Normal FT3:FT4 thyroid hormone ratios in large populations

A normal ratio of Free T3 (FT3) to Free T4 (FT4) thyroid hormones appears to be a basic principle in thyroid hormone economy when no thyroid hormone dosing and no disease interfere.

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.

Comparing across these 3 different studies, you’ll see how amazingly consistent population average FT3:FT4 ratios are among people with healthy thyroid glands in various age and sex categories. There seems to be a standard ratio in blood while TSH is normal:

• The healthy average is approximately 0.31 to 0.34 mol/mol.

This is because the healthy thyroid, healthy pituitary, and healthy metabolism stabilize the balance of FT3 per unit of FT4 in blood.

Keep in mind, however, that these data tend to look more stable at the population level — it conceals some diversity between individuals.

Technical basics

How is the ratio calculated? One can only create a free hormone ratio when measuring both as Free (not Total T3 to Free T4).

Both must be based on FT3 and FT4 from the same blood draw.

Both ought to be measured at a single laboratory, using a standard immunoassay for FT3 and FT4 on a single platform (i.e. Siemens, Roche, Abbott, and so on).

To make a ratio within this system,

1. First, the lab results must be expressed in pmol/L. American units are in weight per volume, but pmol/L is a chemical unit of measure, based on the size of the molecule. If working with American units, The American Medical Association (AMA) conversion calculator provides the conversion factors as
   • FT4 ng/dL x 12.871 = result in pmol/L,
   • FT3 pg/mL x 0.0154 = result in pmol/L.
2. Divide the individual’s FT3 by their FT4. (5.0 pmol/L FT3 divided by 15.0 pmol/L FT4 is a ratio of 0.33 mol/mol).

Most of these studies use pmol/L. Although many research articles have used ng/dL and other units, I prefer studies that use molar units (pmol/L) for the individual blood draws.

Anderson’s data set below was measured in American units, but it is included for its rich and unique data set. It was converted to pmol/L before dividing the average FT3 by the FT4. This enabled comparison to Gullo’s and Strich’s results in pmol/L.

However, this is not ideal. Converting a population’s average ratio in ng/dL to pmol/L (to obtain a ratio of averages) is not the same as obtaining ratios in pmol/L from each individual (an average of ratios).

FT3:FT4 ratios must always be anchored in absolute blood levels. They are an assessment of global metabolic rate, not systemic hypo- or hyperthyroid status.

This example demonstrates how the same ratio may induce hypo or hyper:

• A high ratio such as 0.46 may be seen in people with untreated early Hashimoto’s hypothyroidism before treatment, when FT4 drops below range and their high TSH is stimulating the functional thyroid tissue that remains.
  • TSH receptor stimulation preferentially enhances the T3 side of the T4:T3 ratio of secretion from thyroid tissue.
  • D2 enzyme in peripheral tissues will be upregulated when FT4 is low, enhancing peripheral T4-T3 conversion rate.
• The same ratio of 0.46 may be seen in a person with untreated early Graves’ hyperthyroidism in a hypothetical person with a FT4 near the top of reference range, a high FT3, and 0.001 TSH.
  • This ratio is expected because instead of TSH hormone, TSH-receptor stimulating antibodies are hijacking TSH receptors and overstimulating the thyroid.
  • The ratio may reduce and wobble as hyperthyroidism becomes more severe and FT4 increases, because these antibodies can fluctuate wildly, and hyperthyroidism upregulates D1 and D3 enzymes at different rates in different tissues.

Caution. These ratios don’t apply during thyroid hormone treatment.

Just as the “normal” ratio “in large populations” is not the prescription for the healthy individual within that population, the “normal ratio” is especially not the prescription for the thyroid-disabled, pharmaceutically-supplied individual.

The ultimate goal of thyroid therapy is not to achieve a biochemical target established by another population’s statistical norms. Instead, the goal is to yield appropriate levels of T3 signaling in receptors within an uniquely disabled and dose-manipulated metabolic system.

During hormone treatment, a healthy, optimal FT3:FT4 ratio in blood is individualized to a person’s unique metabolic handicaps and demands.

If you want FT3:FT4 ratio statistics for diverse hypothyroid populations on LT4 monotherapy, see our other articles, such as “Are you a poor T4 converter? How low is your Free T3?.”

As for ratios in people dosing T3 hormone, we don’t have enough published population data yet to create benchmarks for FT3:FT4 ratios in desiccated thyroid or specific stable T4:T3 dosing ratios. Dose ratios and even “number of hours since dose” will inevitably influence the data. Many clinical trials of T3-inclusive therapy have measured Total T3, not Free T3. None so far have collected FT3:FT4 ratios for every individual. We need more research, and better research.

One should neither expect nor force a thyroid-disabled, hormone-dosing person to imitate the healthy average ratio of the undosed healthy population. Thyroid disease and dosing introduce significant shifts in oral hormone absorption and metabolism. The FT3:FT4 ratio and levels in blood that used to support health pre-thyroidectomy might no longer support health post-thyroidectomy. This is mainly because of 3 reasons:

1. A TSH-regulated thyroid gland compensates for — and conceals — underlying metabolic handicaps in T4-T3 conversion in tissues beyond the thyroid gland. Loss of thyroid function gradually or suddenly exposes these handicaps, which differ from person to person. See “Thyroid T3 secretion compensates for peripheral T4-T3 conversion.”
2. GI tract absorption of hormones in pulses is very different from thyroidal secretion of hormone directly into bloodstream at a gentle TSH-regulated sine wave of circadian rhythm.
   1. In people who dose T3 and/or T4, some hormone is influencing, and being influenced by, the GI tract and microbiome even before it enters systemic circulation. Researchers have only begun to study this dynamic.
   2. LT4 monotherapy creates post-dose FT4 peaks. In people without thyroid function, LT4 monotherapy obliterates the natural FT3 circadian rhythm that enables healthy people’s FT3 to rise higher at night, while sleeping.
   3. LT3 dosing creates significant, yet predictable post-dose FT3 peaks and valleys. Therefore, LT3 may be dosed and timed to imperfectly imitate circadian rhythms. The body compensates for FT3 peaks and valleys by continually shifting the metabolic rate of both T3 and T4 hormone throughout the day, as D1 and D3 enzymes are powerfully upregulated by T3 signaling.

Due to these factors, pharmaceutical dose ratios (micrograms of LT4 to LT3 dosed) will never reliably produce the same FT3 and FT4 concentrations in any group of 10 diverse hypothyroid people, and substituting one LT4 or LT3 hormone pharmaceutical with another can have a wide range of results in blood (See L-T3 pharmaceutical equivalency, Part 2: New thyroid science).

Gullo et al’s ratios and reference range

The health status of the study population

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

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.

Remarkable patterns

• 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:

Remarkable patterns:

• 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)”

Partial patterns:

• 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.

Remarkable patterns:

• 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

Anderson’s ratio of average FT3 to average FT4

In Anderson’s 2020 article, the research team’s focus was on atrial fibrillation risk at various levels of FT4, TSH, and FT3. (See our review of their article: “Anderson, 2020: Thyroid hormones and atrial fibrillation.”

Not a true “average ratio”

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

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:

1. TSH in Q1: Lowest TSH in reference, ratio normal
2. 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

This data analysis includes people who have subclinical or overt thyroid disease:

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 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 mol/mol for all four normal TSH quartiles.
• This is a very narrow average. 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 decade from childhood to advanced age, but did not change as much between age 30 and 60. But 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.

When measured in pmol/L, the ratio is consistent and comparable among three large population studies: Gullo et al, 2011’s healthy control group of 3,875 people, Strich et al, 2016’s study of 27,940 untreated patients at all ages, and Anderson et al, 2020’s appendix data set of 26, 524 patients who had all three tests, TSH, FT4 and FT3 completed.

Therefore, these FT3:FT4 ratio findings can assist in identifying metabolic dysfunctions and HPT axis interferences that may otherwise be misdiagnosed or overlooked.

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.

Metabolic principles taught by ratios

1. The FT3:FT4 ratio must always be anchored in a FT4 level.

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.

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 on some cells in tumors, blood vessels, and immune system. As of 2019, scientists have also learned that the secondary metabolite of T4, Reverse T3 (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.

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.

Are FT3, FT4 and TSH levels stable enough over time to assess this ratio?

Yes, especially if you know what time of day the TSH was tested. The TSH fluctuates far more widely than either FT3 or FT4 do during standard laboratory testing hours.

How does the body maintain or alter this ratio?

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.

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.

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.

For example,

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.

• Excess human chorionic gonadotropin (hCG) hormone stimulation of TSH receptors in pregnancy, often raises FT4 and FT3 together, or elevates mainly Free T4 (See “Pregnancy thyrotoxicosis vs just a low TSH due to hCG hormone).
• 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).

For more information, see “The Spectrum of Thyroid Autoimmunity” and “The THIRD type of autoimmune thyroid disease: Atrophic Thyroiditis“

Avoid misapplications of the FT3:FT4 ratio

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 aid interpretation and diagnosis.

After treatment, ranges should never be misused as treatment targets or treatment boundaries. Enforcing biochemical conformity on thyroid-disabled, treated people goes down the dangerous and unethical path of “biochemical bigotry.”

References