

    1. 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

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