Are you a poor T4 converter? How low is your Free T3?

SUMMARY of Midgley et al, 2015

Source:

  • Midgley, J. E. M., Larisch, R., Dietrich, J. W., & Hoermann, R. (2015). Variation in the biochemical response to l-thyroxine therapy and relationship with peripheral thyroid hormone conversion efficiencyEndocrine Connections4(4), 196–205. LINK: https://ec.bioscientifica.com/view/journals/ec/4/4/196.xml

Overview

This scientific article analyzes FT3 and FT4 ratios in a large number of patients with different types of hypothyroidism being treated on standard LT4 monotherapy.

It points out that not everyone has the same healthy rate of thyroid hormone metabolism. TSH cannot detect metabolic inefficiency. Therefore, in symptomatic cases, FT3:FT4 ratio analysis is helpful and an individualized approach to therapy is necessary.

Midgley and team’s analysis divided FT3 by FT4 in pmol/L to obtain a raw ratio. They then further analyzed that ratio to understand how it represented the rate of thyroid hormone intracellular metabolism all over the human body.

The wide range of diversity in thyroid patients’ metabolism of T4 and T3 has significant health implications for people whose thyroid hormone supply is being judged by TSH, which has a secretion rate that is blind to ratios.

Poor converters are at risk of underdose, excess FT4, or low FT3 under our current TSH-biased health care systems. Some patients will not be capable of achieving their individually optimal FT3 levels during TSH-normalized LT4 monotherapy.

Midgley and team suggest that some patients may require T3 dosing to enhance their FT3 supply without causing FT4 excess.

Findings: thresholds for “GD”

They then used an endocrinology research application called SPINA-Thyr to represent the absolute raw FT3:FT4 ratio as a number in that represents how many T3 molecules appear in blood for every T4 molecule in blood, measured “nanomoles per second” (nmol/s).

Since “deiodinase” enzymes in cells are responsible for more than 80% of thyroid hormone metabolism in a state of thyroid health, they called this the “Global Deiodinase” efficiency index, abbreviated “GD.”

Thyroid hormone metabolism is very complex, but so is the physics of any object moving through space over time.

Expressing the FT3:FT4 ratio to represent metabolic efficiency is similar to expressing the speed of a vehicle as kilometers per hour (km/h). We know that underneath that simple speed measurement, the physics of a car’s speed is dependent on complex factors like engine efficiency, wind resistance, the driver’s pressure on the gas pedal, road conditions, the speed of other vehicles nearby, and so on.

Just as we can classify vehicles and drivers by their average speed of travel on certain highways, we can classify bodies as thyroid metabolizers by their FT3:FT4 ratio.

The FT3:FT4 ratio and GD are just two different ways of expressing the net rate at which circulating FT4 drives the FT3 appearance rate, minus the FT3 clearance rate.

Within each separate type of hypothyroidism, you can find “good converters,” “intermediate converters” and “poor converters” of T4 into T3 hormone.

Midgley and team classified them as GD, but each GD level can also be expressed as an equivalent FT3:FT4 ratio. The ratio is easily derived with a calculator.

Metabolic categorySPINA-GDFT3 in pmol/L divided by FT4 in pmol/L
Poor converters on LT4 mono<23 nmol/s<0.25
Intermediate converters on LT4 mono23-29 nmol/s0.25-0.31
Good converters on LT4 mono>29 nmol/s>0.31

Background #1: How and where does T4-T3 conversion happen?

The majority of our T3 supply in thyroid health and in T4 monotherapy is derived from T4 conversion to T3 within cells all over the body, in every organ and tissue that expresses certain enzymes within its cells:

  • Deiodinase type 1 (D1) and / or
  • Deiodinase type 2 (D2).

It is an old myth that most T4-T3 conversion happens in the liver. Scientists that examine the contribution of the liver’s main T4-converting enzyme, D1, have found this to be false. No tissue type in the human body has yet been found to be devoid of D1 or D2 enzymes that can convert T4 to T3.

The human thyroid is a powerful engine of T4-T3 conversion, despite its small size, and despite being largely known as a factory where thyroid hormones are made from raw materials. The human thyroid gland expresses both D1 and D2, unlike rat and mouse thyroids, which only express D1. The density of D1 and D2 expression per volume is higher in thyroid tissue than any other human tissue studied so far. TSH receptor stimulation, even as it rises within reference range, upregulates both D1 and D2 in thyroid gland tissue. The same blood that carries TSH into the thyroid also carries T4 and T3 into and out of the thyroid gland.

However, some people without any thyroid tissue after a total thyroidectomy are more efficient at converting T4 to T3 than people with autoimmune thyroid diseases or partial thyroidectomies.

Therefore, so intra-thyroidal T4-T3 conversion rate is not the only factor, and not even the largest factor. Some bodies are just less efficient at T4-T3 conversion.

Every minute of every day in our bodies,

  • some T4 is being converted to T3 within certain cell types,
  • some T3 derived from T4 is exiting cells and re-entering circulation, and
  • some T3 is being converted to T2 and other non-T3 metabolites.

The net outcome of all these transactions is the FT3:FT4 ratio in our bodies, and the FT3:FT4 ratio or SPINA-GD helps us assess the net rate of T3 signaling as the product of both hormones’ supply and metabolism.

For a scientific review, see “Thyroid hormone journey: Metabolism.”

Background #2: Transport enables T4-T3 metabolism and T3 losses

T4 does not convert while it is floating freely in plasma or serum. In order to convert T4 to T3, Free T4 must be carried into cells that express D1 and D2 enzymes that transform it.

Both Free T4 and Free T3 are continually being carried into and out of cells.

Although some T3 produced from T4 circulates locally within tissues, a large portion of the byproducts of conversion in every tissue will exit tissues and reenter the systemic circulation.

T4 transport into cells does not occur by means of passive diffusion. Thyroid hormones can’t wiggle their way through cell membranes. Instead, transport proteins in the membrane selectively pick up carry Free T3 and Free T4 hormone into the cell.

After T4 is converted to T3 within a cell, T3 spends a variable period of time inside the cell. That new-born T3 molecule may or may not signal in mitochondria or nuclear thyroid hormone receptors before being picked up by other thyroid hormone transporters that carry T3 out of the cell.

Background #3: T3 losses influence the FT3:FT4 ratio

Circulating FT3 is vital for health. Some circulating Free T3 will be needed by cells with no D1 or D2 enzymes or very few or inefficient enzymes.

However,

  1. D1 conversion: Some of the Free T3 in blood will be converted to both active T2 and inactive T2 after it enters other cells where D1 is upregulated.
  2. D3 conversion: Some Free T3 will enter cells expressing D3 enzyme, which focuses on deactivating T3 into an inactive form of T2 hormone.
    • This rate of T3 loss will be much higher in severe illnesses in the syndrome called “Low T3 Syndrome” or “Nonthyroidal Illness Syndrome” (NTIS), as D3 is upregulated by inflammatory cytokines, tissue hypoxia. This can lead to T3 depletion in injured tissues that are dominant in D3, where their intracellular T3 may be even lower than low circulating FT3.
    • Intracellular T3 loss will also be higher in hyperthyroidism or thyroid hormone overdose, since excess FT3 will upregulate D3 to protect receptors from being flooded.
  3. Other conversion: Some FT3 will enter cells that express enzymes that convert it to Triac (TA3), T3 Sulfate, T3 or Glucuronide.
  4. Urine: Some FT3 will be lost in urine, more so when a kidney disorder called nephrotic syndrome or proteinuria is present.

D2 enzyme, which is the main enzyme in the pituitary and hypothalamus, is not the main driver of T3 metabolic losses. D2 is not very efficient at converting T3 into active T2. Its main role is T4-T3 conversion, not T3 catabolism.

Despite the continual rate of T3 loss, some Free T3 entering cells will bypass conversion by enzymes and end up binding to those cells’ receptors in the nucleus and mitochondria.

For a review of the science behind the pathways of T3 loss, see “A complete pathway map of T4 and T3 metabolism and clearance.”

Caution: The ratio or GD is not independent of absolute levels in blood.

A low or high ratio is not necessarily a good or bad thing when taken out of context.

For example, our energy metabolism shifts based on the ratio of protein, carbohydrate and fat we consume. But the total number of calories still matters. We all know that eating less carbohydrate can prevent net caloric excess when eating a lot of protein and fat. A low-carb diet in the context of a low-calorie diet can send strong metabolic signals of starvation, but in the context of a high-calorie diet, it will result in excess despite the ratio.

In the same way, the absolute levels of FT3 and FT4 will determine whether the ratio is “hypothyroid” or “thyrotoxic.” For example

  • A low absolute FT4 level can prevent a high FT3:FT4 ratio from becoming thyrotoxic due to an isolated high FT3, even if the high FT3 singlehandedly lowers TSH.
  • A low absolute FT3 level can prevent a low FT3:FT4 ratio from becoming thyrotoxic due to an isolated high FT4, even if the high FT4 singlehandedly lowers TSH.

The pituitary regulation of TSH may be biased low because of abnormal, yet therapeutic, ratios that nevertheless produce euthyroidism in other tissues of the human body.

Other organs and tissues beyond the pituitary and hypothalamus are not as blind to FT3:FT4 ratios and absolute T3 supply.

All tissues use FT3 to “top up” their intracellular rate of T4-T3 conversion, which differs from tissue to tissue. Not every cell or tissue is equipped with deiodinase type 2 (D2) which efficiently converts T4 to T3 and ushers it into the nucleus of the cell where it was born.

  • A poor converter with a low FT3:FT4 ratio will require more FT4 in blood and a lower TSH to achieve a FT3 at the population mean of mid-reference range.
  • A good converter with a high FT3:FT4 ratio may become overdosed when FT4 is high-normal or mildly high and TSH is low-normal, because their FT3 will be higher in range than the poor converter’s even if their FT4 is the same.

Selections from their introduction

“Although TSH measurement has dominated procedural management of thyroid replacement by its apparent ease and good standardisation, a disturbingly
high proportion of patients remains unsatisfied with the treatment they receive.

This has prompted some authors including our group to question the validity of relying on the TSH level as the sole measure of dose adequacy in L-T4-treated patients.”

As a controlling element, the effective TSH level derived in a healthy normal population cannot necessarily be inferred to be equally optimal for a given patient on L-T4 medication, because the constitutive equilibria between TSH and thyroid hormones, especially FT3, differ in health and disease.”

Patients studied

  • 353 patients (280 women)
  • Average age 56

Patients were analyzed in three separate groups according to the cause of hypothyroidism.

  • 27% Autoimmune thyroiditis
  • 32% Benign thyroid disease after surgery
  • 41% Thyroid carcinoma

TSH and Free T4 were both within reference range, except for suppressed TSH in carcinoma patients.

  • No interfering drugs or illnesses

Patients were divided into three categories for each type of hypothyroidism, based on their ability to convert T4 into T3: Good converters, Intermediate converters, Poor converters, with cutoffs determined by a previous study.

Results

  • Dissociation between FT3 and FT4
  • Disjoint between TSH and FT3
  • Inverse association between TSH and FT3

The poor converters reached significantly higher FT4 concentrations in the circulation than intermediate or good converters but, at the same time, showed significantly lower absolute FT3 levels compared to the other two groups (Fig. 2).

[Figures reproduced with permission: Creative Commons License By-NC 4.0]
Midgley-Variations-2015-Figure2

Figure 2: FT3 (A), FT4 (B) and TSH (C) levels in l-T4-treated patients stratified by disease and conversion efficiency. The disease entities were closely associated with categories of the thyroid volume (see Table 1 and text).

The red box refers to poor converters (calculated deiodinase activity <23 nmol/s),

green to intermediate converters (deiodinase activity 23–29 nmol/s) and

blue to good converters (deiodinase activity >29 nmol/s).

Remarkably, absolute FT3 concentrations were lowest in the poor converter group in all disease categories, while FT4 levels were highest in the poor converters.

Wilcoxon test, revealed significant differences compared to each first group; *P<0.05, **P<0.001. AIT, autoimmune thyroiditis; goitre, goitre post surgery for benign nodular thyroid disease.”

What factors altered T4-T3 conversion efficiency?

  • Thyroid volume was significantly associated with T4-T3 conversion efficiency.
  • Men were more efficient T4-T3 converters than women.
  • L-T4 dosage and Free T4 levels affected conversion in unexpected ways.

We found that a poor converter status was associated with a higher L-T4 dose and higher serum FT4 levels but still lower absolute FT3 concentrations, compared to the more efficient converters.

This paradoxically relates the higher T4 supply to a worsened rather than improved absolute FT3 level.

This is not to say that an increasing dose will not raise on average the FT3 but that the dose response varies widely among individuals, and conversion inefficiency in some patients may outweigh the dose effect in terms of achievable absolute FT3 concentrations.

How can this be explained?

A high L-T4 dose may not invariably remedy T3 deficiency owing to T4-induced conversion inefficiency but could actually hinder its attainment through the inhibitory actions of the [T4] substrate itself and/or reverse T3 (rT3) on deiodinase type 2 activity.

While acknowledging the role of genetically determined differences in deiodinase activity affecting conversion rates, the poor converter status described here appears to emerge mainly as a consequence of the T4 monotherapy itself, induced by the mechanisms discussed above.

Compared to untreated subjects, deiodinase activity and conversion efficiency tend to be diminished in L-T4 treatment.”

The problem of the FT3 – TSH Disjoint

(Read more: “The TSH-T3 disjoint in thyroid therapy“)

“Thus, not even an L-T4 dose in which TSH is fully suppressed and FT4 by far exceeds its upper reference limit can guarantee above average FT3 levels in these patients, indicating an FT3–TSH disjoint.

Dosing strategies solely based on a TSH definition of euthyroidism neglect the important role of FT3, which has recently emerged as an equally significant parameter in defining thyroid physiology (20, 22, 29, 30, 40, 41).

Overall, patients differ widely in the degree of the conversion impairment they suffer.

In two studies, 15% of athyreotic patients could not even raise their FT3 above the lower reference limit on L-T4 (19, 20).

We speculate that L-T4-induced conversion inefficiency could prevent some vulnerable subjects from reaching true tissue normality on T4 monotherapy alone.”

Implications for thyroid therapy

“The T3–T4 ratio is an important determinant of L-T4 dose requirements and the biochemical response to treatment.”

“In view of a T4-related FT3–TSH disjoint, FT3 measurement should be adopted as an additional treatment target.”

“In cases where an FT3–FT4 dissociation becomes increasingly apparent following dose escalation of L-T4, an alternate treatment modality, possibly T3/T4 combination therapy, should be considered, but further randomized controlled trials are required to assess the benefit versus risk in this particular group.”



Categories: Free T3 test, Testing policy

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  1. 23 years of misdiagnosed central hypothyroidism with a normal TSH: Case study – Thyroid Patients Canada
  2. The myths that idolize TSH and denigrate FT3 – Thyroid Patients Canada

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