Infographics for Antibody testing

This post concludes our series on “Developing Infographics for thyroid testing.”

In this post I discuss the scientific basis and potential usefulness of two of our infographic memes:

  1. Thyroid antibody tests (overview)
  2. TSH-Receptor antibodies (TRAb)

Overview of thyroid antibody tests

This image aids in diagnosis of all three types of autoimmune thyroid disease: Hashimoto’s, Graves’ and Atrophic Thyroiditis.

The infographic does something new that other “test list” graphics haven’t done — it gives research-based ranges of incidence rates of autoimmune thyroid disease subtypes for positive antibodies.

It’s very difficult to fit the meanings of all these abbreviations into a small image, so I’ve had to resort to using their current official abbreviations:

  1. TPOAb (Thyroid Peroxidase antibodies),
  2. TGAb (Thyroglobulin antibodies), and
  3. TRAb (TSH-Receptor antibodies) of two subtypes.
    1. TSAb TSH receptor stimulating antibodies
    2. TBAb TSH receptor blocking antibodies

Lab test names:

  • TSI = Thyroid stimulating immunoglobulin test. Looks only for the stimulating type.
  • TRAb = TSH receptor antibody test. Test when suspecting the stimulating antibody only. These tests often *claim* to give results for blocking but usually only give “net” stimulating antibody results.
  • TBII = Thyrotropin binding inhibitory immunoglobulins.*

*See notes under “TBAb Testing challenges in Atrophic Thyroiditis” below

An autoimmune diagnosis is significant.

Autoimmune thyroid etiologies are significant to therapy because they provide a prognosis, a likely pathway of thyroid dysfunction over years to come.

Not all hypothyroid patients are alike. Having hypothyroidism from surgery or radioiodine ablation (RAI) is very different from having hypothyroidism caused by TPO Antibody.

Knowing our specific thyroid antibodies help us predict other health conditions and autoimmune diseases associated with one more than the other. Some health conditions more often appear along with Hashimoto’s than with Graves’ disease, or vice versa. Some conditions like atrophic gastritis are more strongly associated with Atrophic Thryoiditis than with the other subtypes.

It helps both doctors and patients adapt to the therapy as well as the disease when one gives it the right name.

Found in %

[Read the recent post about the full spectrum of thyroid autoimmunity]

The rates clarify to a reader that when both TPO and TG antibodies are both positive, the likelihood is rather higher that a person has Hashimoto’s, but it doesn’t necessarily rule out Graves or Atrophic thyroiditis, either.

The overlaps and gaps between the incidence rates are apparent in the list. A given patient may only have one or two of the three antibodies listed, or they may have all three types at the same time.

On the other hand, the image avoids one overlap. Too long has Atrophic Thyroiditis been considered an insignificant subtype of Hashimoto’s. Here, we do not list AT under TPOAb because it is not caused by TPOAb. Instead, it is associated with blocking TRAb antibodies.

Avoid overtesting.

A key word begins the tagline in the black block: “Confirm.”

This infographic is NOT a guide to continually retesting antibody levels to see whether we’ve succeeded in reducing them by going on an autoimmune protocol diet or dosing selenium 200 mcg a day as some science recommends.

If we can indeed enhance or regain our thyroid gland health by reducing TPO antibodies, results will show in our thyroid hormone levels. Keep your eye on the bottom line.

TPOab and TGab levels will fluctuate up and down now and then, but it is still uncertain whether they have direct cause-effect relationships with our health. Research says that symptoms beyond the thyroid are often associated with these antibody flares, but more research is necessary to understand the mechanisms. Only future research will tell us whether the flare happens simultaneously with a flare of other antibodies or biomarkers we’re not measuring.

Therefore, let’s save the TPOAb and TGAb tests from coming under attack by test-cutting gurus by not overtesting them.

TPO and TG thyroid antibody testing ought to be reserved for initial diagnostic purposes.

What TPO and TG tests tell us

For hypothyroidism, the first-line antibody test is TPOAb. If that result is within reference, test TGAb. If both are in reference, look for signs of Atrophic Thyroiditis (see the next infographic, below).

Once you get a single TPO or TG antibody result that is positive, it tells you everything it can tell you for now, according to the science. It simply and clearly says this:

“you appear to be highly likely to have an autoimmune thyroid disease of one or more types, more likely Hashimoto’s than Graves’ disease or Atrophic Thyroiditis.”

If the antibody titres are high, it says

“the thyroid appears to be under a higher level of attack IF other factors are participating in causing cell death by fibrosis.”

In pure Hashimoto’s, a long “euthyroid” phase of TSH rise usually precedes the final fall of the Free T4 into the hypothyroid zone. Whether the TPO antibodies have participated in thyroid cell damage or not is a question the antibody test can’t answer, so we look to other confirming signs of hypothyroidism that can’t be fully attributed to other causes.

If a hypothyroid patients has measurable TPO and TG antibodies that are not elevated, it does not rule out the third form of thyroid autoimmunity. Atrophic Thyroiditis does not require TPOAb or TGAb; it is caused by the TRAb blocking antibody.

As of 2017, scientists hadn’t yet been able to see TG antibodies as more than a side effect and marker; they don’t seem to cause harm but may result from it (Fröhlich & Wahl, 2017, cited in the meme).

The effect of TPO antibodies on thyroid fibrosis is indirect and very slow; the rate of destruction does not clearly correspond with the antibody titre.

Inflammatory cytokines must participate with the TPO antibody, and the antibody is not capable of acting independently to cause thyroid damage.

For example, TPOAb does not cause fibrosis and cell death in patients with active Graves disease. The TSAb antibody promotes thyroid cell proliferation and inhibits cell apoptosis. While TSAb are in circulation, they seem to protect the thyroid gland from dying, but when TSAb are in remission, tissues are vulnerable to attack by other antibodies and cellular stress. (See Morshed et al, 2018 , 2020)

A separate infographic is necessary to represent the complexity of TRAb antibodies, next.

TSH-Receptor antibodies

This graphic focuses on the less understood and more volatile region of the autoimmune thyroid spectrum. It moves Hashimoto’s and the more common TPO and TG antibodies out of the picture.

The enlightening lessons of this infographic are threefold:

  • Two opposing subtypes of TSH-receptor antibodies lead to Graves’ Disease and Atrophic Thyroditis. TRAb antibody is not just about Graves’ disease.
  • A combination of both antibodies is possible in the same person.
  • One may have a fluctuating hypo and hyper presentation over time.

Patients and doctors should know the prognosis is varied and complex. Multiple pathways exist. If you have Graves’ disease and become hypothyroid, you could end up with Atrophic Thyroiditis. If you have partial thyroid atrophy, you could experience a phase of hyperthyroid Graves.

Signs of antibody activity may continue to occur during therapy for hypothyroidism or hyperthyroidism, and patients may experience remissions as well.

Test for TRAb (blocking and/or stimulating) whenever necessary.

In the case of these two subtyptes of TSH-Receptor antibodies, occasional antibody testing after the initial diagnosis is much more justifiable.

To confirm the diagnosis of all hyperthyroid patients, the first-line test is the TSI or TRAb. It distinguishes the disease from other causes of thyrotoxicosis.

If subclinical hyperthyroidism with low TSH is not due to a flare-up of the TSAb antibody, maybe some other health condition is getting in the way, like a secreting nodule or a nonthyroidal illness.

TBAb Testing challenges in Atrophic Thyroiditis

Testing for blocking antibodies (TBAb) is more challenging because of problems with the assays.

  • Antibody tests are readily available for Graves’ disease TSAb. The usual test is the TSI or TRAb.
  • However, for patients with blocking antibodies or Atrophic Thyroiditis, it may be difficult to access a test that accurately measures their hypothyroid antibody variant.

TBII stands for “thyrotropin binding inhibitory immunoglobulin.” The test measures the degree to which the TSH receptor prefers to bind to the antibody rather than to real TSH molecules. The test adds both antibody titres together. If you have both blocking and stimulating antibodies, the total TBII inhibition will rise and the test result will be a much higher number. TBII does not discriminate between blocking or stimulating TRAb, so the results are interpreted in the context of your results for thyroid hormones and TSH.

The old TBII antibody tests that could be relied on to clearly reveal TBAb antibodies are becoming harder to find, because they worked better for people with blocking antibodies than for people with mild hyper Graves.

Few TRAb antibody tests are developed with the goal of measuring the blocking antibody. There’s little market incentive to refine a TBAb test when the condition is ignored and the antibody is only present in about 10% of autoimmune hypothyroid patients. A recent research report found that some 3rd generation TRAb assays do measure the blocking antibody (Ehlers et al, 2019).

Negative antibody results do not negate a Graves’ or Atrophic diagnosis, but positive results assist to confirm it. Testing the antibody is like a carnival game of whack-a-mole. If you test at the wrong time, which is easy to do when thyroid therapy clouds the lab results, you won’t whack the mole. A diagnosis based on clinical history and other signs ought to be sufficient.

Beyond the TRAb antibodies: their effects

TSAb and TBAb antibodies have immediate effects on our bodies. Many organs besides thyroid have TSH receptors.

The graphic also mentions confirming signs beyond antibody tests in the two autoimmune thyroid diseases with TRAb antibodies: eye signs and thyroid ultrasound. This is helpful because TSH receptor antibodies fluctuate so much that you can’t always catch them in the act when you test.

“Thyroid eye disease occurs only in 25-50% of people with Graves’ disease,” according to Cawood et al, 2004. Too many doctors have overgeneralized that Graves’ disease always presents with “Graves Eye Disease” (also known as thyroid ophthalmopathy). On patients support forums, we see the false assumption resulting in patients with a delayed diagnosis of Graves with mild hyperthyroidism.

TRAb antibody effects on thyroid hormones and TSH

Significant effects on TSH, T4, and T3 are mentioned in the graphic.

TRAb antibodies, unlike the TPO and TG antibodies, immediately stimulate or block thyroid hormone synthesis and metabolism in the thyroid. They can also alter thyroid hormone metabolism and TSH secretion rates.

The TRAb antibodies work by either amplifying, or by blocking, TSH receptor signaling. The TSH receptor is located on the membrane of various cells. At the cellular level, TSH receptor signaling doesn’t just stimulate the thyroid gland’s hormone synthesis, but can also upregulate or downregulate T4-T3 conversion rates in thyroid, hypothalamus and pituitary glands, and in other tissues throughout the body.

The TRAb antibodies can influence T4-T3 conversion rates by upregulating or downregulating deiodinase type 1 and/or type 2 (DIO1 and DIO2) gene transcription.

  • As for modifying DIO2, TSH signaling generates a “cAMP” signal in cells. When either TSH or the TSH stimulating antibody enters a receptor, they elevate cAMP. Deiodinase type 2 (D2) enzymes have cAMP promoters on them, enabling them to be upregulated and downregulated by intracellular cAMP levels. (Canetteri et al, 2000)
  • As for modifying DIO1, in patients with TSAb, the Graves’ disease stimulating antibody is known to upregulate deiodinase type 1 (D1) (Chen et al, 2018). This deiodinase is primarily expressed in thyroid, liver and kidney.

In the hypothalamus and pituitary, Paragoglia and team in 2017 has described Graves antibody’s TSH over-suppression effects through the TSH ultrashort feedback loop. The bulk of the theory of this feedback loop was developed long ago by Brokken, Wiersinga and Prummel, in 2003 and 2004.

[Read about the TSAb antibody effects on over-suppressing TSH]

On the other hand, scientists have not yet investigated the converse of stimulating action on the ultrashort feedback loop, its blockage by the TBAb antibody. Yet that is one possible reason for the extreme and sudden elevation of TSH often seen in cases of atrophic thyroiditis at diagnosis.

In Atrophic Thyroiditis, the absence of thyroid swelling (goiter) in the presence of extremely high TSH is a diagnostic sign.

High TSH without goiter is a contradiction. A high TSH, and high levels of TSH-receptor stimulating antibodies in Graves’ disease, tend to be natural stimulants of thyroid hypertrophy and hyperplasia. It is a natural response in many endocrine glands. Even the goiter seen in iodine deficiency occurs in the presence of elevated TSH, and the goiter in Graves’ disease is present with TSH receptor overstimulation.

Therefore, when high TSH is present while TSH-driven thyroid swelling is absent, it is a valid reason to suspect the presence of TSH-receptor blocking antibodies (TBAb) blocking the trophic effects of TSH hormone.

This meme should encourage practitioners:

  • to develop the skill of palpating and examining a patient’s thyroid gland.
  • to consider an ultrasound a rational diagnostic test for thyroid atrophy.

Therapy challenges

Once doctors are aware of the potential effects of antibody fluctuations during therapy in Graves’ disease and Atrophic thyroiditis patients, they may be less tempted to blame patients for non-compliant dosing.

In Atrophic Thyroiditis and “blocking hypothyroidism” patients, the TSH may occasionally fly high and the FT3 levels drop low, unpredictably, during apparently stable, compliant hypothyroid therapy, for the reasons given above.

If or when treatment instability occurs, such a patient may fall into a hypothyroid state during LT4 monotherapy. They may require LT3 therapy to provide stability during therapy, given that they may not be able to depend on healthy levels of T4-T3 conversion despite high-normal FT4 levels in circulation while on LT4 monotherapy.

Relapse and Remission

Once a Graves / Atrophic patient, always a Graves / Atrophic patient.

One may have a thyroidectomy, but there is no such thing as an antibody-ectomy. Once TRAb have expressed in a patient, the return of either the blocking or stimulating antibody, or both, is possible (Wiersinga, 2019).

TRAb antibody effects in tissues beyond the thyroid (eyes, skin, bones, pituitary) may occur long after the full atrophy, radioiodine ablation, or removal of the thyroid gland.

[Read about remissions and fluctuations in autoimmune thyroid disease. The most likely reason for remission in hypothyroidism is the disappearance of the TBAb antibody, not the reduction in TPO antibody.]

The disappearance of TRAb antibodies on the hypothyroid side can be puzzling to patients and doctors who are used to TPO antibody endurance in Hashimoto’s.

Remission is common with TRAb antibodies. It is seen in approximately 50% of Graves’ disease after methimazole therapy. Anti-thyroid medications are believed to modify TRAb antibody activity.

The reduction of TPO antibodies does not result in fibrosed thyroid tissue coming back to life, but reduced inflammation and oxidative stress in the thyroid gland can restore inhibited thyroid gland function during severe antibody-inflammatory attack. This is one reason why selenium treatment, which raises thyroid glutathione levels, is often recommended for TPO antibody reduction and symptom alleviation in Hashimoto’s (Wang et al, 2018).

Remissions from TSH-receptor blocking antibody production can result in full remission from hypothyroidism, but only if the gland has not undergone significant atrophy or other antibody damage. It is highly likely that many online testimonials of “Hashimoto’s” remission are in fact undiagnosed cases of TBAb remission. (See “Remissions and fluctuations in autoimmune thyroid disease: TRAb.”)

Navigate posts in the series

References

Canettieri, G., Celi, F. S., Baccheschi, G., Salvatori, L., Andreoli, M., & Centanni, M. (2000). Isolation of human type 2 deiodinase gene promoter and characterization of a functional cyclic adenosine monophosphate response element. Endocrinology, 141(5), 1804–1813. https://doi.org/10.1210/endo.141.5.7471

Cawood, T., Moriarty, P., & O’Shea, D. (2004). Recent developments in thyroid eye disease. BMJ : British Medical Journal, 329(7462), 385–390. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC509348/

Chen, X., Zhou, Y., Zhou, M., Yin, Q., & Wang, S. (2018). Diagnostic Values of Free Triiodothyronine and Free Thyroxine and the Ratio of Free Triiodothyronine to Free Thyroxine in Thyrotoxicosis. International Journal of Endocrinology, 2018, 4836736. https://doi.org/10.1155/2018/4836736

Ehlers, M., Schott, M., & Allelein, S. (2019). Graves’ disease in clinical perspective. Frontiers in Bioscience (Landmark Edition), 24, 35–47. http://www.bioscience.org/2019/v24/af/4708/fulltext.htm

Wang, W., Mao, J., Zhao, J., Lu, J., Yan, L., Du, J., Lu, Z., Wang, H., Xu, M., Bai, X., Zhu, L., Fan, C., Wang, H., Zhang, H., Shan, Z., & Teng, W. (2018). Decreased Thyroid Peroxidase Antibody Titer in Response to Selenium Supplementation in Autoimmune Thyroiditis and the Influence of a Selenoprotein P Gene Polymorphism: A Prospective, Multicenter Study in China. Thyroid, 28(12), 1674–1681. https://doi.org/10.1089/thy.2017.0230

Wiersinga, W. M. (2019). Graves’ Disease: Can It Be Cured? Endocrinology and Metabolism (Seoul, Korea), 34(1), 29–38. https://doi.org/10.3803/EnM.2019.34.1.29



Categories: Antibody tests

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