The 7 lessons of the thyroid hormone deiodinases

The recent post “Thyroid hormone journey: Metabolism” is an educational compendium of diagrams, tables and bullet lists that highlight key lessons from the past five decades of thyroid science. It’s like a booklet in a blog post.

The article concluded with summary of seven major lessons taught by the deiodinases.

In this post, I use the “7 lessons” as headings.

Under each numbered heading, I elaborate with some material selected from the longer post:

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.

Deiodinase basics

The three deiodinase enzymes, D1, D2 and D3 (regulated by genes Dio1, Dio2, and Dio3) are collectively responsible for customizing the levels of thyroid hormone signaling in all tissues across the human body.

Two deiodinases convert T4 into T3, and two of the three can convert T4 into RT3. Then, the deiodinases cooperate to convert T3 and RT3 into three types of T2, then two types of T1, then finally T0 (T-zero).

Deiodinases do their work inside the secrecy of our cells by removing iodine atoms one by one from specific positions on the thyroid hormone molecule.

Each time an iodine atom is removed, it becomes free to recirculate as part of our body’s iodine supply (Morrison et al, 2020). That means thyroid patients obtain iodine as they dose thyroid hormones, as deiodination makes iodine available from thyroid hormones from any source.

The hormones created by deiodinases eventually exit the cell and re-enter bloodstream. In this way, the deiodinases cooperate with thyroidal T3 synthesis and/or T3 dosing to co-regulate our T3 thyroid hormone levels in blood.

Each type of thyroid hormone has unique functions at various receptors. The main thyroid hormone receptors are located inside cells — in the nucleus and in the mitochondria — where T3 dominates as the main signaling hormone. Deiodinases can strongly influence how much T3 gets into those receptors. All three deiodinases can diminish intracellular T3 signaling by turning T3 into various types of T2.

T4 and T3 can also both signal before entering cells, at the “integrin αvβ3” receptor on the cell membrane, where they can influence cardiovascular health and the fate of cancer cells (Davis et al, 2018).

Therefore, T4 and T3 thyroid hormone levels and ratios — both in bloodstream and inside cells — are influenced by deiodinases in ways that significantly affect human health.

Deiodinases are not the only pathway of thyroid hormone metabolism, but they account for approximately 80% of the fate of T4 hormone (Faber et al, 1989).

For a full overview of deiodinases’ functions, locations, and hormone transformations see “Thyroid hormone journey: Metabolism.”

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.

The T3 hormone is the highest priority hormone for deiodinases to co-regulate:

• T3 signals at all nuclear hormone receptor subtypes. 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.

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.

D1 is upregulated as T3 supply and T3 nuclear receptor 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.

“Given that DIO1 is positively regulated by T₃, 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 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 receptor signal more powerfully than TSH hormone itself (McLachlan & Rapoport, 2013).

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.

During “nonthyroidal illness syndrome” (NTIS), the thyroid metabolism’s response to severe illness depletes T3 from tissues and blood.

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).

The brain’s thyroid hormone economy is uniquely vulnerable to D2 and/or D3 deiodinase dysfunction together with thyroid dysfunction. In people with deiodinase dysfunctions, standard T4 therapy can be rendered ineffective, and T4 dose increases can be counterproductive.

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 adequatelyLT4-treated hypothyroid patients could be the key element that tips the balance toward behavioral and cognitive dysfunction.“

(Jo et al, 2018)

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.

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.

Deiodinases co-regulate TSH secretion from the pituitary, as local D2 influences thyroid hormone signaling in hypothalamus and pituitary (Paragliola et al, 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.

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.

The primary regulator of D1 and D2 beyond the thyroid gland is not TSH.

Rather, deiodinases are most powerfully regulated by thyroid hormone levels in blood and their level of signaling in receptors:

• D1 is upregulated by higher-normal or high T3.
• D2 activity is enhanced by lower-normal or low T4.

D1 and D2 are also both upregulated by higher TSH, but only in the thyroid gland and other 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. In contrast, TSH receptor stimulating antibodies (TSAb, 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, two types of TSH receptor antibodies (TRAb) interfere with TSH signaling by blocking or stimulating its receptor.

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)

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.

FT3, FT4, and TSH interact to upregulate and downregulate D1 and D2, as noted above (See Lesson # 2, 4, and 5).

Overactive D3 can cancel out the T3-producing activity of D1 and D2. (See Lesson #3 above)

D3 is upregulated in two situations:

• D3 is upregulated as T4 and/or T3 exceed a tissue’s current setpoint, such as hyperthyroidism or thyroid hormone overdose. The main role of this enzyme is to reduce T3 receptor occupancy in the nucleus and mitochondria.
  • Unlike D2, the D3 enzyme shows no limit to its upregulation in hyperthyroidism or T4 overdose, since Reverse T3 levels continue to rise as T4 rises (See “Reverse T3 in the context of health status, dosages, and thyroid levels.”)
• D3 is upregulated by many illnesses, especially those that involve inflammatory cytokines (IL-6), hypoxia (oxygen deprivation in tissues), and tumors. (Vries et al, 2020)

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.

In addition, thyroid gland status can powerfully influence all three deiodinases.

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.

As T3-secreting and D1- and D2-rich thyroid tissue is lost, the body is forced 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.

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.

Fortunately, it is 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

Sometimes blood levels need to overcompensate for the unseen deiodinase imbalances within tissues and cells.

• 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 affect the hypothalamus and pituitary by moving the TSH lower, due to the “TSH-T3 disjoint” seen in thyroid therapy.

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).
  
  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.

Want to learn more?

See the full post from which this material is derived: “Thyroid hormone journey: Metabolism.”

References