In 2016, Dr. Elizabeth McAninch and Dr. Antonio Bianco published a research paper called “The History and Future of Treatment with Hypothyroidism.”
On Dr. Bianco’s research team’s website, deiodinase.org, there is a blog post about this study that includes a wonderful video of Dr. McAninch talking about the historical research they did on thyroid therapy.
Below that video, you will also find an audio file that you can listen to, a 16-minute interview between The People’s Pharmacy and Dr. Antonio Bianco, discussing the percentage of patients who do not fare well on Levothyroxine (L-T4) monotherapy, and the research on combination therapy (L-T3/T4) that needs to continue.
This blog post focuses on the audio interview with Dr. Bianco.
Overall, this is an excellent interview and raises very important concerns about the safety and efficacy of Levothyroxine monotherapy.
All doctors who treat hypothyroidism should listen to it.
We provide some of the transcript of that audio file below in order to provide some further commentary and insight.
Animal extracts and synthetic thyroid hormone
Dr. Bianco explains:
So, the thyroid produces hormones that are important for our body. Every tissue in our body responds to thyroid hormone.
And obviously then when the thyroid doesn’t work so well, the production is decreased, or even ceases to exist, the patients experience clinical symptoms.
And therefore, treatment over the last 100-120 years has been to give back thyroid hormone to the patients.
So it started many years ago, 100 years ago, with patients taking slices of thyroids from animals in breakfast in the morning, warmed up, and just eating that. And obviously we evolved. Then the thyroid extracts were made, thyroid extracts from animals were made in pills and patients would take pills every day.
And most recently, we have synthetic thyroid hormone, which is made by pharmaceutical companies.
It’s important that this synthetic thyroid hormone, although it’s synthetic, is identical to the hormone that is produced by the thyroid. So a patient with hypothyroidism will take a tablet every day, and this tablet contains the thyroid hormone. So the system, the body, doesn’t know the difference between the hormone that is coming from the tablet or the hormone that is coming from the thyroid.
Although the hormone found in synthetic L-T4 preparations is technically bioidentical to natural T4 in the bloodstream, a major issue overlooked by endocrinologists — including Dr Bianco, it appears — is that the hormone cannot replace the gland that secretes it.
In another blog post “All thyroid therapy is artificial,” I discuss how any thyroid hormone therapy is inflexible, while a living thyroid gland’s tissues are flexible and adapt to changing external and internal conditions.
The thyroid gland was meant to help us adapt. When we are on thyroid hormone therapy we are less adaptive to the metabolic assaults that our bodies face. We have a narrower range of flexibility in our thyroid hormone metabolism.
Therefore, thyroid patients’ therapy needs to be carefully optimized so that both thyroid hormone levels — T3 and T4 — are able to support optimal function. We also need careful monitoring to ensure that our therapy stays on track as our bodies go through life.
The assumptions about T4-T3 conversion
The main therapeutic problem Dr. Bianco focuses on is that a pill containing one hormone, T4, cannot play the role of both hormones, T4 and T3. As he explains,
So, what happens is that this T4 — and it’s called T4 because it contains four atoms of iodine in its molecule — it’s actually a pro-hormone.
T4 doesn’t act in different tissues.
It’s a hormone that has a long half-life. It stays in the circulation for many days.
However, it does not trigger any biological effects in different tissues.
In order to do that, T4 needs to be converted to T3. It needs to be activated in our body.
And our body does that. T4 gets converted to T3 in different tissues. And in the circulation, patients that are taking only T4 will have plenty of T3 in the circulation.
So T3 is the molecule that is responsible for the effects of the thyroid gland. So that if you say, well what happens in the brain? what happens in the liver? and skeletal muscle? It’s T3. T3 is the molecule that is active.
But patients with hypothyroidism take T4.
And then we hope — and we wish — that the body will just convert T4 to T3.
And as you said, it is correct. In the last 40 or 50 years, we’ve been taking for granted that just giving T4 or Levothyroxine (that’s what it’s called, the pharmaceutical grade of T4) to patients, [that] it’s enough, because the body will, in its wisdom, produce or transform T4 to T3 and will produce enough T3.
And in fact, yes, conversion of T4 to T3 exists in multiple tissues. And actually I would say there’s almost — hardly are you going to find a tissue in our body that is not able or cannot convert T4 to T3.
However, I think the question — the key question — is, “Do patients with hypothyroidism that are treated with Levothyroxine — do they have normal levels of T3? both in the circulation and inside the tissues?”
There’s plenty of T3, but does it reach the normal levels? That’s the key question.
Because, if we just ask the pituitary gland and we measure TSH, that’s going to be focused mainly on T4 in the circulation.
And how do we know about T3?
So we’ve been taking for granted — again, over these last 40 or 50 years — that serum levels of T3 are normal.
Now, most recently, some studies coming from Japan and from Europe have shown, looking at thousands of patients, have concluded that serum levels of T3 in patients that are treated with Levothyroxine are actually slightly below normal. They’re not normal. They’re about 10-20% below normal.
What is “normal” versus “optimal” T3?
At this point in the interview, Dr. Bianco has been using the word “normal” many times.
He has also given an average figure from studies: “10-20% below normal.”
This can be misinterpreted by doctors and patients who may think he is talking about the laboratory reference range for T3.
No, he isn’t.
In fact, he’s talking about the fact that even within the “normal” laboratory reference range for Free T3, there is a much narrower area of “healthy, normal, and optimal” blood values for T3. (We talk about the problems with reference ranges versus individual “set points” in our Campaign Statement here: “Rationale: Reference ranges.”)
The average level of Free T3 hormone in the blood — in people with healthy thyroid glands — is about the middle of the Free T3 reference range.
In Gullo et al’s 2011 study that included 3,800 healthy control subjects, Free T3 levels were maintained at an average around 4.47 pmol/L. This was maintained no matter where TSH and T4 were within their reference ranges. Free T3 levels were carefully protected by the interplay of TSH and T4.
However, in this same study, over 1,800 patients taking L-T4 monotherapy who had no functional thyroid gland tissue had an average Free T3 level significantly below the “normal” average at the same level of TSH and T4. Some thyroid patients were so far below normal T3 that one wonders how they could function.
But is lower T3 in blood clinically significant?
Bianco takes the conversation one step forward.
So that has [caused] a lot of people to think, and say “Well, is it clinically relevant to have serum levels of T3 that are slightly below normal range?”
The true answer to this question is “We don’t know.” We have no data. There are no studies in which that specific question has been addressed.
So therefore, I think this is a major point of change in the approach of treatment for patients with hypothyroidism. Because there are studies out there showing that serum T3 is below normal.
And why is this important? Again, T3 is THE hormone that triggers biological effects in different tissues.
So that if a patient has a T3 level that is about 10-20 percent below normal, common sense will indicate that probably it’s important. However, if you practice “evidence-based medicine,” we don’t have the clinical studies showing in fact that this is important.
Unfortunately, Dr Bianco is correct about the huge gap in clinical research. There is little research funding for studies that question the efficacy of the favorite mode of thyroid therapy. People are reluctant to learn about what could be wrong with it.
We know that at the molecular level, T3 is “THE hormone” that is necessary, and logically, even a slight drop in T3 levels can be clinically significant.
However, when it comes to thyroid patients as a group, or even people with normal thyroid glands, few studies examine the health outcomes of low T3.
For example, even in the study of cardiovascular disease, in which we know that T3 hormone is central and TSH and T4 do very little, when researchers examine thyroid hormone in relation to risk factors and health outcomes, they turn away from T3 and start to categorize patients primarily by their TSH levels.
And if or when such researchers do look at patients’ T3 levels, it appears that some have already made up their minds that TSH is going to be the biggest difference. They can be blinded to the pattern of data that they see between T3 levels and cardiovascular health, and they can jump to conclusions that Levothyroxine therapy “fixes” all the problems with cardiovascular health when it normalizes the TSH. See our discussion of some research studies in my blog post “Cardiovascular disease research should focus more on patients’ T3 levels than TSH.”
How many patients need T3?
Later in the interview, we learn that many studies of combination therapy have been inconclusive, and yet an estimated 10-20% of thyroid patients are having problems with the standard therapy and could do better on L-T3-T4 combination therapy.
Bianco: However, I have to say that there are about 22-23 clinical trials that were performed all over the world, and the majority of these trials have not been able to document or to demonstrate scientifically that the combination of T4 and T3 is a superior form of treatment for patients with hypothyroidism.
PP: We have looked at the abstracts of some of those trials, and what we usually see is that the investigators write, “Well, we couldn’t document that there was any difference, but there’s a certain proportion of our patients who say they really like the combination and they feel better on it.” It’s certain not all of them, and it’s not even the majority. But some of them do say “I like this better.”
Bianco: Absolutely. That’s correct.
And that has been my experience, and most clinicians’ experience as well.
Some patients can’t live without it.
Why would that be?
It seems that not all hypothyroid patients are the same.
And there’s one study that came out of the UK showing that a small fraction of patients with hypothyroidism, they exhibit what’s called a genetic polymorphism in one of the enzymes that convert T4 to T3. That polymorphism is observed in about 15% of the population. And if you have that polymorphism, you’re more likely to prefer a combination therapy. You are more likely to be successful with a combination therapy of Levothyroxine and T3.
PP: Now Dr. Bianco, you’ve mentioned “a small fraction.” But if that small fraction is 10-15% of the population, we’re talking over a million people in the United States alone.
I mean, I know, it’s a lot of people. The fraction is small, compared to 100%.
But it’s because hypothyroidism is so prevalent, absolutely, you are talking about a lot of patients. Exactly.
Yes, that’s a lot of people. (Read more about the genetic polymorphisms in some of our other blog posts: “REVIEW: DIO1 gene affects T3:T4 ratio.” and “REVIEW: Genes MCT10 and DIO2 and combination therapy.”
However, these estimates of 10-20% of patients are troubling.
What are these estimates based on? The hypothyroid symptoms of treated thyroid patients can’t simply be only due to the DIO2 genetic polymorphism, when we know other factors are involved in altering the T3:T4 ratio.
If estimates are based on doctors’ reports, then how many doctors are likely to report that patients are symptomatic on the therapy that they are managing by normalizing their TSH?
If estimates are based on patients’ self-reports, how many patients are likely to believe their symptoms over their doctor’s interpretation of their “normal” lab results, and their doctor’s explanation that their symptoms have nothing to do with their thyroid hormone levels, but they are in fact depressed, or have heart disease, or have osteoporosis? Those patients are not likely to think there’s anything wrong with their thyroid therapy. In fact, they will likely “feel better” on Levothyroxine than they did on no medication at all.
So it is highly likely that 10-20% is a gross underestimate of patients who are actually experiencing long-term physiological harm by not having their T3 hormone levels optimized.
“I feel better” vs. “I can’t live without T3”
In another part of the interview, the People’s Pharmacy raises the discussion of patients’ symptoms.
PP: Dr. Bianco, at the start of our conversation, you mentioned that there are symptoms of hypothyroidism. We didn’t talk about what they are. But what we have heard from a number of people telling us about their experience with hypothyroidism and its treatment, is people will say “I just don’t feel good on T4 alone. If my doctor adds in some T3, I feel better.” So the symptoms are not as apparent. And you and your colleagues have done some research, very recent, in rats, that suggests maybe these people aren’t making it up.
Bianco: Correct. So what we know is that the treatment of hypothyroid patients with Levothyroxine alone is effective in about 80% of all patients. So in fact, the treatment with Levothyroxine is highly effective. It takes care of 85 — the majority of the patients feel very well.
And we know that because there are about 10 Million Americans that have hypothyroidism.
So we make 85% — 90% — of these 10 Million Americans pretty happy.
However, there is a fraction of patients with hypothyroidism that are treated with Levothyroxine alone that are unhappy. They remain symptomatic. Even though you’re giving Levothyroxine, you’re normalizing serum TSH, they remain symptomatic.
And it’s interesting. They all have a very similar story to tell. They say “I remain unfocused. I remain tired. It’s hard to concentrate.”
And now, the point that you made, that this is somehow resolved by adding T3 to the treatment with Levothyroxine — just adding a combination of Levothyroxine to T3 — it is correct. Many patients will tell you, “I cannot live without T3. I need both T4 and T3.”
We need to stop minimizing patients’ symptoms by talking about them as mere subjective “feelings.”
Dr. Bianco is ethical in repeating what some of his patients say: they “cannot live without T3.”
When we are talking about a patient’s daily cognitive and physical function — a minimal level to be able to perform work and daily activities that most people enjoy — that is not a subjective symptom to be dismissed as a mere “feeling.”
For some thyroid patients, their access to T3 makes the difference between significant disability and ability. Poverty vs. economic productivity. Isolation vs. citizenship.
And when we are talking about the potential long-term harm that has not been studied enough, we know it is not just about symptoms. A person can be non-symptomatic for decades before an organ finally breaks down enough for a disorder to be noticed and diagnosed. Sufficient T3 is the foundation of any human being’s long term health.
Potential biological harm of lower T3 in serum
Dr. Bianco explains that his research proves that even a small drop in blood levels of T3 can result in tissues and organs that are “hypothyroid.”
PP: Tell us about your research.
Bianco: So we’ve been interested in answering these questions that we’ve been discussing so far. For example, “Is having a low T3 clinically relevant?” “Wy [can’t we] normalize serum T3 with Levothyroxine alone?” and “Is there a fraction — or is it true that this polymorphism could in fact change the way we treat patients with hypothyroidism?”
And this is what we did with rats. We recently looked at combination therapy versus monotherapy in rats that had been thyroidectomized, so they were hypothyroid.
And we saw that by giving Levothyroxine alone, you could not in fact normalize serum T3.
This is not news. Researchers in Spain about 20 years ago have shown the same thing.
But what we’ve shown now is that the tissues remain hypothyroid even when TSH is normal and serum levels of T4 are normalized.
So the brain has signs of hypothyroidism. What are these signs? We measured the expression of genes that are responsive to thyroid hormone, and we saw that those genes exhibit a pattern that is compatible with hypothyroidism.
We looked at the liver, we looked at the skeletal muscle. These are all tissues that respond to thyroid hormone, and they all exhibited signs and indications that they remain hypothyroid.
Even though — again — serum TSH and T4 levels were normalized, serum T3 levels were slightly decreased, just like the situation we see in patients.
Only studies with rats can investigate how much T3 is getting into organs and tissues.
This research must be emphasized and we need to understand its implications for humans. It shows that in rats, even when TSH and T4 are “normalized” and T3 was “slightly decreased,” the organs like liver, skeletal muscle and the brain, were still “hypothyroid.”
Even if rats are different from humans, we already know from the research coming out of Dr. Bianco’s lab that certain human organs will suffer more than others when they have to depend on Deiodinase Type 2 to convert T4 to T3, rather than getting their T3 directly from bloodstream. (See my separate discussion of the deiodinases that are responsible for conversion.)
Key message: Listen to patients
As the interview concluded, Dr. Bianco made it clear that patients’ symptoms must be attended to, even in the absence of clinical studies that “conclusively” prove that L-T3-T4 combination therapy is “superior” overall:
PP: Dr. Bianco, what is the take-home message from your research and investigation into this whole issue of T4 and T3 in patients with hypothyroidism that are not thriving?
Bianco: Well, I think the take-home message is [that] the majority of patients do well with Levothyroxine alone. 10-15% of the patients don’t do well.
And doctors need to listen to their patients.
Doctors need to sympathize with their symptoms.
And doctor-scientists need to look for alternatives. Look for new forms of treatment.
And it seems that combination therapy is a valid form of treatment for the small percentage of patients. Some patients do very well. Other patients don’t do well.
Clinical studies have not been conclusive. And I think that it’s because not all hypothyroid patients are the same.
I think there are intrinsic differences in hypothyroid patients. And perhaps there are sub-populations of hypothyroid patients that respond very well to combination therapy and other patients that don’t respond at all to combination therapy.
Our job as scientists and doctors is to identify this sub-population of patients with hypothyroidism that respond to combination therapy and try to help them in that fashion.
So I think that the take-home [message] is that we still have work to do in that small population, that sub-group of patients with hypothyroidism that will respond to combination therapy.
Symptoms are real data. They tell doctors more than blood tests can — they tell us whether there is enough T3 getting into peripheral organs and tissues.
Unlike many other “levels” in blood, levels of thyroid hormones have to be individualized and carefully adjusted. Free T3 levels can significantly affect health — even in minor variations of T3 within the normal reference range.
Each patient is unique.
Each phase of our life is unique.
Doctors absolutely must monitor our Free T3 levels, as well as listen to our symptoms.
And we must give therapy options to thyroid patients.