Thyroid patients excluded from research

Thyroid patients on thyroid therapy are commonly excluded from the study of “Low T3 Syndrome.”

What is “Low T3 syndrome”? Why is it important to study?

This is the phenomenon of T3 thyroid hormone inactivation that often occurs in critical illness and puts their lives in great danger.

Some thyroid patients know from experience that it can also occur during our L-T4 therapy, even if we are not (presently) critically ill, and it can compromise our health.

Because of our research exclusion, medicine has become blind to the potential health risk faced by thyroid patients during their lifelong therapy.

This post addresses two primary audiences who need to know:

  • Patients. You should be aware of the risk you face in the medical system. Your exclusion from research has made some doctors think you are not vulnerable.
  • Researchers. You can fix this. Include us in future research. It will strengthen your study of Low T3 syndrome and its therapy for all patients.

The biological importance of T3 hormone

TriiodothyronineScience acknowledges that a sufficient level of the T3 thyroid hormone is essential for health (see our page “Rationale: Definitions.”)

Many studies have shown that a drop in T3 levels —  even within the statistically normal reference range — can cause harm to a variety of organs, systems, and tissues. For example, the science on thyroid and the heart (i.e. Klein and Danzi, 2007) focuses on the direct and indirect actions of T3 hormone (search their article for the term “T3” and you’ll see).

ThyroxineThe bodies of people with normal thyroid glands actively defend their plasma Free T3 levels (Abdalla & Biondi, 2014).

For example, one study showed the control group of 3,875 euthyroid subjects with normal thyroid glands was able to keep its Free T3 steady at an average of 4.47 pmol/L (reference 2.9–6.0 pmol/L) no matter where their TSH and T4 were located across the entire “euthyroid” range. (Gullo, et al, 2011)

The data show that the relatively steady Free T3 in the upper part of normal reference range was likely maintained by shifting their TSH and T4 levels around their body’s healthy T3 set-point.

Research on Low T3 syndrome

T3 DepletionWhen any human being experiences critical illness, their body’s set-point can lower and they can experience T3 hormone depletion.

This is known as “non-thyroidal illness” or “low T3 syndrome” or “euthyroid sick syndrome.”

The key player in this process is Deiodinase type 3 (D3), the enzyme that inactivates both T4 and T3.

D3 is very sensitive to levels of thyroid hormone above the body’s individual set-point. Hormone levels above the set point trigger a series of shifts in T4-T3 conversion that lead to net T3 depletion.

Read more about the science behind this in our post “Deiodinase type 3 and Reverse T3.”

For decades, medicine believed that Low T3 syndrome was purely an “adaptive” response to illness. It is a very quick way to lower the metabolism and it was thought to be a way to protect fragile systems from energy expenditure and overstimulation.

However, there is a turning point in Low T3 syndrome, yet to be defined, a level of T3 below which the lowering of T3 hormone levels becomes pathological and harmful to the human body.

In disorders involving organs that depend largely on plasma T3 levels (heart, kidney, liver), Low T3 causes further damage and may become too low to permit the organ’s natural recovery. Low T3 syndrome has most frequently been studied in relation to critical illness in these organs.

Research on this syndrome has proven over and over again that the lower the T3 level drops, the higher the rates of morbidity and death.

See a list of many of these studies showing the power of Low T3 to predict death and morbidity, in Table 3 of Rhee et al, 2015). Over and over, with only one study a rare exception, the Low T3 was associated with deleterious consequences such as “increased all cause mortality.”

Low T3 in L-T4 thyroid therapy

According to the theory and underlying molecular biology, illness is not necessary as a trigger for excessive T3 depletion. The body need only sense a thyroid hormone level _above_ its current set-point.

A high-normal T4 maintained by L-T4 therapy can trigger and maintain a chronically low T3. When a patient experiences symptoms due to their low T3, health professionals attempt to resolve it with a higher dose of T4. Even if all thyroid hormone levels are kept within “normal” range, the T4 level alone may be excessive to that individual’s body.

(Gullo, et al, 2011) showed that among 1,811 thyroid patients without thyroid glands on TSH-suppressive L-T4 monotherapy, a significant number were NOT able to defend their Free T3 levels.

The higher their Free T4 was, their lower their Free T3 was. Their T4 level was maintained by a daily dose of hormone while T3 levels dropped.

Gullo et al’s study only included athyreotic patients with suppressed TSH, but other studies have shown that low T3 happens even in autoimmune thyroid disease patients with a “normal” TSH (Hoermann et al, 2013).

Women vastly outnumber men in autoimmune thyroid disease. Women in Gullo et al’s study were almost two times at higher risk of a Free T3 below reference (8.6% in males and 16.4% in females).

Can T3 therapy fix Low T3 syndrome?

A logical research question is about therapy. Can treating critically ill patients with T3 hormone help them?

Probably. But here again, thyroid patients’ exclusion has compromised past research on this question.

Imagine a study of “Low T3 syndrome” that tests a static T3 dose, or a T3 dose adjusted to the patient’s body weight.

This controlled T3 dose is then given to a number of “normal thyroid” patients who are in different states of illness, recovery, and T3 depletion.

Under these experimental conditions, T3 therapy “effectiveness” would depend on:

  1. The degree of T3 deficit in each patient relative to the experimental T3 dosage.
  2. The degree to which an individual patient’s Deiodinase type 3 is actively depleting any external resupply of T3 by inactivating T3 into T2.
  3. The degree to which an individual patient is able to recover naturally via TSH and T3 secretion from their normal thyroid gland.

Each of these dependencies has a corresponding implication:

  1. Giving too little T3 to a patient who is in an extreme T3 deficit may not be enough, so they may die, and it will look like the T3 was not beneficial.
  2. Giving T3 at the same rate it is being depleted may maintain, not raise, their T3 supply. T3 may then be judged as “ineffective.” However, if the patient survives, we don’t know what would have happened if they were NOT given any T3 to maintain levels during the stage of active depletion.
  3. The patients in the treated group AND the control group all have “healthy” thyroid glands. They have the ability to regenerate their own T3 resupply without external T3 therapy. Therefore this experiment cannot distinguish between non-thyroidal and thyroidal T3.

Due to # 3, the whole experiment is on shaky ground. There’s no way it can prove anything conclusive about external T3 supplementation vs. thyroidal secretion.

Future research can be done on L-T4 patients’ recovery. It will not be difficult to find eligible patients willing to participate an experiment that could do the experimental group no harm and could provide significant benefit.

“Low” T3 and the T3 reference range

When studying Low T3 syndrome, some researchers have arbitrarily decided to make the bottom of the T3 reference range their cutoff.

However, the statistical normal reference range is rather irrelevant in critical illness.  The “set point” for T3 (and T4) continually shifts during critical illness. The set point lowers as a person gets sicker, and it rises as they recover.

If a given patient’s Free T3 level is “too far” below their physiological requirements, they are biochemically hypothyroid and their body will suffer, especially in organs and systems that depend more heavily on Free T3 within the circulation.

It is crucial for health not only to maintain T3 anywhere in the “normal” reference range, but for each individual organism to maintain T3 levels within a much narrower “set point” within that range. See what the science says in our section on “Rationale: Reference ranges.”

A deranged thyroid hormone metabolism does not regulate itself by statistical reference ranges defining “normal.” If researchers arbitrarily decide that the lower limit of normal reference range is the cutoff only beyond which “low T3” exists, they may overlook the harm caused by depletion within the lower normal reference range for T3.

Clearly, to determine the progressive level of harm caused by low T3, one must examine groups of patients at varying T3 levels regardless of the statistically-established reference range cutoff.

T3 depletion with a normal or low TSH

Research on “non-thyroidal illness” also shows that severe T3 depletion occurs while TSH is normal or low. That’s why it’s also sometimes called “Euthyroid Sick Syndrome” — because the category “euthyroid” is determined by these patients’ TSH alone. They are TSH-euthyroid (according to the pituitary gland), yet they are absolutely not T3-euthyroid. Even if their sickness induced their Low T3, the Low T3 goes, the more power it has to make them sicker.

In most circumstances, when TSH test interferences are removed, a high or low TSH is an “associated” manifestation “commonly” seen in direct inverse relationship to high or low thyroid hormone levels.  Commonly. Associated.

But this TSH association does not apply to patients during Low T3 syndrome. Why?

At the foundation of any correct biological definition of hypothyroidism is a deficiency of thyroid hormone(s), T3 and/or T4.  Biology tells us that a high TSH can never directly “cause” hypothyroidism.

Let’s review the biology that doctors should have been taught in medical school.

  1. TSH does not enter thyroid hormone receptors.
  2. TSH deficiency makes nobody hyperthyroid.
  3. TSH excess does not create hypothyroidism.
  4. The role of TSH is indirect; TSH secretion increases in response to a level of T4 that is below the body’s set point, and a rise in TSH drives a _healthy_ thyroid to increase T4 and T3 production. TSH also stimulates the body to increase T4-T3 conversion in order to achieve the net result of raising T3 somewhat.
  5. TSH supports, serves and protects T3 — as long as you have a healthy thyroid gland.
  6. However, the healthy “HPT axis” is defined primarily as a TSH-T4 relationship, not TSH-T3.

The final fact is crucial in “Low T3 syndrome.” The healthy “HPT axis” is defined primarily as a TSH-T4 relationship, not TSH-T3.

The T3 hormone, the most essential thyroid hormone for biological function, is excluded from the current HPT axis model. Why?  It simply does not fit the mathematics as neatly.  As mentioned above, the healthy human body shifts TSH and T4 and T4-T3 conversion efficiency in order to _protect_ and _maintain_ plasma T3 levels.  In normal biology, healthy T3 maintenance is a target. Within the normal range, TSH and T4 shift in inverse relationship — but they shift _around_ T3 as target. This is true only in a state of health.

The complete HPT axis model would have 3 variables, but unfortunately T3 does not fit into a two-dimensional line graph, and most journal articles and textbooks are not delivered in 3D.

By imposing TSH measurement on every human being without discernment, medicine has been imposing a model of thyroid health onto thyroid disease and treatment, has been simplifying a 3-way hormonal relationship into a 2-way model, and has been neglecting the most important thyroid hormone T3, blindly trusting that everyone will manufacture enough and be able to maintain T3 levels.

Obviously this HPT axis does not apply to critical illness. Research says it does not apply to L-T4 monotherapy either.

Thyroid patients are likely at most risk

Current guidelines recommend that a TSH test be performed at the time of a thyroid patient’s admission to the hospital. But as explained above, TSH will not be capable of revealing a thyroid patient’s Low T3 state.

When a Low-T3 thyroid patient becomes critically ill, their Low T3 may drop even lower than the low level it has been maintained at for years.

According to the research, the more their T3 level drops, the greater their risk of continued illness and death.

We thyroid patients,

  • WE who are at most risk of having chronic Low T3 because of low thyroid capacity and L-T4 monotherapy,
  • WE whose already low T3 may become even lower during illness,
  • WE who may not be able to recover from Low T3 in critical illness without a thyroid gland that can respond to a raised TSH and secrete more T3,

WE are commonly excluded from the study of “Low T3 Syndrome.”

This is clearly unethical.

Why are thyroid patients excluded?

We hypothesize three barriers to inclusion. All of them can be overcome.

  1. Words create and maintain false categories. If you have a “thyroidal” illness, you do not fit the category of “non-thyroidal illness” even if you have a low T3 level that is just as low as or lower than a person with “non-thyroidal illness.” This exclusion has become ingrained in research methodology. Previous studies of “non-thyroidal illness” have excluded anyone with a thyroid disease diagnosis and anyone taking thyroid medication, so a researcher may feel justified in continuing to exclude them. Besides, it reduces the number of variables that need to be accounted for.
  2. A paradox is more intriguing. “Non-thyroidal illness” presents a puzzle and paradox that naturally raises scientific curiosity:  How is it possible for a person with a _normal_ thyroid gland to experience hypothyroidism due to T3 hormone depletion? In contrast, it has been neither puzzling nor paradoxical to ponder a thyroid patient’s T3 hormone depletion because a) their thyroid gland is damaged and b) L-T4 therapy is commonly believed to entirely remedy thyroid deficiency, so it is assumed (falsely) that Low T3 will not occur as long as TSH and T4 are medically normalized.
  3. Lack of routine Free T3 data collection. Free T3 is rarely tested in monitoring thyroid patients’ therapy. Medicine currently monitors thyroid patients on the basis of their TSH level alone. Only when TSH is outside of range will they check their T4 level, but a T4 level cannot indicate low T3, either. Will anyone consider a thyroid patient’s Free T3 level to be worth testing if their TSH and T4 are within their separate ranges? No, not under the current paradigm in which the TSH test result overrules all other indicators. The system currently prevents any data from being collected that could possibly contradict a TSH-based diagnosis.

If researchers were to remove these artificial barriers, they could begin to ask these important research questions that can improve the lives of patients:

  1. What happens to a Low-T3 thyroid patient when they become critically ill?  If their L-T4 dose and TSH are maintained during illness, will their poor T4-T3 conversion rate get worse according to their state of illness?
  2. What happens to a critically ill, Low-T3 thyroid patient during the “normal” recovery process in non-thyroidal illness?  We know that in “normal” patients, the TSH rises and it stimulates the healthy thyroid gland to secrete enough T3 to kick-start recovery. What if the patient does not have enough thyroid gland tissue to secrete T3 during recovery and has no access to T3 medication?
  3. Does a thyroid patient’s chronic low T3 maintained over years or decades of L-T4 monotherapy contribute to higher risk of chronic illness and shorter life span?

See further questions in our suggested Research Agenda:  Challenges: Research