Thyroid patients are very focused on anti-TPO, but anti-TG is also important. If we have high levels, it can mean, that there is some damage to our thyroid. And did you know that 10% of Hashimotos patients don’t even have anti-TPO, only anti-TG?

Abstact

Thyroglobulin is a large molecule. It’s involved in the manufacturing and storage of thyroid hormones. It’s supposed to stay primarily INSIDE the thyroid. But it’s normal to have tiny amounts floating around in the circul-ation. We can get anti bodies to the thyro-globulin when levels become high, anti-TG.  

Thyroglobulin can release into the circulation in various ways: 

When the thyroid is being destroyed.

When the thyroglobulin contains very little iodine.

When they suddenly contain much more iodine (when one has been iodine deficient and suddenly increase iodine intake by a lot). 

And lastly, in thyroid cancer, TG can get released in connection with the synthetization of hormone. 

We don’t know for sure whether high anti-TG levels are bad for us. But it does play a role in the auto immunity of AITD.

It’s important to test  anti-TG when one suspects AITD, because 10% have only elevated levels of anti-TG, and not anti-TPO. I don’t think many doctors are aware of that fact. 

What is thyroglobulin?

The follicles are the cells producing T4 and T3. We have 3 millions. The follicle wall consists of a single layer of cells surrounding a central cavity, the colloid. It’s those cells in the wall that actually produce the hormones. The colloid is the hormone storage. The size of the follicle varies with how much colloid it contains. The thyro-globulin is both the precursor and the storage of the hormones.

The hormone production is reliant on iodide being pumped into the follicles. The concentration of iodide is 20 to 40 times higher inside the follicle than outside. The follicles makes a large molecule, thyroglobulin.  which is being transported out of the follicle into the colloid. They make up most of the colloid. Each thyroglobulin molecule contains 120 to 140 tyrosine amino acids. These are also critical to the hormone production.  The TPO enzyme is sitting on the inside of the follicles, on the wall facing the colloid. 

In between these hormone producing molecules are the C cells producing calcitonin.

How does the TG antibody recognice/react to the TG molecule?

To what extent the anti-TG  recognizes and attaches to the TG molecule depends on both how much hormone the TG molecule contains, AND how much iodide. See below for the latter. In the process of hormone synthesizing, the surface of the TG molecule changes. And the ability of anti-TG to attach vary with these changes.

A TG molecule contains on average 2,3 T4 and 0,3 T3.How much hormone a TG molecule contains, is dependent on how much iodide it contains. Which has to do with the iodine sufficiency in the body. In healthy people, the antibodies react to the part of the TG molecule that contains the hormones. But in people with AITD, the anti bodies react also to other parts of the molecule.  This means, our immune system is more reactive than healthy people’s.  

Healthy people have polyclonal anti bodies to TG, and  people with AITD have oligoclonal anti bodies to TG. Polyclonal anti bodies are produced by many different B cells. Whereas oligoclonal are produced by just a few B cells. This might be more info than you really need, but the point is, the immune system is different in healthy- and autoimmune people. 

Thyroglobulin in the circulation

Thyroglobulin is produced only in the thyroid. and it is also stored here. But small amounts can be found in the circulation as well. About 10% of healthy people can have some TG in the blood with no issues, for women over 60 the number is 15%. And one can have TG in the circulation  without getting anti-TG. But after destruction of thyroid tissue, like many with AITD experience, with release of large amounts of TG into the blood stream, most people will get anti-TG.  

You can see anti-TG levels in various conditions here:

Frequency of high serum anti-Tg and anti-TPO antibody concentrations in patients with autoimmune thyroidi tis (AT), Graves~ disease (GD), differentiated thyroid cancer (DTC), and nodular goiter (NG), and in normal subjects (N). (From Mariotti S, Pisani S, Russova A, et al. A new solid-phase immuno radiometric assay for anti-thyroglobulin autoantibody. J Endo crinol Invest 1982;5:227; and Mariotti S, Caturegli P, Piccolo P, et al. Antithyroid peroxidase autoantibodies in thyroid diseases. J Clin Endocrinol Metab 1990;71:661, with modifications.)

How is TG entering the circulation?

  1. Transepithelial transport. The TG molecule is released from the apical (top most) part of the thyrocyte into the intracellular space. This is the main way of release where the thyroid is intact.
  2. Destruction of follicles. This happens in people with AITD, when the thyroid is being destroyed. Here you can have a larger release of TG into the blood stream. 
  3. TG release in thyroid carcinoma. In people with thyroid cancer, TG can be released directly in the synthesizes process, when the hormone is made.

Much of this info is taken from Werner & Ingbar (1)

Iodine and anti-TG

When one is iodine sufficient, only small amounts of TG is released into the blood. But if one is iodine deficient, one sees higher levels of TG. This is due to the fact that in iodine deficiency, the thyroid will enlarge (goiter) and TSH will rise. This means, that an  increased TG level can be indicative of iodine deficiency (2). 

But sudden increases in iodine can also cause increased anti-TG levels. 

Graf from "Thyroglobulin Is a sensitive measure of Both Deficient and Excess Iodine in Children and Indicates No Adverse Effects on Thyroid Function in the UIC Range of 100-299 µg/L. UIC stands for urinary iodine secretion

These are measure-ments on children.

One doesn’t know if the anti-TG one sees with iodine supplementation, is lasting, chronic.  I don’t understand that the scientists haven’t looked into that. Michael Zimmermann, a very reliable iodine scientist, writes this. (3)

Anti-TG increase on iodine supplementation because for one thing, anti-TG anti bodies  “recognize” and attach to thyrocytes with high levels of iodine.  I have read this in one of Zimmermann’s studies, but cannot find it again.  I am sure to find it again, and will update then. In the mean time, here is a study showing T cells reacts stronger to thyroglobulin containing more iodine than TG containing less iodine. (4)

Secondly, it might be, that the thyroid release TG when there is a lot of iodine as a protective measure.

This mechanism may regulate
and prevent the liberation of excessive thyroid hormone under changes in iodine intake and may explain why, in the
current populations, Tg is elevated but little thyroid hormone
fluctuation was observed.

And

Tg has been shown, both in vitro and in vivo, to be a potent regulator of thyroid
function at high iodine intake. (5)

In short this means, when there is a lot of iodine available, which could lead to a high production of hormones, TG gets released to prevent us from going hyper.  

You might think, but aren’t there hormones in the TG being released? And yes, there is. But they cannot be “freed” from the thyroglobulin molecule in the blood stream. That has to happen in the thyroid. When the hormones get released from the thyroid, they bind to other protein molecules in the blood, albumin,  thyroxine binding pre albumin(TBPA) and thyroxine binding globulin(TBG). These proteins then release them as needed by the cells. This last paragraph is my own reasoning.

It’s especially after being iodine deficient, one sees an increase in anti-TG when increasing the iodine intake. But one does not usually see anti-TG with increased iodine intake in children. But in adults one does. (6) Starting on a small iodine dose and increasing makes for less increase in anti-TG.

What does anti-TG do to us?

The short answer is, one does not really know what anti-TG does to us. It does not destroy the thyroid.  As I write in , Anti bodies, part 1, Anti-TPO, it’s mainly T and B cells that do that. And one kind of TRAb anti bodies. I will write about that in Part 3. 

One does not apparently see a connection between the presence of anti-TG and severity of AITD.  This is what most texts say.  But anti-TG does play a role in thyroid auto immunity. One can give animals AITD by injecting them with anti-TG. And  pregnant women with high serum anti-TG are more likely to get postpartum thyroiditis. (1) So totally innocent it is not. 

I also finally found a study on the connection between anti-TG levels and severity of symptoms in AITD. Which made me very excited at first, but then I saw it was one of the many bad thyroid studies. Where people are so low on their thyroid levels, it’s really impossible to draw any conclusions.(8) I decided to include this study anyway. These were  people diagnosed with Hashimotos who were not taking thyroid medicine. But they should have. The mean TSH was 3,7, the mean FT4 11,9 pmol/L, T3 1,55 nmol/L. Normal range for T3 is 0,9 to 2,8 nmol/L. 1.55 is LOW. As is the FT4. 

They say they  adjusted for anti-TPO, TSH, FT4 and T3 levels. And that they found, that several symptoms like edema, fragile hair and harsh voice were more severe in people with higher levels of anti-TG. But I don’t think you can say much when they are all too low on their thyroid levels. I am waiting for a study on thyroid patients with good thyroid levels. Then you can really say what is what. So many scientists and doctors don’t know what are good thyroid levels. So much research  is invalid because of this. Many of these participants here were iodine deficient. They had FT4 under 11 pmol/L. FT4 under 11 pmol/L is always iodine deficiency.

But anyway, apparently, seems like those with higher anti-TG felt even worse. Though I am pretty sure, they all felt bad.

TG and anti-TG as a marker of cancer in the thyroid

One uses testing of TG and anti-TG when there is cancer in the thyroid. There should not be much TG in the circulation after removal or radio therapy of the thyroid. If there is, it’s a sign of persistent thyroid tissue, that the tumor is still there or metastases.  

Anti-TG can interfere with the measurement of TG. It can cause falsely low TG levels. (9) So many test for both in cancer cases. 

References

  1. Werner & Ingbar 9th edition. https://doctorlib.info/medical/thyroid/index.html
  2. Niels Knudsen et al. “Serum Tg—A Sensitive Marker of Thyroid Abnormalities and Iodine Deficiency in Epidemiological Studies”. doi.org/10.1210/jcem.86.8.7772
  3. M. Zimmermann & K. Boelaert. “Iodine deficiency and thyroid disorders”, https://doi.org/10.1016/S2213-8587(14)70225-6
  4. L.Rasooly et al. “Iodine is Essential for Human T Cell Recognition of Human Thyroglobulin”. doi.org/10.3109/08916939808993833
  5. J. Farebrother et al 2018. The effect of excess iodine intake from iodized salt and/or groundwater iodine on thyroid function in non-pregnant and pregnant women, infants and children: a multicenter study in East Africa. 

  6. M.B. Zimmermann et al, 2013. “Thyroglobulin Is a Sensitive Measure of Both Deficient and Excess Iodine Intakes in Children and Indicates No Adverse Effects on Thyroid Function in the UIC Range of 100–299 μg/L: A UNICEF/ICCIDD Study Group Report”.  https://doi.org/10.1210/jc.2012-3952
  7. Johannes Ott et al. “Hashimoto’s thyroiditis affects symptom load and quality of life unrelated to hypothyroidism: a prospective case-control study in women undergoing thyroidectomy for benign goiter”. 
  8. Ana Baric et al. 2018. Thyroglobulin Antibodies are Associated with Symptom Burden in Patients with Hashimoto’s Thyroiditis: A Cross-Sectional Study
  9. C.A. Spencer et al, 2005.

    Clinical Impact of Thyroglobulin (Tg) and Tg Autoantibody Method Differences on the Management of Patients with Differentiated Thyroid CarcinomasClinical Impact of Thyroglobulin (Tg) and Tg Autoantibody Method Differences on the Management of Patients with Differentiated Thyroid Carcinomas. https://doi.org/10.1210/jc.2005-0671