This post continues my paraphrase of Jonklaas et al’s 2014 “Guidelines for the Treatment of Hypothyroidism: Prepared by the American Thyroid Association Task Force on Thyroid Hormone Replacement.”
As I’ve explained in my previous post, I’ve decided not to let my summaries of ATA statements be an uninterrupted series of self-justifications and defenses. I’ve decided I need to insert “P. S.” statements under many “ATA: statements” to show the holes in their armor.
These hypothetical “P. S.” statements are what I believe any reasonable, scientific and truly ethical ATA committee would be forced to admit, but perhaps only if they were being carefully cross-examined by a scientifically-knowledgeable lawyer in a legal courtroom and had time to examine their own research literature.
— QUESTION 13a-c. What do we think of synthetic T4-T3 combination therapy?
ATA SAYS: We won’t recommend synthetic T4-T3 combination therapy because it has not yet been proven “superior” to levothyroxine alone and the studies were not long-term. Only a controlled clinical trial, not a trial on an individual patient like you, can prove “superior” benefit and guide us to make a clinical decision.
ATA: Even if you “feel unwell” on levothyroxine, it does not prove including T3 will benefit you. If you are allergic to a filler, try another LT4 brand. If your TSH is high, get it normalized.
ATA: We’ve reviewed our selection of 13 randomized T4-T3 combination therapy clinical trials, and we’ve looked at 4 systematic reviews of such studies.
— P. S. We acknowledge that in 2012 the European Thyroid Association’s guidelines for T3-T4 combination therapy (Wiersinga et al, 2012) also reviewed 13 clinical trials and came up with some positive outcomes. We admit we’ve replaced two of the studies that they reviewed with two different trials of our choice (we replaced Smith et al 1970 and Levitt and Silverberg 2002 with Fadeyev 2010 and Valizadeh 2009), but we won’t say why.
— P. S. We realize these studies’ methods and populations were extremely diverse, so it’s really difficult, if not impossible, to fairly review them as a whole, but we’ve created a table that compares them anyway.
— P. S. We realize that the left-hand column of our table on page 1709-1710 is the only “result” we’ve chosen to tabulate from these 13 studies. We’ve chosen to tabulate “End of study TSH differences between groups” — instead of health outcomes or quality of life outcomes. We would also have to admit that none of our data cells in the table summarize any health outcomes, quality of life outcomes, or patients’ preferences. Any reasonable person would realize that giving the only result as “NS” (not statistically significant) or as a “greater than” or “less than” result (LT4/LT3 < LT4) may make it seem to a reader of the table that most of the studies led to no significant outcome or no benefit of combination therapy over monotherapy.
ATA SAYS: Also, we’re concerned that the studies didn’t include enough men.
— P. S. We know far fewer men than women suffer hypothyroidism, but we won’t say exactly what percentage of men have to be enrolled in these studies to be “enough.”
ATA SAYS: Plus, we think these studies ought to be performed with a sustained-release T3 pharmaceutical that has not been developed yet.
— P. S. We do not say how slim the chances are that the use of a sustained-release T3 alone would have shown superiority at the same dose ratios. But we are interested in pursuing this anyway. It requires pharmaceutical company R&D spending and many approvals to develop a new drug, so you will have to wait for that happen. In the mean time, most patients will have to remain on levothryoxine.
ATA SAYS: Even if adverse events were rare during all these T3-T4 combination therapy studies, we believe the real harm could show up in a longer-term study — and thyroid therapy is lifelong, so they’d have to be really long term.
— P. S. We’ll have to wait a long, long time for those results to come in, and in the mean time you’ll have to use levothyroxine alone.
ATA SAYS: However, we provide some room for flexibility for the treatment of an individual patient. After all our study of this literature, we admit that we didn’t reach unanimous consensus on the issue of preventing all T4/T3 combination therapy in all patients. We only recommend against its “routine use of a trial …. outside a formal clinical trial or N-of-1 trial.”
ATA: Therefore, we do allow some freedom to individual doctors to try this “experimental” therapy on individual patients using N-of-1 methods, but it’s best to limit it to individual cases where the patient has first been “compliant” with L-T4 and all other causes of symptoms have been ruled out, as suggested by the European Thyroid Association (ETA) guidelines for combination therapy.
ATA: But even if individual combination therapy cases are successful, these cases can’t give us the kind of knowledge that we could apply to other cases, so we can’t recommend prescribing T3-T4 combination therapy on a routine basis.
ATA: Maybe we need to focus our research on people with relatively low T3 levels in the presence of a normal TSH to see if they are the subgroup that can benefit. Some research indicates that this is a problem for some people on LT4 monotherapy, especially those with no thyroid gland.
— P. S. Our answer to Question 18 says that ethical thyroid therapy research requires a “representative sample of the target clinical population,” and that there’s a problem with limiting enrollment to “women or minorities” as well as having a too small “sample size” of patients. Because those who have chronic low T3 may be a non-representative “minority” and constitute a small number, we’re not sure how we can ethically target our combination therapy research on a subgroup of people.
ATA SAYS: We don’t think that having genetic mutations in your deiodinases or thyroid hormone transporters makes any clinically relevant difference to your tissue thyroid hormone levels that would justify the inclusion of T3 in your therapy. It’s not worthwhile to get genetically tested. We don’t care what your results are for the DIO2 genetic variant because it has too small of a difference on serum thyroid hormone levels.
ATA: Again, we must mention the fear of lower T4 because it “is thought to be crucial for fetal brain development” and in this form of therapy T4 “may be relatively reduced,” and therefore, we, and the ETA, concur in prohibiting combination therapy during pregnancy.
— P. S. We would admit that we have a lot more fear of a relative, yet small, reduction in T4 than we have of a continually below range T3 level, even though there is a lot of published research backing up the clinical significance of a low T3 level.
QUESTION 14. What do you think about LT3 monotherapy?
ATA SAYS: If you have primary hypothyroidism, synthetic LT3 monotherapy might be okay if you take it 3 times a day for a very short term, such as in preparation for thyroid cancer therapy. We’re familiar with its use in this context, and there’s a clinical study published recently.
— P. S. We admit that we are generally more accepting of T3 monotherapy than we are of T3:T4 combination therapy or desiccated thyroid therapy, even though this therapy involves a supraphysiological ratio of 0:100 T4 to T3, and even though we have only read ONE recent clinical study on T3 monotherapy.
ATA SAYS: We admit that a strength of T3 monotherapy is that this thyroid hormone is already in the active form: it does not have to be converted to another form of thyroid hormone before it gets delivered into tissues and organs.
ATA: However, without the delivery of T4 into tissues that acts as a reservoir for continual deiodination to T3, we don’t know how much T3 is getting into tissues beyond the pituitary and hypothalamus over time. The patient is left entirely dependent on the continual delivery of T3 medication, which has a half life that may vary between 6 hours and 22 hours based on various studies.
— P. S. We’d also have to admit the converse is also true, that delivery of abundant T4 to tissues is not always a reliable reservoir of deiodination to T3. According to our contemporary understanding of the deiodinases, higher levels of T4 even within the reference range will naturally lead to relatively increased ubiquitination (inactivation) of D2 enzyme and upregulation of D3 enzyme. This imbalanced TH metabolism, not normally found within untreated patients except in critical illness, will convert T4 to Reverse T3 at an increased rate, and the net result can be loss of intracellular T3 as well as low bloodstream T3:T4 ratios. We see these low T3:T4 ratios in athyreotic patients on LT4 who have a chronically high-normal T4 level simultaneous with a low T3 level, but we have unfortunately dismissed them as clinically insignificant and have not cared to study their health outcomes. Therefore, even with the delivery of T4 into tissues during levothyroxine monotherapy, we would have to admit that we should be equally concerned about how little T3 may be getting into receptors within tissues beyond the pituitary and hypothalamus.
ATA SAYS: We openly acknowledge that in this form of therapy, higher levels of T3 are required to compensate for the loss of T4, but despite this necessary compensation, we fear the higher T3 levels. We’re very suspicious of this therapy because it creates fluctuations in Free T3 blood levels above reference. We haven’t studied it enough recently to know what is going on in this form of therapy, and we fear that you might lose bone mass.
— P. S. We’d have to admit that we have a bias against T3-dominant therapy that is illustrated by our double standard. We tend to be unconcerned for human health when T4 dominates therapy and suppresses T3, and very fearful when T3 dominates T4 in therapy.
— P. S. As we have shown in our Table 3, p. 1678, we do realize that the D3 enzyme “decreases intracellular T3 levels,” and that its “preferred substrate” is T3 more than T4. In other words, we know that the D3 enzyme prefers to deactivate T3 to T2 even more than it prefers to deactivate T4 to RT3. In light of that table and our understanding of the underlying mechanisms, we’d have to admit we may be overemphasizing the concern that the human body will not clear out a mild excess of T3 above reference range, especially in the absence of T4.
ATA SAYS: We believe T3 monotherapy should be monitored to target a low-normal TSH level. We would also recommend testing Free T3 just before the morning dose and 2 hours after dose to maintain levels within reference range (and there’s no point in measuring Free T4 in LT3 monotherapy). As you get your T3 monotherapy dose adjusted, the fluctuations can put you at risk of periods of undertreatment or overtreatment.
— P. S. Notice that we are also willing to target a low-normal TSH level in this therapy even though no thyroid patients on levothyroxine are allowed to target a lower TSH within range (Question 7d). We would have to admit this is a double standard because we recommend more individualized and optimized care for patients on T3 monotherapy than patients on T4 monotherapy.
— P. S. Notice that we are willing to test Free T3 in this form of therapy, but not in other therapies where we fear supraphysiological T3 levels, such as desiccated thyroid therapy, which we demand must be dosed to TSH alone.
— P. S. Notice that we are willing to acknowledge the risk of undertreatment due to lower Free T3, but again, only in this form of therapy. In other therapies, we will ignore even chronically low T3, but here we are worried about intermittent low T3.
ATA SAYS: In general, it’s inconvenient to the patient to take many doses a day and it’s inconvenient and time consuming for a doctor to manage the therapy. Plus, LT3 is more expensive than LT4.
— P. S. We are very happy to point out that the inconvenience and cost of this therapy will minimize the number of doctors and patients who resort to this therapy. We would have to admit, in all fairness, that these are not clinically significant considerations, but rather a matter of patient compliance and market forces.
— TO BE CONTINUED
— and see my previous post today focusing on their section on desiccated thyroid.
Yes, there is still more to learn from the ATA, and there is even more to learn from intelligent, fair, and ethical scientific dialogue between a thyroid patient and the ATA.
Jonklaas, J., Bianco, A. C., Bauer, A. J., Burman, K. D., Cappola, A. R., Celi, F. 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
In other posts with different aims and methods, I often do provide further references.
Notice I haven’t cited anything else … Why?
This series of posts is meant to be a public conversational dialogue that prods and inspires the ATA and thyroid experts to do further research within their own literature.
I’d like to encourage the ATA and those who know their thyroid science to dig it out and read it carefully, just like I have. You can do your own lit review on the issues I’ve raised in the P.S. Statements — I should not have to always do all the work for you.
If you don’t know where to start with your research, consult our Campaign Statement References. It includes about 200 items, many of which are selectively ignored by the huge reference lists at the ends of ATA guidelines documents.