Many believe, that TRAb is an antibody only people with Graves have.  Many also call them Graves’ antibodies. And that high levels of TRAb is the same as hyper thyroid.  This is not the case. As there are 3 types of TRAb, stimulating, blocking and cleavage. People with hypo thyroid can also have high levels of TRAb, So this antibody is of interest to all with thyroid disease.

Abstract

There are 3 kinds of TRAb or TSHR abs, stimulating, blocking and cleavage; previously called neutral.

Both hypothyroid and hyper thyroid can have high levels of TRAb.

Some Graves’ patients have both blocking and stimulating TRAb. They will fluctuate between hyper thyroid and hypo thyroid.  

One believed earlier, that the third kind of TRAb one had found, was neutral. But now one has realized, this third TRAb can actually cause cell death in the thyroid. That is, it kills thyrocytes.

People with atophic Ord’s (athropic AITD) have much higher levels of TRAb than people with Hashimotos. We mistakenly call both atropic AITD and  AIDT that starts with a goiter, for Hashimotos. But these are two different diseases. You may not have been aware that you had a goiter, but the gland has been somewhat enlarged in true Hashimotos. And the gland keeps it’s size throughout the disease. But in Ord’s, the gland fades away, atrophies. This might be due in part  to these cleavage TRAb s.

When the gland is gone or mostly gone, there will not be high TRAb levels anymore. As all thyroid antibodies are made in the gland.

There is also a section on iodine supplementation and Graves.

What is a TSH receptor?

In order to understand what it is TSHR abs do, it’s useful to know something about the TSH receptor. The TSH receptor is where the TSH hormone binds to the follicles and thereby stimulates the gland to produce hormone. You can see in the figure below, where the TSHR is situated on the follicle. This figure shows where all the various antibodies does their damage. And as I explained in part 1, all antibodies are Y shaped. It’s from a Norwegian endo text book, but I believe you get the picture.

Figure 1. A follicle cell showing where the different proteins attracting antibodies are situated. From Thyroideasykdommer, edited by S.Aanderud and T.Bjøro

The TSH receptor has two parts, unit A and unit B. Between these two there is a hinge region. When the TSH hormone binds to the receptor, the receptor divides in 2 or more places. Some A units are being shed. It looks like these “shed” A units are what drives the autoimmune process in Graves. (1)

TSHR abs/TRAb

There are 3 kinds of TSHR abs, stimulating, blocking and cleavage. When the scientes first discovered that there is a third TRAb, they called it neutral. They believed it did nothing, good or bad. And in many articles, they still call them neutral. But they have realized, these antibodies can actually cause cell death in the gland, that is they can cause thyrocytes to die. (2) It comes about through these abs creating oxidative stress.  You can read more about oxidative stress here

But the TSH hormone and the stimulating TSHR abs can counteract this oxidative stress. It looks like the balance between these 3, TSH, TSHR stimulating abs and the cleavage abs, is crucial for cell death in the gland in Graves’ patients.

Figure 2. Image taken from S.A.Morshed and T.F.Davies, "Graves' disease mechanisms: The role of Stimulating, Blocking and Cleavage Region TSH Receptor Antibodies".

Stimulating TSHR abs bind only to the TSH receptor, and in so doing. competes with the TSH hormone. These antibodies stimulate the synthesis of thyroid hormones. Inducing hyper thyroid. They also cause cAMPcAMP is a kind of messenger.  Increases in cAMP leads to a weakening of the immune system, including it’s ability to fight inflammation and fight bacteria. So not a good thing. (3)

Blocking TSHR abs also prevents TSH in binding to the receptor. The effect can be so strong that it leads to hypothyroidism. Some blocking abs can be weakly agonists, meaning they are mildly stimulating. Those leading to hypothyroidism  are called antagonists.

Cleavage TSHR abs can neither bind to the TSHR nor hinder the TSH from binding to it. They don’t cause an increase in cAMP either. Cleavage abs only bind to the hinge region of the TSHR. Here they can cause cell death through oxidative processes. As mentioned. (2)

I don’t think that the cleavage abs’ role is fully clarified.  And all of this is much more complicated than what I write here. I think though, it’s a limit to what we as patients need to understand. The body is very complex. I will follow up with new info as I learn more. If you want to dive deeper, have a look at the  article above.

Cell death in AITD

Cell death in the thyroid is very important. Of course. This is where the gland gets permanently damaged.  

One thought earlier, that it was only T cells and thyroid antibodies that caused this cell death. Thyrocytes die and the gland shrinks.

But one has realized, there can be other causes as well. Cells can have death receptors. 

There can be defects with the T regulator cells (TREG) which leads to an overproduction of cytokines. These cytokines can then contribute to inflammtion. 

TREG’s play a big role in autoimmunity. These are the T cells that regulate the immune system, that make it possible for the body to tolerate antibodies, and in so doing, hinder autoimmune disease. 

Dysfunction in these TREG cells is very common in people with autoimmune disease. Just so you know, LDN (Low dose naltroxene) can help regulate these TREG cells. You can read about LDN here. With everything I know now, I think I would start LDN if I just got diagnosed with AITD. Then one might be able to stop or lessen the destruction of the gland. Note that I write “might”. LDN is good for AITD no matter what.   

There are death ligands that cause cell death. They interact with death receptors that many cells in the body have, especially cells in the immune system. (4) 

In addition, these cleavage TSHR abs also cause cell death.

So you see, this is complicated. There are many factors affecting cell death in the thyroid. Thyroid issues are very complex over all. I see that Thyroid Patients Canada writes, that these cleavage TSHR abs likely are very important in atrophic hypothyroid, Ord’s. I don’t think  we can draw  strong conclusions at this time. There are MANY things causing cell death in the gland. And not everybody with Ord’s  have TRAb .   So it’s not likely that cleavage TSHR abs are the only reason.

Though there is a circumstance that complicates this. As i have written in part 1, thyroid antibodies are made in the thyroid. After the thyroid is gone, or mostly gone, the antibodies decrease or even disappear. So unless people with atrophic Ord’s have been tested from the start, at diagnoses or thereabouts, one cannot know if they might have had TRAb. I have Ord’s, and I have only a pea sized thyroid left. If that. I don’t have TSHR abs today, but I might have had 20 years ago. 

TRAb levels in thyroid disease

Figure 3. Taken from Werner and Ingbar's 9 edition

Frequency of high serum TSH receptor antibody activity in patients with Graves’ thyrotoxicosis (top) and chronic autoimmune thyroiditis (bottom). In the top panel, the anti bodies were measured as TSH receptor stimulating antibodies (TSHR-SAb). In the bottom panel, the antibodies were measured as TSH receptor blocking antibodies (TSHR-BAb). AT, autoimmune thyroiditis; Eu, euthyroid; Hypo, hypothyroidism; MMI, methimazole; Sub Hypo, subclinical hypothyroidism. 

As you can see, the TSHR abs levels are very high in untreated Graves and in Graves when the Methimazole does not work. Also, the blocking TSHR abs (TSHR babs)  are very high in atrophic AT. But not in goitrous AT, that is, Hashimotos. People with Hashimotos do not get a decrease in thyroid size over time. These tests was taken long before one knew about cleavage TSHR abs. These graphs are from the late 1990ies. Some of that blocking TRAb might have been cleavage TRAb. 

You might find it confusing that I write TSHR abs and TRAb, but I use both names because most people are more familiar with TRAb than TSHR abs.

As I wrote over,  it’s difficult to say, whether all people with atrophic AT have had some kind of TSHR abs at some time or not. Or if 10% never had it, like the graph shows here. We can only know that if a large group with atrophic Ord’s are followed and tested from diagnosis. I don’t think that has been done yet. Other studies find a lower  incidence than this 90%. In this study, they give a overview of many studies on this (4). The study is a bit complicated. But you see, that the results vary widely. It can have to do with HOW they measure. There has been a lot of faulty testing of TSHR abs. They also write a lot about that in the study. 

If it turns out, everybody with atrophic Ord’s have cleavage TSHR, then and only then, can we conclude that cleavage TSHR abs are the main reason why the gland shrivels in Ord’s. But it’s very likely, that these TSHR abs play an important role in Ord’s.

But it is a fact that people with Ord’s have higher levels than any other hypothyroid group. And that the level of TRAb is inversely correlated with the size of the goiter. That is, the bigger the goiter, the less TSHR abs. (4)   

TSHR Abs and pregnancy

I will just mention the importance of close follow up during pregnancy here. Though auto immunity during pregnancy is a big, and very interesting topic. I will have to look into that at some point. There is a lot of info on it in this study (5). 

All TRAbs cross the placental barrier. In the study, they call cleavage TRAbs for “neutral”. As I have written, they used to think they were neutral.

So the fetus can become both hyper thyroid and  hypo thyroid, depending on the kind of TRAb.

Changes of functional properties from stimulating to blocking the TSHR could occur during gestation. Drug therapy is the treatment of choice for hyperthyroidism during gestation. Antithyroid drugs also cross the placenta and therefore decrease both the maternal and the fetal thyroid hormone production.(5)

I just want to mention that there is another treatment for Graves, namely high dose iodine. Which was what one did earlier. You find a study on it here at Thyroid.com (6)

TSHR abs and iodine

I see many in iodine groups with TRAb worrying about iodine supplementation. And no wonder, hyperthyroid must be awful. I have only tried being slightly overdosed, and that is bad enough. 

So how does iodine affect TRAb? For one thing, high dose iodine used to be the only treatment for Graves. You can read a study on this here in Thyroid.com (6) But there are actually several studies on high dose iodine now. The high dose iodine treatment is certainly coming back! This particular study was conducted on a group of patients who could not do the regular treatment with anti thyroid drugs. The results were quite good, have a look yourself. 

Then we have a study on Korean  Graves patients. The iodine intake in Korea is quite high, much like in Japan. In this study, one found no higher risk of recurrence when people continued to have a high iodine intake after ending treatment with anti thyroid drugs. They found no correlation between iodine intake and recurrence.(7)

In this study, they conclude that the jury is out on whether increased iodine intake leads to increase in antibodies. (8) It’s an overview article from this year, 21. But it’s mostly anti-TPO and anti-TG they look at.   

 

But what about having TRAb and starting iodine supplementation being iodine deficient?

This is the big question for most people. It’s difficult to find info on this. But here is a an article by Michael B. Zimmermann where he describes a Danish study.(9) I link to Zimmermann’s study and not the Danish, as there is a lot of good info in Zimmermann’s. The result from this study on 2 groups, one with mild iodine defciency and one with moderate, is this:

A cross-sectional study comparing two Danish cohorts with mild versus moderate iodine deficiency before iodisation reported a significantly increased incidence of hyperthyroidism in individuals with moderate iodine deficiency (96·7 vs 60·0 per 100 000 person-years). This higher incidence was mainly due to an increased prevalence of multinodular toxic goitre in the cohort with initially moderate iodine deficiency compared with the cohort with initially mild iodine deficiency; the prevalence of Graves’ disease was  similar between cohorts

As you can see, there were no increase in Graves with increased iodine intake. Iodisation means adding iodine to the salt. We don’t know how much iodine was added though.  This can vary very much. There was an increase in hyperthyroidism in the the more iodine deficient group, due to autonomous nodules, nodules producing hormone. Never take iodine if you have a hot nodule! 

Of course, we cannot conclude that taking iodine is ok when you have Graves based on this. But we do know that many Graves patients have iodine deficiency . In this Bangladesh study (10), more than 50% were  iodine deficient, 21% were considered excessive and 25% optimal. They make a strange conclusion. That one has to be careful with iodine supplementation so as not increase the incident of Graves!  When the majority was deficient! But anyway, I refer to the study just to show how iodine deficiency plays a role in Graves. 

Conclusion

As you can see, there is a lot more to TSHR abs than we knew before. I hope there will come a time when this will be common knowledge amongst doctors. Blocking TSHR abs is old knowledge, and doctors STILL don’t know about that. It would be so good if everyone was tested for TRAb at diagnosis. Then one could go back and see, yes I did have high TRAb years ago, and now my gland has withered away. In some far distance future , we may have blocking and cleavage TRAbs tested.

High dose iodine does bring TRAb down in many people, as you see from this study (6). but of course, one needs to know what one is doing when it comes to iodine. It is not something one just jumps into. Please don’t do that. Most of us don’t have doctors to help us in this either. I have 2 posts on iodine, low dose, Iodine for beginners, and high dose The iodine protocol

I cannot give advice on supplementing with iodine for someone with Graves. I would test and test my antibodies if I decided to take iodine . I would start low and see what happened to my antibodies. If I wanted to try high dose iodine, I would seek out iodine doctors. People do consultations online now. One such place is Dr. Brownstein’s clinic. Expencive though. 

  1. Frölich,E og Wahl,R. “Thyroid Autoimmunity: Role of Anti-thyroid Antibodies in Thyroid and Extra-Thyroidal Diseases”. doi: 10.1055/s-0035-1559633, link
  2.   S.A.Morshed, T.F.Davies “Graves’ Disease Mechanisms: The Role of Stimulating, Blocking, and Cleavage Region TSH Receptor Antibodies”. DOI: 10.1055/s-0035-1559633, link
  3. C.H.Serezani et al. “Cyclic AMP: master regulator of innate immune cell function”. DOI: 10.1165/rcmb.2008-0091TR, link
  4. T. Diana, P.D. Olivo, G.J. Kahaly. Thyrotropin Receptor Blocking. doi: 10.1055/a-0723-9023link
  5. I. Bucci, C. Giuliani,  G. Napolitano. Thyroid-Stimulating Hormone Receptor Antibodies in Pregnancy: Clinical Relevance, doi: 10.3389/fendo.2017.00137, link
  6. https://www.thyroid.org/patient-thyroid-information/ct-for-patients/volume-8-issue-2/vol-8-issue-2-p-3-4/
  7. Park S.M.  Cho Y.Y.· Joung J.Y.  Sohn S.Y. · Kim S.W.  Chung J.H.  Excessive Iodine Intake Does Not Increase the Recurrence Rate of Graves’ Disease after Withdrawal of the Antithyroid Drug in an Iodine-Replete Area. https://doi.org/10.1159/000375261
  8. C. Teti et al, Iodoprophylaxis and thyroid autoimmunity: an update, Link
  9. M.B. Zimmermann and K. Boelaert. Iodine deficiency and thyroid disorders.  DOI: 10.1016/S2213-8587(14)70225-6
  10. A.J. Gaffar et al. Iodine nutrition status in Graves’ disease: A single-center study from Bangladesh. link