Ingbar and Braverman’s historic study of LT4 monotherapy

As part of my post on “The thyroid gland is a T3 shield,” I reviewed a research article by Ingbar and team from 1982. Wow. What a treasure.

The title of this article is

“Elevated serum thyroxine concentration in patients receiving ‘replacement’ doses of levothyroxine.”

Just look at that title. They began their title with the shocking word “elevated,” not the word “euthyroid,” “normalized” or “normalizing.”

They dared to put the word “replacement” in quotation marks in the title, admitting a healthy doubt that a living gland that flexibly secretes two hormones can be fully replaced by static doses of the less essential of the two thyroid hormones.

As I skimmed their article, I was so fascinated by their scientific honesty and courage that I read it over many times. I followed many of its references to their sources. I looked up the publishing history of the lead author and the senior authors, Sidney Ingbar and Lewis Braverman. In particular, Ingbar’s obituaries left me in awe of his accomplishments.

Just as I have engaged in conversation with several of Robert Utiger’s historic thyroid research articles in a previous post, I wanted to write a series of posts in which I conversed with Ingbar’s article as if I was interviewing the authors, not just writing to contemporary readers.

What’s so great about this 1982 article?

First of all, its fundamental teachings served as an introduction to T4 monotherapy for some physicians who may have been less familiar with it at the time. Ingbar and team revealed how much an individual’s thyroid gland function (or utter loss of function) and metabolic health affects their unique response to LT4 thyroid medication. Individual handicaps including the missing or failed organ in the neck determined how well each person would absorb T4 and then metabolize it to T3 hormone. Pharmaceutical choices would influence Total T3 and T4 hormone concentrations in blood, as well as Reverse T3 concentrations. These metrics correlated with physicians’ observations of patients’ health outcomes and well being.

Ingbar and team concluded with a concept that many thyroid patients and clinicians have learned over years or decades of experience with T3 and T4 hormone measurement, that “the serum T3 concentration correlates better with the clinical state than the serum T4 concentration does,” although the T4 concentration is not inconsequential.

This historic study of Levothyroxine (LT4) therapy is well worth pondering in quotations, commentary, visual illustrations, and comparisons to modern articles.

Beyond its fundamental teachings, this article was also a demonstration of medical ethics and professionalism in research.

Ingbar and Braverman wrote at a point in history when desiccated thyroid (NDT / DTE) therapy was undergoing public, vitriolic attack by some physicians (See our review of Penny and Frasier’s shameful 1980 “study” of children taken off desiccated thyroid and placed on levothyroxine, cited in Biondi and Wartofsky’s 2014 dismissal of desiccated thyroid).

I honor these men for not falling prey to pharmaceutical prejudice or biochemical bigotry. They did not succumb to the simple-minded belief that the statistical norms of healthy people’s thyroid concentrations are prescriptions or prisons for the thyroid-handicapped population, whose treatment sometimes necessitates biochemical exceptions to norms. They did not engage in denigration of the T3 hormone test or T3-inclusive pharmaceuticals or patients’ “non-specific” thyroid symptoms.

Instead of engaging in a Synthroid sales-pitch in a study that examined Synthroid and another brand of levothyroxine, they revealed that not even this proudly-trumpeted synthetic preparation could fully restore the normal biochemistry of thyroid health. This type of hormone preparation, despite its pharmaceutical precision and synthetic purity, elicited a wide range of T4 absorption levels and individualized T4-T3 conversion rates, resulting in distorted hormone concentrations in blood. It could not fully replace the metabolic engine of the living thyroid gland. No therapy can.

But they still tried to make levothyroxine work for as many people as possible. They accommodated its features. They shared their developing scientific and practical understanding of how physicians could evaluate the uncertain health risks of “elevated serum thyroxine.” They pointed out the occasional elevation of T4 came with a significant metabolic handicap not normally present in endogenously hyperthyroid people, a significantly lower level of circulating triiodothyronine (T3).

In this opening article, I provide an introduction to Ingbar and Braverman as scientists and famous endocrinology textbook editors. I situate their article within thyroid science’s medical and historical context prior to 1982. How were diagnostic testing and treatment choices different back then? What shocking things had Ingbar said in some of his earlier publications? This background profoundly shaped the article.

Then, entering “interview” mode, I introduce the basics of the article’s findings on T4 and T3 hormone levels. I interject by contrasting their article with others in thyroid science, especially Jonklaas and team’s article in 2008 about Total T3 levels in T4-treated individuals pre- and post-thyroidectomy.

I conclude by offering some hope for renewing the knowledge and values that Ingbar and Braverman and colleagues shared during this earlier era. It appears that recently, a few leading thyroid endocrinologists have been following the footsteps of this 1982 article.

Who are Ingbar & Braverman? Very famous thyroid scientists.

[Werner & Ingbar’s The Thyroid is now in its 11th edition (Image shown of Braverman & Cooper’s 10th edition, 2013. 912 pages, large format.)]

After I read the article and was duly impressed, I looked more closely at its list of authors.

  • Ingbar, J. C., Borges, M., Iflah, S., Kleinmann, R. E., Braverman, L. E., & Ingbar, S. H. (1982). Elevated serum thyroxine concentration in patients receiving “replacement” doses of levothyroxine. Journal of Endocrinological Investigation, 5(2), 77–85. https://doi.org/10.1007/BF03350495

I was pleased to discover that two famous thyroid scientists, Sidney H. Ingbar and Lewis E. Braverman, were likely the senior mentors on the coauthoring research team, since their names were listed last, as is often customary.

The lead author of this 1982 piece was Sidney’s son, Jonathan C. Ingbar, who has published six items listed in Scopus.

Both Ingbar and Braverman have been prolific authors in the history of thyroid science. These two men co-authored, along with Kenneth Sterling, the seminal article in 1970 titled “Conversion of thyroxine (T4) to triiodothyronine (T3) in athyreotic human subjects.”

They co-authored and edited the “Thyroid Bible” of endocrinology, the textbook Werner & Ingbar’s The Thyroid, now in its 10th edition with updated chapters written by modern authors.

By the time Sidney died in 1990, at age 63, of lung cancer, he had his name on over 350 publications.

Lewis E. Braverman died very recently, on June 10, 2019, at the age of 90. He had 588 publications to his name in Scopus, three of them in the final year of his life.

Braverman, Ingbar’s collaborator in over 60 publications, wrote the leading piece in a set of obituaries honoring Ingbar’s life. (Braverman, 1990). Lawrence C. Wood reminisced:

“[Sidney] had a reputation for creativity and reliability in his research. I once spoke with him about the many ways he was checking and rechecking a particular bit of information for a medical report and recall his comment to me that he was particularly proud that none of his scientific contributions had ever been proved wrong by a subsequent investigator.

“His desire to understand the thyroid gland and to use this information to take better care of thyroid patients will continue to influence us forever.”

Wood, L. E., in Braverman et al “In memorian [Sidney H. Ingbar]”

Historical context

In the years leading up to 1982, Ingbar and Braverman were co-publishing articles about the shifts in T3 and T4 in metabolism.

As of 1982 when this was written, studies of T4-T3 conversion had been ongoing for more than a decade, and people were learning how the human body responded to Levothyroxine (LT4) monotherapy.

Clinical assessment of hypothyroidism, euthyroidism, and hyperthyroidism included a thorough medical examination, symptom tracking over time, cholesterol, basal metabolic rate (BMR), ankle reflex, and other optional biomarkers like ECG and triglycerides. (Ingbar & Braverman cited Evered, 1973 as source)

The thyroid scientific establishment was still managing the huge T3 paradigm shift that began when a British female scientist and Canadian male scientist co-discovered T3 hormone in 1952 (Read about Rosalind Pitt-Rivers and Jack Gross in another post).

Scientists were still learning to appreciate the power of the T3 hormone, with many still clinging to the theory that T4 hormone had significant independent activity in receptors.

Few wanted to believe that T3 was naturally converted from T4 in the body until it was confirmed almost two decades after T3’s discovery, by Ingbar and Braverman. The fact that “T4 converts to T3” became a way to reassure doctors and promote synthetic LT4 monotherapy in the early 1970s.

Historical thyroid pharmaceutical preferences and concerns

However, responsible scientists like Ingbar and Braverman were not boosting T4 monotherapy indiscriminately. They were skeptical about conversion rates, clearance rates, and hormone signaling in receptors. They were focused on asking vital questions like

  • Are thyroid patients getting enough T3 out of their T4?
  • How much excess T4 may be necessary to achieve adequate circulating T3 for the individual?

In 1970, the general opinion of most clinicians was open-minded about the dosage required to render a person euthyroid in their T3 supply. Many were experienced with T3-containing pharmaceuticals like desiccated thyroid (NDT/DTE) and synthetic liothyronine (LT3). Because T3 hormone was not being provided along with T4 hormone and many patients could no longer secrete T3, they understood that the T4 dose naturally had to be exceptionally higher to compensate metabolically for this inherent shortcoming in the medication and the patient.

“It has generally been assumed that maintenance of a euthyroid state with L-T4 requires doses sufficient to raise the serum T4 concentration well above the normal range, since the metabolic contribution normally afforded by T3 is lacking.”

(Braverman, Ingbar & Sterling, 1970; as cited in Evered, 1973)

Ingbar’s 1968 chapter on “The Thyroid” in the Williams textbook of endocrinology confessed a preference for desiccated thyroid but a physician’s choice to use LT4 monotherapy until the regulations were capable of ensuring a reliable potency in desiccated thyroid.

“If this [regulation] were done, the major reason for employing synthetic [LT4] hormone in preference to material of natural origin would no longer exist.”

and

“Despite their theoretical disadvantages and the occasional instances of ineffectiveness or excessive potency, the preparations of natural origin are generally reliable agents that sustain a normal metabolic rate in association with a normal PBI.”

(Ingbar, 1968, p. 254)

Historical context of thyroid testing

The measurement of T4 was historically prioritized as more important than TSH.

The PBI test (protein based iodine) was a well-established diagnostic test that gave an estimate of T4 levels in blood (Evered, 1973). Given the history of the PBI test’s measurement of T4 and its well-known inability to detect T3 hormone in blood, one can understand why they found it so easy to accept T4 monotherapy.

In the 1970s, doctors and scientists occasionally used the TRH-stimulation test, now rarely used, to verify that a suppressed or low basal TSH (their TSH test technology was inexact at lower levels) truly achieved euthyroidism.

They found that sometimes the low or normal basal TSH blatantly underestimated the effectiveness of thyroid therapy to achieve true euthyroidism (Evered, 1973).

Historical studies of T4 overdose

“Are many of our T4-treated patients overdosed?” continued to be a matter of debate, even as more and more doctors were persuaded to switch their patients away from the gold-standard therapy of desiccated thyroid (NDT), the porcine-derived thyroid hormone pharmaceutical. NDT provides both T3 and T4 hormones in a roughly 1 to 4.2 ratio.

Braverman, Ingbar and Sterling’s seminal 1970 study examined the issue of biochemical appearance of overdose without true clinical overdose. They focused on 13 people aged 20-50 years old, two of whom were men, two of whom had thyroid tissue. They were prescribed up to 600 mcg per day of Synthroid (average dose, 409 mcg). This kind of dose would not be permitted today unless a person had a severe malabsorption problem! Yet they did not have overt thyrotoxic symptoms.

“Despite a few borderline toxic manifestations, the general clinical appearance indicated definitely euthyroid status in the majority of cases.”

Their Total T3 concentrations (Free T3 was not measured) varied from 243 to 680 ng/dL, averaging 451 ng/dL (reference range 170-270 ng/dL).

The amount of T3 they “earned” from their high T4 paycheque in blood had little relationship to gross LT4 dosage, since the two men and two women with the highest T3:T4 ratios between 45.2 and 48.6 (T3 ng / T4 mcg /dL) had dosages of 300, 50, 450 and 600 mcg per day.

However, those with higher concentrations of T4 in serum generally converted less of their excess Total T4 into Total T3, confirming what we know today, that as T4 levels rise, T4 converts less efficiently to T3 via Deiodinase type 2 (See “Ubiquitination: The glass ceiling of T4 monotherapy.”)

They hypothesized that due to high T3 clearance rates and different bound:free hormone relationships,

“the over-all rate of T3 production and disposal in these patients would be far less than that in thyrotoxic patients at the same concentration of T3 in the serum.”

They looked forward to the future kinetic studies that would investigate this phenomenon and compare treated patients with autoimmune hyperthyroid patients.

A key finding, now apparently overlooked, was that these 13 patients produced a slightly greater quantity of Tetrac than of T3 hormone.

Tetrac (T4-acetic acid, T4AC) is now known to block receptors on the cell membrane (not receptors in the nucleus) where T4 hormone, Reverse T3 (yes, even RT3), and T3 have significant non-genomic activity (Domingues et al, 2018; Lin et al, 2019). Nano-tetrac, tetrac-like substances, and T3 hormone are currently being investigated for their therapeutic potential against the cancer-proliferating actions of T4 and RT3 at this integrin αvβ3 receptor (See our article reviewing the science on the roles of T4, T3 and Reverse T3 in cancer).

Braverman and Ingbar’s subsequent study in 1973 dosed 11 women with healthy thyroid glands on 300 mcg LT4 per day. This time they performed a kinetic study with radioiodine-labeled T3 to measure T3 distribution, clearance, disposal, and turnover. They even examined Free T3 and Free T4 by dialysis and by means of binding rates to TBG serum transport protein. But they did not measure Tetrac or Reverse T3.

In the 1973 study, they found that their dose of T4 suppressed the thyroid’s uptake of iodine from 28 to 3%, and so the thyroid’s rate of T4 and T3 synthesis had been cut to 9.3% of normal, on average. On this basis, they deduced that most of the T3 arose from T4-T3 conversion.

In people with intact thyroid glands, “approximately one-third of exogenously administered T4 underwent deiodination to form T3.”

To be precise, the “per cent of T4 converted to T3 ranged from 30.2 to 48.0, averaging 35.7 ± 7.2.”

This estimate of “one third” was later confirmed in Pilo’s 1990 study of T3 production in 14 people with healthy thyroids who were NOT dosed on T4. They found an average of 27.3% T4 conversion to T3 (range 16.9 to 42.9%). Pilo’s 1990 study is still quoted and misquoted today for its non-representative averages.

They concluded on the basis of various biomarkers that the 11 normothyroid women had no overt clinical thyrotoxicosis but on one biomarker alone, BMR, they had “subclinical thyrotoxicosis.”

“First, in six of the eight patients, values of the BMR [Basal Metabolic Rate] (+ 8-+ 15%) during suppressive therapy were above the normal range for our laboratory (- 15-+ 5%); however, in none were pretreatment values available.”

“Second, TBG [Thyroxine Binding Globulin] and TBPA [Thyroxine Binding PreAlbumin] decreased during L-thyroxine therapy, changes reminiscent of those found in patients with spontaneous thyrotoxicosis.”

Therefore, for the safety of their patients and the education of other doctors, Ingbar and Braverman’s team recommended average “doses of 0.2 mg [200 mcg] daily” going forward. Some patients still would need more to compensate for poor absorption and poor conversion to T3, but this would be an average.

They then pondered what biomarkers could signify that a person was “subclinically” overdosed. (Braverman et al, 1973).

They cautioned against overreliance on biochemistry, including TSH, as a judge, while so much was still unknown about T4 and T3 conversion, clearance, and signalling:

“The apparent physiological (and clinical) tolerance of euthyroid young adults to slight or moderate excesses of thyroid hormone is well-known.”

“Such apparent resistance to mild excesses of thyroid hormone may merely bespeak the insensitivity of clinical and biochemical indices of thyroid hormone excess currently available.

It might also reflect enhanced activity of pathways for hormonal metabolism that are purely degradative or excretory, i.e., that forestall hormonal action.”

“Finally, … the validity of such judgments will depend upon the extent to which T4 proves to have a metabolic action independent of its conversion [to] T3.”

And this is why, later in 1982, Ingbar and Braverman were far more interested in direct measures of T4, T3, and RT3 in relationship to clinical status than TSH or PBI. They continued their tradition of studies that did not measure the pituitary hormone TSH. No matter how much the “sensitivity” of the TSH test would improve, they never forgot that pituitary TSH was not a thyroid hormone but a localized response to thyroid hormone. They also knew that TSH was a hormone whose secretion, binding and clearance rates were also determined by many complex factors.

This is why they were interested in studying why “apparently excess” thyroid hormone biochemistry yielded definitively “euthyroid” results across the human body.

Ingbar and Braverman never imagined that any reasonable thyroid scientist would ever forget to assess “clinical euthyroidism” by a variety of health outcome measures (not mere biochemistry).

From the very beginning of their research with LT4 therapy, these scientists had been using the principle of a favorable overall result to cast doubt on one isolated biochemical index (binding proteins) and one isolated clinical index (BMR) that seemed a little excessive in some, but not all, individuals.

Ingbar and Braverman’s 1982 research methods

The average LT4 dose in the 1982 study was 191 mcg/day, slightly less on average than the 200 mcg/day that their 1973 study indicated would be a good average dosing target.

Their research methods examined three groups of LT4-treated patients’ T4 levels using three different T4 assay methods to improve accuracy.

They also examined their T3 levels, their T3/T4 ratios, Reverse T3 levels, and RT3/T4 ratio in relationship to their LT4 doses and variables like sex, age, and type of thyroid disorder.

They even threw in a rat study of T4 metabolites for good measure.

Advanced readers: Learn more about their patients and methods.

Ingbar and team’s participants consisted of 49 LT4 treated patients “judged euthyroid by standard clinical criteria at the time that bloods for the study were drawn,” and two control groups for comparison: 10 patients with hyperthyroidism, and 12 patients who were “euthyroid, normal individuals.”

They divided the LT4-treated patients into 3 subgroups treated by different doctors on different LT4 brand medications.

Their most detailed data set (shown in the graph below) was from “Group 3”, a group of 30 patients (only 28 of which had a complete data set). These patients were supervised by Ingbar and Braverman and were all treated on Synthroid brand LT4.

The sex distribution of Group 3 was biased toward women (24 women and 6 men) and there were no seniors over 60 or youth below 20 (range 23 and 57 years of age). The euthyroid controls were age-matched to this group of patients.

  • 16 were treated for “hypothyroidism”
  • 4 for “Hashimoto’s disease,”
  • 9 for non-toxic diffuse goiter (It was formerly common practice to use LT4 to suppress goiter — thyroid enlargement — in people without hypothyroidism)
  • 1 for “a history of radiation to the thyroid area.” (x-ray radiation damage may have caused subclinical hypothyroidism, since the patient was not yet considered hypothyroid)

Doses for 25 of these people were 150 or 200 mcg / day, and other doses were 50 mcg in 1 patient, 100 mcg in 2 patients, and 300 mcg in 2 patients.

Ingbar & Braverman’s T3 and T4 findings

Now that you know the basics, let’s dive into Ingbar & Braverman’s results.

Total T3 levels in LT4 therapy

Ingbar and Braverman’s team were honest scientists. They were not afraid to admit the hormonal distortions of LT4 monotherapy within reference boundaries when it came to the human body’s most active and essential thyroid hormone, T3.

They admitted that patients on LT4 had lower than normal average Total T3 than healthy controls. As a result, they also had a lower than normal average Total T3/T4 ratio than healthy controls.

Technical readers: Click to read about Total vs. Free thyroid hormone measurements.

Throughout, keep in mind Ingbar and team measured Total hormone levels, not Free T3 or Free T4. Thyroid hormone tests were in the process of development.

Total hormone consists of both bound and free hormone. Only free hormones can enter cells.

  • Free T3 is approximately 0.3% of Total T3.
  • Free T4 is approximately 0.03% of Total T4. (Refetoff, 2000)

After thyroid hormones exit cells and re-enter bloodstream, they can become bound to carrier proteins again at the same rate.

The estimate “0.3% free” is approximate. One can’t just divide the Total T3 or T4 numbers to get a correct Free T3 hormone estimate.

The amount that is free vs. bound depends on how much hormone you have in blood, because as T4 or T3 rise, the percent that is bound increases (Attwood, 1979). This is nature’s way of minimizing the metabolic impact of excess thyroid hormone on the human body. Conversely, as T3 and T4 fall, less is bound and more is free.

Free:Bound thyroid hormone ratios also depend on other metabolic influences … such as estrogen therapies and pregnancy, which drive up Thyroxine Binding Globulin levels (TBG) and increase the percentage of thyroid hormone that is bound.

The TBG test was available as of 1977. It is therefore surprising that Ingbar and Braverman did not use it here and consider Attwood’s finding that the T4/TBG and T3/TBG ratios are both increased in cases of hyperthyroidism.

Nevertheless, in most cases where hormone binding proteins, especially TBG, are not altered by LT4 overdose, skewed by pregnancy, estrogen therapies or diseases, the Total T3 is close to the FT3’s position as a percentage of reference range, and the same with the Total T4 generally mapping onto FT4 as percent of reference. (Kolouri et al, 2013, Jonklaas et al, Total and Free thyroxine, 2014)

For example, Jonklaas et al, 2014, who even compared assays using the gold standard “mass spectrometry” assay method (MS) and common immunoassay (IA) found that

“there was fair correlation between total and free thyroid hormone levels regardless of the assay used. For example, T3 (IA) correlated with both FT3 (IA) and FT3 (MS).”

Jonklaas and team found that discrepancies in test results occurred when levels were very high or very low in relation to the norm.

Fortunately, Ingbar and Braverman’s 1982 test results fell largely within normal reference ranges in this study. They used immunoassay methods.

Therefore, it is fair to consider TT3 and TT4 within reference as a general proxy for FT3 and FT4 in terms their approximately equivalent positions in the reference range.

Did your patients have an extremely wide variety of T3 levels? Yes.

“Serum T3 concentration in the Synthroid@ treated patients varied widely between 57 and 149 ng/dl”

Their statement had a minor error: In fact, the variation was from 52 to 149 if you tabulate all the 28 dots on their graph, Figure 5.

The variation between T3 levels was more diverse among patients than the variation for T4 (5.7 to 11.0 mcg/dL).

Why does one person have 149 ng/dL of T3? It appears that one person might have had an autonomous T3-secreting thyroid nodule! (Wong and Volpe, 1981, argued that this is one consideration that makes T3 measurement superior in monitoring LT4 thyroid therapy. See our review article on Wong and Volpe.)

Was the patients’ mean (average) T3 lower than the healthy control group? Yes.

“the mean (91 ± 23 ng/dl) was significantly lower than that of the euthyroid control group (104 ± 14 ng / dl) (p< 0.05).”

These numbers are given as “mean ± SD” which means Standard Deviation. If we omit the outlier with 149 ng/dL T3, the average reduces only a little bit, to 90.1 ng/dL, since the data set had 28 people.

How much T3, theoretically, could an individual lose if their natural thyroid function enabled and their biological need demanded a higher T3 level but their thyroid disorder and therapeutic approach stole it from them?

The mere 13% average difference between these two groups’ averages hides the full discrepancy.

Sadly, we cannot answer this question using this article because Ingbar and team do not provide the full range of T3 levels in the euthyroid control group, nor a pre-post thyroidectomy contrast within individual subjects.

We would have to learn this later in other studies, such as Jonklaas, 2008.

Comparison with T3 findings from Jonklaas et al, 2008

First, let’s ponder Jonklaas’s honest “haystack” graphs showing how deceptive mere averages of T3 concentrations can be.

Unlike Ingbar and Braverman in 1982, Jonklaas and co-authors in 2008 waived their responsibility to examine clinical responses such as symptoms, failed to reason about the causes or consequences of shifts in T3-T4-TSH relationships, and overemphasized clinically-irrelevant averages, T4 gains, and TSH levels. Such secondary and indirect measures as these do not physiologically counterbalance individuals’ loss of the most essential thyroid hormone, T3.

In contrast to Jonklaas’s study, were Ingbar & Braverman’s T3 levels biased by their selection of patients? Yes.

As seen even in Jonklaas’s 2008 data, it matters whether you are looking at people with “benign thyroid disease” and “thyroid cancer.”

Admittedly, Ingbar’s group of patients were too diverse. They included people with a wide variety of conditions and not all of them were treated until they achieved little to no thyroid gland uptake.

Despite the “muddy subject pool” which would have biased their T3 results higher than in a sample of 100% thyroidless people, the averages in Ingbar and Braverman were still surprisingly low.

Can we predict T3 level by measuring T4?

Were the individual T4 levels able to provide any hint or prediction as to the T3 level? No.

“For the treated group as a whole, serum T3 concentrations were significantly correlated with serum T4 concentrations (p < 0.05), but the correlation was not close (r = 0.50).”

In other words, when you look at the individual patients one by one and correlate T3 with T4, a given person’s level of T4 did not have a predictable relationship to their T3 level.

Can we predict T3 level by the LT4 dose?

Could their LT4 dose in micrograms per day give any prediction as to the T3 level? No.

“Wide variation was also noted in ratio of the serum T3 concentration to the daily dose of T4.”

This unpredictability related to LT4 dosage has clinical implications for beliefs about dosing by body weight or age or thyroid disability type.

It provides all the more reason to avoid prejudices about the patient’s dosage.

  • A given dosage of LT4 calculated by kg of body weight will not necessarily provide adequate T3 for the individual.

The study did not discuss it, but the data revealed variable rates of LT4 pharmaceutical absorption via the GI tract. It is well known that T4 is more poorly absorbed through this route than T3 hormone.

This is why we are told to dose LT4 in a fasted state and 4 hours away from calcium, magnesium, and iron to prevent obstacles to absorption. However, we can simply supply a higher dose if the patient has a GI health problem or interfering medications. Therefore, LT4 absorption is not as clinically significant as T4-T3 conversion.

Advanced readers: Click to read about their suggestion of clearance rate variability as an explanation.

Ingbar’s team suggested clearance rate variability as another possible explanation.

This issue has currently fallen off the map of thyroid therapy, but back then, they measured binding proteins such as Thyroxine Binding Globulin (TBG), which binds 75% of T3 and T4 in blood. (Refetoff, 2000)

  • Perhaps the researchers are suggesting that albumin levels are involved, since Total T3 is more bound to albumin in circulation (20%) than T4 is (5%). (Refetoff, 2000) If albumin levels are lower, it is possible that relatively more T3 than T4 will be lost through excretion.

However, the clearance rate fails to explain the discrepancy between treated patients and healthy controls. This is because a shift in albumin and clearance rate can occur in untreated patients, too. It would matter in people with kidney dysfunction (such as nephrotic syndrome or genetic dysfunction in albumin).

However, the human body’s flexible adjustment of clearance rate by T3 and T4 levels would reduce human variation in the ratio and prevent T3/T4 ratio reductions. Again, it fails to explain the discrepancy.

We are left with the individual genetic variation in T4-T3 conversion.

Does circulating T3 level matter for health?

Ingbar and Braverman, did you really believe that absolute total T3 levels in blood made a difference to clinical outcomes?

Yes.

Ingbar’s main conclusion in 1982 was to rely on T3 as a reassurance that patients were not overdosed despite some of them having mildly elevated T4 levels.

“From our experience, it would appear that, in patients receiving levothyroxine, the serum T3 concentration is a more reliable indicator of the metabolic state of the patient than the serum T4 concentration is”

This claim of T3’s priority over T4 is profound, given that they lived in a medical culture that still idolized T4.

It is very surprising to see how they glorified T3 levels to champion LT4 monotherapy at a time when this medical culture was denigrating T3-dominant therapies such as desiccated thyroid (NDT).

Contemporary thyroid science’s ahistorical ignorance

I could highlight many more examples of historical ignorance in today’s thyroid science, but I’ll focus here on Jonklaas, 2008 because I’ve used it as a touchstone above.

How little Jonklaas and team in 2008 cared to learn from the deeper insights of thyroid science history, claiming to be utterly ignorant of Ingbar’s research when they contemplated that some patients had lowered T3 and that their TSH-T4-T3 relationships were distorted:

“Possibly, there is some characteristic of LT4 therapy that does not fully replicate an important but as yet unidentified aspect of normal thyroid physiology.”

Jonklaas and team, what do you mean “as yet unidentified”?

This declares ignorance of what Ingbar & Braverman’s research insights identified, as well as what some of the articles by Hoermann and team have recently identified regarding the modified HPT axis in therapy, such as the TSH-T3 disjoint.

One ought to engage in a more thorough review of thyroid science before declaring that something has not yet been discovered. Scientists long ago had knowledge of the flexible T3 secretion rate and flexible T4-T3 conversion rate performed by normal thyroid physiology. Scientists already knew that “replacement” should be put in quotation marks because it does not “replicate” many aspects of normal thyroid physiology.

This claim in particular confesses ignorance of the thyroid physiology that Laurberg’s 1984 review identified. This review appeared two years after Ingbar’s team’s article. Laurberg cited prior studies of T3 and T4 content in thyroglobulin and compared them with studies of T3-enriched ratios secreted from a living thyroid’s blood vessels in vivo. He clearly explained the aspects of normal thyroid physiology, namely, flexible T3:T4 ratios of synthesis and variable thyroidal T4-T3 conversion rates under TSH stimulation. These were lost in people with thyroid gland failure. He showed that these losses explained the biochemical outcomes of distorted T3:T4 ratios in LT4 therapy. He also admitted these aspects of thyroid physiology could not be “replicated” by LT4 therapy.

Conclusion

Ingbar’s original article, a vast library of concisely-worded deep insights in only a few pages, should be assigned reading for every endocrinologist or thyroid specialist before they treat hypothyroid people with T4 monotherapy.

These are the basic principles doctors should learn in medical school today as a counterpoint to indoctrination in “the” function of “the” healthy HPT axis and the mantra to “understand the gland.” Doctors must understand the loss of the gland and the complexities in its imperfect “replacement.”

Ingbar and Braverman’s team offered a message of guarded optimism at the dawn of the era of T4-monotherapy that is still relevant today.

This is a disease we can attempt to treat with levothyroxine as long as we have humility and honesty about the limitations of each thyroid pharmaceutical and the diversity of each individual’s response to it.

In the era before TSH testing rose to clinical dominance, patients were not crippled with overdose. It’s an outdated ideology to belief that normalizing TSH alone can “control” hypothyroidism. We can only come close to “controlling” hypothyroidism if we first understand how the thyroid-disabled, treated population differs from people with healthy thyroids in their TSH-T4-T3 relationships. Averages and distributions are very helpful as a context for interpreting the differences between various populations of treated and untreated patients. However, we must still carefully attend to the relationship between T3 and T4 thyroid hormone concentrations and health outcomes in each human being.

This 1982 article in many ways was offering to physicians and patients what Hoermann and team did in 2019 in their article on “Functional and Symptomatic Individuality in the Response to Levothyroxine Treatment.” Just as Ingbar and team did in 1982, Hoermann and team show how attending carefully to the profoundly shifted and individualized T3 hormone dynamics during thyroid therapy can make T4 treatment more effective for many people.

But it’s a sobering view of thyroid science history. This article shows you how much our scientists used to know almost 40 years ago, and how much basic knowledge, ethics and professionalism many subsequent thyroid scientists and doctors have left behind.

The contrast between Ingbar & Braverman in 1982, and Jonklaas’ team in 2008 shows how, over the decades, the TSH-T4 therapy paradigm lost touch with its own scientific roots.

Some key leaders left behind basic knowledge of the thyroid’s function as a flexible metabolic engine, the individuality of each person’s T3:T4 secretion ratio in health, and the individually variable T4-T3 conversion rate both before and after thyroid loss.

Some left behind a spirit of open-minded inquiry into the strengths and weakness of each different thyroid hormone pharmaceutical, and the compassionate question of which therapy choice and dosing ratio is best for the individual’s overall health, not just their biochemical statistics.

Several decades of thyroid science’s intense focus on TSH and T4 measurement seem to have lost the connection between thyroid hormone biochemistry and thyroid physiology, and because of that, it lost the connection between T3 levels, T3:T4 ratio, and clinical outcomes in therapy.

Newer editions of Werner and Ingbar’s textbook lost a series of chapters covering the manifestations of hypothyroidism and hyperthyroidism throughout the human body (See “The loss of thyroid clinical knowledge from Werner & Ingbar’s The Thyroid“.)

Sadly, this 1982 article by Ingbar and team has been buried in the archives, only cited by 25 articles to date (only self-cited by the authors once). It has only been cited 3 times since 1993, according to the Elsevier Scopus citation database.

However, there’s hope in renewed interest in Ingbar’s article. It was recently cited by Ettleston and Bianco’s September, 2020 article in The Journal of Clinical Endocrinology & Metabolism, another one well worth reading: “Individualized Therapy for Hypothyroidism: Is T4 Enough for Everyone?”.

  • Tania S. Smith, PhD
    Thyroid science analyst and thyroid patient,
    President, Thyroid Patients Canada

Coming soon

  • Next article, part two, will put the two hormones together and examine the T3:T4 ratios they found in levothyroxine (LT4) therapy, and then introduce the “Ingbar-Braverman diagnostic” for Reverse T3 in the context of the shifted T4 and T3.
  • Then, part three explores the excuses and accommodations they made for LT4 monotherapy.

Throughout, I will continue to comment on what they say in light of what science has revealed as of the year 2020.

References

Expand to view list

Biondi, B., & Wartofsky, L. (2014). Treatment with thyroid hormone. Endocrine Reviews, 35(3), 433. https://doi.org/doi: 10.1210/er.2013-1083

Braverman, L. E., & Cooper, D. S. (Eds.). (2013). Werner & Ingbar’s the thyroid: A fundamental and clinical text (10th ed..). Wolters Kluwer/Lippincott Williams & Wilkins Health.

Braverman, L. E., Ingbar, S. H., & Sterling, K. (1970). Conversion of thyroxine (T4) to triiodothyronine (T3) in athyreotic human subjects. The Journal of Clinical Investigation, 49(5), 855–864. https://doi.org/10.1172/JCI106304

Braverman, Lewis E., Kass, E. H., Tishler, P. V., Stanbury, J. B., Wood, L. C., Epstein, F. H., & Stein, D. I. (1990). In Memoriam [Sidney Harold Ingbar]. Thyroid, 1(1), 5–9. https://academic.oup.com/endo/article-abstract/124/6/3137/2532212

Domingues, J. T., Cattani, D., Cesconetto, P. A., Nascimento de Almeida, B. A., Pierozan, P., Dos Santos, K., Razzera, G., Mena Barreto Silva, F. R., Pessoa-Pureur, R., & Zamoner, A. (2018). Reverse T3 interacts with [alpha]v[beta]3 integrin receptor and restores enzyme activities in the hippocampus of hypothyroid developing rats: Insight on signaling mechanisms. Molecular and Cellular Endocrinology, 470, 281. https://doi.org/10.1016/j.mce.2017.11.013

Ettleson, M. D., & Bianco, A. C. (2020). Individualized Therapy for Hypothyroidism: Is T4 Enough for Everyone? The Journal of Clinical Endocrinology & Metabolism, 105(9), e3090–e3104. https://doi.org/10.1210/clinem/dgaa430

Evered, D., Young, E. T., Ormston, B. J., Menzies, R., Smith, P. A., & Hall, R. (1973). Treatment of Hypothyroidism: A Reappraisal of Thyroxine Therapy. British Medical Journal, 3(5872), 131–134. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1586331/

Farwell, A. P. (2019). IN MEMORIAM: Lewis E. Braverman, MD, MACE, MACP Vol 12 Issue 7 p.3-4. American Thyroid Association, 12(7), 3–4. https://www.thyroid.org/patient-thyroid-information/ct-for-patients/july-2019/vol-12-issue-7-p-3-4/

Hoermann, R., Midgley, J. E. M., Larisch, R., & Dietrich, J. W. (2019). Functional and Symptomatic Individuality in the Response to Levothyroxine Treatment. Frontiers in Endocrinology, 10. https://doi.org/10.3389/fendo.2019.00664

Ingbar, J. C., Borges, M., Iflah, S., Kleinmann, R. E., Braverman, L. E., & Ingbar, S. H. (1982). Elevated serum thyroxine concentration in patients receiving “replacement” doses of levothyroxine. Journal of Endocrinological Investigation, 5(2), 77–85. https://doi.org/10.1007/BF03350495

Ingbar, S. H., & Woeber, K. A. (1968). The thyroid gland. In R. H. Williams (Ed.), Textbook of endocrinology (pp. 105–286). Saunders. http://catalog.hathitrust.org/api/volumes/oclc/10998645.html

Jonklaas, J., Davidson, B., Bhagat, S., & Soldin, S. J. (2008). Triiodothyronine levels in athyreotic individuals during levothyroxine therapy. JAMA, 299(7), 769–777. https://doi.org/10.1001/jama.299.7.769

Jonklaas, J., Bianco, A. C., Bauer, A. J., Burman, K. D., Cappola, A. R., Celi, F. S., Cooper, D. S., Kim, B. W., Peeters, R. P., Rosenthal, M. S., & Sawka, A. M. (2014). Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement. Thyroid, 24(12), 1670–1751. https://doi.org/10.1089/thy.2014.0028

Jonklaas, J., Sathasivam, A., Wang, H., Gu, J., Burman, K. D., & Soldin, S. J. (2014). Total and free thyroxine and triiodothyronine: Measurement discrepancies, particularly in inpatients. Clinical Biochemistry, 47(0), 1272–1278. https://doi.org/10.1016/j.clinbiochem.2014.06.007

Lin, H.-Y., Tang, H.-Y., Leinung, M., Mousa, S. A., Hercbergs, A., & Davis, P. J. (2019). Action of Reverse T3 on Cancer Cells. Endocrine Research, 1–5. https://doi.org/10.1080/07435800.2019.1600536

Laurberg, P. (1984). Mechanisms governing the relative proportions of thyroxine and 3,5,3’-triiodothyronine in thyroid secretion. Metabolism: Clinical and Experimental, 33(4), 379–392.

Pilo, A., Iervasi, G., Vitek, F., Ferdeghini, M., Cazzuola, F., & Bianchi, R. (1990). Thyroidal and peripheral production of 3,5,3’-triiodothyronine in humans by multicompartmental analysis. The American Journal of Physiology, 258(4 Pt 1), E715-726. https://doi.org/10.1152/ajpendo.1990.258.4.E715

Wong, M. M., & Volpé, R. (1981). What is the best test for monitoring levothyroxine therapy? Canadian Medical Association Journal, 124(9), 1181–1183. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1705308/



Categories: Research Reviews, T3 hormone, T4 hormone, T4-monotherapy, Thyroid science history

8 replies

  1. Thank you for this fine review and analysis of Ingbar’s and Braverman’s research, resulting in i.a. this valuable article.

    Unfortunately, Ingbar’s and Braverman’s excellent article was quickly (mis)used for construction of a new diagnosis: “tissue thyrotoxicosis”, resulting in halving of treatment doses for millions of (suffering!!) hypothyroid patients worldwide. And this even despite the fact that serum TSH was unaffected by this, so-called “tissue thyrotoxicosis” … Obviously, no one can win the battle against the creative medicine where any facts can be bent until their opposite, and thus prepared (“facts”) just reaffirms the already existing confirmation bias.

    Actually, it is rather mysterious that the medical profession so eagerly believes in the existence of “tissue thyrotoxicosis”, while it totally rejects the condition “tissue hypothyroidism”, almost always emergeding as a result of treatment with the same synthetic levothyroxine they prefer to treat hypothyroid patients with.

    Best regards from a Dane, and our community online in Norway

    • Thanks very much Anina for your appreciation and your insight on this matter! I agree, there is often an emphasis on tissue thyrotoxicosis more so than tissue hypothyroidism. What our field of thyroid science needs is to understand the interface between blood levels of thyroid hormones (FT3, FT4), transport, metabolism, and signaling. Too often nowadays the assumption is that if there is enough T4 in circulation and the TSH is normalized, all the tissues beyond the pituitary will be supplied with enough T3 for signaling. So good to hear from you in Norway. We are based in Canada but our reach is global, since thyroid science and thyroid therapy is a global issue.

  2. As always Tania, a fine article demonstrating just how much bias there is in current thyroidology towards TSH and T4, and away from T3. When, of when will we get through to current endocrinologists that they are harming patients by not looking at the science and only at protocols.
    Thank you so much from England
    Linda

  3. Another interesting and incisive article. Thank you.

    You wrote, re Synthroid and “another brand of levothyroxine”: “This type of hormone preparation, despite its pharmaceutical precision and synthetic purity,…”

    I’d just like to point out that the whole field of levothyroxine products (in the USA) were so bad, and the manufacturers so unwilling to improve, that they were forced to gain approval as new medicines around the turn of the 20th century. There had been a whole series of recalls.

    Levoxyl in particular was so poor, the company withdrew it and came back to market with a wholly reformulated product.

    I say this to emphasise that all research which quotes and treats levothyroxine doses as if the labelled potencies are accurate could be significantly out. Especially from 20th century.

    • Anyonefort, You’re right on to say what you have, as a counterbalance to my quote! The record for LT4 preparation is far from spotless. And the potency of tablet strength used to be permitted to vary from 90-110% of the stated dose, until the FDA updated the guidelines in the late 2000s to a narrower frame, 95% to 105%, because levothyroxine is a “narrow therapeutic index” drug. The “bioequivalency” guidelines for generics still permit them to be 90-110% of the potency of the target brand name of levothyroxine, so switching between brands is still a roll of the dice for potency.

      At the dawn of the Levothyroxine-dominant thyroid pharma market, Ingbar & Braverman did not know just how much the dosing precision, compared to desiccated thyroid, had been improved.

  4. Thankyou Tania for another fine piece of work to help re-balance the ‘textbooks’ that have had all the useful bits removed.
    Seasons Greetings
    Cath
    ThyroidUK Online community member in England

  5. This is both illuminating AND terrifying for this recently athyreotic patient… (TT for Graves). I’m not sure if my best chances for feeling well without a thyroid are to try to somehow convince the endo, or to jump around endos till I find one who buys into this theory (which to me makes full sense: you can’t remove a gland that produces both hormones, provide the inactive one of the two, and expect all to be well…) I might need a T-shirt printed with “Got Ingbar/Braverman?” Joking aside… really appreciate the info you provide. Although I’m no expert, I know when my body feels well and I’ll refuse to be pawned off with excuses. Just hope despair doesn’t get the best of me first. I’ve always been an active, energetic, slim person… and the thought of facing the exact opposite now is a very dark thought.

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