Among the many excuses commonly heard from doctors about NOT measuring the T3 thyroid hormone and NOT treating hypothyroidism with T3-therapy are that “the half-life of T3 is too short” and “T3 levels vary based on too many factors.” These arguments serve to minimize the importance of the T3 hormone.
However, this 2014 article refutes these excuses:
Abdalla, S. M., & Bianco, A. C. (2014). Defending plasma T3 is a biological priority. Clinical Endocrinology, 81(5), 633–641. http://doi.org/10.1111/cen.12538
- It teaches the biological priority of T3 over all other thyroid hormones. TSH, T4 and the deiodinases merely serve to protect and regulate healthy T3 levels.
- It emphasizes the mechanisms that protect long-term stability and homeostasis of T3 levels in the body and refutes the misconceptions based on its short half-life.
- It stresses the medical importance of testing T3 serum levels and treating chronic dysregulation of T3 hormones to attain the biological standard of T3-based euthyroidism.
The T3 hormone remains of paramount importance, despite the complex biological factors that can interfere with T3 metabolism and inactivation.
Abdalla and Bianco’s main point is that the human body actively “defends” its T3 levels by means of multiple checks and balances. The role of TSH and T4 are only part of the complex process of producing and regulating T3 levels. “The level of serum T3 is a main target around which serum T4 and TSH are adjusted” (p. 636).
However, when the thyroid gland cannot produce sufficient T3, as is the case with hypothyroid patients, part of the T3-defense system is missing or insufficient. The common result is a lack of T3 in serum. In this case, serum T3 is NOT as “well defended” as it is in a healthy person with a fully functional thyroid gland.
The authors openly state that T3 therapy is “a highly controversial area in the thyroid field” (p. 633) and admit that “clinical trials are needed” to discover the clinical consequences of long-term, systemic low T3 levels in hypothyroid patients. Nevertheless they courageously provide strong scientific evidence and biological arguments in favor of combination therapy (T3+T4 medication) for hypothyroid patients low in T3.
T3 treatment may considered controversial, but the biological mechanisms regulating (or dysregulating) T3 serum levels are not controversial. Biological theories can be proven either true or false based on observing how biological functions behave under certain conditions. Biological studies can be more easily controlled and replicated than clinical trials of treatments. Therefore, normal human thyroid hormone biology is a stable foundation for proposing medical treatments.
The summary of the article concludes that T3 therapy must remain a viable option in the treatment of hypothyroidism:
- “Although monotherapy with levothyroxine [T4, Synthroid] is the standard of care for hypothyroidism, not all patients normalize serum T3 levels with many advocating for combination therapy with levothyroxine [T4] and liothyronine [T3, Cytomel]. The latter could be relevant for a significant number of patients that remain symptomatic on monotherapy with levothyroxine, despite normalization of serum TSH levels.”
Details: How the body defends T3
The authors redefine hypothyrodism as T3-dependent instead of TSH-dependent.
They clearly state that it is not TSH or T4, but rather the “intracellular levels of T3” that determine whether a patient is hypothyroid or hyperthyroid (in thyrotoxicosis) (p. 633).
They also point out that the activity of T3 is “tissue/cell specific,” which means a person can have “local hypothyroidism” or “local thyrotoxicosis” in specific organs or cells that lack sufficient type 2 deiodinase (D2) activity to convert T4 into T3 for immediate use by cells.
Therefore, it’s important to understand the “deiodinases” because over 80% of serum T3 is produced outside of the thyroid gland through conversion from T4 to T3 in various bodily tissues.
How D1, D2, and D3 deiodinases impact T3 levels
- D1, Type 1 deiodinase, is “restricted to the liver and kidney” and produces approximately “5 ul/day” of a healthy adult’s T3. “D1 is located in the plasma membrane and thus T3 produced via the D1 pathway exits the cells promptly” and becomes part of plasma T3. Therefore, the D1 pathway provides a very quick method of supplying T3 to all organs via serum T3 levels.
- D2, Type 2 deiodinase, converts T4 to T3 within the cell nucleus, where it “triggers biological effects in the same cell where it was produced” for up to 8 hours, before being released from the cell and becoming part of plasma T3. The majority of plasma T3 is produced through the type 2 deiodinase pathway. It is a slightly delayed and more localized (tissue-specific) process in comparison to D1, since the T3 it creates spends most of its half-life within the cell where it was created, and then the cell secretes and shares T3 with the rest of the body via plasma. The brain locally produces sufficient amounts of its own T3 through “relatively high D2-specific activity” within its cells. The pituitary gland through its own D2 activity can manufacture its own supply of T3 from T4, which makes TSH levels less indicative of low T3 serum and T3 tissue levels throughout the body.
However, the D2 deiodinase (responsible for the majority of our T3 production) can be underproductive due to excess T4:
- “In the presence of T4, D2 is inactivated with an
approximately 20 min half-life, whereas in the absence of T4, its half-life is prolonged to hours. This provides a mechanism through which the production of T3 can be regulated according to the availability of T4.” (p. 635) In other words, in a state of excess T4, if D2 activity was not minimized by reducing its half-life, the body would produce too much T3, resulting in thyrotoxicosis.
- Theoretically, via responsive reduction of D2 activity the brain is thus preferentially protected under thyrotoxic conditions of T4 medical overdose or overproduction by the thyroid gland.
Unlike D1 and D2, the third type of deiodinase, D3, acts as “a sink” for thyroid hormone, a means by which the body eliminates T3 from plasma circulation and disables T3 from entering cell nuclei.
- D3, Type 3 deiodinase, inactivates T3 by converting it into T2. [In another article, it is explained that D3 also converts T4 into Reverse T3 (Marsili et al, 2011, p. 395).] Like D1, D3 is located within the plasma membrane where it has easy access to circulating T4 and T3. By deactivating T3 within the cell/plasma membrane, D3 prevents T3 from entering the cell nucleus where T3 thyroid hormone receptors are located.
- Under normal, healthy conditions (without hypoxia), D3 is found largely in “the brain, skin, and placenta” (p. 635), which could explain common hypothyroid patients’ complaints about “brain fog” and skin problems, due to tissue-specific, local hypothyroidism caused by the deiodinase D3. The brain, therefore, continually inactivates T3 to maintain a safe level of T3 for brain tissues.
- In another article co-authored by Bianco, it is mentioned that “D3 inactivates approximately 80% of daily thyroid hormone production” but this deactivation in healthy humans is localized to high-D3 organs, since “D3 activity has been documented only in the uterus and placenta, with lower expression in the brain, pituitary gland, adrenal gland, and skin.” (Huang & Bianco, 2008, “Ontogeny” section, para. 2). Therefore, the developing fetus is protected from maternal T3-thyrotoxicosis by high levels of D3 in the placenta, and to a lesser yet still significant degree, D3 protects the brain, pituitary and adrenals from T3-thyrotoxicosis.
- However, states of illness are exceptions to this general rule of tissue-localized D3:
- This deiodinase may be largely responsible for what is commonly called Low T3 syndrome or sick euthyroid syndrome, which the authors have renamed “consumptive hypothyroidism.” Consumptive hypothyroidism, they explain, is “a state of systemic hypothyroidism caused by excessive degradation of T3 and T4 via abnormally high expression of D3.” The deiodinase D3 becomes more active “under hypoxic or ischaemic conditions” especially in “the liver, lungs, heart, and brain” (p. 635). In other words, D3 activity, resulting in deactivation of circulating T3, is increased in acute or chronic illnesses in which blood flow or blood oxygen are restricted, as occurs in heart disease, vasculitis, liver disease, or stroke. [As reported elsewhere, in some extreme cases of low-T3 syndrome, D3 has even been found in liver and skeletal muscle, where it is normally undetectable, and higher D3 levels were found in cases with lower T3: Reverse T3 ratios (Huang & Bianco, 2008, p. 151).]
- Under some rare conditions like “infantile hemangiomas,” D3 even “inactivates T3 at a faster rate than it can be produced” (p. 635), and is thus an extreme case of “consumptive hypothyroidism.” [This is explained in another article where it is stated that sometimes “high D3 expression” occurs within tumours (benign or cancerous), especially tumours located in blood vessels. (Huang & Bianco, 2008, “Ontogeny” section, para. 3)]
The half-life vs. stability of T3
Do T3 levels fluctuate wildly due to their short half-life? In short, no.
- “Serum T3 is remarkably stable over periods of days, weeks or months in healthy adult individuals, despite a relatively short half-life (approximately 12-18h).” This is because the majority of serum T3 is produced throughout the body by D1 and D2 deiodinases on a continual basis, every second and every minute of every day.
- “Serum TT3 and FT3 exhibit minimal circadian rhythmicity that is due to a nocturnal increase in TSH secretion” (p. 635). In other words, in patients who have a functioning thyroid gland, TSH (Thyroid Stimulating Hormone) prods the gland to produce more T4 and T3 at night time. To the degree that a patient’s thyroid gland is underproductive, atrophied, removed by surgery, or inactivated by radioactive iodine treatment, this minor circadian ebb and flow would be even more minor (or entirely absent in the case of a surgically removed thyroid).
Do not trust the TSH as a marker of euthyroidism
Does TSH respond accurately to T3 levels? In short, normally, but not always.
- TSH, and in general the “hypothalamus-pituitary axis,” is more sensitive to “circulating T4 levels” than T3 levels (p. 635). This is because the brain can convert its own T4 into T3 through higher organ-specific levels of D2 deiodinase.
- The hypothalamus-pituitary-thyroid axis can be “disrupted to the point that it is no longer capable of reacting adequately to a fall in serum T3″ (p. 637) Disruptions can include acute or chronic illness, or an ineffective thyroid gland that cannot secrete sufficient T3 to make up for a shortfall in tissue T4-T3 conversion.
- In some patients, “Monotherapy [T4-levothyroxine therapy] restores serum TSH levels without normalizing serum T3” as shown in studies of very large numbers of hypothyroid patients (p. 638)
If thyroid biology’s highest priority is to normalize T3 levels, then treatments that align with this priority are biologically more sound than treatments that merely normalize the TSH and/or T4.
Implications for T3 testing
- Test for Free T3, not Total T3, since “only 0.4% of T3 is free” and unbound to thyroid-binding globulin (TBG) and is “biologically available to enter cells and initiate hormone action” (p. 634).
- Test all thyroid hormone levels in order to detect imbalances, especially the imbalances that reveal underlying T3 dysregulation: an excessively low T3/T4 ratio in hypothyroid patients on treatment and excessively low T3/Reverse T3 ratio, even in the presence of a “normal” TSH. Imbalances in the HPT axis may be signs of an increasingly failing thyroid gland and inadequacy of T4 monotherapy to support healthy serum T3 levels and enable T3 (instead of Reverse T3) to reach cell nuclei.
- Consider the patient’s symptoms and overall health as both a sign of, and a determining factor in, T3 hormonal health. Hypothyroidism can be tissue-specific to specific organs based on organ specific illnesses and organ-specific activity of D2 and D3 deiodinases. Therefore, organ-specific T3 levels are NOT necessarily adequate even if serum T3 is normal, and systemic low serum T3 may be caused by by organ-specific illness states.
Implications for treatment of hypothyroidism
- “There is new evidence that patients bearing the Thr92Ala D2
polymorphism might benefit from combination therapy. This genetic polymorphism causes an amino acid change in a critical loop of the D2 molecule that controls its half-life. It is not known how this polymorphism affects D2 function but it could hypothetically disrupt thyroid hormone signalling in D2-expressing tissues, making these cells more susceptible to a reduction in serum T3.” (p. 638)
- Average physiological replacement dosages: “It is estimated that healthy adult subjects produce about 30 ug T3/day, of which about 5 ug are secreted directly from the thyroid and the rest is produced outside of the thyroid parenchyma via T4 deiodination.” (p. 634) However, based on the biological mechanisms presented in this article, it is possible that more than 30 ug/day may be necessary if the thyroid is underactive and/or if D3 activity is higher, deactivating serum T3 within cells of certain organs.
- Timing of three daily T3 doses: Studies of the failure of combination therapy (T4+T3) may have failed because of improper (once daily) timing of doses in many of these clinical trials. “Given the relatively short T3 half-life and the relatively fast absorption of liothyronine [T3 – Cytomel medication], patients receiving a tablet of liothyronine experience a transient increase in serum T3 that subsides during the next few hours. In fact, it has been reported that at least three tablets daily of liothyronine are necessary to avoid peaks of serum T3 that are above the normal range” (p. 638).
Huang, S. A., & Bianco, A. C. (2008). Reawakened interest in type III iodothyronine deiodinase in critical illness and injury. Nature Clinical Practice Endocrinology & Metabolism, 4(3), 148–155. http://doi.org/10.1038/ncpendmet0727
Marsili, A., Zavacki, A., Harney, J., & Larsen, P. (2011). Physiological role and regulation of iodothyronine deiodinases: A 2011 update. Journal of Endocrinological Investigation, 34(5), 395–407. http://doi.org/10.1007/BF03347465