Podcast Transcript: Hypothyroidism Unmasked: The ENT’s Diagnostic Journey

[Dr. Ashley Agan]
What is your protocol when you're seeing patients and you decide, "Okay, we need to look into this possibly being related to Hashimoto's"? We talked about TSHs. I assume you still do TSH, but TSH alone is not sufficient.

[Dr. Dana Gibbs]
Correct. TSH alone is not sufficient. One of the hallmarks of Hashimoto's disease in particular is this relapsing and remitting. When the immune attack is happening, their thyroid gland will release high levels of thyroid hormone in their body. It'll go very high and it'll go very low and very high and very low. One of the things that happens when you have high T4, whether it's coming from the thyroid gland or from an autonomously functioning nodule or from somebody being given levothyroxine, is that it turns off the production of T3.

In thyroid physiology, your body makes T4 and a little bit of T3, and then the T3 goes out into your body cells and T4 is converted to T3 in the target cells. Then the T3 goes to the nucleus, activates the protein cascades, and does all the things that thyroid hormone does to stimulate your metabolism. When you have high T4, it feeds back to the pituitary and the hypothalamus, and not only turns off the production of more T4, it causes a global blocking of the conversion of T4 to T3 throughout your body, which doesn't show if you don't check T3.

The other thing it does is that this high T4, it's a protection mechanism, so high T4 in the setting of Graves disease is a disaster, basically you just burn your whole body up. Your heart rate goes up, everything's terrible. Your body has fail-safe mechanisms to block that. One of them is this fact that it turns down the production of T3. The other one is a parallel pathway. T4 gets turned into T3 by something called type II deiodinase. There is also a type III deiodinase, and that type III deiodinase enzyme takes the T4 and turns it into reverse T3. Reverse T3 is an inactive metabolite, but not really, because it can still bind the receptor.

This is where me and the endocrinologist start to differ because they say reverse T3 is meaningless, it's an inactive metabolite. I'm like, yes, but it binds and blocks the receptor to T3. Even if you have enough T3, if you have enough of this blocker, then the relative function of your T3 is diminished because of that, so I check the reverse T3. Then I also check the total T3. The reason you have to compare reverse T3 to total T3 is because they are both protein-bound. It's the same proteins, and the reverse T3 is just a subset, but they're identical. You're getting an apples-to-apples comparison.

A lot of functional doctors have this weird, fancy calculation that they try to do from free T3 to reverse T3. Then they're going to try to measure the thyroid-binding globulin and the albumin and all this other stuff. I'm like, "Look, that doesn't work. It's not necessary." It creates unnecessary complication that makes this calculation very, very difficult when you can just take total T3, divide by reverse T3, and it ought to be at least 10:1. That's the natural-- In normal people, that ratio is 10:1. If it's less than 10:1, then the person isn't necessarily going to feel good, even if their absolute T3 and absolute T4 numbers are okay.

[Dr. Ashley Agan]
Okay, so saying that again, a patient comes in, their TSH can be high, low, normal, any of those things. You'll check total T3, total T4, and reverse T3?

[Dr. Dana Gibbs]
No, not total T4.

[Dr. Ashley Agan]
You don't even worry about T4?

[Dr. Dana Gibbs]
Total T4, I don't even--- Free T4, I check. The reason I care about free T4 is because that's the substrate to make reverse T3 and T3. A lot of the mistakes that get made with treating thyroid symptoms is, for example, the patient comes in and says, "I feel bad." The doctor believes them and says, "Here, let me give you some T4." That's the standard treatment. Well, the more T4 you give that person, the more reverse T3 they're going to make. Giving somebody T4 can actually make them feel worse if what their defect is high reverse T3 and not enough T3 conversion.

[Dr. Ashley Agan]
In what situations is T4 going to be preferentially converted to reverse T3 as opposed to T3?

[Dr. Dana Gibbs]
Oh boy. It's a big list. High cortisol is one, so stress. Stress, stress, stress.

[Dr. Ashley Agan]
That just tips the scales and pushes things towards reverse T3?

[Dr. Dana Gibbs]
Yes. High cortisol does two things, and this is a totally different lecture, but high cortisol does two things to your thyroid. The first one is it suppresses your TSH. You can be deficient in T4 and T3 and have a normal TSH if you have really high cortisol. The second thing it does is it pushes you towards deiodinase III, which is the reverse T3. The reason it's doing that is because primitive stress, a lot of primitive stress was famine. It was starvation.

What do you not want to do when you're starving? You don't want to burn up all your calories, so let's block that. You can hibernate a little bit until spring when the food comes back, so high cortisol is one. Fluctuating intermittently high levels of T4, which would be what you see in Hashimoto's disease because that's what the disease process is, exogenous T4.

[Dr. Ashley Agan]
Which is like levothyroxine or Synthroid?

[Dr. Dana Gibbs]
Which is like levothyroxine. Calorie restriction diets. Basically, your body can't tell the difference between, "I want to lose 20 pounds," and, "Oh my God, there's a famine." Your body can't tell the difference. Beta blockers, super common. Super common, activates reverse T3 in a big way. There are some other drugs that do the same thing. Cordarone or amiodarone is another one. Then there's a few others that I can't remember right this very second.

[Dr. Ashley Agan]
Those drugs will tip the scales such that there's more production of reverse T3 as opposed to T4 being converted to T3?

[Dr. Dana Gibbs]
Correct. Yes. It can be psychological stress, it can be physical stress. Over-exercising is another physical stress that people forget about. Then severe illness. Most of the literature about reverse T3, the research comes from the ICU. It comes from critically ill people who get what's called euthyroid sick syndrome. What happens in euthyroid sick syndrome is the patient's thyroid will basically shut down and they will have these phenomenally high levels of reverse T3. It's the same thing. Your body's trying to conserve resources so you can live to fight another day, but it can go overboard.

What they've found is that the survival data is really, really bad. If you have high, high reverse T3 in the ICU, your chances of making it out of the ICU drastically diminish. What I'm talking about is basically a very, very attenuated form of euthyroid sick syndrome. Giving them T3 fixes them, whereas giving them levothyroxine does not.

[Dr. Ashley Agan]
Back to our labs, so we said TSH, free T3, and reverse T3?

[Dr. Dana Gibbs]
Free T4, and then the total T3 to measure against the reverse T3. That's the ratio.

[Dr. Ashley Agan]
The ratio is total T—

[Dr. Dana Gibbs]
Total divided by reverse.

[Dr. Ashley Agan]
Divided by total reverse, or is there only one reverse?

[Dr. Dana Gibbs]
No. Reverse T3, there's no free reverse T3.

[Dr. Ashley Agan]
Okay, so it's just reverse.

[Dr. Dana Gibbs]
It's below the detection limit of the test. I wish there was, there's no free reverse T3.

[Dr. Ashley Agan]
When we're talking about reverse T3, it is bound to—

[Dr. Dana Gibbs]
It's a total, it's a total protein-bound number. Yes, you look at that ratio, you look at the total amount of T3 the person has, the total amount of-- I'm sorry, I say the total amount, the free T3, the free T4, and then that total over reverse. That's a test you can order from Labcorp, that ratio. It'll give you the absolute, and the ratio. It's really simple.

What I will find in these patients is that their ratio is 7, 6, 8, 4. The worst I've ever seen was lower than 3, I was like, "Oh my gosh, no wonder they feel terrible." If they are at 12, that's good. If they're at 12 and their absolute level of free T3 is low, then they're still not going to feel great, but that's easier to fix than if that reverse T3 is high enough to make that ratio really crappy.

[Dr. Ashley Agan]
These patients can have normal TSH, right?

[Dr. Dana Gibbs]
They can have normal TSH, they can even have low TSH.

[Dr. Ashley Agan]
What about testing for antibodies? Do you also do look for antibodies?

[Dr. Dana Gibbs]
Yes, I absolutely do, and I mostly do that the first time I see the patient because it gives you an idea of their inflammatory status. It's like the canary in the coal mine. It's the first autoimmune disease people who get autoimmune diseases typically have, and is super, super common. People are like, "Why do I have this?" Well, it's because you have this autoimmune disease. I don't follow the antibodies in as near a regularity as I follow the rest of those five labs.

I will tell you, people will be like, "Oh, those labs are so expensive." I'm like, "No, they're not," because if somebody comes to me and doesn't have insurance, I can get that whole lab set for them for less than $50 for all of them, so they're not actually that expensive, regardless of what the insurance company is saying.

[Dr. Ashley Agan]
For the antibodies, you're checking anti-TPO and thyroglobulin?

[Dr. Dana Gibbs]
Anti-TPO and anti-thyroglobulin. Typically, if the story is right or if the patient has a palpable nodule, I will also check the antibodies for Graves disease, which is the thyroid receptor antibody, TRAb, or the TSI, thyroid stimulating immunoglobulin, just because sometimes you find an autonomously functioning nodule, sometimes you find Graves antibodies, and you do treat those people a little bit different. You can still treat them, but you have to be a little even more careful.

[Dr. Ashley Agan]
Any other labs that you like to look at?

[Dr. Dana Gibbs]
Because this comes along with stress so much of the time, I'm, typically, the first time I'm seeing a patient, going to check ACTH and cortisol, a morning cortisol, to make sure that they are not adrenal insufficient, because they go together. The other thing that really parallels this a lot is insulin resistance. I'm going to check uric acid, I'm going to check fasting insulin, fasting blood sugar, so that I can get a test called HOMA-IR. That's something I learned after ENT residency when I figured out none of these hormones exist in isolation and you can't treat one and then not pay attention to the other ones.

If it's a woman who's over 40, I'm going to check her sex hormones for sure as well, just because that's my practice. Now I wouldn't expect an ENT doctor to do that, of course. This problem rears its ugly head when people's estrogen starts to drop in perimenopause, so that's another thing that I will check.

[Dr. Ashley Agan]
Do you do any imaging, like do you ultrasound the thyroid?

[Dr. Dana Gibbs]
Okay, so let's talk about that. If you have a palpable thyroid, so I feel if I do a thyroid exam, if a person has a uniform, palpable, rubbery, hard, firm thyroid and thyroid antibodies, sometimes I will skip the sonogram and the biopsy. If they have nodules, yes, sonogram, biopsy, you bet. If a person is overweight enough that I can't feel their thyroid and I'm not sure, then yes, I will order a sonogram on those people for sure.

[Dr. Ashley Agan]
Yes, so it's still sticking to your—

[Dr. Dana Gibbs]
Yes, it's still a standard ENT workup, with the addition of a couple of extras.