✅Evidence-Based: Written by a Board-Certified Endocrinologist
In response to the presentation of a new clinical trial abstract at ENDO 2021, one of my readers (thanks, Mike) commented:
I think A LOT of patients are saying I told you so here. But this is very interesting. Especially because it was presented at Endo 2021. I haven’t read the study yet, but I can tell you what’s been written up in the news articles I’ve heard over and over again. So maybe it should get A LOT more research and consideration.
So what’s all the excitement about? If you guessed it’s regarding the age-old controversy of T3 or not T3, bingo. Dr. Thanh D. Hoang conducted a randomized, double-blind trial of desiccated thyroid extract (DTE) vs combination levothyroxine + liothyronine (T4/T3) vs levothyroxine (T4). Each group of hypothyroid subjects was treated for three, 3-month periods, without knowing which therapy they were receiving during each 3-month period. While the results of the trial, in aggregate, showed no statistically significant differences among the groups in symptom scores, 45% of people preferred DTE, 32% preferred T4/T3, and 23% preferred T4 alone.
Let’s pause here for a second and note a couple of things. First, the above information is from third-party summaries of the presentation of the abstract of this study at one of our best, yearly, national endocrine conferences, ENDO 2021. I did not attend this presentation and, as far as I can tell, the full paper has not yet been published, so I know about as much as you do regarding the details of the trial. Second, how awesome is it that Dr. Hoang decided to perform such a study? As I think both supporters and critics of my blog can agree, we need more clarity regarding the use of T3 in hypothyroidism. Studying this topic is really, really hard, in part due to the sheer number of confounding variables that can influence how people with hypothyroidism feel during any predefined treatment period. So, Dr. Hoang, good on you!
Symptom Scores the Same, People Prefer Pig Thyroid
I love the above newspaper headline I invented, because it portends the tribal divide we’re going to see as this article gets discussed on the internet and dissected by the medical community. The pro-T4/anti-T3 contingent is going to point out that there was no difference in symptom scores among the three groups, and they will seek to explain away the preference for DTE and T4/T3 over T4 alone. And they will make some good points. On the other hand, the pro-T3/anti-T4-alone tribe will say – as Mike pointed out – “I told you so!” And they will have some ammunition to back up their contention.
Let’s start with what I expect will be the major criticisms of the study. First, it was fairly small – just 75 people. I do not fault Dr. Hoang for this; I’m sure he had a statistician determine how many subjects would be needed for appropriate power to detect a significant difference in the primary outcomes. And, for those of you who don’t know, doing clinical trials with humans is incredibly hard. People have their own agendas coming into this sort of endeavor; they can be flaky, non-compliant with the protocol, or drop out completely; and any primary outcome that relies on people’s subjective sense of how they feel is inherently less reliable than objective measures.
Nonetheless, it appears that there was no statistically significant difference among the three groups with respect to the primary outcome of symptom scores. BUT, upon performing a subgroup analysis, Dr. Hoang says that individual subjects who weren’t feeling great on T4 alone were the ones who tended to report feeling much better on DTE and/or T4/T3 combination therapy. This squares with both selected studies that have already been done on this topic – including Dr. Hoang’s similar 2013 study – as well as with the experience of many patients across the internet and a smaller number of patients in my practice.
Critics of the subgroup analysis will say that such an analysis is not powered to detect meaningful differences, and I assume that this statement will be correct, if we restrict the scope to evaluating the statistical validity of the subgroup analysis. My complaint about this criticism is that it gets me nowhere, with respect to deciding what to do with the symptomatic, T4-treated hypothyroid patient sitting in my office, who has otherwise “perfect” lab results. I’m not sure if there are other studies of this nature in the pipeline, but my sense is that we are unlikely to gain further clarity by insisting that aggregate study results should always trump using an individual as his/her own control. While regular readers know that I am a big fan of using trial data to inform clinical decision making, I think we need to take the entire corpus of research on the T4 vs T3 issue into account. Even before this study, I believe that we had enough data to argue in favor of a trial of T3 add-on therapy to T4, under certain circumstances.
My sentiment in the preceding paragraph should not be construed to mean that I endorse DTE, nor that I think the preferences of people for DTE over T4/T3 over T4 are ipso facto evidence for the blanket superiority of those treatments. In fact, I am not at all surprised that a larger percentage of people expressed a preference for DTE and T4/T3. Let we walk you through my reasoning.
I can surmise that there was selection bias in the study participants, simply due to the fact that people who enter these types of trials usually have their own agendas. In this case, it would be hypothyroid people who were at least somewhat dissatisfied with their current care and looking for something “new.” I suspect (but do not know) that the average, pre-intervention symptom score for the study participants was higher than the average symptom score for the larger population of hypothyroid people in the U.S. We already know that patients who feel unwell (or less well) on T4 alone are the very patients for whom we are most likely to try T3. Therefore, any clinical trial of this nature should have a bias toward seeing improvement on T3 when using the study subject as his/her own control.
In addition – and this is crucial – we also know that the addition of T3 to T4 often results in transient clinical improvement, presumably due to the stimulant effect of T3 in people who don’t really “need” it as a replacement therapy. This improvement in such individuals typically lasts for weeks to a few months, rarely persisting beyond 6 months if due to the placebo or stimulant effect of T3. It is only the people who continue to feel well on T3, beyond 6 months, who I would consider to truly need that therapy.
Unfortunately, Dr. Hoang’s trial used relatively short, 3-month periods for each therapy, making it impossible to know if the subjects on DTE or T4/T3 would have continued to feel better with continuation beyond 6 months. It is quite possible that some of the people who preferred having some T3 on board would have regressed to their normal (worse) baseline 6 months down the road on that therapy, making the preference percentages for each therapy relatively equal.
Back to First Principles: What About Normal Physiology?
In my T3 Controversies Series, I have written extensively about why pig thyroid (DTE) makes no sense as a thyroid replacement therapy. Notice that I said, “makes no sense,” which should be differentiated from asking whether it works. It makes no sense because the ratio of T4:T3 in most DTE preparations is around 4:1, while the ratio of T4:T3 in the human body is somewhere between 15-20:1. Therefore, a dose of DTE will expose the body to much higher amounts of T3 – a short half-life hormone – than it is accustomed to seeing. Any hormone that reaches a peak within a few hours and then dissipates fairly quickly has the potential to act as a stimulant.
Why should we care, as long as it makes people feel better? Well, I’ve discussed these reasons before, so let’s restrict today’s focus to the fact that DTE has the potential to improve symptoms that may not be due to inadequately treated hypothyroidism. Remember, it has stimulant potential, so people with depression or fatigue, for example, may feel better. They may not always feel better long-term, but they can at least feel better over a 3-month time period.
When DTE is not Treating Hypothyroidism
Let’s consider – more deeply – these patients with “hypothyroid” symptoms that may be due to something other than hypothyroidism. As a thought experiment, consider a person with hypothyroidism who has tried T4 as well as T4/T3, with beautiful labs on paper throughout, but not enough clinical improvement. Assume that a thorough workup has revealed no other explanation for his/her persistent symptoms. Instead of saying “It’s not your thyroid,” and referring the patient back to their primary doctor, should we consider a trial of DTE? Such a trial would not be conducted in the name of thyroid hormone replacement therapy; rather, we would be doing a simultaneous diagnostic and therapeutic maneuver to see if the patient has “DTE-responsive malaise.”
I realize this sounds terribly unscientific and, quite frankly, I need to sit with this idea I just came up with a lot longer, in order to determine how I really feel about it. I hesitate to invent another waste-can diagnosis that has the potential to medicalize something that shouldn’t be. But there is precedent, I think. Consider “steroid-responsive encephalopathy,” which denotes an acute brain condition in people with elevated thyroperoxidase antibodies. Some have called this Hashimoto’s encephalopathy, but most experts agree that the presence of Hashimoto’s has nothing to do with this brain problem, which gets better with steroids. So, without really knowing what the problem is, these patients are treated with steroids and get better, never to discover what caused the problem in the first place.
I suppose I can make another argument in favor of using DTE to bring a patient out of their doldrums, based on my clinical experience. Although I don’t prescribe pig thyroid, I have seen a few people over the years who felt poorly with conventional treatment, got better on DTE, and then were able to transition back to T4/T3 or T4 alone. So perhaps there is a role for DTE as a last-ditch effort to get someone feeling better, regardless of the cause of their symptoms, with the intention to eventually transition them back to a more physiologic and natural replacement regimen with T4/T3 or T4 alone. Again, for a physician-scientist, it is unsatisfying to initiate a treatment without a diagnosis, but if the patient gets better…perhaps that should be our north star.
A reader of mine (thanks, Arthur) recently pointed out that one of the larger Facebook thyroid groups deleted some of his comments questioning their recommendation for more T3 to be given to a woman who already seemed overmedicated. Ultimately, he was banned from the group and told that people like him just “didn’t believe,” and the group has tens of thousands of patient-reported case studies to prove the success of their methods. He rightly expressed concern that this is the behavior typical of a cult.
Just as these online support groups can be heavy on dogma, dismissive of cases that don’t fit their ideology, and light on tolerating the liberal exchange of ideas, physicians can also be stubbornly adherent to old ideas that would benefit from nuanced reexamination. While I do not believe that Dr. Hoang’s new study constitutes a celebratory “I told you so” moment for dissatisfied thyroid patients, I do think it re-raises the important question of when to try T3, what kind of preparation to try, and what dose to use.
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Image Credit: Photo by Benjamin Wedemeyer on Unsplash