What’s wrong with calling TSH, FT3 and FT4 “thyroid function tests”?

A Google search for “thyroid function tests” brought up a definition square at the top of the search results. It says that

“Thyroid function tests” is a collective term for blood tests used to check the function of the thyroid.

A TFT panel typically includes thyroid-stimulating hormone (TSH, thyrotropin) and thyroxine (T4), and triiodothyronine (T3) depending on local laboratory policy.”

(Thyroid Function Tests, WikiDoc.)

What’s wrong with the phrase “thyroid function test”?

It tricks physicians into thinking the only purpose of TSH, FT4 and FT3 is to diagnose primary thyroid gland (dys)function.

“Thyroid function test” is a linguistic red herring. It commands you to “look over here!” (and not over there) when screening for a health problem.

This phrase puts a significant cognitive barrier in the way of analyzing test results in the normal ranges to see beyond the thyroid.

No less than three organs manage the healthy HPT axis: the hypothalamus, pituitary, and thyroid. All three of them are subject to dysfunctions, biological variations, and temporary interferences.

Fortunately, if both TSH and FT4 are performed, an expert analyst may use tools to uncover a disjoint in the TSH-FT4 log-linear relationship that can be concealed within one or both hormones’ “normal” reference ranges. That analysis may reveal pituitary/hypothalamic dysfunction or interference which would otherwise be hidden from a naive interpreter.

However, something more fundamental can go wrong than a gland failure in the HPT axis, and the TSH-FT4 analysis won’t reveal it. The most common dysfunction of thyroid hormone metabolism is called nonthyroidal illness syndrome (NTIS). This name has stuck because it is caused by severe illness and can occur whether or not a person has a “thyroidal” dysfunction. Now we know it compromises both TSH secretion and FT4 metabolism.

The metabolic derangement of NTIS occurs in a significant percentage of people with severe acute and chronic illnesses of all kinds, both in the hospital setting and in the community. Although the acute phase may be benign and inevitable, failure to recover from NTIS during illness can have deadly and costly outcomes.

Fortunately, the FT3 test and the FT3:FT4 ratio can reveal whether the metabolic derangement of NTIS is distorting TSH and FT4 data in an untreated individual with or without thyroid or pituitary dysfunction, and it can also provide information about NTIS severity and stage.

Therefore, if all three FT3, FT4 and TSH tests are performed, and if the expert analyst interrogates the hormone relationships in light of current scientific knowledge, this valuable data can give a three-dimensional view of thyroid, pituitary, and metabolic (dys)function.

Once an analyst is informed about all that these three tests reveal, they will become more aware of what testing only one or two of them will inevitably conceal.

Series summary: The three barriers

This post is part of a series on the cognitive barriers to the analysis of untreated person’s normal-range TSH, FT3, and FT4 lab data. These posts can be read in any order:

1. “Cognitive barriers to analyzing “normal” thyroid lab results“
2. “Are normal thyroid reference ranges risk-free zones?“
3. [this post]
4. “Can a normal TSH rule out thyroid disease?” Coming soon.

A cognitive bias is like a preference to go through one door rather than another.

A cognitive barrier means certain doors to deeper knowledge are locked or entirely hidden from view.

Any cognitive “bias” can become a cognitive “barrier” when it prevents one from examining the medical evidence that is right before their eyes – normal-range TSH, FT4, and FT3 lab data.

In the series introduction, I provided a comparison across medical fields. I outlined how scientists and policymakers in other diseases treat “normal range” values with great skepticism. In contrast, thyroid medicine tends to cling to the clinical and diagnostic significance of its normal reference ranges.

The first barrier (covered in the previous post) is the belief that “normal” range is a zone where thyroid hormones and TSH pose no health risk for any non-thyroidal disorders. For a long time, scientists have ignored non-thyroidal disease risk within the FT3, FT4 and TSH ranges because it is quite clear that very abnormal levels are riskier for untreated people than are normal levels, relatively speaking.

But science is now revealing that imbalanced yet normal thyroid hormones and TSH can negatively affect cardiovascular health, kidney health, liver health, and so on.

This post examines the second cognitive barrier, the common phrase “thyroid function test.” It narrows the mind by narrowing the purpose of the test. It focuses on one corner of the HPT axis, the corner that is most accessible to examination and easiest to blame.

Analyzing two or three hormones at once enables one to gain a more complete perspective, just as using two eyes instead of one enables you to judge depth and distance. In the hands of an intelligent analyst, the TSH, FT4 and FT3 tests uncover so much more information that can promote and protect health.

The third barrier (to be discussed in the next post) is the belief that a normal TSH has the power to single-handedly rule out almost all thyroid disorders — except so-called “rare” pituitary disorders and thyroid cancers. But once you’ve gotten rid of the first and second barriers, this barrier to knowledge is much easier to get out of the way.

Physiology teaches us that a normal TSH is only as effective as the FT3 and FT4 reveal it to be. A normal or abnormal TSH may either fail or succeed at maintaining the untreated individual’s healthy thyroid hormone setpoint.

To conclude, after the discussion of all these cognitive barriers, we must confront the paradox: Why is it part of evidence-based medicine to discourage physicians from analyzing the rich evidence provided by normal-range thyroid lab data? Some people pride themselves on being “evidence-based” when they are simply promoting or conforming to a programme of institutionalized thyroid ignorance within the normal ranges.

It’s time to stop making the upper and lower “limits” of the TSH, FT3 and FT4 ranges into the limits of medical understanding.

Not covering thyroid therapy optimization

In this series, I am not addressing the optimization of treated thyroid patients’ hormone levels within the normal range. That’s an incredibly complex topic. Many types of thyroid disorders exist and can overlap. Many treatment approaches exist. Disease and dosing will combine with genetics and nonthyroidal health conditions to alter a person’s optimal thyroid hormone setpoints.

Instead, I’ll be focusing on the lab data of untreated individuals who still rely on a TSH-stimulated thyroid for 100% of their thyroid hormone supply.

However, this topic is still relevant to thyroid therapy. Cognitive barriers to analyzing untreated people’s normal-range thyroid data are at the foundation of many thyroid therapy mistakes. If a doctor believes “normal” is safe and healthy in every untreated person, their cognitive barriers will also become barriers to optimizing thyroid therapy rather than merely normalizing their biochemistry.

Overview: what TSH-FT4-FT3 hormone relationships can reveal

A major problem with most approaches to these hormones is their isolation from each other as separate lines on a lab report.

The diagram below summarizes the way that the three hormones act in synergy during health, keeping each other’s levels and ratios in balance.

• The TSH-FT4 relationship can reveal hypothalamus or pituitary dysfunction, or pituitary TSH secretion interferences, and by doing so, it distinguishes between pituitary and primary thyroid failure if the TSH-FT4 disjoint is severe.
• Combined, FT3 and FT4 feedback on TSH can reveal additional nonthyroidal causes of TSH secretion inhibition in borderline cases.
• The FT3:FT4 ratio reveals global metabolic function and can identify nonthyroidal illness in untreated individuals.
• The FT3 and FT3:FT4 ratio rises in response to TSH-receptor stimulation (by TSH or by antibodies) when the thyroid is healthy.

These hormone relationships are not limited by reference range boundaries. Why should our minds be limited by those boundaries?

Each type of thyroid, pituitary, and metabolic disorder has a distinctive distortion of these ratios and relationships.

The distortions in the HPT axis can be seen even when two hormones or all three are within range.

Mild imbalances or failures in one area can be compensated by an adjustment in another area. For example, mild thyroid failure can be compensated by a higher level of TSH that elevates or maintains FT3 as FT4 begins to fall.

However, severe degrees of failure cannot be compensated by HPT axis adjustments:

• Thyroid gland failure (loss of FT4) becomes a problem when it is no longer compensated by high TSH that stimulates T3 synthesis and T4-T3 metabolism in remaining thyroid tissue,
• Pituitary TSH secretion failure (loss of TSH or less bioactive TSH) becomes a problem when it is no longer compensated by a healthy thyroid’s basal TSH receptor function and peripheral T4-T3 metabolism,
• Hyperthyroidism (disorders of TSH receptor hyperfunction) becomes a problem when it is no longer compensated by reduced TSH and by a faster rate of T4 and T3 clearance,
• Metabolic failure (loss of FT3, if chronic), becomes a problem when it is no longer compensated by TSH-stimulated thyroidal T3 production.

These are the failures can become pathological if chronic and untreated.

Please be aware that some of these failures may coexist in the same person. There is nothing preventing a person with primary thyroid failure from also having TSH receptor-stimulating antibodies, T3-secreting thyroid nodules, less bioactive pituitary TSH, or metabolic failure.

When two or more etiologies combine, they can cloak each other’s characteristic HPT axis distortions. For example, when thyroid and pituitary failure coexist, the TSH will not be capable of rising high enough to stimulate a failing gland. If the TSH is still “normal,” the individual’s genuine hypothyroidism may be missed.

The rest of the article provides an introduction to the ways that shifts in TSH-FT4-FT3 relationships reveal thyroid, pituitary, and metabolic health in untreated individuals — in the hand of a well-educated analyst.

Hypothalamus & pituitary gland function

1) Central hypothyroidism

Disorders that compromise hypothalamus and pituitary to diminish the quality or quantity of TSH are called “central hypothyroidism” or secondary hypothyroidism.

Central hypothyroidism is often misunderstood as being a biochemical pattern of low TSH with a low FT4. But it can also manifest as inappropriately normal TSH and/or less bioactive yet normal TSH, and FT4 may also be in the low-normal range. (Persani et al, 2019).

Fortunately, when FT4 is tested alongside TSH, a well-trained analyst will be able to identify cases of central hypothyroidism. Even when manifests within the normal range, it is characterized by the loss of the normal inverse relationship between TSH and FT4.

In addition, FT3 testing can detect otherwise hidden cases of hypothalamic failure (tertiary hypothyroidism). Loss of TRH receptor stimulation in the pituitary leads to the synthesis of TSH molecules with reduced bioactivity. In such cases, the pituitary may still be healthy enough to secrete normal or mildly-high levels of less-bioactive TSH. As a result of the poor quality of TSH, as FT4 falls to the low end of range or lower, the FT3:FT4 ratio will be lower than it is in the early stages of untreated primary thyroid gland failure (Hoermann et al, 2020). In addition, if the patient is not severely ill, the FT3:FT4 ratio will not fall as low as it does in “nonthyroidal illness syndrome” (NTIS), discussed below.

Despite hiding in the low-normal range, central hypothyroidism can compromise a patient’s overall health and lead to disability and health care costs. As mentioned in part two of this series, “Are normal thyroid reference ranges risk-free zones?“, some individuals have a healthy thyroid hormone setpoint that is high-normal. When FT4 and FT3 are both low-normal, such an individual will be hypothyroid.

Unfortunately, central hypothyroidism is largely believed to be “rare” because it is rarely diagnosed, and it is rarely diagnosed because people believe it to be “rare.” This is a catch-22 that makes patients with pituitary failure highly vulnerable to misdiagnosis (See Waise & Belchetz, 2000 “Unsuspected central hypothyroidism” and our article “Why is central hypothyroidism so difficult to diagnose?“)

The widespread belief that fewer people are harmed by failure to diagnose than by overdiagnosis has driven “TSH-reflex” screening, in which FT4 testing is only triggered when TSH is high or low. This system fails to detect central hypothyroidism within the normal TSH range (Beck-Peccoz et al, 2017; See “23 years of misdiagnosed central hypothyroidism with a normal TSH: Case study.”)

3) Pituitary TSH secretion interferences

Even when the hypothalamus, pituitary and thyroid glands are healthy, TSH can be inappropriately prevented from rising above the normal range by many variables beyond thyroid hormones:

• age,
• pregnancy status,
• certain drugs,
• TSH-receptor antibodies,
• endocrine disruptors in foods, products, and the environment,
• chronic fasting and/or obesity,
• the time of day of the blood draw, and
• season of the year of the blood draw

(Haugen et al, 2009; Paragliola et al, 2019; Thambirajah et al, 2022; Chatzitomaris et al, 2017; van der Spoel et al, 2021).

Many of these features are discussed in our most popular blog post. It gives treated thyroid patients the tools to “trick the TSH” : “7 ways to raise TSH without reducing thyroid dose”

One of the most significant natural variables is time of day.

In healthy untreated individuals, TSH varies far more than FT3 and FT4 during lab testing hours. In light of this fact, it’s very puzzling that no instructions are given about the time of day or fasted state when blood is drawn for TSH.

Due to the logarithmic nature of TSH response, the absolute degree of TSH fluctuation increases in the upper half of reference range or beyond and collapses at the lower end of reference range or below.

In contrast to the variability of TSH is the stability of FT4 and especially of FT3, in any untreated, healthy individual.

Physicians sometimes tell patients this old myth: “FT3 levels vary too much from hour to hour, and that’s why FT3 is rarely tested.” Where do physicians get this false idea? They want to believe there is a good reason why FT3 is not tested. No, the opposite is true.

In untreated people, on average, FT3 and FT4 are more stable than TSH on an hour by hour basis during lab testing hours. In an experiment measuring hormones every 20 minutes, the average FT3 in 29 people fluctuated only between 5.3 and 5.7 in a reference range of 3.5-6.5 pmol/L over the 24 hour cycle (Russell et al, 2008).

For practical purposes, FT3 is usually measured between 7am and 5pm, so the circadian variation will not be influenced by the peak FT3 levels achieved while sleeping.

The TSH, FT3, and FT4 circadian rhythm is an aspect of healthy thyroid physiology that illustrates a key principle useful in interpreting lab data: The hormone that moves the least is actually the most important of the three and the most vital one to protect. FT3 is the target hormone of the HPT axis, and TSH is an upstream lever that fluctuates as widely as necessary to adjust the thyroid’s secretion rate and ratio, which adjusts FT4 and defends FT3. (See Hoermann et al, 2022, “Principles of Endocrine Regulation”)

Compared to changes in TSH, which take 12 repeated tests to discern disease progression from subclinical toward overt hypothyroidism, it takes a much smaller change of 15% of the value of FT3 and FT4 and fewer lab tests (only two!) to reveal a “clinically significant change” in thyroid disease progression to overt (uncompensated) thyroid failure (Karmisholt et al, 2008).

Once thyroid dysfunction is known, the FT4 and/or FT3 are more effective at discerning clinically significant changes that directly affect health risk and tissue thyroid status. In such cases, an isolated TSH becomes the less necessary and often misleading test.

3) Disorders of TSH excess

In addition to reducing the TSH, some disorders of the pituitary can also increase TSH values.

One is the TSH-secreting pituitary adenoma (TSHoma). Excess TSH from an adenoma is not controlled by negative feedback as thyroid hormone levels rise. Formerly considered rare,

“The incidence of TSHoma has increased, likely due to improvements in biochemical and imaging modalities allowing more accurate diagnosis”

(Timmons & Mukhopadhyay, 2020)

Another pituitary anomaly is “macro-TSH,” in which the larger and less-bioactive TSH molecules, sometimes bound to immunoglobulins, clear more slowly from bloodstream and result in a falsely normal or falsely high TSH. Some people consider this an assay interference, but it is a natural TSH variant that assays have not yet discovered how to discriminate (Hattori et al, 2018).

Most of the advice about macro-TSH and TSHoma focus on people with elevated TSH, but macro-TSH is also possible in people with a normal TSH who would otherwise have a low-normal, low or suppressed TSH. (Hattori et al, 2018; Kadoya et al, 2017)

Metabolic dysregulation: Nonthyroidal illness syndrome (NTIS)

Illness-induced metabolic dysregulation used to be called “low T3 syndrome,” and was once misnamed “sick euthyroid syndrome” because TSH was often misleadingly normal. It is now more commonly called nonthyroidal illness syndrome (NTIS), because it is caused by non-thyroidal illnesses even in people without thyroid disorders. However, the name is misleading, because the syndrome of metabolic derangement undoubtedly involves “thyroidal” failure. Even a healthy thyroid’s hormone secretion rate fails to compensate for metabolic derangement and can fail to aid recovery of health.

NTIS occurs in a significant percentage of individuals in hospitals and intensive care units, as well as in severe chronic diseases of the heart, liver, kidney, lungs. It is seen in severe viral and bacterial infections, traumatic injuries, and after major surgeries.

Although NTIS may often be benign and almost inevitable in the acute phase, chronic metabolic T3 depletion is pathological. It is a significant contributor to mortality rates in hospitals when a rising TSH fails to aid recovery from T3 depletion in a timely manner, especially when TSH apathy also permits T4 to fall low (van den Berghe, 2014; DeGroot, 2000/2015).

Diagnosing NTIS

Fortunately, this thyroid metabolic syndrome can be easily diagnosed with a full panel because it distorts TSH, FT3, and FT4 hormone relationships in characteristic ways in untreated people. (Chatzitomaris et al, 2017)

The most distinctive feature is a very low molar FT3:FT4 ratio with the FT3 significantly below the population mean, and often a low Total T3.

In NTIS, Total T3 usually falls lower than FT3 (Warner & Beckett, 2010). Nevertheless, the FT3:FT4 ratio measured in pmol/L is strong enough to diagnose the presence of this condition in an untreated individual, even when both hormones are in range (Yu et al, 2018). During NTIS, intracellular metabolic losses of T3 and T4 can overcome “normal” free circulating levels of thyroid hormones in bloodstream.

If a physician needs to rule out primary thyroid failure during severe illness, a full panel with FT3 and FT4 (or Total T3 and Total T4) testing is needed (Braithwaite, 2015).

In contrast with the usefulness of the FT3:FT4 ratio, an isolated TSH test is not diagnostic of thyroid failure vs. metabolic failure during severe illness. TSH is not only diminished by local metabolic derangement in the hypothalamus and pituitary, but may be further reduced by poor nutrition, high-dose glucocorticoids and other TSH-inhibiting drugs.

Therefore, NTIS can mimic pituitary gland failure and cloak primary thyroid gland failure within the normal or subclinical TSH range, making TSH-only testing utterly inappropriate as a “thyroid function” test.

Other metabolic derangements occur, such as a rise in RT3 hormone per unit of its prohormone FT4. RT3 is not a risk-associated biomarker, but a signal of the existence of NTIS, which raises its production rate and slows down its clearance rate. However, RT3 tests are becoming hard to find.

NTIS staging and severity

Some people have even claimed that thyroid testing is an “expensive distraction” largely due to the need for training to interpret results (Premawardhana, 2017). A strong motive exists to justify the common practice of doing nothing by promoting the practice of testing nothing and therefore, knowing nothing.

People who express such dismissive opinions are victims of ignorance themselves, unaware of the diagnostic clarity of the FT3:FT4 ratio.

For example, in cardiovascular diseases, especially heart failure, mortality rates are associated with high levels of a hormone called NT-proBNP, which is secreted by a heart under stress.

As shown in this Kaplan-Meier survival graph below, having a low FT3:FT4 ratio significantly reduces survival rates in the lower and higher NT-proBNP level cohorts. (Brozatiene et al, 2016).

Every time the line drops, people are dying as time is passing.

In Brozatiene’s study, the TSH level was insignificant to mortality.

Most of the time, during acute or chronic NTIS, the TSH is deceptively low or normal. An elevated TSH may be seen even in persons with healthy thyroid glands during the transient NTIS recovery phase (Langouche et al, 2019; Braithwaite, 2015).

Recovery from NTIS is not inevitable. Mortality rates rise higher if the TSH fails to rise to stimulate a healthy thyroid and promote recovery, because this mechanism’s failure permits the FT4 or T4 also to fall (Warner & Beckett, 2010; van den Berghe, 2014; Braithwaite, 2015.)

The severity of metabolic FT3(TT3) depletion, and its low level per unit of circulating FT4(TT4), are the key biomarkers associated with higher mortality and morbidity rates (Wang et al, 2022; Hong et al, 2022: Yuan et al, 2021).

However, one should always consider the hormone ratios. In Brozatiene’s study, the data showed that the FT3:FT4 ratio was more significant to mortality than Total T3 levels and isolated free thyroid hormone concentrations.

When an illness is milder or in its chronic phase, all the hormone ratio distortions described above may be hidden within the reference ranges, but still have adverse impacts on health (Xu et al, 2016; Gao et al, 2021).

What can be done even when NTIS is confirmed?

A common practice in medicine is to avoid testing unless the test is on the pathway toward a treatment.

Unnecessary debate surrounds NTIS and has stalled the development of effective treatments, leading to many unnecessary deaths. It is shameful that many physicians and scientists who capably distinguish between acute versus chronic inflammation fail to distinguish between acute versus chronic NTIS.

But if a person really wants to figure out the mechanisms of NTIS, a diagnosis can save lives even though clear diagnosis and treatment guidelines are not yet available.

Research gives hints at effective treatments:

• NAC (N-acetylcysteine), (Yan et al, 2017)
• Better nutrition in the ICU setting (Jacobs et al, 2019).
• A rat study proved that a high NT-proBNP level can be lowered by dosing liothyronine (LT3) to achieve euthyroid status in cardiac tissue (Wang et al, 2020). The titration of the dose makes the difference to tissue levels, and many T3 treatment studies treated with too little T3 too late.
• Pre-treating children with T4/T3 combination (desiccated thyroid extract) before surgery minimizes the severity of post-surgical NTIS.

If more physicians and scientists were aware of the frequency at which NTIS contributes to an unnecessary death rate, adverse events, and expensive hospitalizations in people with and without thyroid failure, more would be done to aid recovery.

Remove the cognitive barrier.

Consider the absurdity of the phrase “thyroid function tests” in a different area of medical practice. This phrase is routinely misapplied to testing patients who have no thyroid gland function and who are being monitored while on thyroid therapy. It’s like saying sex hormone tests are “menstrual function tests” when used in males or postmenopausal females. In this case, the TSH test alone is a “pituitary TSH response test,” and that’s all it is.

It is not my intention to shame or police individuals’ language use, but to educate and enlighten. The term “thyroid function test” is not necessarily a sign that there’s something wrong with the individual who uses it. They may simply be unenlightened and unaware of the narrow-minded presumptions implied by it.

This is firmly institutionalized language. It would be as hard to change it as it was to replace “policeman” with “police officer” instead.

Therefore, institutions are responsible for leadership. People involved in medical education, laboratory communications, and health care policy ought to think twice about using this terminology.

Many lab reports give HDL:LDL cholesterol ratios. Perhaps someday we may see an index of the TSH-FT4 relationship on a lab report, or the FT3:FT4 ratio with a range.

References

The reference list for this series is in a separate post.