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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Background #1: How and where does T4-T3 conversion happen?
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Background #2: Transport enables T4-T3 metabolism and T3 losses
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Background #3: T3 losses influence the FT3:FT4 ratio
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Caution: The ratio or GD must be interpreted in context.
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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.”