Please circulate this widely to help science win the upper hand over rigid opinions.
The table shown above is a clinical research-based pharmaceutical conversion estimate.
It’s from Hoang et al’s 2013 randomized clinical trial comparing NDT (desiccated thyroid extract, DTE) and LT4 monotherapy.
The old tables are still in wide circulation based on the US Pharmacopoeia Drug Information, 2000, which is not based on a rigorous clinical trial of hypothyroid patients.
- The old tables in wide circulation say that 60 mg DTE is pharmaceutically equivalent to 100 mcg LT4. They inflate the potency of DTE.
- In contrast, Hoang et al’s recommended table found that 60 mg DTE was equivalent to 88 mcg LT4.
Hoang’s table is a relative improvement, a minor adjustment in the right direction.
It is still potentially misleading.
In this review, I outline the strengths and weaknesses of Hoang et al’s clinical trial.
Although it was based on diverse thyroid patients and was a controlled trial, it had core design flaws that could make even “88 mcg LT4” too high an estimate of equivalency to 60 DTE for many thyroid patients.
- 1. Failure to target biomarkers of tissue T3 sufficiency
- 2. Failure to optimize pituitary and thyroid biochemistry
- 3. Failure to account for patients’ thyroid gland health
- 1. Fix the old “US Pharmacopeia” tables. (Even Hoang’s is better than the old ones.)
- 2. Question the assumption that we are all “average” thyroid patients.
- 3. Question the assumption of TSH-based euthyroidism.
- 4. Do better comparative clinical trials.
- 5. Make conversion tables with ranges.
Believe it or not, Hoang’s team conducted the FIRST trial of this type.
It is a “Randomized, double blind cross-over study.”
In 2014, the American Thyroid Association (ATA) published updated Guidelines for the Treatment of Hypothyroidism that stated,
It is a strength to be pioneers traveling into new research territory. At the same time, this statement is also a shocking admission of the ATA’s four decades of neglect to gather evidence regarding the supposed “superiority” of LT4 monotherapy over desiccated thyroid.
The strengths of Hoang’s trial included many noted by the ATA authors.
The sample size of 70 was twice the size needed for one of the outcome measures they set, the TSQ-36 score (thyroid symptom questionnaire), according to the ClinCalc Sample Size Calculator.
The age range was 18 to 65. There were 53 female and 17 male patients, which is acceptable since the vast majority of hypothyroid patients are female.
A strength was the diversity of patients with many etiologies of primary hypothyroidism Exactly 50% were autoimmune hypothyroid patients, the most common cause of hypothyroidism (in larger populations, mainly Hashimoto’s, and a smaller cohort with Atrophic Thyroiditis). Many other studies focus only on one type of patient, such as those with total thyroidectomies.
This study also included a wide range of pharmaceutical doses, although both were limited at the lower and upper end of range due to their chosen TSH target.
- LT4 dose range 75–225 μg/d
- DTE dose range 43–172 mg/d dosed 1x/day
Patients were randomly allocated to try LT4 first or DTE first. They spent 16 weeks on one therapy, and then at “crossover,” spent 16 weeks on the other therapy.
The study included measures of cardiovascular health (heart rate and blood pressure), weight, cholesterol, triglycerides, and SHBG (sex hormone binding globulin.
To measure psychological outcomes, patients took no less than eight (8) clinical surveys.
The conclusion was rather underwhelming, but we should all celebrate that they achieved near equivalency on average:
Reasonable scientists and thyroid patients should think critically about the weaknesses of the study.
However, I disagree with some of the ATA’s critiques of Hoang’s study that they considered weaknesses (in Jonklaas et al, 2014).
Many of the ATA’s criticisms were based on fear, opinion, and ignorance in the place of scientific evidence.
For example, the ATA decried Hoang’s failure to measure the brief “excursion” of T3 concentration above reference 3 hours after a larger DTE dose. Yet the ATA authors admitted that “The clinical consequences of such serum T3 excursions are unknown.”
Their double standard is revealed in the fact that the same ATA guidelines document claimed the superiority of LT4 monotherapy despite the fall of T3 levels below reference. They try to make excuses for their favourite therapy by saying “the significance of perturbations in serum triiodothyronine [T3] concentrations within the reference range or of mildly low serum triiodothyronine concentrations is unknown.”
It is an infamous characteristic of thyroid therapy arrogance to make prohibitions based on the supposedly unknown.
There is a lot that is known.
DTE is by no means a new medication seeking entry into the thyroid pharma marketplace, but the only therapy option prior to 1948. DTE’s T3 excursions above reference were known to leading thyroid scientists like Utiger, who dismissed them as inconsequential to health based on his clinical experience with desiccated thyroid therapy, together with observing TSH’s inability to suppress in some patients with high T3 peaks while dosing T3.
In contrast, LT4 monotherapy was strongly promoted in the 1970s without any double-blind controlled trials comparing it with DTE, accepting the unknown harm to those on LT4 who suffer T4-T3 conversion handicaps.
Pharmaceutical prejudice, once entrenched, ensured LT4 monotherapy was acceptable even for patients yielding chronic low T3, despite the known and mounting evidence of high mortality rates from low T3 levels in critical illness.
In contrast to the ATA’s 2014 skewed opinions based on the supposedly unknown, I identify weaknesses in Hoang’s study that are based on known scientific evidence from other published research.
Unlike the ATA’s 2014 authors, Thyroid Patients Canada does not take sides in a foolish battle between DTE and LT4.
1. Failure to target biomarkers of tissue T3 sufficiency
The most significant design flaw was the failure to optimize any other health outcome measures except for a TSH between 0.5 and 3.0 uIU/mL, within a the laboratory’s reference range of 0.27-4.20 uIU/mL.
A wiser research group admitted this was a core flaw of their own comparative study, which had measured far more biomarkers than Hoang’s.
Celi et al (2010, 2011) made TSH the only target of their comparative trial of LT4 monotherapy with LT3 monotherapy. In their third and final publication on this clinical trial, they stated that defining euthyroidism by TSH alone was a serious flaw:
What Yavuz, Celi and team mean by “generalized euthyroidism” were all the measures of T3 signaling or “hormonal action” in T3 receptors throughout various organs and tissues. They found a distinct disjoint between TSH and other meaures of T3 sufficiency.
As a result of this flaw, Hoang’s study failed to optimize patients’ health in BOTH the LT4 monotherapy arm and the DTE arm of the study.
Hoang’s study reveals pharmaceutical equivalency on the basis of mere “pituitary euthyroidism,” which had mildly positive outcomes for DTE.
Health outcome biomarkers
Insignificant differences were discovered in mildly reducing the average total cholesterol on DTE, while both arms of treatment had an average almost exceeding the laboratory reference of <200 mg/dL
|DTE: 190.87 ± 34.70||LT4: 195.68 ± 35.19|
The only statistically significant health improvement on DTE was weight loss (-3 lbs. on average).
|172.87 ± 36.37||175.73 ± 37.68|
Symptoms and quality of life were only mildly improved on DTE.
|9.78 ± 4.33||10.97 ± 4.89|
|127.81 ± 13.06||125.65 ± 13.27|
2. Failure to optimize pituitary and thyroid biochemistry
A second core flaw was that this trial, while “normalizing” TSH to a target 0.5 to 3.0 range, neither the TSH, nor the Free T4, nor the Total T3 were optimized.
These are two different medications. One has a significantly greater T3 content and lower T4 content.
Changing from LT4 to DTE will suppress TSH to different degrees in the same individual given their different T3 content.
Changing medications will also yield significantly different T3:T4 ratios in blood in the same individual.
- LT4 mono yields an unnaturally low T3:T4 ratio (higher FT4, lower T3)
- The low ratio is more extreme in poor converters.
- DTE yields an unnaturally high T3:T4 ratio (lower FT4, higher T3)
- The high ratio is more extreme in good converters.
Therefore, dosing to a TSH range will fail to optimize individuals according to their variable individual response to two different pharmaceuticals.
Even considering the TSH alone, they permitted the TSH to rise in DTE therapy.
|DTE: 1.67 ± 0.77||LT4: 1.30 ± 0.63|
The researchers reported that the TSH range filled the width of their target:
- “0.56 to 3.0 μIU/mL for the DTE period”
- “0.51 to 3.0 μIU/mL for the L-T4 period”
However, there is no health outcome rationale for targeting a TSH range as high as 0.5 to 3.0 in a study that compares thyroid therapy modalities. It was the arbitrary decision of the researchers to choose this TSH range.
Their range was too high on the high end, given that 85% of the untreated healthy population has a TSH lower than 2.5 uIU/mL (Hamilton et al, 2008).
Their range was also too high on the low end, given that patients with little to no thyroid tissue often require TSH levels below population reference range to achieve markers of tissue euthyroidism:
- Biomarkers such as heart rate, body weight, bone turnover, etc. (Ito et al, 2017)
- Pre-thyroidectomy or pre-RAI T3 or Free T3 levels (Ito et al, 2012, 2017, )
- Disappearance of hypothyroid symptoms without appearance of hyperthyroid symptoms (Larisch et al, 2018; Ito et al, 2019)
Yet in Hoang’s study, instead of permitting TSH to be as low as it is in the healthy population, they raised the lower permissible target TSH from 0.27 to 0.5.
The prevention of any TSH levels below 0.5 would have been more harmful to health outcomes in the DTE arm, especially those taking higher doses of DTE. Dosing with T3 hormone is clinically proven to suppress the TSH more powerfully when both levels are within reference range (Celi et al, 2010, 2011, Yavuz 2013).
Free T4 and Total T3 results
As a result of their arbitrary TSH targets for dosing, the research team could not keep Free T4 within reference range in DTE, where it dropped to -5% below reference on average.
|DTE: 1.36 ± 0.31||LT4: 1.24 ± 0.19|
The mean FT4 was
- -5% below reference (DTE)
- 54% of reference (LT4)
Given the low average FT4, it is questionable whether patients had enough Free T3 to compensate for loss of local tissue T4-T3 conversion.
|DTE: 138.96 ± 47.26||LT4: 89.13 ± 19.48|
Mean *Total* T3 was
- 65% of reference (DTE)
- 24% of reference (LT4).
If Free T3 and Free T4 had both been measured, patients’ ratios while on LT4 could have been used to divide them into tertiles by this estimate of global T4-T3 conversion efficiency as Midgley et al, 2015 have done.
3. Failure to account for patients’ thyroid gland health
The next design flaw was to fail to take into account patients’ diversity of thyroid status, choosing instead to average all of the results into a single cohort.
Thyroid gland status has a major impact on a thyroid patients’ dosage and T4-T3 conversion efficiency as estimated by FT3: FT4 ratios while on LT4 monotherapy.
According to Midgley et al, 2015, among patients with the least amount of functional thyroid tissue (total thyroidectomy) are found the poorest T4-T3 converters, and “poor converters” are also to be found in autoimmune thyroid disease.
Among the 70 patients studied by Hoang et al, 2013,
- 50% had “autoimmune” hypothyroidism of varying degrees,
- 20% had “idiopathic” hypo (unknown cause),
- 14.3% Post-RAI,
- 11.43% Post-surgical (could have been subtotal thyroidectomy),
- 4.3% Post-radiation.
As a result of this design flaw, the clinical variable of thyroid disease etiology was not taken into account as variable in optimizing a thyroid patient’s dosage to health outcomes.
This could have easily been done by the authors of the research study.
Now consider the research cited above on the lower TSH needed by thyroidectomized and post-RAI patients with significant thyroid atrophy.
This means that disallowing TSH lower than 0.5, when the population reference range goes down to 0.27, would have been more harmful to health outcomes in those who had a smaller amount of functional thyroid tissue.
Consider the T4-T3 conversion rate differences in patients with no thyroid tissue versus those with partial thyroid function, published in Midgley et al, 2015.
- “Carcinoma” = total thyroidectomy (TSH suppression is permitted for many)
- AIT = Autoimmune thyroid disease
- Goitre = variable levels of thyroidectomy for enlarged thyroid
In the graphs, the red boxes are the poor converters. They have lower FT3 despite higher FT4 in levothyroxine monotherapy.
A simple ultrasound could have investigated the relative extent of autoimmune thyroid atrophy (thyroid volume loss) and autoimmune fibrosis (echogenicity results) and correlated these data with FT3:FT4 ratio … if only they had chosen to test Free T3 as well.
Continue to Page 2: Solutions
How should we read and use Hoang’s recommended table? How can we move forward? Read my 5 recommendations.
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Categories: NDT / Desiccated thyroid