T3 is not always converted from T4

not all t3 comes from t4Choosing Wisely Canada, in its campaign to prevent “unnecessary” Free T3 testing in hypothyroidism, says this at the opening of their justification: “T4 is converted into T3 at the cellular level in virtually all organs.” (1)

Such a statement makes it seem like T3 hormone only originates from T4 hormone.

Admittedly, debate and uncertainty has surrounded the issue of how much T3 the thyroid gland creates from scratch. (2)

But in the absence of definitive proof until now, doctors have chosen to believe their pet theory — that T3 always comes from T4, even within the thyroid gland.

Recently scientists have proven, in a 2017 article, that a healthy thyroid gland can and does form T3 hormone directly, without the aid of T4’s prior existence. (3)

The declaration was very confident and clear in the title of Citterio et al.’s article, “De novo triiodothyronine formation from thyrocytes activated by thyroid-stimulating hormone.”

“De novo” is a Latin phrase that means “starting from the beginning, anew.”

This is revolutionary and potentially paradigm-shifting knowledge. We can’t let this fade into the dust-heaps of ignored scientific research.

THE ROOT OF MEDICAL PRESUMPTIONS

Dismissing “de novo” T3 generation from the thyroid has been a pillar of justification for standard T4 hormone monotherapy since it was championed in the 1970s.

As Abdalla and Bianco stated in 2014, it was at that time still unknown how much of our thyroid-secreted T3 derived from “intracellular thyroglobulin digestion” or from “deiodination” (T4 conversion by removal of an iodine atom). (2)

Not knowing for certain meant that doctors were choosing to hypothesize whatever they wanted to believe. They chose to believe that damaged or removed thyroid gland tissue could be fully replaced by T4 hormone alone.

If the thyroid gland is only a T4-factory, then ALL the potential imbalances in T3-T4 ratios are entirely the responsibility of the deiodinase enzymes that convert T4.

But if the thyroid gland is also a T3-factory, it means something important for a patient’s health to have their thyroid gland killed off by autoimmune attack, destroyed by radioactive iodine therapy, or surgically removed.

Here’s their (mistaken) reasoning, in my paraphrase:

“If a thyroid creates only T4 hormone, then WE can imitate the thyroid gland and only give patients T4. Because the very same enzymes that convert T4 to T3 within the thyroid gland are also at work outside the thyroid gland, the rest of the body can convert enough T4 to T3 outside the thyroid gland.”

In addition, this false belief has justified dismissing Free T3 testing in hypothyroid therapy.

If a thyroid gland can only convert T3, not create T3, then why measure the end-product hormone (T3) when you can just measure the raw material (T4)?

This is the assumption behind the blanket statement that  “T4 is converted into T3 at the cellular level in virtually all organs.” (And by the way, “Virtually all organs” implies that some organs don’t convert. Can you tell us, dear endocrinologists, which organs you think don’t convert T4 to T3 at the cellular level and why you only care about those that do?)

IMPLICATIONS FOR THYROID HEALTH

“De novo” T3 synthesis has profound implications for the way we see thyroid function.

It means that the HPT axis (the interaction between hypothalamus, pituitary and thyroid glands) may exist not in order to maintain normal T4 and TSH levels, but rather to defend plasma T3 levels.

The HPT axis is modeled on T4-TSH relationship because in health, T3 levels are steady and therefore do not mathematically correlate with TSH or T4.

The HPT axis model we currently have IGNORES T3, the most essential thyroid hormone, and the presumption is that it is a by-product whose level and fluctuations matter very little to health as long as the TSH and T4 are within normal equilibrium.

Going against this model is an alternative understanding of thyroid hormone regulation that has been building since the early 2000s.

In both mice and humans, it appears that “the hypothalamus–pituitary–thyroid axis is wired to preserve serum T3” in the context of health. (2)

The living thyroid gland’s role in preserving T3 in serum is crucial:

“Experimental evidence indicates that in the absence of T3-producing deiodinases, the hypothalamus–pituitary–thyroid axis resets and is capable of defending serum T3.” (2)

In other words, the living thyroid gland can actively compensate and correct for any imbalances in T4-T3 conversion in order to maintain serum T3.

However, is the reverse true? can deiodinases compensate for the loss of a thyroid gland?  Abdalla and Bianco ask this. (2)

IMPLICATIONS FOR THYROID DISEASE

The answer is NO, the deiodinases can’t compensate for the loss of a healthy thyroid.

The healthy thyroid gland is required to maintain serum T3 levels over time.

In studies of thyroidectomized rats, the rats that had genetically handicapped enzymes for T4-T3 conversion were NOT able to maintain serum T3 levels because they lacked a thyroid gland. (2)

Consider the alteration thyroid hormone status that occurs in various thyroid diseases that alter T3 secretions from the gland or remove the thyroid entirely. Even before you add medications that supply thyroid hormone or reduce thyroidal secretion, you have a pathological T3 hormone status, and the deiodinases can’t entirely compensate for these thyroidal distortions.

IMPLICATIONS FOR THYROID THERAPY

Layered on top of the complexity of thyroid disease are the medical manipulations of thyroid hormone therapy.

No form of thyroid hormone replacement can create T3 de novo, not even medications that supply T3 hormone.

No pill can vary its level of T3 secretion to adapt to biological changes in health status and medications.

The dream that thyroid hormone dose is adequately adjusted when TSH is normalized is just that — a dream. A medical fantasy.

WHAT OUGHT TO BE THE GOAL OF THYROID THERAPY?

If the aim of thyroid therapy is to imitate normal thyroid biology as much as possible, you have to understand what the goal of thyroid biology is.

If thyroid gland in health alters its rate of T3 de novo synthesis to achieve the goal of maintaining Free T3 levels in serum, then it is biologically INCORRECT to titrate patients’ thyroid hormone doses to anywhere within the normal TSH range.

But if, on the contrary, the biological goal of thyroidal secretion is NOT to normalize the TSH or T4 level (this is the medical system’s goal and target), but rather to supply the bloodstream with an ever-changing ratio of T4 and T3 hormones that maintains steady upper-normal reference Free T3 levels in health, then that’s a huge paradigm shift in therapy.

The logical conclusion of this research is this:

The thyroid hormone dose as well as the ratio of T3 and T4 in the dose should adapt as necessary to target an optimal Free T3 level in serum. 

And since it is impractical to continually test Free T3 levels on a monthly basis, the patient, who knows what hypothyroidism signs and symptoms are, should be permitted to fine-tune her T3 dose strength and timing within a healthy range, as a healthy thyroid gland would do, and just as diabetes patients are given control over their insulin.

REFERENCES

(1) Canadian Society of Endocrinology and Metabolism, & Choosing Wisely Canada. (2017, June). Endocrinology and Metabolism: Five tests and treatments physicians and patients should question. Retrieved January 17, 2019, from https://choosingwiselycanada.org/endocrinology-and-metabolism/

(2) Abdalla, S. M., & Bianco, A. C. (2014). Defending plasma T3 is a biological priority. Clinical Endocrinology, 81(5), 633–641. https://doi.org/10.1111/cen.12538

(3) Citterio, C. E., Veluswamy, B., Morgan, S. J., Galton, V. A., Banga, J. P., Atkins, S., … Arvan, P. (2017). De novo triiodothyronine formation from thyrocytes activated by thyroid-stimulating hormone. The Journal of Biological Chemistry, 292(37), 15434–15444. https://doi.org/10.1074/jbc.M117.784447

 

Leave a Reply

Please log in using one of these methods to post your comment:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s