Biondi and Wartofsky’s 2014 dismissal of desiccated thyroid

The Wrongful Dismissal of Desiccated ThyroidBernadette Biondi and Leonard Wartofsky’s article in 2014 titled “Treatment with Thyroid Hormone” summarily dismisses the use of desiccated thyroid medication in thyroid therapy.

Tracing the logic of their dismissal back to their citation, a 1980 research article, reveals a fallacious chain of argument based on a very thin foundation.

This pathway of reasoning promotes mistaken assumptions and long-standing medical biases against this alternative mode of thyroid therapy.

These biases are largely founded on the fear of the unknown and the unwillingness to carefully investigate the reasons why desiccated thyroid therapy can often yield no signs or symptoms of hyperthyroidism despite higher T3 in lab results.

Appeals to fear are at the root of many logical fallacies, such as the “slippery slope” fallacy that basically reasons that if we do X, then by a long and implausible series of chain reactions, it will “cause” horrible effect Y.

Fear of T3 hormone supports logical leaps to unnecessary and damning conclusions about desiccated thyroid therapy.

Fear also promotes false analogies from small, limited studies to general practice.

Biondi and Wartofsky provide this brief argument that cites two articles:

“The inappropriate use of thyroid extracts in euthyroid and hypothyroid patients can result in thyrotoxic symptoms and severe adverse effects (135). Some cases of thyroid storm have been reported during the inappropriate use of thyroid hormone extracts (136).”

Article #136 is far too easy to refute as a basis for dismissing desiccated thyroid — it’s merely fearmongering. It’s a single case study of a compounding pharmacy’s dosing error that led to a woman’s massive overdose that was successfully managed in hospital.

Far more numerous cases of T4 medication overdose have been reported, and depending on how well a patient converts T4 to T3, they can lead to extremely high T4 and T3 levels that require hospital management. In 1988, an article reported that 75% of prescriptions in the US were for Levothyroxine, and “in 1986, the American Association of Poison Control Centers Data Collection System documented 2,231 acute exposures to thyroid preparations” (Gorman et al, 1988). This same article said “the acute ingestion of levothyroxine (T4) poses a difficult clinical problem,” and reported that Levothyroxine overdose has yielded Total T4 levels as high as 180 mcg/dL (normal 4 to 11 mcg/dL) and Total T3 levels as high as 1,031 ng/dL (Normal 92-270 ng/dL).

Medicine has not dismissed Levothyroxine monotherapy just because it has been misused or overdosed.

Therefore, my article examines closely only their first source cited, #135, which reported high T3 levels on desiccated thyroid therapy.

PENNY AND FRASIER’S 1980 STUDY

Source 135 in Biondi and Wartofsky’s article is this:

It is unfortunate that Biondi and Wartofsky did not look further than this article to support their sentence’s fearful claim about “serious adverse effects.”

It’s even sadder that this article’s data reported NO serious adverse effects on desiccated thyroid therapy but it is used to support a sentence that claims adverse effects.

The 1980 article’s title is misleading:

“Elevated serum concentrations of triiodothyronine in hypothyroid patients.”

These are not just any hypothyroid patients. They were 14 children maintained in an euthyroid state despite having elevated T3 levels.

In addition, their higher T3 was not the most important thing about them, but this became the focus of the researchers.

This 1980 article they cite is a study of 14 children between the ages of 6.2 to 18.2 years old who had been using desiccated thyroid for a period from 2.7 to 13 years.

These children were reportedly “clinically euthyroid,” which in 1980 meant more than just that their TSH was in range: back then, it meant they had no clinical signs or symptoms of either hyperthyroidism or hypothyroidism. Many older studies of hypothyroidism tested heart rate, body temperature, cholesterol, and ankle reflex, not just TSH, T3 and T4. This study reported data on height and weight.

All the children’s heights and weights were normal. If they were truly overmedicated over the long term, they might have had bone and muscle wasting and weight loss.

Their daily dose ranged from 97 to 157 mg of desiccated thyroid, which was within an acceptable range given the children’s body weight.

According to the article, each individual patient had maintained this steady daily dose for the full duration of those years up to the time of study. This is a little hard to believe since the children had apparently grown at a normal rate over 2.7 to 13 years and would likely have started at a lower dose and increased their dose as they got older.

THEIR T4 AND T3 LEVELS

How elevated was their T3?

Upon measuring their T4, T3 and TSH at baseline on desiccated thyroid, the researchers found the usual inverted T3:T4 ratio (T3 higher in its range than T4 in its range).

However, in their lab results, T4 and T3 were inverted to an extreme:

  • their Total T4 was low within reference range at 7.6 +/- 2.0 ug/dL (ref. 4.2 to 15.0 ug/dL) and
  • their Total T3 averaged above the reference range: 393 +/- 114 ng/dL (ref 70.0 to 220.0 ng/dl).

However, the detailed data shows that the group’s average was skewed +10% higher by two outliers who had 732 and 518 ng/dL of T3.

One of the 14 children’s levels of T3 was 201 (under the top of range at 220).

The next three T3 values were 229, 265, and 266, which are not “severely elevated.”

I reproduce their table below within the terms of copyright law, which permits fair use for the purpose of critique.

Penny-Frasier-DTE-1980-table

TIMING OF THE BLOOD TEST

Importantly, they fail to mention how many hours after a dose of desiccated thyroid the blood draw was taken.

In 1980 it was understood that the half life of T3 was short. In the 1970s researchers had discovered that four hours after T3 ingestion, the serum levels of T3 rise significantly.

We can reasonably assume that the researchers knew this and that they chose to draw blood within the serum T3 at its highest peak post-dose.

Secondly, we do not know if they instructed the children to take their medication as a single daily dose. They do not mention this, only the total daily dose in milligrams.

Once-a-day dosing would NOT be normal for a person taking as much desiccated thyroid per kilogram body weight as they were taking. Once-a-day dosing would result in a higher T3 peak than twice-a-day or 3x a day dosing.

Thirdly, the researchers did not do more than one blood draw per patient to verify their results were not due to laboratory error.

Nor did they draw a blood sample two or three times in a 24 hour period to report the daily range of T3 fluctuations within their patients.

If these were their peak values for T3, what value was the trough before the next dose? What was the average?

It is reasonable to assume that some of these children had an average and low T3 range that was well within the reference range, and that these results were obtained at the highest peak T3 after a single daily dose.

NORMAL T3 LEVELS IN CHILDREN

They also did not find an age-matched control group of 14 or more children with healthy thyroid glands to see what their T3 levels were.

Today we know that children have higher T3 levels than adults: “The reference range of total triiodothyronine (T3) is 80-220 ng/dL in adults and 125-250 ng/dL in children.” (Medscape, Triiodothyronine, 2014).

THE CHILDREN’S TSH LEVELS

Meanwhile, these children’s TSH on desiccated thyroid therapy varied from 0.5 to 5.0, but yielded an average TSH of 1.3.

While it is true that early TSH test technology was not very good at detecting very low TSH levels, their low, average and high values showed that TSH was not suppressed in most, and could even be at top of the TSH range.

This raises a serious question.

If these children were taking too much T3 hormone, and if their lab results show they had that much T3 in serum, then why wasn’t their TSH completely suppressed as it would be in most adults under these circumstances?

NOBODY NOTICED A PROBLEM FOR THE PRIOR 13 YEARS.

Next question: If these children’s blood T3 had resulted in any clinical symptoms in the past, why wouldn’t their dose have been lowered by doctors over the period of 2.7 to 13 years they had been taking this medicine?

Was it likely that 14 children’s doctors were collectively blind and negligent over such a long term as to overdose them on a form of thyroid therapy that was still commonly used in practice?

These TSH data, taken together with their clinical history and the known fluctuations of T3 in serum, demonstrate the children were not in fact overdosed.

THEY SUDDENLY SWITCH THEM TO LEVOTHYROXINE

However, the researchers decided that because their T3 lab result numbers were abnormal, the children were at risk, so they immediately switched all the children to Levothyroxine and continued to study them.

Their fear of isolated, transient higher T3 compromised the study.

They did not simply lower their dose of desiccated thyroid and watch, wait and see what happened three months later.

On a lower dose, would their TSH go up, and would clinical signs and symptoms ensue?

We will never know, because these doctors tried to protect their patients from an unknown potential harm and switched them immediately to their preferred therapy modality.

RESULTS ON LEVOTHYROXINE

These researchers were very happy to report that the children’s lab numbers conformed to their expectations on Levothyroxine (L-T4) therapy.

They were most pleased with keeping their TSH almost the same between desiccated thyroid extract (DTE) and L-T4 therapy.

(Their TSH average in fact rose from 1.3 to 1.6, but the range was still 0.5 to 5.0).

The researchers did not think it was problematic to raise their TSH slightly.

They doubled their T4 levels:

  • T4 levels rose from 7.6 ± 2.0 μg/dL on DTE to 11.7 ± 2.5 μg/dL on L-T4 (ref. 4.2 to 15.0 ug/dL)

They cut their T3 by more than 1/3 to a position 11% below their T4 in the reference range:

  • T3 levels fell from 393 ± 114 ng/dL on DTE to 157 ± 23 ng/dL on L-T4 (ref 70.0 to 220.0 ng/dl)

In fact, they seemed quite pleased with themselves to have inverted the T3-T4 ratio entirely and to make T4 dominate over T3 in their therapy.

The study did not continue to follow up with these 14 patients to discover how euthyroid they were after months or years on Levothyroxine therapy.

THE INVERTED T3:T4 RATIO

This article demonstrates a common failure in thyroid therapy research, a refusal to acknowledge that T3-T4 ratios are significant in therapy.

Let’s look at the ratios in these children more closely. Simply dividing their average T3 numbers by their T4 numbers yields a T3:T4 ratio shift from 51.7 to 13.41, which shows a significant relative shift.

However, because T3 and T4 are in different units of measurement (ng/dL versus μg/dL), mapping the shift as a percentage of the reference range puts it in clearer perspective.

The reference-range-relative ratios are as follows:

On Dessicated, T3 was at 215% of reference and T4 at 31% of reference range, which yields a reference-range relative ratio of 6.9:1 of T3 to T4.

On Levothyroxine, T3 was at 58% and T4 69% of range, a range-relative ratio of 0.84:1 of T3 to T4.

The ratios are extremely different.

The ratios give a clue to understanding how desiccated thyroid enables patients to maintain clinical euthyroidism over many years despite higher and fluctuating levels of T3.

Specifically, these patients’ T3 heights and their much lower T3 fluctuations are counterbalanced by a significantly lower T4 level.

With less T4 in serum, it is a fact that fewer T4 molecules are available to become T3 beyond bloodstream, for example, in tissues such as bones or muscle.

Moreover, we now know the body has a safety valve to reduce temporary excess T3 levels in tissues. When T3 exceeds any organ or tissue’s set point, deiodinase type 3 (D3), which is an enzyme expressed in every organ and tissue, swiftly comes into action and converts larger quantities of T3 into T2. Deiodinase type 3 is the same enzyme that converts T4 into Reverse T3 whenever T4 is in excess, and D3 prefers to break apart T3 more than any other thyroid hormone (Gereben et al, 2008).

In terms of simple mathematics, lowering T4 and providing fluctuating but higher T3 in serum can nevertheless yield lower and less fluctuating levels of T3 in tissues beyond bloodstream.

In contrast, in true hyperthyroidism, seen in Graves’ disease, T4 hormone is significantly higher than 31% of its reference range, and T3 levels may be continually higher than 200% of reference, rather than fluctuating in and out of reference.  It is clear from Graves’ disease patients’ very different symptoms and lab results that Deiodinase Type 3 is not able to keep up with their T4 and T3 production, even though D3 successfully produces in them elevated levels of Reverse T3.

As mentioned earlier, thyroid medication overdose results in levels of both T4 and T3 that are elevated.

In desiccated thyroid therapy, however, a patient is not overdosed when T4 is relatively suppressed while T3 is relatively elevated.

Likely due to these children’s unique ratio of T4 and T3 levels, they were not suffering from hyperthyroidism for the past 2.7 to 13 years.

Medical dismissal of the T3:T4 ratio in thyroid therapy is behind the long-standing medical assumption that one isolated thyroid hormone value outside a statistical reference range is dangerous, and that T3 above range is the most dangerous thing of all.

One must interpret all thyroid laboratory results in the context of a patient’s thyroid health status and therapy type. The relative position of TSH and T4 and assessment of clinical status by other means can reveal that a peak T3 above reference is not necessarily pathological.

PENNY & FRASIER’S FALSE CONCLUSIONS

Now that we’ve examined the methods and results of this article, let’s see how the 1980 article’s researchers step by step to reach an unfounded and fearmongering conclusion about desiccated thyroid therapy.

First, Penny and Frasier puzzle over the children’s euthyroid status on DTE:

“The elevated concentrations of T3 that were present in our patients while they received USP thyroid did not lead to any symptoms or signs of hyperthyroidism.”

However, they then cite two studies in which symptoms of hyperthyroidism appeared in people with elevated T3 levels on DTE: one study of 36 adults and another of 2 children.

Regarding these two other studies, they state

“It is curious that only a minority of patients with elevated serum T3 concentrations, associated with the administration of USP thyroid or thyroglobulin, had thyrotoxic symptoms and/or signs develop.”

Apparently, among these 36 adults and 2 children in the two other studies, thyrotoxic symptoms were in the minority.

They go on.

“The reason for this is not readily apparent. One possible explanation might be a variable pattern of serum T3 levels during the 24 hours after the ingestion of USP thyroid. Previous reports indicated that the T3 elevations seen after the ingestion of USP thyroid may be transient. However, we have no data bearing on this point for our patients.”

The researchers had no data bearing on this point — not because it was unavailable, but because they chose not to collect such data.

Next, they claim on false pretenses that L-T4 is natural but DTE therapy is unnatural:

“The results of this study show that the administration of levothyroxine sodium in a single daily dosage of 4.2 ± 0.6 (SD) Mg/kg mimics the normal physiology of T4 secretion and T3 generation. Replacement therapy with USP thyroid in equivalent amounts leads to severely elevated concentrations of T3 and is unphysiologic.”

Their phrase “the normal physiology of T4 secretion and T3 generation” makes it seem like only T4 is secreted from a thyroid, after which point T3 is generated.

They confirm their belief in this disproven theory by stating that on L-T4 therapy,

“circulating T4 is derived from GI absorption, and circulating T3 is only derived from peripheral conversion. The level of T3 should be relatively low.”

Today no endocrinologist would believe that T3 is “only derived from peripheral conversion,” since a thyroid gland secretes T3 hormone.

Yet the vast majority of endocrinologists believe today, as did these researchers, that T4 monotherapy is physiologically correct merely because it can yield TSH, T4 and T3 within normal reference limits.

They fail to restate their own claims from their Comment section, that

“the T3 content of porcine and human thyroid glands is quite high.”

Their claim is based on a prior study (Chopra et al, 1973) that showed a widely varying T4 level and widely varying ratio of T4 and T3 in thyroid gland tissue between healthy subjects, hypothyroid subjects, and subjects with Graves’ disease.  There is no static T3 content in a human thyroid gland, but it can be high.

Therefore, they logically reason that

on DTE, “the level of T3 in the serum should be higher than if it were only derived from T4.”

Therefore they admit in their analysis that DTE results of lower T4 and higher T3 are just as physiologically expected

However, they do not re-admit this in their conclusions, since it could  rationally lead to the conclusion that DTE therapy is actually physiologic, especially in light of their normal TSH and T4 levels.

Instead, they build up to a faulty cause-effect statement that has no basis in their experiment, an “X leads to Y” statement:

“Replacement therapy with USP thyroid in equivalent amounts leads to severely elevated concentrations of T3.”

False.

DTE as they dosed it does not necessarily “lead to” severely elevated concentrations of T3.

It depends on how you dose it, and the T3 peak can be very transient.

Let’s look at their determination of “equivalent amounts,” which would be shocking today.  If you look at product monographs for desiccated thyroid therapy today, none of them claim, as this 1980 article does, that “100 mg of USP thyroid is equivalent to 100 mcg of levothyroxine sodium” (they claim this on the authority of Sawin, et al, 1978).

Let’s summarize the limitations of their study:

1) They measured only peak T3 levels, not averages, and failed to report time after dose or report any other measurements during a 24 hour period despite knowing that T3 levels fluctuate when orally dosing T3.

2) They only measured 14 children, not adults, although children have higher levels of T3, and they could have easily found some adults on DTE to study.

3) They made assumptions that these children’s DTE and L-T4 were “equivalent amounts” on the basis of dose per kilogram, TSH and T4 within range, and a 1978 study that claimed 100mg – 100 mcg equivalency, but they discounted non-equivalence in T3:T4 ratios in the drug composition and T3:T4 ratios in serum; and finally,

4) Several of their patients did not in fact have “severely elevated” concentrations of T3. One of the results was within range and several others were only slightly higher.

Therefore, a claim of “Replacement therapy with USP thyroid in equivalent amounts leads to severely elevated concentrations of T3” is a false generalization.

Their ultimate conclusion engages in fearmongering and damning of DTE therapy in all patients regardless of dosage and age:

They write

“The long-term effects of such superphysiologic concentrations of T3 in growing and developing individuals is not known. We believe that our data add additional support to the opinion that the therapy for hypothyroidism with USP thyroid should be abandoned.”

Given that they assume from their study that superphysiologic T3 always goes hand in hand with DTE therapy, how could they claim its long term effects are unknown?

Could not they have found 14 adults who had been on DTE since childhood and studied their health status? Yes, they could have.

Instead, the researchers preferred to leave us with the pathos appeal of children at risk of a supposedly unknown horrible future.

BIONDI AND WARTOFSKY’S CONCLUSIONS

Let’s now return to the statement in 2014 by Biondi and Wartofsky that cites this article as proof:

“The inappropriate use of thyroid extracts in euthyroid and hypothyroid patients can result in thyrotoxic symptoms and severe adverse effects (135)”

1) “The inappropriate use”

— of course, no thyroid hormone should be used inappropriately, but should be dosed appropriately. Why not discuss its appropriate use? Apparently this is not a desirable discussion.

2) “Can result in thyrotoxic symptoms and severe adverse effects”

— As you can see, the only evidence of thyrotoxic symptoms and severe adverse effects in citation 135 comes from their brief literature review of two earlier studies in which thyrotoxic symptoms were rare.

Biondi and Wartofsky’s sentence, despite its limitations (“inappropriate use … can result”) contains loaded language, “thyrotoxic symptoms and severe adverse effects.” These symptoms and effects cannot logically be based on the core research data in item 135, which showed no thyrotoxic symptoms and no severe adverse effects in the 13 patients with elevated T3 levels.

After they make this statement, they defer to the 2012 ATA guidelines which disallow DTE “particularly due to content of a nonphysiological proportion of T3.”

You can see that the 1980 research article’s view of “nonphysiological proportion of T3” is echoed in recent guidelines.

TOO FEARFUL TO BE PROVEN WRONG

There is such fear of nonphysiological T3, and also of DTE in therapy, that no one has yet bothered to collect and publish the data in adult patients on DTE.

Meanwhile an untold number of thyroid patients lives full lives without any symptoms of thyrotoxicosis or illness on DTE, despite temporarily high T3 levels and continually suppressed TSH levels.

These large numbers of happy and healthy DTE patients are apparently beyond the reach of thyroid therapy researchers, who would prefer not to analyze their thyroid hormones and TSH levels and all their other health factors to understand why they are so healthy.

Therefore, one can only presume thyroid therapy research is being held back by an additional fear:

The fear of being proven wrong by research on DTE that uses fair research methods.

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