Therefore, these FT3:FT4 ratio findings can assist in identifying metabolic dysfunctions and HPT axis interferences that may otherwise be misdiagnosed or overlooked.
In this post, I provide graphs, quotations, and discussions from Gullo, Strich, and Anderson as I present their FT3:FT4 ratio results, and I rely on science to present the mechanisms by which the ratio is adjusted in relationship to TSH in people not dosing thyroid hormones.
In health, the average FT3:FT4 ratio and range at various levels of TSH is an indicator of the normal and healthy thyroid gland and thyroid hormone metabolism to TSH, and the TSH’s normal response to thyroid hormones.
These hormone relationships are often abnormal in various types of thyroid disease and systemic illnesses. The TSH-FT3:FT4 relationship will also distort if the pituitary and hypothalamus’ co-adjustment of TSH secretion is abnormal.
In health, the presence of a normal FT3:FT4 ratio reflects the efficiency of the three deiodinases D1, D2, and D3 cooperation to metabolize thyroid hormones at various rates throughout all tissues in the body at various ages.
The ratio may be abnormal if deiodinase genetic polymorphisms hinder, if substances or medications interfere, or if severe illness distorts the normal balance among the D1, D2 and D3 enzymes.
The ratio of FT3:FT4 can be judged low, normal, or high. Science provides us with a reference range for the ratio’s normal values at various levels of TSH, at various ages, with slight differences between males and females.
I also discuss the reliability and precision of testing FT3 and FT4 via common immunoassays available at laboratories today. This understanding is essential to assessing the validity and precision of the ratio calculation in everyday clinical practice.
I conclude by showing that the FT3:FT4 ratio has many potential practical uses: It can fine-tune diagnosis, reveal interferences, and in future, it may light the pathway to individually optimized therapeutic ratios in thyroid disease and other chronic diseases.
Copyright fair dealing note
Quotation, paraphrase, and reproduction, annotation, and adaptation of graphs and tables from copyrighted scientific publications is acceptable within the terms of Canadian and US copyright “fair dealing” and “fair use” for purposes of education and review: See copyright law info
Summary: What is the normal FT3:FT4 range and average?
Gullo and team discovered that the average ratio among healthy controls throughout the normal TSH range (divided into quintiles) is approximately 0.32-0.33 pmol/L per quintile in a population with an average age of 49 years.
Anderson’s 2020 TSH data set coincidentally fits almost perfectly with Gullo’s range and average. Mid-range ratios of average FT3:FT4 in the table are approximately 0.33 pmol/L for all four normal TSH quartiles.
This is how narrow the average is among many people’s FT3:FT4 ratios. The average conceals the full range of individual diversity within any given quartile or quintile of TSH.
Gullo and team found the reference range for the ratio was from 0.20 to 0.50 pmol/L. This reference range is calculated, like most laboratory ranges, as the 95% interval, omitting the 2.5% high and 2.5% low outliers. It represents the wide range of normal human variation in the ratio.
In Anderson et al’s 2020 data, including values outside the normal TSH reference range, the lowest ratio was 0.24 and highest ratio was 0.53. This is shifted only slightly higher than Gullo’s reference range of 0.20 to 0.50.
Note that Anderson’s data set was not screened for overall health or thyroid health because the data set explored associations with disease, even within the reference range.
In addition, Strich found that the FT3:FT4 ratio decreased decade by decadefrom childhood to advanced age, but did not change as much between age 30 and 60. When excluding all persons who had an abnormal weight for their age, the ratios narrowed down further, maintaining the average of 0.33 after age 20 even into the 80s.
Anderson’s ratio average within TSH Normal Q1-Q4 is 0.3325 and the average age of the population was 64.9 years. This data fits within Strich et al’s average ratio within TSH Normal Q1-Q4: it was 0.345 in the 60-70-year-olds category.
Gullo’s average ratios were 0.32 for all healthy controls, with an average age of 49 years. The control subjects’ sex and age data were F = 3,224, M= 651 and 2,927 <60 y and 948 >60 y.
For women in Gullo’s study, the ratio was only slightly lower (0.32) than it was among men (0.33), which fits with Strich’s findings for sex differences.
For persons over 60 in Gullo’s study, the ratio was slightly lower (0.30 for older women, 0.31 for older men). This fits with Strich’s findings of a mildly reduced ratio in older age groups when including all persons regardless of their body weight.
1. The FT3:FT4 ratio must always be anchored in a FT4 level.
The problem with ratios is that they are relative expressions. The important question answered by the FT3:FT4 ratio is “how much FT3 is circulating per unit of FT4?”
It’s an important question. The FT4 level alone is as uninformative as the FT3 level alone. The ratio matters to health. FT3 and FT4 are partners in a dance, not metabolically equivalent to each other.
However, the answer, the ratio, does not tell you if you have overall too much or too little of both hormones. Ratios must be grounded or anchored in levels:
Chronically deficient supply from both hormones combined can produce hypothyroidism, even if the FT3:FT4 ratio is elevated, and
Chronically excessive supply from both hormones can produce thyrotoxicosis, even if the FT3:FT4 ratio is lowered.
An individual’s healthy thyroid hormone homeostasis targets a window of “optimal” T3 supply to cells throughout the body, below which is hypothyroidism and above which is thyrotoxicosis.
Free T4, not Free T3, is the natural “anchor” for the FT3:FT4 ratio.
This is because in the TSH-driven thyroid hormone economy, T4 hormone will always be more abundant in blood than T3 hormone. The FT4 reference range is approximately 10-25 pmol/L while the FT3 reference range is approximately 3-6.5 pmol/L. It makes sense to divide the smaller concentration by the larger.
The FT4 level, by being converted to T3 at a variable rate, yields part of the T3 (FT3) level in blood. Most, but not all, of the untreated person’s circulating T3 (FT3) supply will be derived from intracellular T4-T3 conversion, as cells engage in 2-way exchange of thyroid hormones with blood. The body’s rate of T4-T3 conversion is always “topped up” by a flexible amount of T3 (FT3) from daily thyroidal secretion.
Therefore, at any given FT4 level, FT3 levels are “anchored” to their major metabolic donor, FT4. As the TSH-guided thyroid gland and peripheral metabolism work together, the body’s T4-T3 conversion rate plus thyroidal FT3 yield a total supply of T3 hormone to cellular receptors.
In addition, FT4 also performs some limited types of non-genomic signaling at the “integrin” cell membrane receptor. (As of 2019, scientists have also learned that RT3 is in fact an actively signaling hormone at this receptor.) See our review at “Cancer scientists point finger at T4 & RT3 hormones.”
2. Low FT3:FT4 ratios and low FT3 are more pathological than an isolated low FT4.
This is because T3 hormone is the most potent signaling hormone in the nuclear receptor and in mitochondria.
This basic principle is most profoundly illustrated by T3 monotherapy, in which sufficient FT3 supply, often above the FT3 reference range, enables a hypothyroid individual to thrive on T3 alone, in the absence of FT4 from blood.
Higher FT4 cannot compensate for lower FT3, but a higher FT3 can compensate for lower FT4.
Click to read practical examples of ratios anchored in FT4 levels
1. When people obtain higher-normal FT4 levels, it may meet a higher metabolic demand in the individual.
The FT3:FT4 ratio still matters to health:
Euthyroidism: In a person with a healthy high-normal setpoint, a normal or mildly lower FT3:FT4 ratio may prevent thyrotoxicosis and result in euthyroid status despite a high-normal FT4.
Thyrotoxicosis: Raising the ratio while the FT4 is high-normal will more likely result in tissue thyrotoxicosis.
This is often seen in subclinical Graves’ hyperthyroidism, or “T3-toxicosis,” where only the FT3 is elevated.
It is also seen in patients with an autonomous T3-secreting thyroid nodule.
Hypothyroidism: In some states of chronic illness, the paradox of a high FT4 and low FT3 still induces tissue hypothyroidism.
As the TSH rises to high-normal during recovery, it stimulates more T4 secretion. However, the ratio in blood may be lowered by a very high rate of T3-T2 conversion in cells, which may overcome thyroidal T3 secretion rates. A higher-normal (or even mildly high) FT4 is incapable of compensating for a lower level circulating FT3. See “Ataoglu: Low T3 in critical illness is deadly, and adding high T4 is worse.”
2. Conversely, when people obtain lower-normal FT3 and FT4 levels, the lower levels may fall to meet a lower thyroid hormone demand in the individual.
The FT3:FT4 ratio still matters to health:
Euthyroidism: An elevated ratio while the FT4 is anchored to a low-normal level may obtain a healthy euthyroid state.
In early untreated Hashimoto’s thyroiditis, a lower FT4 with a very high FT3:FT4 ratio is the natural result of remaining active thyroid tissue being overstimulated by higher TSH, which increases intrathyroidal and extrathyroidal T4-T3 conversion rate, as well as T3 de novo synthesis rate. If the FT3 is high enough, the patient will be symptom-free.
Thyroid tissue T3 synthesis is essential to maintaining this high FT3:FT4 ratio (Hoermann et al, 2020).
Hypothyroidism: A lower or normal ratio anchored to a low or low-normal FT4 level will result in tissue hypothyroidism.
This is seen in the most common forms of chronic, pathological “low T3 syndrome” (nonthyroidal illness, NTIS) when patients fail to recover the FT3 levels needed for health recovery.
It is seen in patients after advanced Hashimoto’s, advanced Atrophic thyroiditis, severe central hypothyroidism, or a total thyroidectomy, if treatment is delayed or withdrawn. The severe and deadly manifestation is called myxedema coma.
Thyrotoxicosis: This is only seen in rare cases.
An extremely elevated FT3:FT4 ratio can be achieved by means of T3-secreting thyroid nodules that can suppress the rest of the thyroid gland’s T4 secretion rate.
Alternatively, in Graves’ disease, the TSH-receptor antibody can stimulate a very small thyroid fragment incapable of much T4 secretion, while enhancing T4-T3 conversion rates throughout the body, especially via D1 enzyme in the thyroid, liver, and kidney. This may yield a FT3 high enough to exceed an individual’s setpoint, even if both hormones are still within reference range or FT4 is mildly low.
Advanced scientific readers: Technical details
Seeing the FT3:FT4 ratio “anchored” in FT4 respects the physiological methods by which the body provides T3 sufficiency to all organs and tissues by means of the bloodstream.
Supply and metabolism can be seen from two perspectives:
Measurable bloodstream ratios and levels of FT4 and FT3 with health implications, and
Estimated cellular levels of T3 receptor occupancy derived from intracellular metabolism, in response to bloodstream FT4 and FT3 ratios and levels.
Both ways of seeing the anchored ratio have health implications.
1. Bloodstream ratios and levels
An average FT3:FT4 ratio of 0.33 anchored to the average FT4 level in the population is a mathematical statistic that cannot represent the ideal ratio and level of every individual in the population. Thyroid hormone setpoints are highly individualized in health. Description is not a prescription, but it is a point of reference for large populations.
The range of FT3:FT4 ratios found in healthy people, from 0.20 to 0.50, will likely result from
Lower ratios (closer to 0.20) anchored to high-normal FT4 levels (22 pmol/L) and
Higher ratios (closer to 0.50) anchored to low-normal FT4 levels (10 pmol/L)
These reciprocal relationships exist because D1, D2, and D3 enzymes can shift their activity to prevent excess and deficiency.
Low or low-normal ratios are more likely to be associated with pathology throughout the FT4 range.
In untreated people with healthy thyroid glands, low ratios are more likely to be caused by metabolic dysfunction during illness, in the presence of a normal TSH. If low ratios are chronic, they can perpetuate illness.
During illness, a higher rate of T3 losses will occur in spite of higher FT4 in blood, yielding a lower ratio. A higher FT4 downregulates D2 and upregulates D3, while a lower FT3 and excess RT3 downregulates D1 enzyme.
Low ratios, therefore, often induce tissue hypothyroidism while high FT4 can cause excessive T4 signaling at the integrin receptor on the cell membrane.
High or high-normal ratios are more likely to be ambiguous in their outcome. This is because the human body is equipped with D3 deiodinase enzyme, which is triggered by higher FT3 levels and is capable of converting excess T3 to inactive forms of T2.
The enzyme D3 is apparently not inactivated by extremely high levels of thyroid hormone substrate, but its activity is upregulated in states of T3 excess such as Graves’ hyperthyroidism, where one sees higher levels of RT3 than those found in critical illness.
Isolated high FT3 is more vulnerable to D3 inactivation than when FT4 is also elevated. When the burden of T4 inactivation is reduced by lower FT4 level (T4 is normally the more abundant hormone), D3 enzyme can then focus more of its activity on deactivating the isolated elevated FT3.
FT3 may still be deceptively elevated in blood due to excess T3 secretion, but unseen by assays, high rates of T3 inactivation in cells can prevent too much T3 from flooding nuclear receptors in cells. Only by measuring T2 levels and by measuring T3-sensitive biomarkers can one estimate the global and tissue-specific rates of T3-T2 inactivation.
2. Cellular perspective
“Cellular T3 (derived from x% FT4) + FT3” yields a general estimate of supply of T3 hormone to receptors in cells throughout the human body.
The “x%” conversion rate is a variable rate of global T4-T3 conversion.
Unfortunately, “x%” can only be an estimate. The conversion rate is not entirely predictable across healthy human beings because various health factors shift D1, D2 and D3 enzymes’ relative activity in converting thyroid hormones.
The complex synergy between T4 and T3 thyroid hormones, along with their very different signaling pathways, prevents anyone from doing simple math with a single, static conversion rate at all times.
For example, in the most famous kinetic study, Pilo et al, 1990, the researchers found
An estimated average of 27.3% of the T4 supply converts to T3 every day in 14 people with a TSH between 1-2 mIU/L
Yet the research team found a range of estimated T4-T3 conversion rates from 16.9 to 42.9%.
There is no static 80/20 rule of 80% of daily T3 supply derived from T4-T3 conversion, despite common statements found in scientific articles. The estimate is derived from Pilo and team’s 1990 average and from earlier studies that influenced Pilo. However, the daily T3 supplied by healthy T4-T3 conversion rate varied widely from 58% to 93% across the 14 healthy humans (Pilo et al, 1990)
The average rate is non-representative. The distribution of T4-T3 conversion rates and T3 secretion rates across the 14 healthy people was rather random. The lack of a strong central tendency in Pilo’s data set means it’s inappropriate to use the statistical average as a representation of “the” healthy or ideal conversion rate in all human beings at all times.
A healthy range of variable T4-T3 conversion rates exists in the thyroid hormone economy for very good reasons:
Human diversity in metabolic demand. Each person’s metabolic setpoint for thyroid hormone supply is unique and differs from another healthy person’s.
Fluctuating demands over time. As a person goes through life, metabolic stresses shift metabolic demands and therefore, we need flexible hormone supply rates and metabolism rates over time, as well. Pregnancy is an illustration.
The healthy thyroid gland flexibly compensates for T4-T3 conversion shortfalls. Variable TSH-stimulated T3 secretion rates and T3:T4 secretion ratios will “top up” the individual’s T4-T3 conversion rate to meet their metabolic demands for bloodstream supply of both hormones (See our research review, “Thyroid T3 secretion compensates for T4-T3 conversion.”)
Pharmaceutical equivalence is different from a FT3:FT4 ratio.
One cannot say that 3 units of FT4 is always equal to 1 unit of FT3, even though two thyroid hormone pharmaceuticals absorbed via GI tract yield a 3:1 ratio as the most accurate average estimate of equivalency. Pharmaceutical equivalence in terms of micrograms of dosage is very different from the hormones’ metabolic relationship as FT3 and FT4 concentrations in blood (See L-T3 pharmaceutical equivalency, Part 2: New thyroid science).
Summary of applications
Most of this article focuses on norms that are useful for diagnosis, before therapy.
Diagnosis is a necessary phase before treatment, and that’s where the un-treated population’s norms and averages belong.
Diagnosis is enabled by understanding the average and wide range of human diversity prior to intervention.
Knowing the norms helps us gain insight into the normal operation of the thyroid hormone economy.
Knowing the averages and ranges helps one distinguish a healthy individual difference from the average from one or more pathological disabilities that require intervention.
However, thyroid function goes far deeper than biochemistry. Thyroid science is about understanding the physiology and microbiology that drives the biochemistry, and how the biochemistry drives signaling. Thyroid biochemistry is just one of the “Four definitions of thyroid status.” It is one aspect of a larger system that creates, modifies, and uses thyroid hormones.
Once a diagnosis is made and verified, with the aid of the FT3:FT4 ratio, the journey of treatment has begun to find the individual’s optimal FT3:FT4 ratio.
A healthy, optimal FT3:FT4 ratio is individualized. Just as the “normal” ratio “in large populations” is not the prescription for the healthy individual within that population, it is especially not the prescription for the thyroid-disabled, pharmaceutically-supplied individual.
A diagnosed, thyroid-hormone-treated individual thyroid patient is part of a very different population. It is fundamentally different because their hormones originate, in whole or in part, from a different supply (pharmaceuticals), and their unique type of thyroid disease and its treatment must compensate for metabolic handicaps and often a distorted TSH response to their thyroid hormone ratios.
See more discussion in the final sections below titled “Applications ….”
Why the ratio is only between Free hormones
Only Free T3 and Free T4 can be used in the calculation of this ratio, because only Free (unbound) hormones can be transported into cells where conversion occurs via D1, D2, and D3 throughout the body.
It is metabolically irrelevant to make a ratio between Free T4 and Total T3, or between Free T3 and Total T4.
In addition, the ratio between Total T3 and Total T4 will be very different because the ratio of bound to free differs greatly between T3 hormone and T4 hormone, and because binding to transport proteins increases as hormone levels rise. The HPT axis adjusts thyroidal secretion to maintain Free hormone concentrations as Total rises (as Total T4 rises in pregnancy, while Free does not rise as high).
Gullo et al’s ratios and reference range
The health status of the study population
Click to expand section
In Gullo’s study, the health of the control group was described:
“Clinically euthyroid subjects with serum TSH<0.4 or >4.0 mU/L were excluded under suspicion of subclinical hyper- or hypothyroidism.
Subjects positive for anti-TPO and/or anti-Tg antibodies and/or with hyperechogenicity or pseudo-nodular pattern at thyroid ultrasound examination were also excluded.
As [the data set was subdivided] for athyreotic patients, also subjects in this group were subdivided by gender (F = 3,224, M = 651) and age (2,927<60 y and 948≥60 y).
None of these control subjects had ever been treated with thyroid hormones or antithyroid drugs.”
The average FT3:FT4 ratios
In Gullo’s Table 2, the TSH reference range was divided into 5 levels. At every level, the controls’ FT3:FT4 ratio was 0.31 to 0.33 pmol/L.
The FT3:FT4 ratio’s reference range
The FT3:FT4 ratio was given a reference range and population average in Gullo et al, 2011 in pmol/L, where the 3,875+ untreated healthy controls were contrasted with 1,811+ treated patients.
Gullo’s healthy controls’ mean was 0.32 (IQR 0.27–0.37) pmol/L in a reference range from 0.20 to 0.50 pmol/L, while the LT4-treated patients had a lower ratio represented by the skewed standard deviation curve.
Strich’s 2016: Effects of age on FT3:FT4 ratio
This study was conducted in Israel using data from 527,564 blood samples between January 2011 and September 2013, which were all tested on the same commercial immunoassays “Cobas kits used on modular analytics E-170 analyzer, Roche Diagnostics.”
They then excluded 422,012 samples that were excluded “due to lack of one parameter, mostly FT3.”
First, a caution: There’s a temptation to presume that a lower FT3:FT4 is “healthier” just because it is “normal” for older people. However, compare the decrease seen in the first table with the lack of a ratio decrease in the final table, which shows data only among those with normal body weight for their age and sex.
The health status of their study population
Click to expand details
Exclusion criteria were:
No samples with positive titres of anti-TPO or anti-TG antibodies often found in autoimmune thyroid disease.
No samples in patients treated with levothyroxine (L-T4) thyroid hormone, anti-thyroid medications (methimazole, propylthioracil / PTU), recombinant thyrotropin (pharmaceutical TSH injected before radioiodine ablation), all antiepileptic drugs, lithium, or glucocorticoids.
No samples that had TSH above 7.5 or below 0.2 mIU/L. This removed those most likely to be ill or to have permanently altered thyroid physiology (“virtually all patients between the upper normal limits and this level have been shown to revert back to ‘normal’”). The expanded range permitted some TSH levels beyond the statistical reference range to reveal the influence of lower and higher TSH levels.
After all exclusions, the main data set included all three hormone levels for 27,940 persons, including 10,227 males and 17,713 females. Most of the samples were from younger people, and the full age range was from 1 year to 110 years with a mean of 24.07 ± 16.25 years old.
Table 1: Full data set by age
Notice that the decades of age are distributed unevenly. They are in 10-year age groups until age 40, but the age groups 40-60 and 60-80 each cover 20 years of age. Given their full data range cited above, the >80 category includes persons up to age 110.
The FT3 and FT4 were both higher in younger children. Human development apparently demands more thyroid hormone in circulation.
The FT3 is the only perfectly linear data set, significantly decreasing with age.
Within each decade, until 60 years of age, as TSH increased from Q1 to Q4, the FT3:FT4 ratio also increased.
However, after 60 years of age, the increase in TSH did not always result in an increase in ratio.
Anomaly: Age 60-80 in TSH Q1 stands out as an abnormally high FT3:FT4 ratio amid lower ratios.
Table 2: Ratios analyzed
Another table provides further statistical insight into this data set, revealing the strongest trends across age groups and ratios:
The FT3:FT4 ratio remains almost steady per decade on average between ages 20 and 80, except for a mild dip in the 40-60 age range category.
The FT3:FT4 ratio is high in youth and low in age, mainly because of the influence of TSH on the ratio.
The most perfect trend exists between TSH and the FT3:FT4 ratio, which expresses the way in which TSH enhances the FT3:FT4 ratio in blood more strongly in youth than in age.
Strich and team’s analysis noted that
“In the pediatric and young adults, until age 40, there was a positive and significant correlation between TSH and FT3/FT4 ratio (r = 0.08; P < 0.001), but in the older groups, this correlation decreased to nil as age increased (from 0.04 to −0.08)
This trend, i.e. the decreasing correlation with age was linear and significant (r = −0.94, P = 0.02)”
The TSH-FT3 trend only applies to age 60.
Strich and team write about the positive linear correlation, excluding the point at which it turned into a negative correlation:
“Until 30 years of age, there was a significant positive linear correlation of TSH with FT3 (r = 0.14; P < 0.001), while in the above 30 groups, no positive correlation was noted.”
They omitted the observation of the negative trend from age 30-40 to 40-60.
The heat map reveals no trend in the TSH-FT4 relationship across all the decades, only a fall in the 40-60 age category.
However, Strich and team make this odd observation:
“There was a negative correlation between FT4 and TSH (r = −0.02, P = 0.01) up to age 80.”
This reveals the research team’s desire to overemphasize a correlation between TSH and FT4 across the decades where the correlation is weak. Notice that the “r” value of -0.02 is very far from anything (the value r = 1 means a perfect positive correlation and the value r = -1 means a perfect negative correlation), and therefore giving the “p” significance level for this nonsignificant correlation is pointless.
As for the influence of gender, the researchers write:
“In general, both FT4 and FT3 are slightly lower among females for each TSH quartile (data available upon request).”
No tables are provided, but Gullo’s 2011 data set reveals that the “slightly lower” levels and ratio are a very slight difference across the sexes (for example, 0.31 versus 0.32). It is not worth one’s time to request the data.
Strich’s data set only with normal BMI
Next, Strich and fellow researchers focused the data set only on the subgroup with normal BMI (body mass index). They did this “because of reports that these parameters can affect the thyrotropin–thyroid axis,” citing several prior studies.
Indeed, obesity and metabolic syndrome can influence TSH-FT3-FT4 relationships significantly (Wolfenbuttel et al, 2017). In addition, unhealthy aging may involve muscle wasting and loss of bone mineral density along with other illnesses and lower levels of physical activity.
In this “healthier” data set, there was no longer a decline in the FT3:FT4 ratio after the age of 20.
The odd anomaly in the TSH Q1 of the age group 40-60 years of age was greatly minimized.
Strich’s discussion section provided insights into the normal HPT axis’s “effect of increasing TSH on FT3/FT4 ratio”:
“We have previously suggested that this phenomenon could be an in vivo reflection of the previously reported increase in the in vitro activity of deiodinases in response to increasing TSH concentrations.”
In other words, previous laboratory bench studies (in vitro) on tissues revealed that deiodinases D1 and D2 increase activity in response to increasing TSH concentrations, and this new data shows that the TSH effect on FT3:FT4 ratio exists in living organisms as well.
As for the influence of age, Strich and team reason that if rat studies represent the same phenomenon in humans, it is likely largely due to D1 decreasing with age, not receptor sensitivity decreasing with age:
“In aging rats, there are data showing a decline in the activity of type 1 deiodinase [D1] but no similar decline in thyroid hormone receptor expression or activity.”
A critique of Strich’s interpretations in the discussion section
This is a digression. Click to reveal if you are interested.
The research team makes puzzling and contradictory observations about the decrease in FT3:FT4 ratio in aging.
People from families with longevity, as well as older people in good health, often have a higher TSH and lower FT3 and FT4 levels. Therefore, Strich and team observe that
“If reduced metabolism is in fact a protective mechanism, it may explain why people who have lower FT4 and FT3 and also have a lower FT3/FT4 ratio are still alive at an older age.”
However, the data set with normal BMI shows no significant reduction in FT3:FT4 ratio after age 20. This removes the need for any hypothesis about reduced metabolism being “a protective mechanism.”
Why imply that a low FT3:FT4 ratio is protective?
Strich correctly note that in other studies of fetal tissues and damaged tissues deiodinase type 3 (D3) is upregulated.
However, they then gently imply that because this D3 deiodinase “protects fetal tissues,” it is also protecting damaged tissues and elderly people’s tissues:
“This deiodinase degrades T4 intracellularly to reverse T3, and one could speculate that increasing degradation of this type with age would dampen the effect of TSH on the FT3/TF4 ratio because more T4 is degraded to reverse T3 instead of to T3.”
There is no need to imply that TSH’s effect needs to be dampened in age, because
Again, the FT3:FT4 ratio did not decrease in age in populations with normal BMI.
Also, a higher FT3:FT4 ratio is not damaging in young people who have very high ratios.
And, as mentioned above, healthy elderly persons do not have damaged tissues to protect with a lower ratio.
The direct opposite of the idea that a lower FT3:FT4 ratio is “protective” outside of fetal life is found in other research. Consider the association of low T3 syndrome (low FT3:FT4 ratio and high RT3) with high rates of morbidity and mortality in almost every type of chronic disease (Bianco et al, 2019; and see “Ataoglu: Low T3 in critical illness is deadly, and adding high T4 is worse.“).
Doctors must learn how to distinguish between acute and chronic low T3. Different conditions apply to the often inevitable and temporary low T3 state in the “acute” phase of nonthyroidal illness syndrome (NTIS) and the pathology of “chronic” low T3 in a state of nonthyroidal illness (Van den Berghe, 2014).
Reading the insights from Van den Berghe and others regarding NTIS recovery leads to a more rational conclusion: When the body is ready to recover, if either the TSH fails to rise, or a rising TSH fails to stimulate replenishment of FT3 from the thyroid (long before RT3 levels fall and metabolic imbalance is corrected), then the health outcomes are dismal. Essentially, the body’s failure to recover adequate FT3 and FT3:FT4 ratios when the body requires FT3 to heal its tissues is seemingly what prevents recovery of tissues.
Other research directly contradicts the implication that “damaged” tissues in diseases like cancer are protected by lower T3 levels binding to receptors in cells. Higher-normal levels of RT3 and FT4 can send signals on a very different receptor on the cell membrane, the integrin receptor, and there they can cause cancer to proliferate (See “Cancer scientists point finger at T4 & RT3 hormones.”)
Based on the deeply discerning level of cancer-thyroid research by Davis and team, one must learn to distinguish the genomic receptor signaling of FT3 in the nucleus, which is often benign, from FT4 and RT3 non-genomic signaling at the cell membrane, which can become pathological under certain states of illness.
This study did not calculate each person’s FT3:FT4 ratio and then average the ratios. Therefore, what you see below is a “ratio of averages,” rather than a true “average ratio.”
Nevertheless, perhaps because the results included so many individuals, the mathematical calculations of the “ratios of averages” appear to map on to Gullo’s and Strich’s data quite well.
The health status of the study population
Click to reveal section
The only exclusion was persons treated with levothyroxine (LT4).
This was not a healthy cohort, because they desired to discover associations with prevalence rates of cardiovascular disease and other chronic conditions itemized in their appendix.
However, their use of the reference range boundaries enabled the data set to exclude high and low values.
The normal quartile values are highlighted in the table below.
Ratios of average FT3 and FT4 across normal quartiles
Their raw unadjusted data set revealed the way in which using TSH levels as a lens usually results in flattening the FT3:FT4 ratio within each quartile (middle row).
Ratios in the middle row, Normal TSH quartiles:
TSH in Q1: Lowest TSH in reference, ratio normal
TSH in Q4: Highest TSH in reference, ratio normal
In the middle row, the average TSH per quartile ranged widely, from 7% to 74% of reference (67% variation), since the range of TSH was the basis on which the quartiles were formed. However:
FT4 varied little across the row, only decreasing from 37% to 27% from Q1 to Q4 (10% variation), hardly changing at all from Q2 to Q3.
Likewise, the FT3 varied even less across the row, from 23% to 17% from Q1 to Q4 (only 6% variation), hardly changing at all between Q1 and Q3.
Thirdly, the ratio of average FT3:FT4 held almost constant across the row, from 0.33 to 0.34. This is because the ratio of the average FT3 and average FT4 conceal all distinctions among individuals and the true range of ratios within each quartile.
Anderson’s ratios beyond the TSH normal quartiles
Click to reveal if you are interested.
The low TSH and high TSH levels both had higher FT3:FT4 ratios. This is because the most common cause of hyperthyroidism, Graves’ disease, has the TSH-receptor stimulating antibody (TSAb). The TSH may be low or absent, but the TSH receptor is not empty. In fact, it is the opposite. The TSH receptor is bound to an antibody that can be more potent than TSH itself. The antibody elevates the FT3:FT4 ratio in blood and lowers TSH secretion rates. (See Research: TSAb antibody and TSH)
As you can see, when you view the data set through the lens of FT3 or FT4 quartiles, a wider range of FT3:FT4 ratios will appear.
The top row, FT4, has the widest range of FT3:FT4 ratios within the normal range. This is largely because of two principles in thyroid biology:
Deiodinase type 2 (D2) is less efficient at converting T4 hormone to T3 when it is abundant in bloodstream, and is more efficient at conversion when T4 levels are lower, due to the vulnerability of D2 enzyme to “ubiquitination.” (See a review at “Ubiquitination: The glass ceiling of T4 monotherapy.”)
TSH generally has an inverse relationship to FT4 but not to FT3. When FT4 is low, TSH rises to add TSH-Receptor stimulation to the thyroid gland, thereby enhancing the ratio of T3:T4 secreted by the thyroid gland, as explained above.
Again, the High TSH and High FT3 categories have high FT3:FT4 ratios because TSH-receptor signaling levels are high in Graves’ hyperthyroidism despite lower TSH concentrations of TSH, as explained above.
How to convert American units to pmol/L
Anderson’s data set was measured in American units. It was converted to pmol/L before dividing the average FT3 by the FT4 to enable comparison to Gullo’s FT3:FT4 reference range.
Free thyroxine (FT4) Result in ng/dL x 12.871 = result in pmol/L
Free triiodothyronine (FT3) result in pg/mL x 0.0154 = result in pmol/L
The conversion rates are different for FT3 and FT4 because American units are in weight per volume, but pmol/L is a chemical unit of measure, based on the size of the molecule. FT4 is a bulkier molecule with 4 iodine atoms while FT3 has only 3 iodine atoms.
Are today’s FT3 and FT4 laboratory tests precise and reliable enough to yield this ratio?
Yes. Most manufacturers’ FT3 immunoassays are trustworthy for routine clinical and diagnostic purposes, especially when one understands the test’s technical performance when compared with FT4 assays.
Naive critics often fail to distinguish between technical precision and reliability on the one hand, and poor standardization among manufacturers and methods on the other hand.
The research on FT3:FT4 ratios above has been done using different standard immunoassays (Gullo used an unnamed assay in Italy; Strich used Roche; Anderson used Abbott) and despite their various technical shortcomings, they are remarkably in concordance with each other.
For advanced readers: Click to expand
According to an international committee that assessed standardization of thyroid hormone assays after the newer immunoassays were in circulation, both FT3 and FT4 assays are approximately equal in reliability and precision.
However, the assay manufacturers have not yet calibrated their absolute results to the gold standard LCMS method. (Thienpont et al, 2010). They usually vary less than 11% from the standard assay for calibration, and <11% is the target.
“Correlation coefficients to the cRMPs [conventional reference measurement procedure] ranged for FT4 (FT3) from 0.92 to 0.78 (0.88 to 0.30).
Within-run and total imprecision ranged for FT4 (FT3) from 1.0% to 11.1% (1.8% to 9.4%) and 1.5% to 14.1% (2.4% to 10.0%), respectively.
Approximately half of the manufacturers matched the internal QC [quality control] targets within ~5%”
(Thienpont et al, 2010)
The assays with lower means will normally have a lower reference range to suit each manufacturer’s technological bias. Assay-specific reference ranges are necessary to prevent inaccurate diagnosis.
Of course, the FT3 assay is more likely to be biased too low on the low end of reference when samples from unhealthy people (with nonthyroidal illness and persons on levothyroxine (LT4) monotherapy) are included in the calculation of reference ranges.
However, the use of anonymous or insufficiently screened samples is an error in the laboratory’s reference range research methodology, not a problem with the technical quality of the assay.
Another protection against assay bias is a clinician’s knowledge. A physician should be aware of the extremely tall and non-skewed curve of healthy FT3 values (almost 50% of healthy people are near mid-range) and FT3 values by age (see Strich et al’s data above). This knowledge can aid in interpreting low-normal FT3 values as unusual for a person’s age and concurrent FT4 level.
To assess the quality of FT3 and FT4 assays, one can also look at the methods sections of research articles that rely on these assays. Responsible researchers using FT3 and FT4 assays, such as those by Hoermann and team, will always report on the reliability and precision of their FT3 assays. They generally find them to be of good quality in comparison to FT4 and TSH assays.
Given the relatively equal quality of the two assays across many manufacturers, if one trusts FT4 to assist in diagnosis when TSH is in the subclinical zones, one should also trust the FT3 assay to refine diagnosis and to adjust therapy.
When measuring FT4, it makes sense to test Free T3 so that a metabolically meaningful ratio can be calculated.
Thienpont and team concluded, for both Free T4 and Free T3 assays,
“a majority of assays had acceptable quality of performance when measuring samples from nondiseased individuals;
however, some assays would benefit from improved precision, within-run stability, and between-run consistency.”
Therefore, despite the “acceptable quality,” improvements are still necessary.
As the nightly peak is reached in TSH levels, the FT3 echoes its rise, achieving the highest FT3 levels while we sleep. The rise in FT3 in the hours before rest and the high FT3 levels at night work in synergy with many other hormones that peak at these times in the 24-hour cycle. (People who dose thyroid hormones either lack a FT3 rhythm, or have a different rhythm based on dosing times.)
In the healthy HPT axis, FT3 drops in the morning hours, but the change during these hours covers a very small percentage of the FT3 reference range.
Naturally in people with healthy TSH-driven thyroids, the FT3:FT4 ratio is higher during the night than it is during the day. However, the ratio used in clinical practice and research is based on daytime measurements during laboratory hours.
Stability of FT3 over longer periods of time
Abdalla & Bianco (2014) point out the stability and precise adjustment of T3 levels over days, weeks and months in healthy people, a stability that is more remarkable than it is for TSH and T4:
Serum TT3 and FT3 exhibit minimal circadian rhythmicity that is due to a nocturnal increase in TSH secretion.
Otherwise, serum T3 is remarkably stable over periods of days, weeks or months in healthy adult individuals, despite a relatively short half-life (approximately 12–18 h).
The healthy human body optimizes its individualized FT3:FT4 ratio along with its levels of FT3 and FT4 within a very narrow band within the reference range.
In the bloodstream, the ongoing rate of T4-T3 metabolism and transport will add FT3 to the supply from variable secretion rates and ratios from the thyroid gland, plus any pulsatile absorption from daily hormone dosing.
As TSH rises, the stimulation of a thyroid increases, and the levels of FT3 and FT4 as well as the FT3:FT4 ratio normally rise (T3 rises more than T4 does) in a state of gland health and metabolic health.
For advanced readers: Click to expand
Two things happen in healthy thyroid tissue as TSH rises:
TSH-receptor stimulation in the thyroid gland also stimulates D1 and D2 enzymes that convert T4 to T3 as blood flows through thyroid tissue.
When these two rates (synthesis + internal thyroid hormone conversion) are combined, it yields the “secretion ratio” of hormones released from the thyroid gland into circulation. By this means, TSH stimulation increases the T3:T4 ratio produced per unit of TSH, enhancing FT3 in blood. (Laurberg, 1984)
This T3 boosting function of TSH in the thyroid gland is called the “TSH-T3 shunt” (Berberich et al, 2018).
TSH-receptor signaling also simultaneously enhances the D1 and D2 enzymes found throughout the rest of the human body, since these enzymes are expressed to varying degrees in every organ and tissue.
The widely variable rate and ratio of thyroidal secretion is what enables the human body to maintain and recover individually-customized, steady optimal FT3 levels and FT3:FT4 ratios in blood day to day, week to week, and month to month despite metabolic challenges, except for periods of severe illness.
The thyroid gland’s secretion flexibility within the TSH reference range is wider than many scientists have believed. The widespread, often un-cited mantra of the thyroid gland secreting only 20% of a person’s daily T3 supply, and of the thyroid gland secreting a 16:1 ratio of T4 to T3 in mcg/day (or 14:1 molar ratio), is based on a gross misinterpretation of the data in the main source, Pilo et al, 1990, that provided these average ratios in 14 subjects who had a TSH between 1 and 2 mU/L. (See a science-based critique of this idea of a single healthy ratio in our post “Meet a person with the perfect T3:T4 thyroid secretion ratio“)
More than one research study during the early era of intense “kinetic” studies of thyroid hormone economy show that thyroidal T3:T4 secretion ratios as well as rates vary widely among healthy individuals. (Laurberg et al, 1984)
This flexible ratio of secretion enables the thyroid gland to lead and support recovery from nonthyroidal illness syndrome (NTIS). During recovery, TSH can rise temporarily above reference range to replenish normal hormone supply before normal deiodinase function is re-established (Bacci et al, 1982; Brent et al 1986; Feelders et al, 1999).
How can the FT3:FT4 ratio enable the calculation of global T4-T3 conversion rate?
The bloodstream FT3:FT4 ratio reflects not only T4 and T3 supply but also the net product of different rates of T4-T3 conversion in tissues and organs throughout the body, including thyroid gland tissue.
The global rate of T4-T3 conversion is reflected in the FT3:FT4 ratio. No other biomarker yet discovered can come closer to assessing the status or bias of overall thyroid hormone metabolism.
For advanced readers: Click to expand
First, unbound (free) FT4 and FT3 are carried into cells on a wide variety of transporter proteins.
Next, T4-T3 conversion occurs inside cells that express D1 or D2 enzyme. In cells that express D1 or D3 enzyme, T4 can be converted to RT3 and T3 can be converted to inactive forms of T2. (D1 can perform both metabolic actions.)
After binding to receptors, or failing to bind to them, thyroid hormones are continually being transported out of cells at the same rate that hormones enter the cell, to keep equilibrium within the cell and surrounding tissues and blood (Bianco et al, 2019).
In this way, cells “donate” much of their metabolized thyroid hormones back to the bloodstream, along with any T3 and T4 that was not transformed by a deiodinase while flowing through the cell.
The 2-way exchange of hormone between bloodstream and cells happens every minute of every day, but some tissues may exchange hormone at a slower rate (bones, for example).
Each tissue in the body converts T4 and T3 at different rates to adapt bloodstream hormone levels to that tissue’s current metabolic needs. Some tissues are more efficient at converting FT4 than others that depend more on FT3 supply.
The FT3:FT4 ratio can be used to calculate a more refined result than the ratio itself, called “Global Deiodinase efficiency” (GD), using the free SPINA-Thyr endocrinology research application (Midgley et al, 2015; Dietrich et al, 2016; See an overview of the program: “Analyze thyroid lab results using SPINA-Thyr.”)
The “GD” quotient is based on the understanding that there is a continual two-way exchange of circulating thyroid hormones with cells that metabolize thyroid hormones throughout the human body, and a clearance rate and hormone binding rate that corresponds to the level of thyroid hormones in blood.
Differential diagnoses enabled by the FT3:FT4 ratio in light of TSH
When healthy thyroid tissue expressing D1 and D2 is present, a higher TSH usually enhances the T3 side of the FT3:FT4 ratio.
Before treatment with thyroid hormone, when a normal or high TSH does not result in the normal or elevated FT3:FT4 ratio expected, something is amiss with
thyroid gland function,
poor D1 or D2 deiodinase function or elevated D3 deiodinase, and/or
poor TSH hormone quality or TSHR signaling interference.
As for TSHR signaling interference, TSH concentrations in blood do not always correspond with the rates of TSH-receptor (TSHR) signaling because substances other than TSH, like TSH-receptor antibodies, can bind to the TSHR and boost or invert its signal.
Not just TSH concentration, but TSH-receptor signaling, influences the FT3:FT4 ratio.
When the FT3:FT4 ratio is inappropriate to TSH concentrations, the mismatch enables further diagnostic discernment of abnormalities in thyroid hormone supply and the TSH secretion’s response to that supply.
Autoimmune hyperthyroidism, or…?
An inappropriately normal or low FT3:FT4 ratio in the presence of low or suppressed TSH can distinguish special forms of hyperthyroidism that do not elevate the ratio from the more common forms that do.
Graves’ TSH receptor-stimulating antibodies have the unique ability to enhance D1 deiodinase (most dominant in thyroid, liver, and kidney) (Chen et al, 2018) via enhanced TSHR signaling, even when TSH is absent from circulation. Patients with T3-dominant ratios are more likely to have not only higher titres of TSAb but also lower or absent concurrent titres of blocking antibody TBAb (McLachlan & Rapoport, 2013).
Autonomous functioning thyroid nodules can elevate the ratio, as well (Wong & Volpe, 1981; Ridgway et al, 1973), even when TSAb antibody is not present.
“Subclinical” hypothyroidism, or…?
An inappropriately normal FT3:FT4 ratio in the presence of mildly elevated TSH can distinguish early thyroid gland failure from central hypothyroidism or less bioactive forms of TSH. These other forms of hypothyroidism may require further investigation to prevent other health problems.
During early thyroid failure in Hashimoto’s thyroiditis, elevated TSH secretion will raise the FT3:FT4 ratio significantly via T3 synthesis and upregulation of D1 and D2 in remaining functional thyroid tissue (Hoermann et al, 2020). If the FT3 is enough to compensate for the lower FT4, the patient may remain without hypothyroid symptoms until the gland is further damaged.
In central hypothyroidism of the tertiary (hypothalamc) variety, the quality of TSH is compromised by low hypothalamic TRH secretion or the inability of the pituitary to receive TRH signals (Persani et al, 2019). See “Why is central hypothyroidism so difficult to diagnose?” Such patients require investigation of other hypothalamic and pituitary hormone deficiencies that can cause health problems beyond hypothyroidism.
Macro-TSH, anti-mouse antibodies and IgG-associated TSH have been found in cases of TSH over 2.5 mU/L among infertile women. (Hattori et al, 2018). These cases may have been infertile due to insufficient thyroid gland stimulation and lowered hormone secretion.
Hashimoto’s thyroiditis or …?
An abnormally low or normal FT3:FT4 ratio in the presence of extremely high TSH > 80 mU/L can distinguish Atrophic thyroiditis and/or Blocking hypothyroidism (caused by the TSH-receptor blocking antibody, TBAb) from pure Hashimoto’s thyroiditis without TBAb titres.
In “Blocking hypothyroidism” (Tagami et al, 2019), high levels of TSH may be unable to stimulate even a fully healthy thyroid gland (revealed by ultrasound) to secrete enough T4 and T3 hormones, resulting in an abnormally non-elevated FT3:FT4 ratio.
Diagnosis affects treatment because some cases of blocking hypothyroidism may lead to full remission shortly after treatment, and antibodies may later return or fluctuate between stimulating (Graves’ hyperthyroidism) and blocking hypothyroidism , potentially causing unstable thyroid therapy (Takasu et al, 2012). This potent, volatile form of thyroid autoimmunity remains largely undiagnosed in a significant population of “Hashimoto’s” patients (For numeric estimates, see “Overlooked: How many Hashimoto’s patients with TSH-Receptor antibodies?“).
FT3:FT4 ratio is lowered in TBAb antibody activity because TSH receptor stimulation is not just blocked but lowered below baseline TSHR signal levels, downregulating D2 and D1 enzymes in the pituitary, in the thyroid, and throughout the body. The TBAb antibody is a TSH-receptor “inverse agonist” not just an inert receptor blocker (McLachlan & Rapoport, 2013).
The FT3:FT4 ratio supports antibody detection because many newer TRAb antibody tests are methodologically unable to report the titre of TBAb blocking antibodies when they are present alongside or instead of TSAb antibodies (McLachlan & Rapoport, 2013; Lytton et al, 2018).
Ultrasound thyroid measurements, lack of goiter, and unreasonably fluctuating TSH-FT4 relationships also confirm diagnosis. The antibody can even prevent goiter (thyroid swelling) normally seen when TSH is elevated, but cases with goiter are more likely to lead to remission (Takasu et al, 2012).
Learning about FT3:FT4 ratios requires more than understanding and imitating population norms and averages. The science of the normal ratio is just a starting place.
The key is in the title of this post: “Large populations” have a pattern that enables diagnosis.
The normal pattern and range exists because of normal thyroid physiology and normal cellular signaling pathways.
Diagnosis is about understanding which aspects of the normal system have failed. However, diagnosis does not tell us the way back to health.
Description of a healthy population is not a prescription for a healthy individual.
Even though average FT3:FT4 ratios exist in large, healthy populations when viewed through the lens of TSH quartiles, optimal thyroid hormone levels, if not FT3:FT4 ratios, are diverse for each thyroid-healthy individual in the untreated population (see “Individual thyroid ranges are far narrower than lab ranges“)
In addition to an optimal ratio, we each have an optimal level of T3 receptor signaling, a metabolic setpoint, even in health (Abdalla & Bianco, 2014).
The individually unique level in health is hidden behind a statistical norm.
FT3:FT4 ratios are individually optimized for each individual in health.
Biochemical norms and ranges of health are not treatment targets for individuals with variable degrees and types of disease.
Applications to thyroid therapy
Disabled individuals require more than simple mimicry of the norm or average FT3:FT4 ratio found in large untreated populations.
The existence of a norm is not a demand for the individual, and especially not a thyroid-disabled and thyroid hormone-treated individual, to imitate the statistical norm.
This is because a thyroid disability means a person lacks some of the physiological equipment to properly metabolise the average ratio in blood, and may have a disabled thyroid metabolic function.
Every cell where an antibody or genetic flaw may interfere is also a metabolic machine.
The pituitary and hypothalamus adjusts the TSH, which is not just a thyroid-gland-regulating hormone but also a modifier of thyroid hormone metabolism via TSH-receptor signaling. It is highly likely that many mild and moderate cases of central hypothyroidism (inappropriate TSH secretion) remain undiagnosed while being treated for a primary thyroid failure. (See Screening for central hypothyroidism during thyroid therapy)
At the cellular level, TSH-receptor antibodies can profoundly distort not only thyroidal secretion rates and ratios, but also the rate of thyroid hormone metabolism throughout the body.
Once these interconnected machines and signals are broken and misaligned, the body may need a different mix of fuel, a profoundly different FT3:FT4 ratio, to make the whole system function.
By analogy, “Humpty Dumpty,” the proverbial egg-man from the famous nursery rhyme, has fallen off the wall. The shell (biochemistry) is broken, but the insides are also misaligned and now incomplete or misshapen. Thyroid gland supply and metabolic machines may be missing, biased, harassed by antibodies and other diseases and their medications. Each “Disabled Humpty Dumpty” may need a newly designed shell shape (biochemical ratio and level) to accommodate and realign the interior to obtain optimal function of their unique system.
In thyroid therapy, hormones must be recalibrated and accommodated while understanding how FT3:FT4 ratios and TSH adapt to various thyroid diseases and their diverse therapies.
Click to read more therapy detailsand an example
Paradigm: normalization vs. compensation.
Thyroid treatment, after diagnosis, is not synonymous with biochemical normalization.
Therapies aim to help a body achieve better function despite the presence of a permanent functional disability. Therefore, an adaptive, beneficial therapy for an individual can look very abnormal.
Normalization hides disability from view, but does not necessarily overcome it.
Because thyroid disabilities are more complex than biochemistry, therapy is not about making a mere biochemical abnormality disappear.
The goal is not to make an individual’s lifelong thyroid disabilities and vulnerabilities invisible in a population screening test.
The goal is not to make chronic systemic diseases of the hypothalamus and pituitary gland, thyroid gland, or thyroid metabolism disappear from a country’s list.
Thyroid gland failures and metabolic disorders are just as significant as diabetes and heart disease. They must remain visible to help us diagnose and manage them wisely.
A paradigm of standardization vs. diversity
There is no single therapy that fits all thyroid disabilities. Diverse therapies shift biochemistry adaptively, so there is no single biochemical ratio that fits all thyroid-disabled individuals. Biochemical optimization is a journey, not a static endpoint.
Medicine must learn to accommodate a wide variety of therapeutic, adaptive hormone ratios that meet individuals’ needs. We cannot judge treated individuals only by biochemical population averages, nor imprison the treatments within the statistical ranges of an untreated population.
Disease and treatment can shift the range of “healthy” FT3:FT4 ratios. In a treatment for a disease, “healthy” biochemistry may be abnormal because it must be compensatory.
Sometimes treatment means overcompensation of the average FT3:FT4 ratio in one direction or another, because the main point is to get enough T3 into receptors, not just imitate a statistical norm in blood.
A disabled individual often needs crutches or a wheelchair, medications that not merely biochemically replace and imitate, but compensate for disability at a cellular level.
What requires compensation?
Each thyroid patient’s unique thyroid gland disabilities and pituitary disabilities, thyroid hormone metabolic disabilities, and concurrent chronic illnesses will change the way their bodies respond to normal, average FT4 levels, FT3 levels and FT3:FT4 ratios.
A person without a thyroid is missing the human body’s largest metabolizer of thyroid hormone.
A person with a dysfunctional pituitary is unable to boost deiodinase function by raising TSH.
A thyroid-disabled person with a set of thyroid deiodinase handicaps and thyroid hormone receptor dysfunctions is at the mercy of their pharmaceutical supply: both their dose level and their dosing ratio.
Each pharmaceutical therapy choice will entail a different ratio. The average and range of FT3:FT4 ratios of people dosing levothyroxine monotherapy will differ from those among people dosing desiccated thyroid (DTE/ NDT). Neither group’s average and range of FT3:FT4 ratios will mimic the normal average in the healthy population, yet each individual’s ratio ought to be therapeutic, compensating for their unique disabilities.
The TSH is also different in thyroid disease and therapy
A treated person’s supply of thyroid hormone and their FT3:FT4 ratio is no longer TSH-regulated, nor is it limited by the functional capacity of the pituitary gland and thyroid gland. Instead, their treatment is compensating for a permanent system failure in TSH feedforward functionality, which includes not only driving a thyroid gland but boosting deiodinases to shift thyroid hormone metabolism.
When the thyroid hormone supply is even partially replaced by a pharmaceutical source, TSH becomes functionally less necessary or unnecessary to drive supply.
TSH is not a fuel, but a functional signaling messenger that drives a natural organ of supply and central metabolism, and a messenger that tweaks peripheral metabolism.
TSH and a thyroid are not always necessary to drive hormone supply and boost metabolism, but enough T3 in receptors is always necessary to drive cellular function.
TSH plays a different role in monitoring thyroid therapy than in screening for thyroid disease prior to therapy. TSH is a signal of local pituitary thyroid hormone supply and metabolism, not a judge of global thyroid hormone supply and metabolism. In the hypothalamus and pituitary, TSH is differently responsive to a nonthyroidal, manually driven supply coming through a pharmaceutical pathway.
Disease, combined with therapeutic intervention, causes a TSH-T3 disjoint. This is a fundamental disjoint. It is a core problem that TSH (and not even TSH plus FT4) is capable of acting as a proxy for T3 sufficiency in blood, let alone T3 sufficiency in tissues beyond the hypothalamus and pituitary gland.
A person with a disabled thyroid can no longer compensate for thyroid metabolism handicaps by raising TSH and secreting a higher T3:T4 ratio. A chronic FT3 deficiency in blood can go unnoticed, hidden under a TSH normalized, lowered or even suppressed by high-normal FT4 levels.
A pharmaceutical supply is now part of the system, and it’s not a perfect thyroid gland replacement.
Thyroid hormone pills don’t come in individualized ratios,
Pills don’t deliver hormone in 24-hour sine wave rhythms,
Pills can’t automatically adapt to shifting biological demands like aging and dietary intake, and
Pills can’t metabolize themselves the way a thyroid metabolizes its own hormone products.
Since T3 takes biological priority in every organ, tissue and cell, TSH must adapt to accommodate therapy and disability.
Ultimately, the judge of appropriate FT3:FT4 ratio optimization is health. Logically, health outcomes ought to improve compared to pre-treatment, and inappropriate adjustments of the FT3:FT4 ratio and levels will cause harm to the individual.
If a therapy works well despite abnormal biochemistry, don’t try to fix what isn’t broken.
An example of compensatory therapy
Thyroid hormone therapies for the severely handicapped thyroid metabolism may need to be extreme. I offer myself as one example among many diverse possibilities.
Diagnosis: I have autoimmune atrophic thyroiditis, without any signs of Hashimoto’s. I did not have any goiter (swelling) at diagnosis with a TSH over 150. At my first ultrasound at the age of 46, my thyroid attained the shape and size of two flattened raisins (0.5 mL). I am also a very poor T4 converter with two homozygous DIO1 deiodinase polymorphisms.
Therapy challenges: Long after my thyroid’s shrinkage, likely occurring around age 30-32, my TSH receptor antibody crippled my already handicapped thyroid hormone metabolism by blocking TSH receptors located throughout my body. On LT4 therapy, my FT4 level converted at highly variable rates, yielding a continually shifting and often elevated TSH that did not correspond to FT4 or FT3. At one point my TSH was nearly suppressed by a high-normal FT4 and then rose to 18.8 mU/L after a tiny dose reduction that hardly reduced FT4 at all.
Eventually, my chronically low FT3 and a ratio as low as 0.14 pmol/L had health outcomes, after a three-year-long apparent TBAb flare. It harmed my cardiovascular health and mental health, and it was costly for my healthcare system to manage my many emergency hospital visits, specialists, and expensive tests.
Therapeutic solutions: My current T3-dominant therapy since 2016 compensates for my thyroid gland, metabolic handicaps, and autoimmune handicaps. I’m on T3 monotherapy. Liothyronine (synthetic T3) hormone dosing alone controls the supply the most active and high-priority hormone in the absence of FT4 in blood.
I don’t have a “ratio” because my FT4 is below the assay’s detection. However, to give you an idea of how high my ratio is, my optimal ratio if I theoretically had a FT4 of 1.0 pmol/L (range 10-25) would be around 6-7 pmol/L (range 3.5-6.5) when measured 12-15 hours after my most recent dose.
This form of therapy also suppresses TSH even at euthyroid, healthy T3 doses. This is because dosing causes FT3 to fluctuate, and during peak post-dose FT3 levels, the body’s metabolism prevents thyrotoxicosis by converting a significant portion of T3 hormone to TSH-suppressive metabolites such as Triac and 3,5-T2.
I have recovered from my severe health crisis of 2016 and have had good health since then, despite some problems with underdose during the first year, and underdose after a medication change, and an unsuccessful attempt to reincorporate T4 hormone into my thyroid therapy (angina-like cardiovascular pain returned). Since I am stable and well, there is no need to return to T4-inclusive therapy and risk a harmful hormone imbalance during the transition.
My experience, as well as published research and others’ clinical experience, shows that the human body can adapt and thrive by manually balancing T3 supply in the absence of T4, while allowing the body to metabolize T3 to its various byproducts.
What I’ve learned:
This TSH receptor antibody is more powerful than TSH and affects more than the thyroid. The antibody can trigger pathological signaling cascades, and cause diseases of the eyes, bones, skin, and cardiovascular system, but its manifestation differs from person to person.
The antibody can distort deiodinase function. The thyroid hormone cellular machinery can be harassed by antibodies that cannot be controlled or removed, and some antibodies (TSH receptor antibodies) harrass more than the thyroid gland.
The antibody attack can continue long after a thyroid gland is atrophied by the TSH receptor antibody, or chemically ablated by radioactive iodine, or surgically removed. There is no such thing as an antibody-ectomy.
This TBAb antibody often evades current TRAb antibody assay technologies (McLachlan and Rapoport, 2013; Lytton et al, 2018). The TBAb antibody is not part of screening or diagnosis in autoimmune hypothyroidism. Myths abound about atrophy being “end stage Hashimoto’s,” when it is not caused by the well-known TPO antibody. Based on the prevalence rates of TBAb in Hashimoto’s and Graves’ disease, potentially hundreds of thousands of cases worldwide could be misdiagnosed. As a result, thyroid therapy instability due to TBAb is often blamed incorrectly on poor LT4 absorption or patients’ noncompliance.
FT3:FT4 ratios at thyroid hormone levels need further research in relation to health outcomes.
Population averages hide individual diversity.
Research on health associations of FT3:FT4 ratios is ongoing across many disciplines, but the studies are scattered throughout medical literature and are difficult to gather.
The literature on health outcomes also has a huge blind spot: Most of the studies that associate FT3:FT4 hormone ratios with health exclude treated thyroid patients.
This neglect occurs because scientists often prefer not to explore the complexities of thyroid disorders and treatment.
However, the study of the treated, thyroid-disabled population’s FT3:FT4 ratios can give insight into how therapy-manipulated ratios can affect health outcomes.
FT3:FT4 ratio adjustment, and even the achievement of abnormal ratios, may be therapeutic in diseases beyond thyroid failure.
Thyroid hormone dosing can compensate for conditions that distort thyroid hormone metabolism and ratios without harming the thyroid gland. Therapeutic FT3:FT4 ratio adjustments could prevent crises and promote healing in many fields of medicine.
Diagnosis often entails lifelong therapy, but thyroid therapy may be beneficial even temporarily during recovery from acute conditions that are influenced by FT3:FT4 ratios.
“Optimized” FT3:FT4 ratios in therapy may need to be as diverse as the overlapping types of non-thyroidal and thyroid disabilities for which they compensate.
Not everyone has size 7 feet that fit size 7 shoes. A FT3:FT4 ratio of 0.37 may be just right for a teenage female, but it would be surprisingly high for a senior citizen.
The person with a missing leg or arm is much like a person with a missing or damaged thyroid gland. Just as a person needs more than an aesthetically pleasing prosthesis (mechanical arm or leg), a person with a disabled gland needs a customized FT3:FT4 ratio, not just a “normal” one, to fit their metabolic needs.
Even the “average ratio” found in health may be pathological for an individual thyroid-disabled person who cannot metabolize it in ways that meet their unique metabolic demands.
In all types of disease, disabled persons need as much mobility (function) and freedom from pain as possible. Sometimes that means a functional prosthesis looks very different from the original limb (a person’s pre-disease FT3:FT4 ratio and levels). Consider the unique shape and function of Terry Fox’s prosthetic limb that enabled him to perform his amazing run for cancer across much of Canada. Normalcy is not the same as functionality.
Just as disabled people deserve ramps and wider doors that respect their wheelchairs and prostheses, the normal population’s reference ranges and averages shouldn’t become the ultimate judge and the prison of treated disabled people. Often in diseases, sometimes higher doses of natural substances are needed to compensate for dysfunctions, and involving patients in the cost-benefit assessment is ethical.
Thyroid therapy history has seen too many mistakes caused by researchers and doctors forcing individuals’ TSH, FT3 and FT4 biochemistry to conform to the reference ranges found in thyroid health. They have for too long been blind to the wide range of FT3:FT4 ratios that remove symptoms and signs of hypothyroidism in thyroid-disabled individuals. The widest diversity of truly euthyroid levels and ratios exists among treated patients, and the narrowest individualized precision is nevertheless required to achieve tissue euthyroidism, both in thyroid health and in thyroid diseases. (See “Biochemical bigotry: Enforcing normalized thyroid lab results“.)
How can we use FT3:FT4 ratios? One eye ought to be on FT3-FT4 and TSH ratio-metrics, while another is on more meaningful health targets and outcomes:
Biomarkers of T3 signaling at various FT3:FT4 ratios in diverse organs including brain, cardiovascular system, kidney and liver, not just pituitary and hypothalamus;
Large-scale population studies that show measurable health outcomes of FT3:FT4 ratio adjustments during the treatment of chronic diseases.
Treated thyroid patients’ quality of life and thyroid symptom relief at various FT3:FT4 ratios within and beyond reference ranges, on all types and combinations of thyroid therapy.
There will be hope for many suffering patients when doctors are given freedom and encouragement to test FT3, FT4 and to calculate their ratio, to use the full range of thyroid pharmaceutical tools to adjust the ratio in any direction that a particular type of disease suggests, and finally to collaborate with patients in achieving better quality of life and symptom outcomes.
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