The leaky buckets analogy of thyroid hormone metabolism

Thyroid hormone metabolism is a very complicated system.

A visual analogy sometimes goes a long way to assist comprehension.

Throughout the body, there are at least six major pathways for T4 transformation or excretion, and at least six major pathways for T3 transformation or excretion.

In the visual, the fluid represents circulating thyroid hormone concentrations.

  • T4’s metabolic pathways can be thought of as a large bucket of T4 hormone levels with six holes in it. The leaks from the holes represent five major types of hormone transformations (T3, RT3, T4S, T4G, Tetrac) and one pathway for urinary loss of untransformed T4.
  • T3’s metabolic pathways can be imagined as a smaller bucket of T3 with another six holes in it. The leaks are similar to T4’s pathways (3,3′-T2, 3,5-T2, T3S, T3G, and Triac, and urinary loss of T3) and involve similar mechanisms.

These six pathways for each hormone have been known by thyroid scientists since the late 1970s (Wiersinga et al, 1979). Key scientists have each contributed along the way. Our current state of knowledge is reflected in more recent review articles (Kohrle, 2019; Mondal et al, 2016; Senese et al, 2014; and van der Spek et al, 2017).

Therefore, this model is scientifically informed, despite its cartoon-like simplicity.

This post will expand upon the analogy and summarize the metabolites and processes, without getting into the finer details.

It also discusses how the natural metabolic system shifts during thyroid function loss and thyroid therapy, and comments on therapeutic implications.

Advantages of the “leaky buckets” analogy

This visual has several major advantages over traditional scientific flowchart-like models that focus on molecule shapes:

  • Time: This model emphasizes the continual flow of T4 and T3 into their respective metabolic pathways over time.
  • Multiple pathways: Most models only show T4 converting to one or two thyroid hormones (T3 and RT3) and entirely omit urinary losses.
  • Input and output: Most models focus on supply, but concentrations in blood are determined by the balance between appearance rates (input) and clearance rates (output).
  • Flexibility: The model’s faucets remind us that the system is capable of flexible adaptation as well as dysfunctional imbalances.
  • Co-regulation: Each part of the system plays a role in the metabolic process, and the TSH hormone is not in charge of every part of the process.

Disadvantages: What the “leaky buckets” do not communicate well

No analogy is perfect. Any model intended to highlight certain aspects will fail to represent other aspects of a complex system. Keep in mind the following things that aren’t shown in this model:

  • If your thyroid gland is damaged, non-functional, or removed, some or all your T4 and T3 may need to come from thyroid hormone pharmaceuticals. The model does not reveal how the whole system can shift when thyroid function loss and treatment intervene.
  • This model artificially separates T4 from T3 and its other metabolites. However, all thyroid hormones travel side by side in blood and through cells, not in separate streams.
  • It does not visualize organs or tissues beyond the thyroid gland. It can’t show the degree to which liver, kidney, muscle, bone, brain, fat, or tumor cells contribute to each leak in each bucket.
  • This model omits Thyronamines (TAMs) because scientists believe their pathways of creation may derive further downstream, such as from T2 hormone, and because they are mostly intracellular, not circulating, thyroid hormones.

However, this article will discuss many of these aspects below.

The complexity of the thyroid metabolic system

If only thyroid hormone metabolism were as simple as twelve leaks in two buckets! The analogy represents a system that is far more complicated than a set of buckets, holes, leaks, and taps.

If you have a leaky boat or leaky household plumbing because they are damaged, old, or poorly constructed, some leaks can be fixed while others can get larger. But even a boat or household plumbing isn’t as complicated as the human body. In real life, people have concurrent illnesses, medications, genetic uniqueness in enzyme expression, and so on.

Effective thyroid therapy is an exercise in monitoring and therapeutically adjusting metabolic pathways so that the result optimizes the individual’s health outcomes — at least until the next test result shows a change.

The natural source: The TSH-stimulated thyroid

At the top of this image is the TSH-regulated thyroid gland providing the source of all T4 and a variable percentage of daily T3 supply. The thyroid and both its faucets (secretion) are co-regulated by a TSH receptor knob.

It’s common to say that a thyroid gland is “regulated” by TSH. However, it is more accurate to say it is “co-regulated” by TSH. A thyroid’s health, and thus its ability to respond to TSH, is dependent on many factors, such as congenital disorders, iodine supply, antioxidants, and nutrition.

TSH increases every aspect of thyroid function including iodine uptake, synthesis of T4 and T3 from raw materials, the efficiency of D1 and D2 enzymes expressed by the thyroid, and transport of hormones out of the thyroid gland.

Contrary to widespread belief, the thyroid gland is not limited to providing only 20% of one’s daily supply of T3 in health, and it is not limited to secreting a 14:1 to 16:1 ratio in health, as commonly stated.

This is one major reason why the leaky buckets visual is needed. Scientific data reveal the flexibility that such oversimplified claims conceal. Science informs us that the T4:T3 ratio of secretion can be adjusted. Thus, each faucet in the model also has its own handle for adjustment.

Highly variable and individualized secretion ratios

In Pilo’s famous 1990 study, the ratios of T4 and T3 secretion from the thyroid were quite variable among 14 healthy men and women, all of whom had a TSH between 1 and 2 mU/L.

The statistical average (mean) ratio of thyroid secretion was around 16 mcg T4 to 1 mcg T3.

Hypothetically, if a person with a 6:1 ratio suddenly started secreting T4 and T3 at a 72:1 ratio, they could become T3-deficient and have an oversupply of T4.

Each individual’s thyroid secretion ratio and rate attempts to adapt to the strengths and weaknesses in their extrathyroidal metabolism.

However, keep in mind that almost all kinetic studies were biased by acute overdose of iodine, which can limit the secretion of T4 and T3 and could potentially shift their secretion ratio. (See “Question Pilo’s study: Iodine dosing biases T4:T3 secretion“)

One may think that 14 people is too small a sample, and it is. But all “kinetic” studies of thyroid hormone metabolism, including Pilo’s 1990 study (most of them were performed in the 1980s), had very small sample sizes. This is because the experimental procedures were highly complex, with multiple measurements being performed in a hospital over about 8 days. These studies, despite all their methodological flaws, are the basis of what we think we know about thyroid hormone metabolism in living humans.

Variable peripheral T4-T3 conversion rates

In the same kinetic study by Pilo (1990), the estimated average T4-T3 conversion rate was 27.3%.

However, population averages are very poor representations of the wide range. Even in health, the T4-T3 conversion rate may vary widely from person to person, as seen in the following graph I’ve constructed from Pilo’s data tables:

Pilo’s study only estimated “peripheral” T4-T3 conversion, meaning conversion beyond the thyroid gland. The study did not include the thyroid gland’s internal conversion rate, which contributed to the secretion ratios and amounts of T4 and T3, described above.

A conversion rate of 27.3% does not mean that all 27.3% of T3 obtained from T4-T3 conversion was measurable in blood as Total T3 hormone. This means that on average, 27.3% of Total T4 converted to T3 hormone, even at the same time that T3 converted to other metabolites and more T3 came from a thyroid gland.

The best lesson to learn from a study like this is the wide range of human variation. Unfortunately, people tend to remember only the statistical averages and then imagine that there is little room for individual deviations from the average.

Leaders in endocrinology in the 1980s and 1990s strongly promoted a one-size-fits all model for LT4 thyroid treatment, and so they decided to de-emphasize the human diversity of T3 secretion and intra-thyroidal hormone metabolism in a state of health.

T4 only has one source, but T3 has two sources.

As shown in the visual analogy, two T3 streams pour into one T3 bucket.

The T3 concentration bucket is filled not only by the thyroid’s T3 faucet (and/or pharmaceuticals), but also by a significant leak in the T4 bucket, representing body-wide T4-T3 metabolism.

T3 hormone is the only T4 metabolite that has a natural backup system for its production.

Whenever the human body provides multiple pathways to achieve the same goal, the redundancy is a major clue to physiological priorities. It usually means that the goal is very important, likely very essential for health.

It illustrates the body places a very high biological priority on the supply of circulating T3 to bloodstream.

It also highlights the role of the healthy TSH-regulated thyroid gland as a defender of plasma T3 (Abdalla & Bianco, 2014; See “The thyroid gland is a T3 shield. Defend the unshielded.“).

The healthy thyroid as FT3 defense system

Defending FT3 does not mean targeting a specific FT3 level at the statistical average (mid-reference range) in every person.

Instead, it means defending the individual’s optimal FT3 (always in relationship to FT4), wherever it needs to be for their health.

The primary purposes of both TSH-driven secretion and T4 metabolism are to adjust circulating T3 levels to meet an individual’s overall and tissue-specific T3 demands (Bianco et al, 2019; See “Thyroid T3 secretion compensates for T4-T3 conversion“).

The feedback loop that regulates TSH is not a simple mirror image of the thyroid’s response to TSH.

  • On the one hand, in the thyroid gland, a rise in TSH normally increases the T3 side of the T4-T3 ratio of secretion.
  • On the other hand, in the pituitary gland, the TSH negative feedback loop, which regulates TSH secretion, is primarily a response to FT4 levels, and only secondarily by naturally produced FT3 levels, as statistics reveal.

This illustrates the partnership between two major systems (thyroidal secretion and peripheral metabolism) that work together in health. A healthy thyroid enables the body to use TSH to defend circulating T3 concentrations in case of problems with peripheral metabolism.

As a result, within the normal range in healthy people, FT3 levels are so individualized that the population’s FT3 levels as a whole do not correlate with TSH at all — except for a slight increase of FT3 at higher-normal levels of TSH.

In a state of thyroid health, the metabolic system and HPT axis prioritize T3 defense over TSH and FT4 defense at an individual level. This is why FT3 is so individualized. TSH and T4 are means of maintaining healthy circulating FT3 and intracellular T3 signaling levels.

Free T3 must be defended because it constitutes the supply of active hormone to every tissue throughout the body. Our cells interpret FT3 in the context of FT4 entering them at the same time. FT3 entering the cell is capable of “topping up” each tissue’s unique intracellular T4-T3 conversion rate.

The FT3 is the variable that makes up for an individual’s unique metabolic imbalances and intracellular losses of T4 and T3 to non-T3 pathways.

In some tissues that efficiently convert T4 and do not need as much FT3, enzyme activity can shift. Intracellular metabolic pathways can often get rid of mildly excess local T3.

To understand how the thyroid acts as a FT3 defense system, we also have to understand how population-wide levels of FT3 and FT4 differ from individuals’ levels over time.

The individualized FT3 level is extremely stable in each individual over 6 weeks, as revealed by Ankrah-Tetteh and team in 2008. FT3 is adjusted to a specific level within reference range that meets their metabolic demands in relation to their concurrent FT4 level.

Note that the lab tests in Ankrah-Tetteh’s study occurred at the same time every day.

Many doctors mistakenly think that FT3 varies the most in an individual, but that’s not true.

  • The largest FT3 variation exists at a population level, between individuals. One individual’s narrow, optimal FT3 can be very different from another person even if the two people have the same TSH and FT4 levels.
  • Within an individual, FT3 levels have incredible stability from day to day, week to week, and month to month, while their TSH and FT4 wander around FT3, adjusting the FT3 and fine tuning it constantly every day. That’s where you see the FT3-defense system at work.

An individual’s TSH fluctuates far more than FT3 and FT4 over a 24 hour period, and the TSH can be significantly lower at 3pm than at 8am. The FT3 levels do not change much during lab hours, but they will be about 10-20% higher while sleeping. The mild sine wave of daily FT3 rhythm promotes health and longevity (See “The significance of the TSH-FT3 circadian rhythm“).

This is a system that engages in “relational stability” — its stability is flexible and always in relation to individualized metabolic demands and stressors. See the paraphrase of Hoermann et al’s article on this topic:

Let’s now move further downstream in the leaky buckets analogy.

The metabolites (leaks in the buckets)

Imagine that each hole in each bucket represents a filter (enzyme) installed in it that changes the fluid color (hormone type). Each hormone that leaves each bucket is not just a loss of T4 or T3. Newly formed hormones can have other important bodily functions.

The size of each hole in the buckets can change based on the amount of fluid in the two buckets, as well as other factors. For example, mild hyperthyroidism (high FT4 and high FT3) can increase the speed of T4-Tetrac conversion and urinary loss of T4 and T3.

You may imagine (not shown) additional buckets to catch each stream of fluid leaking out of these two buckets. Each metabolite’s concentration is also regulated by “leaks” as it gets changed into other metabolites and lost in urine.

T4 metabolites

  • T3 (Triiodothyronine): The most active thyroid hormone metabolite, usually more abundant than Reverse T3. It is created from T4 via deiodinase type 1 (D1) and type 2 (D2) enzymes.
  • Reverse T3 (RT3): The less active form of T3, created via Deiodinase type 3 (D3) enzyme, regulated by the Dio3 gene. Some RT3 is also created by D1 enzyme.
  • Tetrac (occasionally called TA4): Tetrac can sometimes be more abundant in blood than RT3, according to their respective reference ranges. Tetrac is more TSH-suppressive than circulating T4 and T3. Scientists have not yet identified the enzyme that creates Tetrac from T4.
  • T4 Sulfate (T4S): This is created by the sulfotransferase enzyme, mainly located in the liver. Adding a sulfo group to T4, creating T4S, prepares it for excretion through bile and then through the intestines.
  • T4 Glucuronide (T4G): This is created by UDP-glucuronosyltransferases (UGTs), mainly located in kidney and liver tissue. Like the sulfate pathway, transformation to T4G also enables excretion through bile and through intestines, but UGT enzymes are regulated by different signals than sulfotransferases.
  • Urinary T4 clearance: Various processes are involved in co-regulating the binding proteins in serum that control how much T4 is free or bound. T4 binding to proteins in blood can slow down urinary clearance. Even in health, T4 is lost through urine, but some kidney and liver disorders, as well as excess T4, can increase the rate of T4 urinary loss.

T3 metabolites

  • Active T2 (3,5-T2): This hormone is capable of performing T3-like activities in mitochondria, as well as a few unique actions that T3 does not perform. However, it does not replace any of T3’s essential nuclear hormone signaling functions. Scientists propose that this metabolite is created mainly by D1 enzyme.
  • Inactive T2 (3,3′-T2): Like Reverse T3, this hormone lacks an iodine atom in the location that binds to nuclear hormone receptors. It is not known to have any signaling potency. This hormone is created by two pathways — both from T3 via Deiodinase type 3 (D3) and from RT3 via type 1 (D1) enzyme.
  • Triac (occasionally called TA3): See Tetrac above. This hormone is more abundant during LT3 monotherapy than in untreated people or people on LT4 therapy. Like Tetrac, it also has potent TSH-suppressive effects. It is likely created from T3 by the same unknown enzyme that creates Tetrac from T4.
  • T3 Sulfate (T3S): See T4 Sulfate above: T3 Sulfate is created from T3 by the same enzymes, and this pathway enables T3S excretion. In low-T3 states, more T3S appears in bile and a small fraction can be converted back to T3 by enzymes in gut microbiota.
  • T3 Glucuronide (T3G): See T4 Glucuronide above: T3G has the same family of enzymes and the same pathway of excretion.
  • Urinary T3 clearance: See T4 urinary loss above: Similar mechanisms apply to urinary T3 loss. T3 is more vulnerable to higher rates of urinary clearance than T4 during certain illnesses and during extreme cold stress.

As you can see, there are many pathways besides RT3 that can “steal” circulating FT4 and divert it away from T4-T3 conversion.

There are also many pathways that can “steal” circulating FT3 after it enter cells, breaking apart T3 before it can reach receptors in the nucleus.

A future post will discuss these metabolites and their health effects in more detail. For more information, see Kohrle, 2019; Mondal et al, 2016; Senese et al, 2014; and van der Spek et al, 2017 in the reference list.

The thyroid-disabled metabolic system is different.

As mentioned above, the model can’t show the difference between the healthy-thyroid system and the thyroid-disabled system, especially after treatment intervenes.

People without thyroid function cannot benefit from a normalized TSH like people with healthy thyroids.

As revealed in research by Hoermann and team (2013), there’s a significant metabolic shift in the TSH-FT3 relationship at a population level.

During LT4 monotherapy at higher doses that are necessary to replace thyroidal T4 secretion, TSH responds mainly to the FT4 level and largely ignores an abnormally low FT3, as shown in the following two graphs.

(Graph A is the same graph already shown above)

As you can see when comparing the two graphs above, without the thyroid’s adjustment of circulating FT3, a normalized TSH alone fails to defend FT3, as it would normally do in people with healthy thyroids.

Contrary to common belief, it is not normal for FT3 to fall as TSH rises within range. This only happens in thyroid-disabled, LT4-treated people. This is a disabled metabolic system.

In healthy people, the “log linear” inverse relationship with TSH only occurs with FT4, not with FT3. The TSH-FT4 system remains intact during thyroid loss and thyroid hormone therapy as long as the hypothalamus and pituitary retain healthy function.

This difference between the TSH-FT4 relationship and TSH-FT3 relationship occurs because the preferential increase in T3 secretion per unit of TSH is the responsibility of mechanisms within the thyroid gland, not the function of peripheral metabolism or the pituitary gland.

This loss of thyroid-FT3 defense systems and the retention of pituitary-FT4 sensitivity is metabolically significant to therapy. It means that a “normal” TSH and “normal” FT3 do not necessarily yield optimal health within to a thyroid-disabled system.

NOTE: In contrast to LT4 monotherapy, during LT3 hormone or desiccated thyroid therapy, TSH responds with abnormally swift suppression as one comes closer to clinical euthyroid status. This was shown in experiments in the 1970s. See “A Dialogue with Utiger: T3-based thyroid therapy over-suppresses TSH“).

Conclusion: We need more than just better visual models, we need a paradigm shift.

Visual models are powerful tools that can help people see large-scale biological systems through different lenses.

Unlike many TSH-centric and T4-centric visual models and verbal claims, this visual analogy of “leaky buckets” emphasizes the fact that the system is not tied to rigid hormone ratios.

This system is flexible. It is vulnerable. It is individualized. T3 supply is subject to just as many intracellular metabolic losses as T4 supply.

My hope is that this visual analogy can help to nudge ethical, intelligent physicians and scientists to shift the paradigm of thyroid therapy.

One of the major challenges of thyroid therapy is that scientists have underestimated the potential for metabolic imbalances and both T3 and T4 losses once the thyroid gland’s vital partnership with TSH is broken.

The entire “peripheral” thyroid hormone system beyond the thyroid gland and pituitary gland is more vulnerable to metabolic imbalance during thyroid function loss and thyroid therapy. Individualized adjustment of T4-T3 secretion ratios and rates is lost, and one now relies on manual adjustment of pharmaceutical dosing.

One cannot expect a thyroidless metabolic system to conform to the statistical norms of a thyroid-equipped system.

In a metabolic system without thyroid function, one cannot presume that a biochemical statistical abnormality is always a pathology. In disability and therapy, abnormal levels and ratios can be either therapeutic or pathological.

Biochemical overcompensation may be necessary to achieve euthyroid intracellular T3 signaling throughout the body. Not every human body will interpret circulating FT3 and FT4 in the same way because enzyme activity and thyroid hormone signaling is variable and hidden within cells.

Once FT3 and FT4 enter cells, their metabolism is largely invisible to biochemical measurement, but their measurement still matters. Hormone ratios (FT3:FT4, RT3:FT4, TSH to FT3) can be analyzed in light of scientific knowledge in order to assess what may be going on within cells.

The current thyroid treatment guidelines focus far too heavily on the statistical normalization of TSH. The TSH has little direct control over all these metabolic pathways, and its benign control is mediated through a healthy thyroid gland that secretes at variable rates and ratios.

Symptoms and multiple biomarkers, not TSH measurement alone, ought to inform clinicians who diagnose and who monitor thyroid therapy. TSH cannot reveal the metabolic responses of tissues beyond the hypothalamus and pituitary. But other biomarkers (such as FT3:FT4 ratios, cholesterol for T3-regulation of liver function, eGFR for T3-regulation of kidney function) can reveal the effects of thyroid hormone signaling in cells all over the body.

We need to move toward a therapeutic paradigm that provides flexible, individualized compensation for unseen T3 and T4 metabolic imbalances within cells.

Metabolic T3 and T4 gains and losses ought to receive appropriate individualized (over)compensation. Individual health outcomes ought always to be prioritized over mere biochemical statistical targets.

References

Click to reveal reference list

Abdalla, S. M., & Bianco, A. C. (2014). Defending plasma T3 is a biological priority. Clinical Endocrinology, 81(5), 633–641. https://doi.org/10.1111/cen.12538

Bianco, A. C., Dumitrescu, A., Gereben, B., Ribeiro, M. O., Fonseca, T. L., Fernandes, G. W., & Bocco, B. M. L. C. (2019). Paradigms of Dynamic Control of Thyroid Hormone Signaling. Endocrine Reviews, 40(4), 1000–1047. https://doi.org/10.1210/er.2018-00275

Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2013). Is pituitary TSH an adequate measure of thyroid hormone-controlled homoeostasis during thyroxine treatment? European Journal of Endocrinology, 168(2), 271–280. https://doi.org/10.1530/EJE-12-0819

Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2016). Relational Stability of Thyroid Hormones in Euthyroid Subjects and Patients with Autoimmune Thyroid Disease. European Thyroid Journal, 5(3), 171–179. https://doi.org/10.1159/000447967

Köhrle, J. (2019). The Colorful Diversity of Thyroid Hormone Metabolites. European Thyroid Journal, 8(3), 115–129. https://doi.org/10.1159/000497141

Mondal, S., Raja, K., Schweizer, U., & Mugesh, G. (2016). Chemistry and Biology in the Biosynthesis and Action of Thyroid Hormones. Angewandte Chemie (International Ed. in English), 55(27), 7606–7630. https://doi.org/10.1002/anie.201601116

Senese, R., Cioffi, F., de Lange, P., Goglia, F., & Lanni, A. (2014). Thyroid: Biological actions of “nonclassical” thyroid hormones. The Journal of Endocrinology, 221(2), R1-12. https://doi.org/10.1530/JOE-13-0573

van der Spek, A. H., Fliers, E., & Boelen, A. (2017). The classic pathways of thyroid hormone metabolism. Molecular and Cellular Endocrinology, 458, 29–38. https://doi.org/10.1016/j.mce.2017.01.025

Wiersinga, W. M. (1979). The peripheral conversion of thyroxine into triiodothyronine (T3) and reverse triiodothyronine (rT3) [PhD, University of Amsterdam]. https://inis.iaea.org/collection/NCLCollectionStore/_Public/11/544/11544357.pdf



Categories: Thyroid hormone conversion, Thyroid Hormones, Triac & other metabolites

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