Endocrine Societies at Odds Over Advice on T3 for Hypothyroidism

February 17, 2015

Two leading US endocrine societies — the American Thyroid Association (ATA) and the American Association for Clinical Endocrinology (AACE) — are at odds over the specific advice that should be given to doctors regarding the use of triiodothyronine (so-called T3) in patients with hypothyroidism who do not fare well on levothyroxine treatment (T4) alone.

The ATA and AACE both recommend levothyroxine as first-line therapy for patients with hypothyroidism; in fact, the latest ATA guidelines advocating this stance were published just at the end of last year and conclude that levothyroxine monotherapy is effective in treating approximately 80% to 90% of hypothyroid patients.

However, with these new recommendations, there has been a slight change in the ATA's stance regarding T3, which it had previously advised against using altogether.

ATA's guideline opens the door for more T3 testing and unwarranted T4/T3 treatment.

A number of patients (and some physicians) swear by adding T3 to T4 (so called "combination therapy") when they still have hypothyroid symptoms despite taking T4. But there are concerns about side effects such as atrial fibrillation when T3 is used.

The ATA thus concludes there is "insufficient evidence" to routinely combine T3 with levothyroxine in the treatment of hypothyroidism, but it does not explicitly rule out use of T3 under certain circumstances.

The stance taken by the prior combined AACE/ATA guidelines from 2012 is similar, said Dr Jacqueline Jonklaas (Georgetown University Washington, DC), cochair of the ATA task force that authored the new ATA guidelines. In addition the prior guidelines (Endocr Pract. 2012;18:988-1028) did in fact refer to "unresolved issues raised by studies that report that some patients prefer and some patient subgroups may benefit from a combination of L-thyroxine and L-triiodothyronine."

But AACE president Dr R Mack Harrell (Memorial Healthcare System, Hollywood, Florida) said AACE has declined to endorse the new ATA guidelines, specifically because it disagrees with the advice regarding T3.

Speaking with Medscape Medical News for an article last month regarding Thyroid Disease: 10 Questions Patients Should Ask, he said: "The ATA new hypothyroidism guidelines are just loaded with speculation on whether adding T3 is the right thing to do."

But Dr Robert Smallridge, president of the ATA, and Dr John C Morris Jr, secretary/COO of ATA, have taken issue with this comment, stating that it is "incorrect." A "careful analysis" of the guidelines will indicate that the ATA's position is to "recommend against the routine use of 'adding T3' for patients with hypothyroidism," they reiterate.

In fact, all parties recognize that some physicians and patients do indeed use T3, and Dr Harrell himself has acknowledged that "everybody who does thyroidology for a living has a few patients who may benefit from T3."

The issue was discussed at length during a symposium at the ATA meeting last fall, which was covered by Medscape Medical News in a feature article, and the current dispute seems to center on the specific advice given by each society with regard to when to utilize this approach.

"To clarify our previously imprecise language, the ATA's guideline opens the door for more T3 testing and unwarranted T4/T3 treatment," Dr Harrell said.

But Dr Jonklaas argued: "To use Dr Harrell's metaphor about the door, we did not open the door. The door is already wide open, as can be illustrated by a Google search of T3....We are seeking to ensure that the traffic of therapy through the door is based on rational and sound science that will protect and enhance the health of our patients with hypothyroidism."

The Devil Is in the Detail

Dr Harrell explained that he would like to provide "a more nuanced and accurate view of what we [at the AACE] meant."

In this newest guidance, the ATA "presents scientific evidence on the processing and action of T3 that is carefully researched and dispassionately catalogued without a hint of conjecture. Indeed, the scientific rigor of the ATA's Hypothyroidism Guideline Committee members is beyond reproach," he asserted.

But, Dr Harrell added, it is the belief of the AACE that "in the text of the document, the ATA tacitly supports monitoring of T3 levels in hypothyroid patients," which "directly and indirectly may promote the overuse of combination T4/T3 therapy or overtreatment with T4."

In fact, this issue was specifically addressed in a 2013 AACE/US Endocrine Society Choosing Wisely statement, which advised against routine monitoring of free T3, he said.

This is "because the T3 level can be misleading. In most patients, a normal thyroid-stimulating hormone [TSH] level indicates a correct dose of levothyroxine," the two societies concluded at the time.

"Thyroid-hormone overtreatment (with T4 and/or T4/T3) is specifically what we have tried to prevent with [this]…Choosing Wisely statement," Dr Harrell asserted, and he pointed out that members of the ATA Clinical Practice Guidelines Committee "consciously chose not to endorse" the 2013 Choosing Wisely recommendation.

But ATA Says It Doesn't Recommend Routine Monitoring of T3

But Dr Jonklaas told Medscape Medical News: "The issue is not whether T3 levels can be misleading. The issue is that we do not yet understand what T3 levels signify, and we do not yet know whether T3 levels might be significant or important for our patients. We discussed this uncertainty in our guidelines."

And, she stressed, "We do not recommend routine monitoring of T3 levels in patients in our [new] guidelines.

We do not recommend routine monitoring of T3 levels in patients in our [new] guidelines.

"We provided background information from research studies in both humans and animals in which T3 levels were studied in order to explain why there is an interest in T3 therapy originating from both patients and physicians,"

Following this discussion, "we specifically pointed out that we could not make a recommendation about use of T3 levels in clinical practice, as the data were preliminary and investigational in nature," she explained.

Furthermore, "We recommend that patients who do not do feel well taking levothyroxine would be best served by clinical studies in which any potential benefits of T3 could be carefully documented and any potential side effects could be carefully checked for."

And the ATA did not, as "erroneously stated by Dr Harrell, choose not to endorse the Choosing Wisely statement, which was published in 2013.

"Our comment, made in October 2014, was that differences of opinion exist about the importance of T3 levels, and we cited the Choosing Wisely statement and a recent review article as an illustration of this difference of opinion," Dr Jonklaas noted.

Some Patients Use T3: Both Agree More Research is Needed

Despite the recommendations against routine use of T3, "We acknowledged that some endocrinologists do use T3 to treat their patients, and we expressed our concern that such patients, particularly elderly patients, would be adequately monitored for side effects," Dr Jonklaas told Medscape Medical News.

"Patients and physicians are already very interested in T3 therapy, and closing our eyes to this will not serve as 'T3 prohibition' and make this interest go away," she adds.

And acknowledging this interest "should not increase the likelihood that T3 is used. We hope that encouraging research into this topic will lead to better understanding of therapy for hypothyroidism and allow us to prevent problems with use of treatments that are ineffective or dangerous."

Patients and physicians are already very interested in T3….Closing our eyes to this will not serve as 'T3 prohibition' and make this interest go away.

Indeed, this position "is not inconsistent with Dr Harrell's statement [in the 10 Questions story] that 'everybody who does thyroidology for a living has a few patients who may benefit from T3,' " Drs Smallridge and Morris observed.

Dr Harrell concluded: "AACE fully appreciates the ATA's discussion of nascent T3 science in the treatment of hypothyroidism guideline, but…disagrees with interpretation of this new T3 information and the translation of this new science into clinical practice."

Drs Smallridge and Morris said the ATA "strives to achieve the best treatment for all hypothyroid patients, and it is clear that more research in this area is needed. This is clearly stated in our guidelines and in this we agree with Dr Harrell."

Dr Morris has no relevant financial relationships. Dr Jonklaas has conducted research on a triiodothyronine product funded by ITL Pharma (Kingsport, TN). She is also planning a research project using levothyroxine gel capsules funded by Institut Biochimique, Lugano, Switzerland. She has no financial interests in either product.

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