Meet deiodinase type 1 (D1): The philanthropist enzyme

In this educational post, I introduce our thyroid hormone conversion enzyme “deiodinase type 1” (D1) in the personality of “The philanthropist” as I draw on many scientific articles.

Of course, D1 is a genderless enzyme. I am personifying “her” in the image of a human female in a social role to bring the unseen world of thyroid hormone activity to life, and to make concepts more familiar to us.

A philanthropist is “one who makes an active effort to promote human welfare : a person who practices philanthropy” (Merriam-Webster). Further, philanthropy is defined as “goodwill to fellow members of the human race, especially: active effort to promote human welfare,” and “an act or gift done or made for humanitarian purposes.” “Philanthropy is giving money for a purpose or cause benefiting people who you don’t personally know” (Merriam-Webster).

I characterize D1 enzyme by a few of her philanthropic traits:

1. Her dependency on positive feedback from one of her own products, T3, which encourages her to work harder,
2. Her service of cleaning up Reverse T3 (RT3) from the bloodstream environment while making more T3, and
3. Her generosity to enrich circulating T3 for other cells to use, as long as you invest in her with enough T3.

A robust D1 enzyme can be a burden to the hyperthyroid patient, especially when T3 is driven up and out of control by the TSH-receptor stimulating antibody.

However, a robust D1 enzyme can be a strong benefit to the treated hypothyroid patient. This is likely the enzyme that enables patients on T4 monotherapy to achieve FT3 levels in the upper-normal reference range while FT4 is near the top of reference range or beyond. D1 enzyme can also be directly enhanced by dosing T3 or desiccated thyroid.

Even in thyroid health, when people don’t need to rely on thyroid hormone dosing, D1 is naturally part of the symbiotic balance of deiodinases that enables T3 sufficiency and metabolic flexibility. Healthy D1 function supports T3 levels, liver and kidney health, and a natural TSH-FT3 circadian rhythm.

I’ll go through each of the claims in the title image, one by one. As you ponder the diagrams, quotations, and metaphors, you’ll better appreciate the strengths and vulnerabilities of your D1 enzyme and the Dio1 gene.

Deiodinase basics

As one thyroid scientist has expressed it,

“Deiodinases are envisaged as guardians to the gate of thyroid hormone action mediated by T3 receptors.”

(Köhrle, 2000)

Based on our larger “Thyroid hormone journey: Metabolism” post, this optional section briefly covers all three deiodinases’ roles and locations in the body:

D1: “I’m empowered by T3 hormone’s signals from the nucleus of cells.”

Philanthropists often become energized by the stories of the good things that have been accomplished by their generosity to others.

In much the same way, the philanthropist enzyme D1 is empowered by hearing signals that some of her labor is making a difference.

One of the chief characteristics of D1 is her powerful upregulation by T3, one of the products of her own activity.

The concept that the T3 end product feeds further T3 production was expressed eloquently shortly after it was discovered:

“triiodothyronine [T3], the end product of thyroid hormone synthesis, positively regulates one of the key enzymes in its production.”

(Jakobs et al, 1997)

This discovery was surprising to scientists. The method of stimulating D1 enzyme does not describe a negative feedback loop, a feature commonly seen in other hormone systems.

“the human type 1 deiodinase (DIO1) gene is markedly stimulated by T3, just the opposite of what would be expected in a typical feedback loop.”

(Maia et al, 2011)

In a negative feedback loop, excess production lowers the production rate, just as rising T4 lowers the TSH, and vice versa. Instead, deiodinase type 1 is most powerfully driven by a positive feedback loop.

It has now become commonplace for scientists to refer to the power of T3 hormone to enhance D1 enzyme activity:

“D1 is a T3-dependent protein” (Larsen & Zavacki, 2012)

“DIO1 … transcription is positively regulated by T3” (Egri 2016, p. 19)

“this enzyme is under positive control of T3 itself” (Peeters & Visser, 2000/2017)

However, all the emphasis on D1’s upregulation by its own product could give the false impression that D1 is entirely self-regulated.

In fact, D1 is incapable of pulling herself up by her own bootstraps when T3 is low.

As you can see, D1’s activity depends on other sources supplying T3 to the cells where she is expressed. While she is empowered by the product of her activity, she needs a larger supply of T3 than that which she alone produces. Others have to invest in her.

Two other sources contribute to the T3 supply that drives the T3-D1 feedback loop.

First of all, T3 comes from TSH-driven T3 synthesis in thyroid gland tissue. As TSH stimulation rises, more T3 is synthesized “de novo” (anew) from iodine and tyrosine.

This newly created T3 gets transported into D1-expressing cells located in the thyroid, liver, kidney, and elsewhere.

In those cells, T3 may bind to receptors in the nucleus and send a signal to the Dio1 gene to “upregulate” — to create more D1 enzymes so that D1 can perform thyroid hormone conversion activity at a higher rate.

Secondly, T4 secreted from the thyroid gland enters D2-expressing cells found inside the thyroid gland and in many tissues throughout your body. There, D2 converts T4 into T3 hormone. After T3 binds to the D2 cell’s receptor, it exits the cell and can enter a D1-expressing cell where it can bind to its nuclear thyroid hormone receptors.

Recently, evidence has revealed that D2 enzyme is sensitive to TSH upregulation in the thyroid gland, with a peak upregulation at 100 mU/L (= 1 mU/mL) and then declining at higher TSH concentrations (Jang et al., 2020).

Fortunately, T3 hormone is not the only substance or hormone that upregulates D1 enzyme. It’s just that among all the factors that can change D1’s expression (quantity) and activity (productivity), thyroid hormone signaling is the most powerful:

“The expression and activity of D1 are modulated by a variety of hormonal, nutritional, and developmental factors, the most potent being thyroid hormone.”

(Ohguchi et al, 2008)

By what mechanism does thyroid hormone “modulate” D1? If we understand the mechanism, we can understand how to enhance D1 and gain more control over thyroid hormone disorders.

Scientists have discovered that in rodent liver and kidney,

“Dio1 is a T3-dependent gene under TRβ1 control“

(van Beeren et al, 2012)

Therefore, the more direct “upregulator” of D1 is the type of receptor that sends the T3 signal to D1.

The human thyroid hormone receptor beta (TRβ1) is common type of thyroid hormone receptor that is dominant in D1-rich tissues like the liver and kidney. The THRB gene that regulates this receptor is also expressed in modest amounts in the D1-rich thyroid gland (Human Protein Atlas).

When the TRβ1 receptor sends its signal, “thyroid response elements” located on other nearby molecules like D1 can receive the signal.

“TREs” are thyroid hormone response elements. In 1995, scientists discovered two TREs on the DIO1 enzyme:

“The human DIO1 gene … contains two thyroid hormone response elements, both contributing to the T3 responsiveness of the human DIO1 promoter (Toyoda et al. 1995, Zhang et al. 1998).”

(Maia et al, 2011)

Essentially, the DIO1 gene is equipped with two “ears” to “hear” the signal sent by T3 when it binds to its receptor in the nucleus.

DIO1 has two TREs, not just one, to boost her sensitivity to the signal from the TRβ1 thyroid hormone receptor:

“Both TREs contribute equally to T3 induction.”

(Toyoda et al, 1995)

What else can enhance the signal of the TRβ1 besides T3? A few other thyroid hormones can, but they are either less potent than T3 (10x less potency = T4, and 30x less potency = RT3), or are found at much lower concentrations than T3 and have a shorter half-life (Triac). (Jeyakumar et al, 2008; Mondal & Mugesh, 2017; Visser, 2018).

TSH receptor signaling has a double influence on D1 in the thyroid gland, mediated indirectly by its generation of a “cAMP” signal in cells. This cAMP signal upregulates thyroidal T3 synthesis and D2 enzyme, both of which boost Free T3 levels entering D1-expressing cells:

In the image above, the TSH receptor is the sender of the signal, but the image of “Mr. TSH” is missing for a reason:

• TSH is not the only substance that activates this receptor.

The TSAb antibody-driven T3-D1 cycle in autoimmune hyperthyroidism

As Graves’ disease antibodies increase, a rising FT3:FT4 ratio is partly due to TSH-receptor driven rates of T3 synthesis.

As explained by Citterio and team, thyroglobulin (the thyroid gland’s major protein involved in synthesis) behaves uniquely in response to the TSH receptor (TSHR) signal. The TSAb antibody’s unique signaling behavior changes the TG synthesis process to increase T3 production more so than increasing T4 production:

“TG [thyroglobulin] processing in the secretory pathway of TSHR-hyperstimulated thyrocytes alters the structure of the iodination substrate in a way that enhances de novo T₃ formation, contributing to the relative T₃ toxicosis of Graves’ disease.”

(Citterio et al, 2017)

In other words, when a TSHR antibody-stimulated thyroid gland ramps up its efficiency in creating T4 and T3 from raw material, it preferentially increases T3 synthesis at a higher rate than it increases T4 synthesis, skewing the ratio of secretion in favor of T3.

D1’s role is to amplify this T3 investment: D1 pays “compounded interest” on the T3 production rate.

When TSH is elevated, the largest inflation in D1 activity in the human body is seen in the thyroid gland itself. Thyroid gland tissue has the richest expression of both Dio1 and Dio2 RNA per unit of volume, on average, according to the Human Protein Atlas consensus data. It’s a smaller gland than the liver in terms of total volume, but the thyroid’s capacity to upregulate D1 deiodinase expression, when stimulated to do so, is immense.

“In vitro thyroid perfusion studies have shown that the T3 content of thyroid secretions is higher than would be expected from the T4/T3 ratio of thyroid hydrolysate, and that the major mechanism is deiodination of T4 to T3. 

(Laurberg, 1984)

Overall, both thyroidal D2 and D1 that produce the higher FT3:FT4 ratio in gland thyroid secretion in patients with high TRAb antibody levels, but in severe cases, D1 upregulates more than D2 does because of the T3-D1 positive feedback loop:

“expressions of DIO1 and DIO2 mRNA were higher in GD thyroid tissue than that in normal thyroid tissue. Especially, DIO1 mRNA in GD thyroid tissue was significantly higher than that in normal thyroid tissue.”

(Chen et al, 2018)

After thyroidal T3 is secreted into bloodstream, then D1 upregulation by T3 also occurs in liver and kidney:

“In hyperthyroid patients DIO1 expression is also upregulated outside the thyroid gland, which is reminiscent of the fact that in rodents Dio1 is highly sensitive and positively regulated by T3“

(Bianco et al, 2019)

In Graves’ disease, this positive feedback cycle driven by TSH-receptor antibodies and T3 signaling can easily spin out of control.

But hyperthyroidism is not D1 enzyme’s fault. She is just doing what she normally does in health. Blame the TSAb antibodies that first drive D2 enzyme and the thyroid gland, which then supply the excess T3 that drives her to convert more T4 to T3.

This diagram now integrates what I’ve discussed so far — the signaling pathways that lead to T3-upregulation of D1.

The two TSH-receptor driven pathways feed T3 to D1, which then produces more T3 from its enhanced T4-T3 conversion activity.

There’s one element I could not fit into the diagram, something that can replace one or more of these factors in persons with thyroid handicaps:

• Pharmaceuticals that provide T3 hormone, such as synthetic T3 (liothyronine) and desiccated thyroid extract (DTE / NDT).

They also directly upregulate D1 when they achieve higher Free T3 concentrations, boosting the individual’s T4-T3 conversion further.

What can stop D1 from escalating T4-T3 conversion too far?

Reduced TSH secretion and lower TSH receptor stimulation. The normal operation of the HPT axis in response to rising T3 levels is to decrease TSH-receptor stimulation of the thyroid gland. This will decrease new T3 synthesis in the thyroid gland. It will also decrease the activity of D2 in the thyroid and in other tissues expressing the TSH receptor, which will secondarily decrease D1 escalation and keep T3 levels in check.

Elevated D3 enzyme activity. Deiodinase type 3 is the “first responder” enzyme that arrives on the scene of T3 excess. D3 is upregulated by higher levels of T3 signaling. D3 will increase the rate of T4 to RT3 conversion, and more importantly, the rate of T3 conversion into a less active form of T2.

Reduced transporter expression. Transporters are required to carry T3 into cells before it can interact with deiodinase enzymes, which face the inside of the cell (Paragliola et al, 2020; Bianco et al, 2019). The T3 does not just wiggle and push its way into the cell. In a study by Muzzio et al, 2014, they discovered:

“High levels of T3 down-regulated the expression of these transporters whereas methimazole induced hypothyroidism and increased transporter expression. Take together, this suggests that transporter genes are negatively regulated by thyroid hormone.”

(as reviewed by Mendoza & Hollenberg, 2017)

D1 can be disrupted or upregulated by a wide variety of other substances, nutrients and health conditions. However, that’s too complicated for this article and will be explained elsewhere.

However, in a severely hyperthyroid state, the two major systems that can limit both T3 and T4 escalation are unavailable or insufficient.

• Lowering TSH secretion can’t stop the cycle after TSH secretion is already suppressed by excess T4 and T3. In autoimmune hyperthyroidism, the TSH receptor is being hijacked by antibodies. TSH receptor signaling will be high while TSH is low.
• Elevated Deiodinase type 3 (D3) activity is already happening. However, in severe hypothyroidism, D3 activity is often not enough to prevent highly elevated T4 and T3 in blood from causing symptoms of thyrotoxicosis. D3 is more effective at preventing thyrotoxicosis in mild or subclinical cases. Severely hyperthyroid people have the highest RT3 levels among humans, demonstrating that as D3 escalates its activity, it may insufficient to counteract the degree of D1 escalation fed by T3 from an overactive thyroid.

PTU (Propylthiouracil), a Graves’ disease pharmaceutical, is a potent D1 inhibitor. It is effective at reducing D1’s activity not only in the thyroid gland but elsewhere in the body where D1 is expressed. PTU is used in severe hyperthyroidism, often in combination with methimazole or carbimazole, but PTU is not the first choice for milder cases due to higher risk of side effects (Yu et al, 2020). Treating hyperthyroid D1 with PTU does not resolve the root of the problem. It just reduces the T3 amplification.

D1: “As T3 rises, I clear out more RT3, and I convert more T4 to T3.”

Now let’s talk more about what D1 does that is so philanthropic.

Her statement above makes D1’s two roles clear:

• Her “major clearance role” is the clearance of RT3 and sulfated hormones, and
• Her “major productive role” is the conversion of T4 to T3.

D1 is most famous for her role of converting T4 to T3, but it’s stated second for a reason. D1’s first priority is not to deiodinate T4 to T3. The D2 enzyme performs that role far more efficiently than D1 (Bianco et al, 2019).

Maia et al, 2011, express D1’s priority system of “substrates” this way:

rT3 > T2S >> T4 (5′)

T4S > T3S > T3, T4 (5)

(Maia et al, 2011)

T4S, T3S and T2S are “T4 sulfate” etc. The double “>>” means “significantly greater than.” This is the elaboration of Maia and team’s concise explanation:

(5′) = hormone “inactivation” pathway	(5) = activation pathway
1. RT3 → 3,3′-T2	1. T4S → T3S
2. T2S → T1S	2. T3S → T2S
3. T4 → RT3	3. T4 → T3
	4. T3 → 3,5-T2

D1 is such a non-discriminatory philanthropist that she can de-iodinate all forms of thyroid hormone in both directions, if necessary, depending on the concentrations of each hormone entering D1-expressing cells, as shown in our waterfall meme:

D1 is located between D3 and D2 because she can perform some of their tasks.

However, D1 is not as specialized as her colleagues are at converting T4 to T3 (D2 is focused on that) or converting T4 to RT3 (D3 is more focused on that task, but in fact D3 prefers to convert T3 to T2, not shown).

As shown, D1 can indeed convert T4 into RT3. But because of her priority system, D1 destroys far more RT3 than she creates.

D1’s main role of clearing RT3 and sulfated hormones is cleaning up less useful hormones and “scavenges” iodine from them for recycling.

RT3, T4S and T3S are like empty glass or plastic bottles that can be cashed in at the bottle depot for a refund.

D1’s preference for converting RT3 makes her clean up more RT3 than she converts from T4. This is what makes D1 perform as a powerful net donor of T3 and T2 to bloodstream when thyroid function is normal.

RT3 and sulfated thyroid hormones have far lower concentrations in blood than T4, but they maintain their lower concentrations partly because of D1, and partly because D3 does not make too much RT3 in a state of health.

Since we don’t measure RT3 and T2 hormones routinely and they are low-priority hormones, we can easily take for granted D1’s role. Every hormone she breaks up gives a little donation to us.

D1 releases free iodine that can be re-used by a healthy thyroid to make new thyroid hormones:

“Since D1 catalyzes the deiodination of rT₃ and its sulfate much more efficiently than T₄, hepatic D1 is recently considered as a “scavenger” of these inactive iodothyronines from circulation.

This scavenger function seems of particular importance in the patients of hypothyroidism caused by iodine deficiency.”

(Too et al, 2017)

Scavenging of iodine is a role performed by ALL deiodinases, but in the case of D1, the high-priority hormones being processed are generally less potent (RT3) and inactive at thyroid hormone receptors (sulfates), and this is why scientists call her the “scavenger” enzyme.

In addition to the iodine required for a thyroid gland’s hormone production, our overall health requires iodine sufficiency.

The iodine content of orally dosed thyroid hormones is often overlooked by patients and doctors. Some patients are being advised that they aren’t getting enough iodine if they aren’t dosing it on top of obtaining it from dietary sources. But every time they dose T4 or T3 hormone, they are ingesting iodinated hormones. Approximately 80% of T4 and T3 will become de-iodinated in the body. As a person doses thyroid hormone, it becomes is part of one’s total iodine intake.

Next, processing RT3 and sulfates also prevents these hormones from building up in blood. RT3 has some minor signaling activity that can worsen some chronic diseases, and T3S is not very useful outside of a hypothyroid state.

D1’s valuable service of clearing RT3 from blood

D1’s valuable service of clearing sulfated thyroid hormones from blood

D1: “Give me T3 ‘money,’ and I’ll donate a lot of my converted T3 to blood for other cells to use.”

By donating T3 back to the circulation, D1 is of service to all organs and tissues that require more Free T3 than that which D2 efficiency and thyroidal T3 productivity can give them.

All tissues rely on some circulating T3 to top up their T3 receptor occupancy rate (Bianco et al, 2019).

Many studies have emphasized the intracellular location of D1 enzyme (near the cell membrane and its transporters) as a reason for its tendency to donate T3 back to bloodstream.

D1 functions largely as a donor of T3 to bloodstream because of her location in each cell. It is anchored to the cell membrane.

“Since D1 is a plasma membrane protein, it offers ready access of circulating T4 to the enzyme and facilitates the entry of the D1-generated T3 into the plasma.

Therefore, D1 contributes to the circulating T3 concentration, but has minimal contribution to the intranuclear T3 content.”

(Zaitune et al, 2019)

This theoretical principle that intracellular location shapes deiodinase function was demonstrated in early tissue-specific studies. They showed that T3 appears to remain inside D1-expressing cells for less time than it remains in D2-expressing cells:

“In cells expressing D1, the T3 residence time inside the cells is relatively short, that is, ~30 minutes, whereas in D2-expressing cells the residence time is several hours.“

(Bianco et al, 2019)

But let’s not look at the thyroid hormone economy only from the cell’s perspective as a T3 loss or T3 gain to itself. The body is a community of interdependent cells. D1-expressing cells are efficient exporters of T3 hormone because other cells, whether nearby or far away, need that extra T3 supply.

In some tissues, Free T3 is not just an extra “top-up”; it’s the main diet. The D1-dominant liver and kidney are utterly reliant on T3 from circulation plus the average 30 minutes of T3 residency time of each newborn D1-T3 molecule converted from T4.

In liver and kidney, approximately 50% of the thyroid hormone receptor pool is filled by circulating Free T3 hormone. That is not just a “glass half full” perspective. It is the liver’s required receptor occupancy rate, its healthy target. The other 50% of receptors is always empty for a good reason.

“it is estimated that about half of the TR [thyroid receptor] pool in liver and kidney cells is occupied with T3 derived from the circulation, a figure that has been confirmed experimentally.

In other words, the circulating level of FT3 in euthyroid individuals provides the cell nucleus with sufficient T3 to occupy about half of the TRs, respectively activating or suppressing genes that are positively or negatively regulated by T3, eventually leading to downstream biologic effects.

The other half of the TRs in these organs remain empty but do exert biologic effects by repressing genes that are positively regulated by T3.”

(Bianco et al, 2019)

Empty T3 receptors are not silent. Unlike other types of hormone receptors, thyroid hormone receptors everywhere in the body are always actively signaling, whether or not they are occupied by T3 hormone.

In a digital machine communicating “1” and “0,” the zeros are not meaningless or empty signals. Similarly, T3 occupancy merely toggles the signal from an act of gene transcription to an act of gene repression.

The liver and kidney D1 enzymes are not entirely unselfish. They donate T3 partly to themselves. What they generously give back to circulating T3 is part of their required supply of T3 hormone for health. The feedback loop feeds them part of their own T3.

This self-feeding loop makes the following reasoning of Bianco & da Conceição seem puzzling:

“D1 … does not contribute significantly to the local control of thyroid hormone signaling.

This is explained by its localization in the plasma membrane, which facilitates rapid exit of D1-generated T3 back to the circulation.“

(Bianco & da Conceição, 2018)

It often seems like articles written since 2005 are taking sides in favor of D2, as if there is a competition between enzymes to make the most T3 and keep it as long as possible before giving it to other cells.

The “rapid exit of D1-generated T3 back to the circulation” is not a weakness of D1. The authors failed to mention the rapid reentry of circulating Free T3 back into the D1-expressing cell.

One may just as easily criticize an athlete competing in the Olympics of breathing out too rapidly. For every quick exhale, the athlete compensates with a quick inhale.

Similarly, there is no net deficiency of T3 caused by a rapid exit of T3 from a D1-expressing cell, otherwise human athletes would not have livers or kidneys to sustain their admirable strength and endurance.

Part of the reason for the short residency time (30 minutes) of each T3 hormone within D1-expressing liver or kidney cell is the nature of tissue in which D1 is expressed. The thyroid gland, liver, and kidney are organs that exchange hormone quickly with bloodstream.

One cannot imagine that the residency time of 30 minutes is too short if it fulfills the T3 signaling needs of these organs for a long human lifetime. Their exchange rate rapidly replaces the T3 that exits the D1-expressing cells with new T3 and soon-to-be-converted T4 that enters the cell.

Does it matter how many times T3 cycles through cells every hour as long as receptors are occupied at the appropriate rate?

Bianco and team’s more recent article even appears to shame DIO1 for adding more RT3 to the bloodstream than it cleans up, which is not logical given the evidence of its preference for clearing out RT3:

“[DIO1’s] presence in the plasma membrane precludes it from significantly affecting local TH signaling; its products, T3 and reverse T3 (rT3), rapidly exit the cells and enter the systemic circulation.”

(Bianco et al, 2019)

Where is the honor given to the D1 enzyme that hunts for RT3 and T3 sulfate to eliminate them from circulation? D1 is so versatile that it can convert any hormone in a state of excess (if provided with enough T3 to power it) and it is capable of recycling them all to free iodine for our body’s use. We should be thankful for the rapid exit of free iodine from D1-expressing cells.

What would happen if D1’s function were compromised? Indeed, D1 could be compromised directly by a D1 polymorphism, or a thyroid, liver or kidney disorder. It could also be compromised directly at its very power source of T3 if there was a dysfunction in D2 as a T3-donor to D1, an overactivity in D3 enzyme, or a failure in the function of the TSH-regulated, T3-synthesizing thyroid gland. As a result, T3 levels could drop.

“as long as TH transmembrane transporters are available, T3 from plasma will enter cells at levels that occupy half of the TR pool [in liver and most tissues].

Conversely, a drop in plasma T3 will reduce TR occupancy in most tissues as well.

For example, studies in rats estimate that a mere 10% drop in plasma T3 levels reduces liver and kidney TR occupancy by ~15%.

These changes are of course magnified in patients with hypothyroidism or hyperthyroidism in whom plasma T3 levels may fluctuate markedly.

(Bianco et al, 2019)

A drop in T3 occupancy rate in a tissue has a definition: local tissue hypothyroidism. Local hypothyroidism is a state of dysfunction. Tissue hypothyroidism, if it becomes a chronic state of nonthyroidal illness, can worsen every chronic disease and put life at risk (van den Berghe, 2014).

The human brain has uniquely high thyroid receptor occupancy rates that do not have much of a margin for error in the direction of a shortfall:

“Studies performed in rats using labeled T3 and T4 molecules indicate that TRs [thyroid receptors] are almost fully occupied with T3. In other words, glial cells produce so much T3 that almost all TRs in the brain are bound to T3″

(Bianco et al, 2019)

In general, D1 is poorly expressed in brain. Most of the brain’s TR occupancy in a state of thyroid health is served locally in the brain by Deiodinase type 2 (D2) converting T4 to T3 in glial cells. This enzyme is counterbalanced by Deiodinase type 3 (D3) in astrocytes converting excess T4 to RT3 and excess T3 to inactive T2, as explained by Bianco and team in 2019.

However, brain cells still have to thank the system of T3 generation and T3 transport across the blood-brain-barrier, including D1’s role. The brain’s need for 20% incoming Free T3 is served by the thyroid gland, D2, and finally topped up by D1:

“limited amounts of circulating T3 also reach neurons through MCT8 [thyroid hormone transporters], contributing with ~20% of the intracellular T3 in the cerebral cortex.”

(Bianco et al, 2019)

Consider the overall thyroid hormone economy as a complex system of interrelated and stacking variables. The philanthropist is just as important as the profit business owner and the retail service laborer.

The philanthropist can’t give T3 and remove RT3 very efficiently unless she receives T3.

In the case of mild or temporary hyperthyroidism, isolated T4 excess, or isolated T3 excess, the human thyroid metabolic system is like an agile off-road vehicle, well equipped to handle potholes and bumps in the road of supply and demand. D1 enzyme’s T3-amplifying efforts are kept in check by the the HPT axis, the D3 enzyme, and other mechanisms of transport and metabolism.

D1 enzyme becomes both more necessary and more vulnerable in the more severely disabling conditions on the hypothyroid side:

• Those who cannot secrete enough bioactive TSH to drive a healthy thyroid (people with central hypothyroidism) fortunately do not need TSH hormone to drive D1, but they still need just enough T3 provided by D2’s conversion rate to contribute to their D1-rich tissues’ T3 occupancy rates.
• Those whose thyroid gland is significantly disabled, atrophied, or removed (people with primary hypothyroidism) also need enough T3 to drive D1 in remaining D1-expressing tissues. If they derive their T3 largely from pharmaceuticals, having an optimized FT3 supporting D1 will enable them to more efficiently metabolize their pharmaceutical T4 supply.
• Those whose D2 enzyme is genetically handicapped or chronically downregulated by a chronic disease or its treatment will rely on either thyroidal T3 or pharmaceutical T3 to feed their D1 enzymes. The D1 enzyme may then partly compensate for the inefficiency of their D2 in brain and other crucial organs that would normally not need as much circulating T3 as a top-up. Those with multiple DIO1 and DIO2 polymorphisms without compensatory thyroidal T3 may have relatively more need for pharmaceutical T3.
• Those who suffer from intermittent TSH-receptor blocking antibodies (found in Hashimoto’s, Graves’ disease and Atrophic thyroiditis patients) may have their TSH receptor signaling blocked or inversely agonized to varying degrees. Their downregulated D2 and/or lower thyroidal T3 synthesis may require T3 pharmaceutical compensation for the duration of their antibody flare. (See “Remissions and fluctuations in autoimmune thyroid disease: TRAb“)

A single individual can be afflicted with more than one of the above conditions. Thyroid disabilities are as diverse as the genetics and environment of each individual. It’s difficult to judge one person’s hypothyroid condition as more “severe” than another’s. A person with a fully atrophied or fibrosed thyroid may be just as handicapped as a person with a total thyroidectomy. Thyroid status is not only based on lab test numbers or diagnostic category, but on T3 receptor occupancy (Paragliola et al, 2020).

The loss of functioning thyroid gland tissue is the most significant D1 enzyme handicap, since the thyroid gland, despite its small volume is one of only three major organs expressing a significant and highly variable portion of the body’s D1- and D2-enzyme-expressing capacity and all of its T3 synthesis capacity.

“D1 enzymatic activity modulates the serum levels of T3, while D2 and D3 fine-tune the intracellular availability of T3.”

(França et al, 2020)

Natural FT3 circadian rhythm is one of the major outcomes of thyroidal T3 synthesis amplified by thyroidal D1. A significant daily TSH-driven FT3 peak is associated with human longevity (Jansen et al, 2015).

In people with healthy thyroid glands, D1 in the thyroid and D1 elsewhere in the body play a key role in making the nightly FT3 peak higher. The nightly peak in TSH upregulates thyroidal D1, D2, and thyroidal T3 de novo synthesis. The peak FT3 level occurs while people sleep, synchronizing with other hormones in our bodies that have a nightly peak. See “The significance of the TSH-FT3 circadian rhythm”

The long half-life of D1 makes the effects of circadian FT3 rhythm linger. Deiodinase type 2 (D2) has a short half-life of 20 minutes when T4 is at euthyroid levels, and this is extended to a few hours when T4 is low (Bianco et al, 2019). In contrast, D1’s half-life is much longer.

“The half-life of D1 protein is >12 h”

(Maia et al, 2011)

To do the math, D1’s life is 36x longer than D2’s at euthyroid levels of T4.

Therefore, if the circadian rhythm’s peak upregulates D1, the extra D1 enzymes stay around for quite a while longer than D2.

Even in the dose-dependent and artificial peaks and valleys induced by synthetic T3-T4 combination therapy and desiccated thyroid therapy, D1’s extended half life should be kept in mind as a lingering metabolic benefit after the swift fall from the post-dose T3 peak. By means of D1’s compound interest on the T3 investment, T3 is a gift that keeps on giving, especially if one doses 2 or more times a day. (See “Free T3 peaks and valleys in T3 and NDT therapy“)

Conclusion: Free T3 is a window on D1’s activity.

The philanthropic roles of D1 enzyme point to the importance of circulating Free T3 in the thyroid hormone economy, and they ought to help us reflect on what Free T3 testing reveals — and what it cannot reveal on its own.

(Free T3 is the portion of Total T3 capable of entering cells on transporters and reaching the nucleus to perform signaling. Total T3 is often measured when FT3 could be artificially inflated by blood thinners and severe illnesses that can skew the bound:free ratio.)

When critics of the Free T3 test dismiss its value, they often point to tissues expressing D2, such as brain or brown adipose tissue (BAT), where local T3 receptor occupancy rates can differ significantly from circulating T3.

Bianco’s many scientific publications are rooted in his deep knowledge of D2 enzyme in particular, but he does not dismiss T3 testing. Instead he regularly points out that in a state of thyroid health, circulating T3 is incredibly stable and appears to be an important target of thyroid biology, despite T3’s short half life. This T3 stability from day to day and week to week in a healthy individual, however, stands in contrast with the turbulence and diversity of local, intracellular T3 levels and thyroid hormone (TH) signaling in some tissues:

“The tranquility of the plasma T3 levels contrasts with a stormy intracellular environment of a large number of tissues, in which T3 levels and TH signaling rapidly increase or decreases whereas serum T3 concentration remains unchanged.”

(Bianco et al, 2019)

Notice the quote above says “a large number of tissues,” not “all tissues.” All tissues matter, and not all tissues have a disjoint between “T3 levels” in blood and “TH signaling” in cells.

One must not be prejudiced against the tissues that are not rich in D2 or D3, since D1-dominant tissues are those whose thyroid hormone deficiency or excess is more directly reflected by FT3 levels in blood.

For example, liver T3 receptor occupancy status, and therefore liver health in general, is sensitive to Free T3, since

“TRβ predominates in the adult liver, where TH signaling is mostly a reflection of circulating levels of T3.”

(Bianco et al, 2019)

No matter where the FT4 falls, a low T3 associates with various liver dysfunctions. In a study of 144 patients in a liver clinic,

“Low fT3 values but not TSH and fT4 were associated with higher liver stiffness and higher NAFLD fibrosis score, respectively.

fT3 and TSH values correlated significantly with indices of liver disease including INR, albumin, ALT, AST, bilirubin, and platelets.

In multivariate analyses, a low fT3 was independently associated with high NFS scores [NAFLD fibrosis scores](OR 0.169, CI 0.05-0.54, p = 0.003) and was also associated with high liver stiffness readings (OR 0.326, CI 0.135-0.785, p = 0.001).”

(Manka et al, 2019)

TSH was only associated with some of these variables, while the low FT3 was the common denominator.

In chronic illness, cause and effect between health status and T3 levels are as integrated as they are in the D1-T3 feedback loop. Certainly, liver disease can upregulate D3, which leads to T3 depletion, but poor D1 function and low T3 will also create a poor environment for liver health.

When the most vital D1-rich organ, the thyroid gland, is incapacitated, it creates a significant D1 handicap, seen most clearly in the significantly lower FT3:FT4 ratio in athyreotic patients on LT4 monotherapy (See “Gullo: LT4 monotherapy and thyroid loss invert FT3 and FT4 per unit of TSH“). Some patients, mostly older females, are forced to endure chronically low Free T3 levels while only their TSH is measured and normalized, according to standard policy.

TSH is not an indicator of the health of D1-dominant tissues because neither the hypothalamus nor pituitary are D1-dominant tissues. Instead, TSH concentrations are regulated by D2-dominant tissues (Bianco et al, 2019). This makes TSH a biomarker that correlates more strongly with FT4 rather than FT3 levels. TSH often remains apathetic to isolated T3 deficiency by refusing to elevate in response, both in illness (van den Berghe, 2014) and in thyroid therapy (See “The TSH-T3 disjoint in thyroid therapy“).

In the context of hypothyroid therapy, a medical system that exalts a normalized TSH over an individually-optimized FT3 is one that protects only the D2-expressing organs in the hypothyroid patient. (The patient is usually blindly presumed to have a strong D2 enzyme beyond the thyroid and pituitary glands). Such a medical system is careless of the fate of the D1-expressing organs like the liver that may be subjected to years or decades of medication-induced chronic low T3.

In addition, the Free T3 test one of the best judges of Deiodinase type 1’s current activity status when measured more than 12 hours after a T3 dose (T3 dosing peaks are predictable). If FT3 is low, D1 function is low at the time of the test. When FT3 is high, D1 function is high. This is a natural consequence of T3 and D1 half-lives, T3 clearance rates, and the speed of intercellular T3 transport and exchange in tissues that richly express D1.

However, the FT3 in isolation from other hormones says little about D2 or D3 status or the level of thyroid hormone signaling in D2-rich tissues. Symptoms and local tissue biomarkers are necessary to discern thyroid status in such tissues

The FT3:FT4 ratio is often more diagnostic of the complex factors that support D1 function and T3 supply, including thyroid gland function and D2 status.

During standard T4 monotherapy, one may gain insight into D1 enzyme’s relative expression and activity by seeing where the Free T3 falls when a hypothyroid person is subjected to conditions that are known to diminish or suppress D2 enzyme activity while making no difference at all to D1 regulation — high-normal Free T4 levels and low TSH levels. An extremely low FT3:FT4 ratio in T4 monotherapy, such as a FT3 near the bottom of range with FT4 near top of range, logically points to low D1 activity and expression, though that is the evident tip of the iceberg.

One may also test RT3 and assess it in light of both FT4 and FT3 supply to rule in or out a status of “nonthyroidal illness” with abnormally high D3 expression and lower D2 activity. These could be causing low T3 which then produces secondary low D1 function.

Ethically, a medical system ought to give T3 pharmaceutical support to chronically poor converters of T4 hormone who lack a thyroid to compensate for poor D1 and/or D2 function. Individual optimization of FT3 and FT4 levels to health outcomes and symptom resolution is the ultimate physiological purpose of therapy.

• Tania S. Smith, Ph.D.
  Thyroid patient and thyroid science analyst,
  President, Thyroid Patients Canada.

References