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:
- Thyroid antibody tests (overview)
- 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.
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 %
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:
- TPOAb (Thyroid Peroxidase antibodies),
- TGAb (Thyroglobulin antibodies), and
- TRAb (TSH-Receptor antibodies) of two subtypes.
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.
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)
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.
TSAb and TBAb antibodies have immediate effects on our bodies. Many organs besides thyroid have TSH receptors.
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 a hypothyroid patient presents before thyroid therapy with very high TSH (over 80) without any goiter (thyroid swelling) in response to that TSH, that paradox itself is the strongest sign that it’s not merely Hashimoto’s but is more likely Atrophic Thyroiditis instead.
Therefore, we may need to test to confirm remissions, relapses, and shifts between hypo and hyper whenever they result in confusing or contradictory TSH, FT3 and FT4 results and symptoms. If it’s not a flare-up of the antibody, maybe some other health condition is getting in the way, like a secreting nodule or a nonthyroidal illness.
Beyond the antibodies: their effects
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.
Too many doctors have overgeneralized that Graves’ disease always presents with “Graves Eye Disease” (Thyroid ophthalmopathy). On patients support forums, we see this mistake resulting in patients with a delayed diagnosis of Graves with mild hyperthyroidism. “Thyroid eye disease occurs only in 25-50% of people with Graves’ disease,” according to Cawood et al, 2004 (a citation there was not enough room to include).
A separate infographic is necessary to represent the complexity of TRAb 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, you could end up with Atrophy. On your way to Atrophy, you could be interrupted by 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.
Thyroid hormones and TSH
Significant effects on TSH, T4, and T3 are mentioned in the graphic because these antibodies, unlike the TPO and TG antibodies, immediately stimulate or block hormone synthesis and metabolism in the thyroid and pituitary.
The TRAb antibodies can alternately mimic or block direct and indirect TSH signaling on deiodinase enzymes. They can upregulate or downregulate T4-T3 conversion rates in thyroid, hypothalamus and pituitary glands, and in other tissues throughout the body.
Citations on the infographic point to the evidence regarding antibody effects on pituitary TSH secretion and T4-T3 hormone conversion rate.
Paragoglia and team in 2017 has described Graves TSH suppression effects through the TSH ultrashort feedback loop, but the bulk of the theory of this feedback loop was developed by Brokken, Wiersinga and Prummel in 2003 and 2004.
On the other hand, the converse of stimulating action on the ultrashort feedback loop is one possible cause of the extreme and sudden elevation of TSH at the onset of atrophic thyroiditis.
In Atrophic Thyroiditis, the absence of thyroid swelling (goiter) in the presence of extremely high TSH is abnormal. A high TSH, and high levels of TSH-receptor stimulating antibodies in Graves’ disease, are natural stimulants of thyroid hypertropy and hyperplasia. It is a natural response in endocrine glands. Even the goiter seen in iodine deficiency occurs in the presence of elevated TSH. When high TSH-driven thyroid swelling is absent, it is a valid reason to suspect the presence of blocking antibodies.
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.
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 patients, the TSH may occasionally fly high and the FT3 levels drop low, unpredictably, during apparently stable, compliant hypothyroid therapy. If or when this 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.
(I am planning to write a future post in which I illustrate data from a published case study of huge hypo-hyper fluctuations causing lab test paradoxes and anomalies. I can strengthen their conclusions with my own case study data revealing wide fluctuations during therapy.)
TBAb Testing challenges in Atrophic Thyroiditis
Antibody tests are readily available for Graves’ disease TSAb. The usual test is the TSI or TRAb.
For Atrophic Thyroiditis, it may be difficult to access a blocking antibody test that accurately measures this variant.
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 milld hyper Graves.
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. If you have blocking antibodies, your TBII results can be much higher than a person with only stimulating antibodies. 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.
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 affects only about 10% of autoimmune hypothyroid patients. A recent research report found that some TRAb assays do not live up to their claims that they can measure the blocking antibody.
Remission and relapse
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 50% of Graves’ disease after methimazole therapy.
Remissions from blocking antibody production can result in full remission from severe hypothyroidism, but only if the gland has not undergone significant atrophy yet. It is highly likely that online testimonials of Hashimoto’s remission are in fact cases of TBAb remission. The reduction of TPO antibodies does not result in fibrosed thyroid tissue coming back to life.
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.
Once a Graves patient, always a Graves 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 always possible. TRAb antibody effects in tissues beyond the thyroid (eyes, skin, bones, pituitary) may occur long after the full atrophy, ablation or removal of the thyroid gland.
Navigate posts in the series
- Developing infographics for thyroid testing
- Infographic: Screening for hypo
- Infographic: Tests to optimize thyroid therapy
- Infographics for antibody testing
Upcoming posts in the works
- “Optimal is individual” infographic memes that explore population averages and not-so-optimal levels vs. examples of diverse individual optimal levels of TSH, Free T4 and Free T3 in various therapies, and on no therapy.
- “Pooling is D1-D2 dominance” A post that features infographics about the thyroid science regarding reverse T3 and symptoms at higher levels of T3 during therapy.
Categories: Antibody tests