When you are on standard levothyroxine (LT4) monotherapy (Synthroid, Eltroxin, Levothyrox, Tirosint, and so on) are you a “good converter” of T4 to T3 hormone?
Would you likely be better off on a T3-inclusive therapy?
Find out by skimming our review and application of this scientific journal article:
- 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 efficiency. Endocrine Connections, 4(4), 196–205. LINK: https://ec.bioscientifica.com/view/journals/ec/4/4/196.xml
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 compared FT3 to FT4. They then further analyzed that ratio using the SPINA-Thyr endocrinology research app to understand how the FT3:FT4 ratio 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 alone.
Thyroid hormone metabolism rates vary from tissue to tissue, organ to organ. “Poor converters” of T4 hormone usually remain highly efficient converters of T4 within the pituitary gland and hypothalamus, the organs that regulate TSH secretion. Meanwhile, beyond the pituitary, the rest of the human body’s thyroid hormone metabolism is more vulnerable to T4-T3 conversion inefficiency. In hypothyroid people, a TSH-regulated healthy thyroid gland’s T3 secretion is no longer there to compensate for metabolic inefficiency.
As a result of metabolic differences between the pituitary, hypothalamus, and the rest of the body, a high-normal FT4 will prevent TSH from rising high enough to signal hypothyroidism when the FT3 falls low-normal levels in circulation.
Therefore, when TSH is used as the primary judge of “adequate” dosing, poor converters on levothyroxine alone are at risk of underdose, excess FT4, or low or low-normal FT3.
Some poor converters will not be capable of achieving their individually optimal FT3 levels during TSH-normalized LT4 monotherapy.
Midgley and team suggest that some patients with poor conversion may require T3 dosing to enhance their FT3 supply without causing FT4 excess.
FT3:FT4 ratio thresholds for T4-T3 conversion efficiency
Next, Midgley’s team 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).
- See our walkthrough “Analyze thyroid lab results using SPINA-Thyr“
Since two “deiodinase” enzymes (D1 and D2) located in certain 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.”
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.
Just as we can classify vehicles by their mileage or fuel economy, we can classify human bodies as poor thyroid metabolizers by their FT3:FT4 ratio.
The FT3:FT4 ratio and SPINA-GD are just two different ways of expressing the net rate at which circulating FT4 contributes to the FT3 appearance rate, minus the T3 and T4 clearance rate.
Within each separate type of hypothyroidism, you can find “good converters,” “intermediate converters” and “poor converters” of T4 into T3 hormone.
|Metabolic category||SPINA-GD||FT3 in pmol/L divided by FT4 in pmol/L|
|Poor converters on LT4 mono||<23 nmol/s||<0.25|
|Intermediate converters on LT4 mono||23-29 nmol/s||0.25-0.31|
|Good converters on LT4 mono||>29 nmol/s||>0.31|
The average FT3:FT4 ratio in healthy adults rarely falls outside the 0.31 to 0.34 range, as shown in multiple studies (See “Normal FT3:FT4 thyroid hormone ratios in large populations“). The ratio is higher in youth and childhood.
In contrast, adult patients without any thyroidal T3 secretion who are maintained on LT4 dosing alone will tend to have a ratio that averages 0.27 and some can fall below 0.20 (See “Gullo: LT4 monotherapy and thyroid loss invert FT3 and FT4 per unit of TSH“)
However, the ratio is not a valid target for thyroid hormone dosing! It is simply an index of metabolic efficiency under LT4 treatment conditions given a certain level of thyroid gland function. Measuring the ratio over many lab tests establishes a person’s “metabolic fingerprint.” The ratio will change if they become pregnant, severely ill, or add T3 dosing.
Here’s an analogy. Using the FT3:FT4 ratio to represent metabolic efficiency is similar to estimating the mileage of a vehicle. Some vehicles get better mileage than others. The physics of a car’s energy demand is dependent on complex factors like speed, engine efficiency, wind resistance, road conditions, gasoline quality, the speed of other vehicles nearby, and so on. If you change any of these variables, the car’s mileage will change.
How does one optimize therapy, not just “normalize TSH”? It’s about finding a patient’s individualized optimal FT3 supply in the context of concurrent FT4 availability and clinical signs and symptoms. Optimal is individual. Each patient on LT4 alone will have a narrow “optimal” range of FT3 and FT4 levels that depends on their T4-T3 metabolic efficiency.
However, one can generalize that during LT4 monotherapy, FT3 is rarely optimal below the healthy population’s mean of 50% of reference range, as shown by a later study by Midgley’s team (See “2018 study shows T3 in upper half of reference range relieves hypothyroid symptoms“).
Therefore, the FT3 and FT4 ratio, together with their absolute levels, provide metabolic information that supplements the pituitary-specific TSH negative feedback response. It assists a physician to optimize and individualize the dose to the patient’s metabolic efficiency, which often differs from the FT4’s “mileage” of T4-T3 conversion within the pituitary and hypothalamus.
Caution: Convert from U.S. (imperial) lab units BEFORE dividing FT3 by FT4.
US lab units are like inches and pounds. Molar units (picamoles per liter) are like metric units, and they are based on chemistry calculations of the molar weight of the molecule.
T4 has a different conversion factor than T3 does because T4’s molar weight is larger.
- FT4 unit conversion: https://unitslab.com/node/121
- FT3 unit conversion: https://unitslab.com/node/120
No, you can’t make a ratio if one of the hormones is measured as Total, not Free. FT3 is approximately 0.3% of Total T3, but the ratio of Bound:Free hormone is not the same from person to person, and it may change over time within an individual.
Caution: Beware of “ratio skew” due to different lab reference ranges.
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Midgley’s research team uses the following lab reference ranges:
FT3: 3.1 to 6.8 pmol/L
FT4: 10 to 22 pmol/L
The thresholds for “poor converter” and so on are also based on the relationship between their lab’s FT3 reference range and FT4 reference range.
- If your lab’s FT3 range is lower but the FT4 range is similar, your ratio will be skewed lower.
- If your lab’s FT4 range is lower but the FT3 ratio is similar, your ratio will be skewed higher.
How to adjust your ratio
Thyroid Patients Canada provides a Google spreadsheet people can copy or download. It even includes a worksheet that converts US units into Pmol/L.
To adjust for ratio skew, convert your results to Midgley’s lab ranges using the following steps:
- Calculate your lab result’s “percent of reference range.”
- Take your result, such as FT4 12 pmol/L (10-20), and subtract the low end of your range. For example, 12 minus 10 = 2
- Divide the result by the width of your reference range. For example, 2 units divided by a 10-point range gives you 0.20. That means your lab result is 20% of range.
- Use your % of reference range to calculate what your result would likely be if tested at Midgley’s lab.
- Using the 20% calculation, it would be 0.20 x 12 for Midgley’s range width. The result of this example is 2.4
- Then add the bottom of Midgley’s reference range, which is 10. 2.4+10 = 12.4 pmol/L
After both FT3 and FT4 have been separately adjusted to Midgley’s lab ranges, you can then divide the FT3 by FT4 to get your “adjusted FT3:FT4 ratio.”
Why does this skew happen?
Laboratory reference ranges are not just based on the health status of the population. A large portion of the difference from lab to lab is based on the bias of the FT3 and FT4 assay manufacturer’s technology.
Measuring FT3 involve a lot of special technology and indirect calculation because a concentration of 3 pmol/L cannot be seen with the naked eye. The technology relies on chemicals that emit colored light, and translating that color into a number!
This is why blood drawn at the same time from the same person will yield a different absolute pmol/L result if it is shipped to two different labs.
For example, Abbott Architect platforms will yield lower absolute FT3 results than Roche. Therefore, Abbott FT3 tests need a lower reference range to account for the bias of their technology.
This bias in technology occurs because manufacturers have not calibrated their machines to the gold-standard international LCMS assay methodology yet.
Today’s FT3 and FT4 immunoassays are of high quality in terms of precision and reliability. They were improved significantly around 2005-2008. Precision, however, does not mean the same thing as accuracy. Accuracy would mean coming close to the absolute standard of the LCMS assay test result. Precision means that if you put the blood through the machine many times, your results will vary less than 5% from each other (intra-assay coefficient of variation, %CV). Most lab tests have to be below 10% before they are considered good quality.
Background #1: How and where does T4-T3 conversion happen?
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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).
Some cells express D1: They are mainly located in thyroid, liver, and kidney.
Other cells express D2: Most tissues outside of the liver express D2, but they are highly concentrated in tissues like pituitary, brain, bones, brown/beige fat, and muscles.
Other cells do not express D1 or D2, and their health will rely on FT3 entering cells from circulation. Many of these cells are in our heart, so that’s why our cardiovascular system is so sensitive to low or low-normal FT3.
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
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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
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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.
- 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.
- 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.
- Other conversion: Some FT3 will enter cells that express enzymes that convert it to Triac (TA3), T3 Sulfate, T3 or Glucuronide.
- 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 must be interpreted in context.
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A low or high ratio is not necessarily a good or bad thing on its own.
Here’s an analogy based on diets. 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.
SUMMARY of Midgley et al, 2015
From the 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.”
From Midgley, 2015: 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.
From Midgley, 205: Summary of results
- Dissociation between FT3 and FT4
- Disjoint between TSH and FT3
- Inverse association between TSH and FT3
[Figures reproduced with permission: Creative Commons License By-NC 4.0]
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).
“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.”
Midgley, 2015: 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.”
Midgley, 2015: The problem of the FT3 – TSH Disjoint
“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.”
From Midgley, 2015: 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.”
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