Biochemical pathway maps are an important aspect of medical education and medical problem-solving. They help us to view a network or series of chemical reactions in cells.
In this article, I present a comprehensive science-based pathway map showing all the major pathways of both T4 and T3 hormone metabolism, also including their urinary clearance.
I also offer a secondary pathway map zooming in on T3 metabolism and clearance alone, which is meant to be an appendix or companion to the more T4-centric map featuring both hormones.
If you find this article too complex and scientific for your taste, I recommend my previous post, which offered a visual analogy of these pathways for beginners and laypeople — “The leaky buckets analogy of thyroid hormone metabolism.”
The pathway maps I display here are based on a thorough review of the science. Fragments of the full pathway map have been portrayed in many thyroid science publications since the 1970s, and I show some of those fragments at the end of the article.
However, it is currently difficult to find a complete metabolic map that includes all the major pathways of T4 and T3 at a glance.
A complete visual showing of both hormones’ metabolic and renal losses is an essential tool for troubleshooting challenging cases — especially during thyroid therapy or illnesses when several health conditions and treatments create metabolic imbalances and make lab results unusual.
Most visual models lack various parts and fail to show T3 pathways alongside T4 pathways. Most portrayals of T3’s pathways are T4-centric.
Most only reveal two of the three different T2 hormone metabolites, and
Most omit the sulfates, the glucuronides, and acetic acid combos Triac and Tetrac. The T4-Tetrac conversion pathway is greatly enhanced during illness, and Tetrac is a potent TSH suppressant (Everts et al, 1994, 1995).
On a much larger scale, metabolism and clearance are part of a larger system that also includes thyroid hormone supply, transport and signaling. Nevertheless, it is useful to have a comprehensive view of the downstream fate of circulating hormones.
In this article, I first present the main T4 and T3 pathway map, followed by the T3 pathway map.
Then, I discuss the rationale and sources that contributed to its design:
- Why physicians and patients need a complete T4 and T3 pathway map — The many problems in diagnosis and thyroid therapy that result from narrow views.
- The communication goals that guided the design of the full pathway map.
- How the new map was constructed from other pathway maps found in medical research articles.
It’s my hope that a more complete pathway map could become a medical problem-solving tool in doctor’s offices and an aspect of thyroid medical education.
The main pathway map
As you can see, I’ve used color coding and shading to emphasize the importance and complexity of deiodination without revealing all the details of this pathway.
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.
A future post will discuss these metabolites and their health effects in more detail.
The T3 pathway map
This map is intended as an appendix to the main map above. As you can see, it is the same in its overall shape because the very same enzymes and pathways are involved.
Placing T3 in the center of the wheel does not reduce the number of arrows encircling it, but it does reduce the number of steps before arriving at T1 via deiodination.
When you look back and forth between the two maps, you’ll see T4 and T3 pathways are equal in number and nature.
However, that does not mean the same percentage of T4 and percentage of T3 is lost by a given pathway. Some pathways (such as D3 enzyme) are more efficient at deiodinating T3 than T4, and others (such as D2 enzyme) are far more efficient at deiodinating T4 than T3.
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. Some scientists propose that this metabolite is created mainly by D1 enzyme, but we still aren’t sure. What we do know is that 3,5-T2 becomes overabundant in illness when D1 is downregulated by low T3 (Dietrich et al, 2015). I suggest that 3,5-T2 may be a biological backup system for short-term T3 loss during acute illness, and D1 may be 3,5-T2’s clearance pathway.
- 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.
- 3-T1 hormone is the final metabolite of T3. It has no known effects, and may simply be an intermediate step of iodide removal before it becomes T0 (Tyrosine), the basic amino acid, which is a building block for many proteins in the body.
- 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.
T1AM
T1AM, also known as 3-Iodothyronamine or 3T1AM, is synthesized via an unknown pathway, but its power over health is significant.
It is the true anti-T3 thyroid hormone. When dosed in large quantities, this hormone and its metabolite, T0AM, can cause
- a reduced metabolic rate,
- reduced body temperature,
- slower heart rate, and
- reduced cardiac output.
T1AM is more abundant within cells than within circulation.
Why do we need a complete thyroid hormone pathway map?
An intelligent reader may well ask, “Why is yet another pathway map needed, given that so many exist already?”
Thyroid hormone metabolism is commonly taught as a simple, introductory overview for beginners. Standard medical education provides only the tip of the iceberg. Making thyroid hormone metabolism seem simple helps to maintain the widespread belief that thyroid therapy is always simple.
On the other end of the spectrum, advanced scientific reports honestly portray the full complexity of thyroid hormone metabolism, but they tend to visualize only part of the system at a time. Many scientific pathway maps (reproduced below) display hormone molecule structures and take up a lot of visual space, and this results in the omission of certain aspects that are not the focus of the particular article.
As a result, one or more of the following features is missing from most of the existing metabolic pathway maps for T4 hormone:
- Most pathway maps are limited to displaying T4-T3 conversion, and sometimes Reverse T3 (RT3).
- Older pathway maps included urinary clearance, but more recent ones exclude it.
- Few pathway maps place T4’s metabolic pathways side by side with T3’s pathways.
- No visuals reveal all of T3’s metabolic and clearance pathways at a glance.
Each missing component matches common blind spots during thyroid therapy that can lead to harm.
1. Most pathway maps are limited to displaying T4-T3 conversion, and sometimes Reverse T3 (RT3).
This limitation in metabolic pathway maps has caused a rift between two extreme schools of thought regarding thyroid hormone metabolism:
- Within standard medicine, some hold to an extremely simplistic TSH-centric and T4-centric approach.
- Within alternative medicine, some hold to an extremely simplistic “T3-versus RT3″ dualistic approach.
While the alternative medicine camp tends to treat suffering patients with more compassion and often with more success, both extreme views are based on narrow models that may result in mistaken diagnoses, thyroid therapy mistakes and harm to patients.
Both perspectives would benefit from a broader view of the full set of metabolic variables.
1 a. The TSH-centric and T4-centric approach
In conventional thyroid medicine, history has focused scientists and physicians on T4-T3 conversion. The inevitability of T4-T3 conversion in every human being was a major feature in the promotion of LT4 monotherapy in the 1970s and 1980s.
As thyroid science became increasingly TSH-centric in the 1980s and 1990s, T4-T3 conversion seemed more and more like the may metabolic pathway of significance. The efficiency of T4-T3 conversion via D2 enzyme within the pituitary and hypothalamus explains TSH’s normal mathematical log-linear response to Free T4 in people without central hypothyroidism.
Of course, informed thyroid scientists and some endocrinologists understand that far more than T4-T3 conversion is involved, but most thyroid medical education is simplified for the average general practitioner managing diagnostic screening and LT4 monotherapy for primary hypothyroidism. Thyroid cancer, hyperthyroidism, and complex cases are ideally referred to endocrinologists, but many of them are specialists in other areas of metabolism such as diabetes. It has become very rare to find a physician or specialist who understands more than the T4-T3 conversion pathway.
A T4-centric pathway map that focuses on T4-T3 conversion fails to account for many puzzles. For example, it cannot fully explain the degree to which an individual’s metabolism has become dysregulated by a non-thyroidal illness.
Therefore, Reverse T3 (RT3) is sometimes included in pathway maps.
But even a T4-T3-RT3 pathway map fails to explain many important aspects of thyroid hormone metabolism during thyroid therapy. Changes in thyroid hormone supply, T4-T3 conversion rates and T4-RT3 conversion rates do not account for all FT4 or FT3 changes and abnormal TSH responses. The abnormal TSH response to T3 oral dosing, for example, may have a lot to do with T3 conversion to Triac, and with localized poor D3 and D1 expression in pituitary and hypothalamus which may prevent T3 conversion to two types of T2. In addition, some changes and abnormalities may have to do with non-deiodination pathways.
In the face of metabolic uncertainty and complexity, many people cling more resolutely to the comforting simplicity of TSH-centric and T4-centric views, defending a limited paradigm’s policies (and their own careers) with great vigor.
A metabolically narrow view can easily resort to extreme measures to deny the realities it fails to explain scientifically.
When a patient has chronic hypothyroid symptoms despite normal TSH and thyroid hormones, reductive guidelines teach physicians to shift the blame to non-thyroidal illnesses, or even to suspect that the patient is inventing symptoms through a process of “somatization” (Jonklaas et al, 2014).
Patient-blaming and shaming is an unethical and anti-scientific TSH-centric defense system that many patients have experienced when they encountered thyroid therapy challenges. (See “2019 ATA article engages in patient-blaming and doctor-shaming“)
No wonder many suffering patients have resorted to self-funded alternative medicine approaches to receive more respectful, compassionate and effective treatment. It’s unfortunate that many can’t find metabolically informed physicians within their society’s standard health care system.
1 b. The“T3-versus RT3” dualistic approach
In some alternative medicine and thyroid patient communities, this narrow view of the metabolic pathway map has led to another extreme approach.
Working with the widespread assumption that Reverse T3 and T3 are the two alternative pathways for T4 metabolism, this narrow view perpetuates unscientific myths about the T3-stealing and T3-blocking properties of RT3. While T3 and RT3 engage in an epic battle between good and evil, the heroic thyroid doctor and sometimes the experienced patient advisor intervenes to save the suffering victim. Promoters of RT3-lowering protocols tend to increase T3 dosing and lower T4 dosing to clear RT3 faster, claiming that the RT3 hormone itself (not the enzyme that creates it) functions as a toxin or metabolic brake.
This approach is not focused on TSH normalization, but on another set of rigid biochemical targets: a low-normal or low RT3 and a FT3 in the upper quadrant of reference range. FT4 is usually mid-range and TSH is low in range or below.
Some camps are adamant that this biochemical profile is “optimal” for all treated thyroid patients. This narrow view optimal biochemistry is based on certain patient experiences and certain types of clinical experience, but it lacks published research studies to back it up. Repetition — across multiple websites and popular books by health care professionals and clinics — makes the claims seem truer.
Many intelligent, compassionate people, including physicians with “MD” after their names, have believed and promoted the limited dualistic logic without looking deeply into what many decades of science really says (See “RT3 inhibits T4-T3 conversion. How worried should we be?” and “Deiodinase Type 3, not RT3, plays the T3-blocking role“).
On the one hand, this extreme view achieves success in many cases where the TSH-centric and T4-centric approach has failed patients.
Raising low FT3 levels by means of hormone dosing (regardless of RT3 targets) can certainly help many hypothyroid patients recover from poorly optimized thyroid therapy or a chronic T3-depleting illness. Yet the rare opportunity to find a doctor who specializes in this area may cost them a lot of money, and the tests and treatments may not be available in their region or country.
On the other hand, manipulating the T3/RT3 ratio in blood may be a superficial shift for some patients whose metabolic and urinary losses will continue.
Neither reducing RT3 or raising T3 has any direct control over an illness-induced overactive deiodinase type 3 (D3) enzyme that depletes T3 from cells and local tissues. Both excess T4 and excess T3 can trigger a rise in D3 enzyme expression.
A shift away from T4 intake toward T3 intake is not likely to reduce excess conversion of T3 to 3,5-T2 or Triac. Nor does an RT3-reducing protocol always stop illness-induced high T3 urinary clearance rates.
When a RT3-reducing, FT3-raising protocol fails to achieve its goals, once again scapegoating and blame may follow, as some will blame iron, cortisol or diet, and others will blame patients for not doing it properly.
Therefore, both schools of thought can result in patient-blaming and scapegoating when their narrow view fails to accommodate therapeutic reality.
What compassionate thyroid specialists and suffering thyroid patients need is a more complete and scientifically sound conceptual model. Hopefully a deeper understanding of many pathways’ interactions will allow them to set aside rigid views of what will be biochemically optimal for each unique, thyroid-disabled individual.
2. Older pathway maps included urinary clearance, but more recent ones exclude it.
This omission mainly occurs because urinary clearance technically does not qualify as a “metabolic” pathway when T4 and T3 are lost without being transformed.
Nevertheless, for practical purposes, urinary T3 and T4 deserve a place on metabolic pathway maps.
They serve as an important reminder that not all Free T3 (FT3) and Free T4 (FT4) is destined to be transported into cells, metabolized in cells, or achieve signaling activity. Sometimes an urinary loss will cause TSH elevation, and sometimes it will not.
Without urinary loss, a pathway map does not fully represent the “loss” side of the thyroid hormone economy and can lead scientists and clinicians to hypothesize only a problem with absorption or every other pathway except urinary loss.
Click to expand section
Studies that dismiss the health significance of urinary T3 or T4 losses tend to focus on people who have enough healthy thyroid function to compensate for losses (Cai et al, 2014), not on severely hypothyroid people on thyroid therapy.
Endocrinologists have long ago been reminded that urinary losses matter far more when a person has little to no thyroid function to replace lost hormones (Fonseca et al, 1991). More recently, Benvega et al, 2015 have cautioned that it is very common to jump to conclusions about gastrointestinal malabsorption of levothyroxine (LT4) being the cause of increased LT4 requirements, reduced FT4 and elevated TSH during thyroid therapy, without considering increased urinary losses of thyroid hormone.
Urinary loss without appropriate thyroidal or pharmaceutical compensation can potentially destabilize pregnancies and worsen nonthyroidal illnesses. It has also destabilized thyroid therapy to the point of severely elevated TSH and severe hypothyroid symptoms (Soh et al, 2015; Chandurkar et al, 2008).
However, urinary losses do not always result in an elevated TSH when more T3 is lost than T4. The hormone TSH is also lost in urine at different rates than thyroid hormones (Cai et al, 2014). The rate of TSH loss can be increased in nephrotic syndrome or renal failure, and more TSH is lost when TSH is higher (Yoshida et al, 1988). In addition, many drugs treating concurrent illnesses can oppress TSH and prevent it from rising normally in response to lost thyroid hormones (Haugen et al, 2009). A normal or mildly elevated TSH may misclassify a person as euthyroid or “mildly hypothyroid” when they are in fact objectively hypothyroid in low serum FT3 and/or FT4 thyroid hormone levels.
Urinary losses depend to some degree on the ratio of hormone that is bound versus free. Free thyroid hormones are more subject to urinary loss. A significantly larger fraction of T3 is free hormone, since approximately 0.3% of T3 is free, while 0.03% of T4 is free (Refetoff, 2000), and therefore T3 is potentially more vulnerable to urinary loss if T3-specific binding proteins are reduced. Significantly more T3 than T4 is bound to albumin. Many health conditions can change the amount or affinity of binding proteins during thyroid therapy, and when the total hormone supply is limited by dosing, this change will increase or decrease free hormone availability and the amount that is subject to renal loss.
Different kinds of plasma binding proteins (TBG, albumin, transthyretin) bind T3 and T4 at different rates and with different levels of affinity. A rise in TBG may occur due to a rise in estrogen levels, but a fall in circulating albumin may occur due to illness. When albuminuria and TBG loss occur during nephrotic syndrome, a type of kidney dysfunction, not only free thyroid hormones but bound thyroid hormones may be lost (Soh et al, 2015).
Our current state of medical blindness to urinary FT3 and FT4 losses during thyroid therapy has resulted in scientists jumping to conclusions with incomplete data sets.
For example, in their study of recombinant human thyrotropin (rhTSH) during levothyroxine (LT4) treatment after a total thyroidectomy for thyroid cancer, Beukhof and team discovered a loss of Total T3 and Free T3 during the high TSH phase, without any significant change in total or free FT4 or RT3. They suggested a reduced D2 enzyme activity was the likeliest cause. Beukhof’s team even suggested increased T3’s non-deiodination metabolic clearance pathways.
However, Beukhof did not consider the winter urinary T3 losses in LT4-treated patients (Gullo et al, 2017), nor did they suspect rhTSH would have any direct effects on the kidney’s processing of T3 hormone. TSH receptors are located in the kidney, and therefore, TSH receptor signaling can independently affect kidney function (Sellitti et al, 2000), including the rate of urinary loss of thyroid hormones. As of 2020, rhTSH took the sole blame for decreased kidney function, despite this effect also being significantly associated with an isolated drop in FT3 (Saracyn et al, 2020).
On the other end of the spectrum, the risk of a mistaken diagnosis of hypothyroidism may occur when measuring urinary hormone levels and not measuring circulating thyroid hormone levels at all (Wiersinga & Fliers, 2007).
In our TSH-centric era of thyroid therapy, it is too tempting to misinterpret a rise in TSH as a result of LT4 malabsorption, to blame higher TSH (but not FT3 loss) for kidney dysfunction, or to misinterpret a normal TSH to mean that nothing is going wrong with T4 or T3 clearance (or TSH clearance).
The kidney cannot directly regulate the rate of TSH secretion, but shifts in kidney health can affect the rate of TSH loss and T3 and/or T4 loss. This is why both serum free and total thyroid hormones, kidney function, serum and urinary albumin ought to be on the table during the metabolic assessment of puzzling cases with suspicious symptoms.
Given the difficulty of arriving at accurate conclusions about mysterious losses in T3 and/or T4 during thyroid therapy, where else do these urinary losses belong, other than in the context of T3 and T4 metabolism?
3. Few pathway maps place T4’s metabolic pathways side by side with T3’s pathways.
One of the most common mistakes in thyroid therapy is to judge Free T4 and Free T3 separately by their reference ranges, in isolation from each other, and often through the lens of TSH.
But the human body never interprets FT3 or FT4 in isolation from each other.
T3 and T4 metabolism are so symbiotic that both sets of pathways truly belong together in the same visual. A concise visual can make this possible.
Although the complexity can be overwhelming, a pathway map showing both hormones’ fates should inspire physicians and patients to learn more about the mechanisms that govern these pathways.
A “binocular” view of both hormones’ intracellular journeys could greatly assist with interpreting both generalized thyroid symptoms and organ- and tissue-specific thyroid symptoms during thyroid therapy.
4. No visual reveals all of T3’s metabolic and clearance pathways at a glance.
Many T4-centric pathway maps cover selected aspects of T3 metabolism. The most complete maps illustrate T3’s conversion to two types of T2, within a corner of the full T4 deiodination pathway including RT3. These maps do not include T3 conversion to sulfates, glucuronide, Triac, or urinary loss.
T4-centric models often make it seem as if T3’s appearance is entirely dependent on T4. However, this is only the case in LT4 monotherapy in a person with no thyroid function. T3 has a highly variable rate of T4-independent supply in thyroid health, in thyroid disorders, and in the full range of thyroid hormone therapies.
In addition, T4-centric models often make it seem as if T3’s disappearance is entirely dependent on its subsequent deiodination to T2. However, circulating and intracellular T3 suffer many non-deiodination losses, including T3 sulfate and glucuronate, Triac, and urinary loss.
Even in the main map I’ve constructed showing both hormones, the complexity of T4 and T3 metabolism pushes T3 and its metabolites into a corner of the map, which makes it seem less important. T4-centric models can cause a visual distortion of the clinical reality, because T3 losses are just as important, if not more clinically important, due to the far greater potency of T3.
The time has come for a T3-centric pathway map, in context.
A T3-centric pathway map makes sense given the centrality of T3 signaling to thyroid hormone status in every tissue and organ.
However, a T3 pathway map ought to be used as an appendix or supplement to maps that focus on T4 or both hormones. As mentioned above, the human body never interprets Free T3 in isolation from the level of Free T4 capable of entering cells, and being filtered through the kidney, at the same time.
The message of a T3 pathway map is that T3 metabolism and clearance reduces the amount of Free T3 that gets into receptors.
T3 does not always need to be represented as a T4 dependent. Most T4-centric pathway maps omit the supply source and do not specify how much T4 or T3 is from a thyroid or a pharmaceutical. Likewise, a T3-centric pathway map can zoom in on the downstream fate of Free T3 without specifying the T3 source(s) as a thyroid gland and/or T3 pharmaceutical, and/or T4 pharmaceutical or T4 from a thyroid.
When a T3-centric pathway map is interpreted in context, the greater detail it provides may go a long way to reducing medical myths about intracellular T3:
- One myth is that more intracellular T3 always hides in cells when FT3 is low in a poor converter on LT4 monotherapy.
- Another myth is that intracellular T3 always builds up in cells and floods receptors when FT3 is mildly high during T3-dominant therapies that maintain mid-range or lower FT4.
Both myths presume the existence of surplus intracellular T3 based on no evidence. They appear to overgeneralize from untreated early autoimmune hypothyroidism or hyperthyroidism, which are very different from therapy-induced FT3:FT4 ratios.
As for the complexity of TSH response to Free T3, the full pathway map includes many T3-degrading enzymes and clearance pathways that the pituitary and hypothalamus lack. It is a reminder that TSH is a local tissue response and is not omniscient.
Anyone who calls themselves a thyroid therapy expert ought to consider the rates of various T3 losses. A metabolic shift may explain the correlation or conflict between circulating FT3 levels, concurrent FT4, TSH, and clinical presentation.
Communication goals for a full pathway map
A comprehensive pathway map is not a tool for the diagnosis of overt primary hypothyroidism or hyperthyroidism, which is usually quite simple. Instead, it is for challenging or puzzling cases, often within thyroid therapy and/or metabolism-distorting illnesses.
It should facilitate metabolic detective-work and critical thinking by raising the following questions:
1. What are all the pathways that co-regulate how much Free T4 is capable of being carried into cells, and how much intracellular T4 will convert to T3?
2. What are all the pathways that co-regulate how much Free T3 is capable of being carried into cells, and how much intracellular T3 will be capable of signaling in receptors before being converted to another hormone?
To begin to answer these questions, it helps to have a concise science-based visualization that illustrates all the pathways without too much scientific detail.
A tension always exists between content inclusion/exclusion and visual design, so a designer must make some difficult choices.
Inclusion and emphasis
It ought to include all the major pathways that can steal T4 and/or T3 from cells and from circulation.
- To illustrate T4 metabolism, it should include both T4-T3 conversion and T4 conversion to major non-T3 metabolites.
- To illustrate T3 metabolism, it should also include all pathways of T3 conversion to non-T3 metabolites.
- It should emphasize deiodination pathways via D1, D2 and D3 enzymes and hint at the complexity of these pathways.
- It should include urinary clearance of both unmetabolized T4 and T3 to remind us that not all circulating FT4 and FT3 is destined to enter cells.
Exclusion and de-emphasis
No visual model can ever encompass the full complex reality.
It does not normally include supply pathways. The complexities of thyroid gland function, T3 and T4 synthesis, and pharmaceutical thyroid hormone absorption are generally beyond scope. Let other models focus on non-metabolic methods of supplying T3 and T4 to blood.
It does not normally include transmembrane transport and receptor sensitivity, as these are complex factors commonly excluded from most metabolic maps.
It does not normally include names of organs and tissues where enzymes are commonly located. This is because these enzymes are often found in more than one tissue. Explanatory text or additional images can supply tissue-specific information.
It does not normally reveal all that happens to metabolites further downstream. Each metabolite is subject to subsequent metabolism, until all that remains are free iodide and tyrosine molecules.
It may de-emphasize hormones found in very low levels in circulation. It may omit hormones that are mainly intrathyroidal (like DIT) and de-emphasize those that are mainly intracellular (like T1AM).
And finally,
It should omit quantitative estimates of “normal” thyroid hormone metabolism. This is because individualized metabolic flexibility is a rule even in health. Mimicry of statistical norms achieved in health is not the goal of thyroid therapy. There are many possible pathways to achieving euthyroid intracellular T3 signaling during thyroid therapy. Therapy may need to overcompensate for chronic metabolic handicaps, and by doing so, it may discover an atypical route to achieve global euthyroid status for the individual.
Visual design considerations
In the past, many pathway maps were designed for scientific journals in black and white print format.
In today’s digital world, a map designed for widespread circulation needs to be capable of traveling as a color image file. At least some of it needs to be readable when shared on social media. The full image should be readable on small handheld devices.
If or when the map does not easily fit onto a small screen, an additional image may supply a zoomed-in section, as I’ve done by supplying a T3-centric map.
A map for an informed patient and their physician will be more like a subway map, similar to Roche’s metabolic pathway maps. The features worth imitating are the visual patterns using colors, arrows, shapes, text alignment and graphic repetition.
However, a pathway map for non-biochemists may sacrifice Roche’s technical details, such as molecule shapes, enzyme names, and chemical reaction types.
As you’ll see below the complete pathway maps, many almost-complete pathway maps are so scientific and technical that they become obscure to the average physician and patient without extensive annotation or explanation.
Scientific sources
Copyright note: Quotation, paraphrase, and reproduction, annotation, and adaptation of graphs and tables from copyrighted scientific publications is acceptable within the terms of Canadian and US copyright “fair dealing” and “fair use” for purposes of education and review: See copyright law info
I provide the following metabolic pathway maps in chronological order.
- Wiersinga, 1979
- Engler and Burger, 1984
- Mondal et al, 2016
- Jongejan et al, 2020
- Kohrle & Bieberman, 2019
Over time, the complete metabolic map of thyroid hormones has changed and expanded. Some scientists have given a general overview, and others have zoomed in and expanded particular sections.
In addition to the scientific visuals displayed below, I relied on many sources to verify the accuracy and completeness of the T4 and T3 pathway map. The following reviews are major sources:
- Peeters and Visser, 2000
- Wu et al, 2005
- Kohrle, 2019
- Senese et al, 2014 and 2019, and
- van der Spek et al, 2017.
From Wiersinga’s thesis (1979)
Click to reveal this section and its visuals
The components of Wiersinga’s original visual models are shown in slightly blurry typeface.
My annotations are in color and in a clearer typeface, providing data from the text and other images in Wiersinga’s thesis.
Strengths of the original visual
- Emphasizes the difference between deiodination to T3 and RT3 versus non-deiodination pathways
- Mentions the complexity of de-iodination (removal of iodine) by showing iodine removed from the inner ring vs. outer ring to form T3 and RT3
- Includes “T4 in urine” as a separate pathway
- Includes T4G, T4S, and “Deamination / Decarboxylation” — It covers all the major pathways
Weaknesses of the original visual
- Fails to reveal T3 pathways. The omission makes the graphic entirely T4-centric. It may imply to readers that T3, located on the “deiodination” side of the graphic, is not subject to the same “non-deiodination” pathways as T4.
- Focuses on elements that are less necessary to non-scientists, such as the huge molecule structure of T4 in the middle, which is not even labeled “T4”
- Says “Deamination / Decarboxylation” to name the processes without specifying Tetrac and T4AM as metabolic products. This makes the graphic obscure for non-scientific readers
- Lacks visual emphasis, partly due to the 1979 academic thesis as the medium of display and lack of color.
Another issue, which is not quite a strength or weakness, deserves some expansion:
Problematic: Numeric estimates
One of the major problems with Wiersinga’s model was its estimates of average conversion rates.
I decided to add further estimates that Wiersinga had left out of the visual. I added “Avg:” or the symbol of approximation (~) as a reminder that it is only an estimate.
However, averages are not representative of health. Decades of scientific reports have revealed significant human diversity in metabolism. (See “Question Pilo’s study: The wide range of thyroid hormone adaptation.”)
Given the widespread misuse of statistical averages to limit combination thyroid therapy to 1:14 to 1:20 dose ratios, I decided it was important to include some of Wiersinga’s ranges. They were obtained from an additional model on page 5:
As with Wiersinga’s larger pathway map, this one also does not account for downstream T3 metabolism. The top of the model is focused on the thyroid gland, while the horizontal arrows between the three boxes represent peripheral conversion. Urinary clearance is not mentioned.
It is cluttered with numeric estimates, which can be both confusing and misleading.
This model does not try to account for 100% of T4’s metabolic fate and excretion in any human being, nor does it account for T3’s losses.
This is why including numbers can be very problematic.
When physicians see averages without knowing the full range, they may think there’s more stability from person to person than there truly is. Even when ranges are given, they do not explain what makes them so wide (pathology or natural human variation?).
Numeric estimates vary based on the presumptions and methods of the estimators. Wiersinga’s thesis claimed that deiodination to T3 or RT3 accounts for an average of 81% of T4’s fate (33% to T3 and 48% to RT3). However, the text of the thesis explained that:
“about 80-90% of T4 is converted to T3 and rT3 (Chopra 1976; Gavin et al 1977).”
In 1984, Engler and Burger presented several different pie charts showing the metabolism of T4 to RT3, T3, and “other pathways” that show that the 80% estimate reduces to 71 and 65% in various disease states while the T3 piece of the pie shrunk the most.
What are the major lessons of these graphics, beyond the complexity of the system?
1. Thyroid hormone metabolism is a very flexible system, even in health.
Presenting the ranges communicates the truth of individuality, instability and uncertainty in the fate of T4 hormone.
2. Statistical averages can be deceptively reassuring about unhindered metabolism during thyroid disease and therapy.
The healthy TSH-stimulated thyroid gland can compensate for a wide range of imbalances by altering the ratio and rate of T4 and T3 secretion.
But in thyroid therapy, many people do not have this ability. The thyroid-disabled individual must either convert more T4 into T3, or dose T3 hormone to make up for the loss.
Illness also causes imbalances, since some enzymes and pathways are upregulated while others become less efficient.
- Some people may deiodinate 70% of T4 to T3/RT3 pathways because they have more significant urinary losses, or a higher rate of conversion to Tetrac, Sulfates, or Glucuronides.
- Others may deiodinate 90% of their T4 to T3/RT3 and dedicate less to non-deiodination pathways, but the percentage deiodinated to T3 may be much lower in illness.
Therefore, it’s better not to put numeric statistics on most general-purpose metabolic pathway maps unless the designer explains how the data were derived. Numeric estimates ought to remain in the context of primary experimental research reports that explain their methods. Visuals are often reproduced on their own, and they can be interpreted out of context.
Engler & Burger, 1984
Click to reveal this section and its visuals
One of the most conceptually complete metabolic pathway maps was produced in 1984.
Unfortunately, it labeled the pathways only with the obscure scientific terms for metabolic processes such as “conjugation.” It did not name any specific thyroid hormones beyond T4, but it implied them to the highly educated reader.
Therefore, I’ve added color annotations for clarity regarding the hormones that may be produced by the processes it mentions.
Engler and Burger placed T4-derived “iodothyronines” (thyroid hormones T3, RT3, T2 and T1) in three boxes around the T4 molecule:
- Above the molecule, some T3, RT3, T2 and T1 avoids being metabolized by any non-deiodination pathways.
- On the left, some T3, RT3, T2 and T1 is metabolized by the “Conjugation” pathway (thyroid hormone sulfates and glucuronides).
- On the right, some T3, RT3, T2 and T1 is metabolized into Triac, Tetrac, and Diac and Monoac by deamination, as well as T3AM, rT3AM, T2AM, and T1AM by decarboxylation.
In the lower middle, one sees what happens when the link between the two rings is broken (ether link cleavage, ELC), forming diiodotyrosine (DIT). This hormone is quickly broken down into non-extractable iodine (NEI) and iodide. In my discussion of Mondal et al, 2016, below, I explain why I’ve omitted DIT from the complete pathway map, based on more recent research.
The graphic omits urinary loss of unmetabolized hormones. Their full article frequently discusses urinary iodine, but only once mentions urinary T4-T3 conversion rates.
The graphic includes a lot of repetition. Besides the three “iodothyronines” boxes, the capitalized “DEIODINATION” boxes appear two times, and the “monodeiodination” boxes appear five times. Deiodination and monodeiodination are almost synonyms.
While the repetition is highly inefficient, it makes the model conceptually more complete. It teaches the viewer that deiodination occurs even to sulfated, glucuronidated and acetic acid thyroid hormones. For example, one can correctly deduce from this pathway map’s region on the right (in purple) that Triac can be conjugated to form both TA3S and TA3G.
However, this pathway map fails to explain a major exception. Its implied principle is that every possible thyroid hormone variant can be deiodinated in every possible way. Scientists have discovered in more recent years that T4S and T4AM do not become de-iodinated to their T3 counterparts in vivo:
- T4 Sulfate cannot be deiodinated to T3 Sulfate. This is because the sulfate group gets in the way of removing that particular iodine atom. T4S can only convert to RT3 Sulfate. (Peeters and Visser, 2017; van der Spek et al, 2017)
- T4AM does not convert to T3AM (Piehl et al. 2011).
Therefore, T4 is not the origin of every other thyroid hormone. T3 is the origin of T3 Sulfate, and T3 is the origin of T3AM.
These broken T4-T3 deiodination pathways are yet another justification for viewing a T4-centric pathway map side by side with a T3-centric pathway map. Sometimes the starting point is T3, not T4.
In fact, Engler and Burger reminded readers in their article that T4, via all its metabolic pathways, is not the origin of all iodide that has been removed from thyroid hormones. They calculated that T3 (which also has a thyroidal origin in health) and its metabolites account for 35 to 40% of the urinary iodide obtained from deiodination.
Mondal et al, 2016
Click to reveal this section and its visuals
Mondal and colleagues provide a much more recent map than Wiersinga’s, but without percentages.
I’ve borrowed the concept of a circular wheel of metabolites around a central T4 from this graphic.
The hormone names are in such small print that I felt it necessary to enlarge them.
I’ve also annotated with colored text and colored shading to emphasize deiodination (pink region), since it was not emphasized in the black and white original.
Mondal omits one pathway that Wiersinga and I have included: Urinary loss. This is because Mondal and team are focusing on “biosynthesis” of thyroid hormones, which is the very opposite of clearance.
Mondal also omits subsequent deiodination of T3 (and rT3), and does not show that T3 is capable of becoming Triac (TA3), T3S, or T3G.
I have omitted DIT (diiodotyrosine) from my model because this hormone’s main purpose is as a building block in the thyroid gland’s synthesis of T4 and T3. It is not a major fraction of circulating thyroid hormone.
Further, DIT is primarily a byproduct of thyroid function. In a study of people with low thyroid function on stable LT4 therapy, DIT was below the limit of detection (Faber et al, 1988). The very small amount seen in peripheral circulation during health is correlated with thyroid gland secretion (van der Spek et al, 2017).
DIT’s formation by oxidative degradation in macrophages or leukocytes is not seen in any nonthyroidal illnesses except severe bacterial sepsis, where circulating DIT builds up to levels equaling their elevated RT3. It is proposed that in such cases, the deiodination of DIT is also significantly slowed down both within the thyroid gland and in peripheral tissues, leading to its buildup in serum (Meinhold et al, 1991). When DIT is dosed pharmaceutically, it is rapidly de-iodinated and less than 1% appears in urine (Meinhold et al, 1987).
Also, I chose to omit T4AM from my model because circulating T4’s conversion to T4AM in living humans and rats is still not evident, according to Kohrle. The non-deiodination step is theorized to occur further downstream after further deiodination of T4 (see Köhrle & Biebermann’s map below).
Jongjean et al, 2019
Click to reveal this section and its visuals
Jongjean and team provide a complete downstream map of deiodination all the way from T4 down to T0 (T zero).
Interestingly, it is shaped like a diamond. This is because there are 3 iodine molecules to remove one at a time from T3 and RT3, but then there are only 2 iodine atoms to remove one at a time, and finally, there is only 1 iodine atom left to remove.
In the original graphic, the horizontal lines next to T4 and T3, pointing to the left beyond the diagram, connect to Tetrac and Triac.
Therefore, this map is a useful tool, but it only focuses on deiodination plus T3 and T4 hormone’s acetic acid pathway.
Köhrle & Biebermann’s proposed pathways to T1AM
Click to reveal this section and its visuals
T1AM is also called “3-Iodothyronamine” or 3T1AM.
T1AM is a powerful hormone whose effects on the body cannot be ignored. Its quantity may sometimes equal that of T4 hormone, but it can oppose some of T3’s actions by reducing body heat and lowering heart rate.
The formation of T1AM is still mysterious.
Scientists now question the former assumption that it can be derived from T4 in vivo (Piehl et al, 2011).
Hackenmueller’s study found that “T1AM biosynthesis can be inhibited by the antithyroid drugs MMI and KClO4” and therefore likely involve the thyroid gland:
“These unexpected results lead to the conclusion that like T4, T1AM is either
(Hackenmueller et al, 2012)
• a direct product of the thyroid gland, or
• a product of another cell population that expresses NIS and TPO or homologs in functional form, or
• is a metabolite of another thyroid gland product that does not arise from extrathyroidal metabolism of T4.”
Recently, it was discovered that the “AM” format requires decarboxylation by a special enzyme in the intestine (Hoefig et al, 2015).
Köhrle & Biebermann
More recently, others propose a transformation by the decarboxylase enzyme that may begin not with T4 but with RT3, T3, T2, or T1 (Köhrle & Biebermann, 2019; Laurino et al, 2018, 2019).
Köhrle & Biebermann suggest this possible derivation:
There was no visual space for dashed arrows extending from T2 or T1 to T1AM in my inclusive pathway map, but I include them in the T3-centric pathway map.
Conclusion
Visuals can be powerful.
- On the one hand, limited visuals have the potential to limit thyroid therapy and imprison patients in ineffective treatment strategies. They can even limit thyroid science.
- On the other hand, comprehensive visuals that portray a complete system have the potential to solve thyroid therapy puzzles and put an end to many patients’ suffering.
Thyroid hormone metabolism and clearance is a complex system. It is very tempting to “dumb it down” to accommodate the limited medical education of most physicians and patients.
Other health disorders often have more comprehensive pathway maps available. Steroid metabolism — including cholesterol, adrenal hormones and sex hormones — is more often visualized in all its complexity.
It is tempting to limit the cost of thyroid medical testing and therapy adjustments so that other disorders can be the focus of time, energy and expenditure. Disorders such as diabetes, heart disease, and cancer, are currently considered a higher priority.
Like putting blinders on horses, an incomplete metabolic and clearance map may prevent physicians from seeing where problems can occur during severe illness or thyroid therapy.
If a problematic pathway cannot be visualized, it may be assumed not to exist.
The omission of key pathways may limit medical time, energy and expenditure by maintaining ignorance. But this can eventually cost more in the long run.
When thyroid therapy normalizes TSH but cannot achieve the primary metabolic goal of body-wide euthyroid T3 signaling levels, it can potentially worsen many other chronic illnesses and make recovery difficult or impossible. How many specialists will be consulted? How many emergency visits? How many more days are required in hospital ICU wards?
Poorly adjusted thyroid therapy also causes long-term human suffering from chronic symptoms, which may be entirely unnecessary with adjustments to circulating FT3 and FT4.
Hopefully, an inclusive visual model may inspire a desire to learn more about each pathway. It may also defend and promote effective thyroid therapies that truly compensate for an individual’s acute or chronic metabolic handicaps.
- Tania S. Smith, PhD
Thyroid patient and thyroid science analyst
President, Thyroid Patients Canada
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Great content as always!
Hi great work and I think very helpful. I have struggled with these issues and getting doctors to actually try and find out whats going on rather than just making adjustments to dosages. I know its not quite the same concept but Ive found some of the diagrams in this paper https://www.frontiersin.org/articles/10.3389/fendo.2017.00163/full
very helpful as well.
Hi Rob, yes that is a very good article. Thanks for linking it. I often cite Chatzitomaris et al, 2017, and I’ve used their deiodination image in another article or two. They do have some good images in there, for sure. As you can see it is also coauthored by Hoermann, Midgley and Dietrich, among several others, and we often cite the research articles of Hoermann’s team because of their scientific insights that go past thyroid dogma. Their visual model of pathways goes down the Deiodination path to the 3 types of T2, which is way more than many others do. Yet they only briefly cover non-deiodination pathways in a few sentences here and there, summarizing ideas from other articles that go more into depth. They use the wording more common in the 1950s, “triiodothyroacetate, and tetraiodothyroacetate” instead of saying “triiodothyroacetic acid,” Triac or TA3 and Tetrac or TA4, which makes it hard to understand if you don’t know what they are likely referring to.