Antibody status may hide thyroid dysfunction under a normal TSH

This article is part of a series of examples that illustrate why a normal TSH cannot rule out thyroid disease or dysfunction.

In a recent series of posts, I revealed the science revealing distortions in the HPT axis due to age and sex (See “Age bias may hide hypothyroidism under a normal TSH“).

Antibody distortions of TSH-FT3-FT4 hormone relationships are often more significant than the distortions of age or sex.

The science reveals that certain antibodies can distort TSH independently of FT3 and FT4 levels. This post will review scientific evidence of TSH manipulation by two types of antibodies:

1. Thyroid peroxidase antibodies (TPOAb), which are responsible for Hashimoto’s Thyroiditis and may cause varying degrees of hypothyroidism. Whether they can directly “cause” TSH- thyroid horomone distortions is less clear than the fact that they are associated with TSH-FT4 distortion.
2. TSH receptor antibodies, (TRAb) of three subtypes: a) Stimulating (TSAb) antibodies cause Graves’ Disease hyperthyroidism, b) Blocking (TBAb) can cause transient TSH-blocking hypothyroidism, and/or c) Cleavage TRAb may combine with TBAb to cause permanent thyroid gland atrophy. Stimulating antibodies are known to distort TSH (Brokken et al, 2023; Prummel et al, 2024), and blocking antibodies are associated with TSH-FT4 distortion during thyroid hormone treatment for hypothyroidism, especially in patients with Graves’ hyperthyroidism who may have a hypothyroid phase, or who may become hypothyroid after thyroidectomy (Paragoglia et al, 2019), radioioidine ablation, or thyroid gland atrophy (Takasu & Matsushita, 2012).

To complicate the clinical picture, thyroid patients may have two or more of these antibodies at the same time, most commonly, concurrent TPOAb and TRAb. The effect of one antibody on TSH may be diminished or amplified by another antibody’s effect on TSH.

Here I focus only on antibody interference with TSH concentrations and TSH molecule bioactivity. The post will not discuss other antibodies, such as heterophile, anti-mouse, anti-TSH antibodies, and so on, which cause interference with TSH and thyroid hormone assays.

How can antibody status hide thyroid dysfunction within the normal range?

An individual’s antibody-positive or antibody-negative status can contradict the effect of mildly lower or higher thyroid hormone levels and prevent TSH from rising above or falling below the laboratory’s reference limits.

The scientific evidence is clear. If physicians wish to prevent misdiagnosis and mistreatment of autoimmune thyroid patients, they must understand how TSH response to thyroid hormones may be amplified or lowered by antibodies.

Table of contents

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Relevance to thyroid treatment

This post, unlike others in the series, must address antibody activity not only before treatment, but also during treatment.

• Prior to treatment, antibodies can affect a patient’s hormone levels and interfere with diagnosis.
• During treatment, antibodies may interfere with conventional TSH-based monitoring — unless a patient is blessed to have a physician who is informed about antibody-driven TSH distortions.

Thyroid autoimmunity often persists during treatment. Antibody titres will fluctuate based on many factors, some of which scientists don’t yet understand. Some types of antibodies (most often TRAb) can go into remission. But there is always the possibility of relapse. Even if a person has a total thyroidectomy, there is no such thing as an “antibody-ectomy.”

Some TSH-distorting effects of antibodies have only been revealed to scientists who study thyroid therapy and/or thyroidectomized humans or laboratory animals. Antibody effects on TSH can be amplified during severe hypothyroidism and/or thyroid therapy.

Preface: Antibody prevalence rates

Autoimmune thyroid disease (AITD) is caused by three types of antibodies.

• Thyroid peroxidase antibodies (TPOAb) identify Hashimoto’s thyroiditis (HT), which may cause hypothyroidism if thyroid cell damage becomes extensive.
• TSH receptor antibodies (TRAb) are most commonly seen in active Graves’ Disease (GD). In addition, the blocking (TBAb) and/or stimulating (TSAb) antibodies are also seen in some patients with Hashimoto’s Thyroiditis and Atrophic Thyroiditis (AT).
• Thyroglobulin antibodies (TGAb) often coexist with TGAb and/or TRAb and their elevation can confirm AITD status when TPOAb and/or TRAb are negative. However, they have an undetermined role in causing thyroid cell damage.

The following prevalence rates are gathered from Fröhlich & Wahl’s review:

The antibodies are presented as overlapping ovals in a Venn diagram because two or three may coexist in an individual.

Prevalence rates of TRAb fall lower in Hashimoto’s and Atrophic Thyroiditis because the TRAb antibody titres fluctuate and may disappear entirely after causing transient “blocking hypothyroidism” or permanent thyroid gland atrophy.

An individual with negative (normal) TPOAb may be positive for either TGAb or TRAb, and therefore, a negative result on one or two antibodies cannot rule out autoimmune thyroid disease. Some cases of HT and and AT are “seronegative,” not involving either elevated, or even detectable, TPOAb or TRAb antibodies (Anila et al, 2016). However, permanent damage from HT / AT can be seen in a thyroid gland ultrasound, and actively blocking TBAb antibodies are distinguished by low to no uptake on a radiographic thyroid scan when TSH is normal to elevated.

Çavuşoğlu and colleagues, 2010, have visualized thyroid antibody status by TSH levels within and slightly beyond the normal range. They show that the frequency of TPOAb-positive status increases at both ends of the TSH spectrum:

The graph above has a U-shaped pattern, demonstrating that TPOAb and/or TGAb are prevalent in all forms of autoimmune thyroid disease, including Graves’ disease, which causes hyperthyroidism.

Prevalence rates for TPOAb depend on

• sex (female, higher prevalence), and
• iodine status (higher iodine, higher prevalence)

The male/female prevalence of thyroid autoimmunity varies from study to study. Çavuşoğlu found a 5:1 female to male prevalence for both TPOAb and TGAb combined, although only 5% of individuals in their population were positive for both.

A study by Latrofa and colleagues in 2013 found that the use of iodized salt increased the prevalence of TPOAb antibody positivity in their population, especially among those who had signs of Hashimoto’s Thyroiditis in a thyroid gland ultrasound:

In the general population, disease prevalence rates are much higher for autoimmune hypothyroidism (Hashimoto’s and atrophic / blocking hypothyroidism) than they are for autoimmune hyperthyroidism (Graves’ disease).

Therefore, the reference interval for TSH can be biased significantly higher if the local laboratory administrators do not exclude TPOAb-positive serum samples from their reference range determinations, or if they arbitrarily decide to arbitrarily raise the upper limit to reduce the number of hypothyroid diagnoses in females and the elderly:

In Amouzegar’s study above, “Values in excess of 40 IU/ml are considered for the presence of TPOAb.”

This is why the National Association of Clinical Biochemists has stipulated that TSH reference limits ought to be based on TPO-antibody-negative populations (Demers & Spencer, 2002).

How TPOAb distort TSH-FT4 relationships

Most people have assumed that TSH rises because FT4 falls lower during TPOAb antibody attack, which defines Hashimoto’s thyroiditis.

But in fact, that’s not the whole story. The TSH-FT4 correlation is inflated by TPOAb.

In 2015, Brown and colleagues quantified the distortion. They found that positive TPOAb status skews the HPT axis even more powerfully than advanced age.

Here is how the authors explained the relationship depicted in the TPOAb graph:

“• at free T4 of 10 pmol/l, TSH was 131% higher in the presence of TPOAb (95% CI: 104, 161%), adjusting to

• a 63% increase at free T4 of 15 pmol/l (95% CI: 54, 73%).

• At free T4 of 20 pmol/l, the effect was a 15% (95% CI: 32, 28%) increase.”

(Brown et al, 2016)

It’s important to note that TPOAb does not just lower the FT4. It distorts the log-linear relationship between TSH and FT4.

The TPOAb-driven TSH distortion occurs across the entire reference range of FT4, which means that a low TSH can be moved up into the normal range by these antibodies.

• This is fortunate for patients who are hypothyroid as their TSH rises, since their FT4 and perhaps FT3 will be tested, and they will be diagnosed.
• This is also fortunate for some patients whose TSH rises above range, because some people will remain euthyroid if enough TSH stimulates more T3 secretion from the thyroid, maintaining their FT3 levels as their FT4 drops.

On the hypothyroid side, how many people really have a FT4 of 10 pmol/L concurrent with a TSH that is “normal”?

As one can see in the scatterplot below, very few people in Brown’s study had a FT4 of 10 pmol/L with a TSH at or below 2.2 mIU/L. (The pink shaded region includes values below FT4 of 12 pmol/L and TSH of 4.0)

According to their model above, the ones with a normal TSH and a FT4 of 10 pmol/L were not likely to be TPOAb positive, but that does not mean they were euthyroid. One would have to know what their concurrent FT3 level was.

Brown et al’s exclusion criteria for their reference population were as follows:

• Not a diverse ethnic/racial group. Bussleton, Australia is a “predominantly Caucasian population.”
• Not likely to suffer iodine deficiency, as it is “an iodine-sufficient region.”
• Not taking known medications that may influence TSH or FT4, based on the individual’s self-report as they completed a survey. Excluded on this basis were “128 individuals on thyroxine treatment; 4 on antithyroid drug treatment; and 39 on drugs affecting pituitary–thyroid axis function or thyroid function tests (including amiodarone, phenytoin, carbamazepine and lithium carbonate).”
• After biochemical analysis, the following were excluded: “4 with low free T4 accompanied by inappropriately low TSH suggesting hypopituitarism” and “2 with [extremely] outlying free T4”

Therefore, Brown and colleagues’ screening system had flaws:

• It could not rule out other forms of thyroid dysfunction besides TPO-antibody-positive autoimmune thyroid disease, and
• It could not exclude whose TSH was distorted by chronic mild to moderate nonthyroidal illnesses that do not require hospitalization.

TPOAb-positive autoimmunity is the most common type because immunoassays for these antibodies are readily available. The epidemic of Hashimoto’s in iodine-replete regions has led to a biochemical stereotype of hypothyroidism itself. Physicians and scientists now seem to imagine that all forms of hypothyroidism — autoimmune or not — will amplify TSH to the same degree that it does in Hashimoto’s thyroiditis, so that as FT4 falls below range, TSH rises over an arbitrary threshold of 10.0 mU/L.

Alas, if a person does not have TPOAb antibodies amplifying their TSH and it remains in the “subclinical” TSH zone, antibody-naive physicians will imagine they have a “milder” degree of hypothyroidism than a patient with Hashimoto’s. But in fact, their FT4 and FT3 levels may be just as low, or lower, than a person with Hashimoto’s with an elevated TSH who is offered treatment. The arbitrary 10 mIU/L threshold between different “grades” of subclinical hypothyroidism has been biased by TPOAb.

If a hypothyroid individual has TPOAb-negative status, a person’s TSH may be prevented from rising above of the “normal” range. It will look like they don’t have hypothyroidism at all.

What are the implications for missed diagnosis when TSH is normal?

1. Failure of preventive thyroid care in Hashimoto’s

The graphics above show that thyroid hypofunction and TSH compensation begins within the normal TSH range.

In early Hashimoto’s, many patients suffer the missed opportunity for preventive medicine before treatment is necessary.

Fortunately, one may reduce the damage caused by antibodies in the presence of oxidative stress in their thyroid tissue. For example, one may dose selenium and myo-inositol (Nordio & Basciani, 2017) and ensure vitamin D (Talaei et al, 2018) and iron levels (Ashraf et al, 2017) are optimal for healthy thyroid function.

Such measures may reduce permanent thyroid damage and delay the progression to overt, symptomatic hypothyroidism, and delay the onset of lifelong thyroid hormone treatment.

2. Failure to diagnose non-Hashimoto’s hypothyroidism

What happens if you don’t have TPOAb positivity to send your TSH high enough to flag your hypothyroid status to your physician?

False generalization from Hashimoto’s to non-Hashimoto’s leads to the dismissal of symptoms. Physicians may wonder “why are you complaining of symptoms with a normal TSH when most of my Hashimoto’s patients don’t feel symptoms despite an elevated TSH?”

Hashimoto’s TPOAb antibody attack is not the only cause of hypothyoidism. Other patients may be symptomatically hypothyroid despite a normal TSH:

• Autoimmune atrophic thyroiditis, which can occur at any age, and does not require TPOAb or TGAb because it is driven by the TSH receptor-blocking antibody instead (Takasu & Matsushita, 2012).
• Patients with atrophic thyroiditis may have flares of the TSH-receptor stimulating antibody, which can falsely normalize TSH secretion by interfering with the pituitary’s TSH-receptor feedback loop (Paragliola et al, 2019; Brokken et al, 2003; Prummel et al, 2004)
• Undiagnosed congenital hypothyroidism, missed at birth due to poor screening.
• Multinodular goiter with “cold” nodules that are less responsive to TSH stimulation.
• Iodine deficiency and/or iron deficiency, or other dietary or environmental endocrine disruptors.
• Patients with any degree of pituitary TSH secretion dysfunction due to central hypothyroidism, severe illnesses, or drugs that lower TSH.

Therefore, non-Hashimoto’s patients may suffer a delayed diagnosis based on a failure of TSH to escalate as expected.

Some physicians are so poorly educated beyond the TSH hormone that they have begun to imagine that high TSH levels “cause” hypothyroid symptoms. No scientist has yet proven that excess TSH receptor signaling can cause hypothyroidism.

Even in a study of frankly hypothyroid individuals with extremely high TSH levels, the TSH levels did not correspond with the severity of thyroid symptoms and signs, while T4 and T3 did (Meier et al, 2003). Even though TSH usually correlates with thyroid symptoms, TSH levels do not cause thyroid symptoms (unless there is a TSH secretion problem). Instead, the thyroid’s response, or failed response, to TSH stimulation causes inappropriate thyroid hormone levels (even within the normal reference range), which cause thyroid symptoms.

3. Failure to diagnose some cases of TPOAb-positive hyperthyroidism

At the other end of the spectrum, hyperthyroid TPOAb positive people may suffer a delayed diagnosis of hyperthyroidism if their TPOab antibody flare is not strong enough to lower their TSH.

This is relevant because about 80% of Graves’ hyperthyroidism patients are TPOAb positive (Fröhlich & Wahl, 2017).

Some Graves’ disease patients have stages of remission from hyperthyroidism during which Hashimoto’s antibodies and/or Atrophic thyroiditis antibodies can damage their thyroid gland. Some can fluctuate from hypothyroid to euthyroid to hyperthyroid over 10 to 25 years. Others will have a “smoldering” antibody pattern over time. (See Takasu & Matsushita, 2012; Bandai et al, 2019 and “Remissions and fluctuations in autoimmune thyroid disease: TRAb“.)

Imagine being tortured by a two- or three-way tug of war between two types of TSH-receptor antibodies and a TPO antibody. Then you are unlucky to have a TSH “snapshot” at the wrong time, showing it is “low-normal,” when TSH wasn’t normal two weeks ago, and it likely won’t be normal next month.

A person’s TPOAb may continue to keep their TSH in range while their FT3 and FT4 levels are inappropriate for their individual demands.

The logarithmic nature of TSH response to thyroid hormones means that a very small change in a low-normal TSH is metabolically equivalent to a large change in a high-normal TSH.

At the bottom of the TSH reference range, a 15% difference would bump up a TSH of 0.35 to 0.4 TSH. Consider that 15% is just a statistical average, and some individuals saw a TSH inflation greater than 15% even at the low end of range.

Secondly, TSH is also powerfully regulated by the TSH-receptor antibody, which is found in 10 to 20% of Hashimoto’s patients, as well as a larger percentage of Graves’ disease and atrophic thyroiditis patients.

• The stimulating antibody, TSAb, can reduce or suppress TSH at the pituitary gland independently of thyroid hormone concentrations, even if a patient is euthyroid (Brokken et al, 2003; Prummel et al, 2004).
• The blocking antibody, TBAb, can operate through the same mechanism to elevate TSH even if a patient doesn’t have low FT4, or to maintain the TSH in range when thyroid hormone concentrations should normally fall.

How does this happen? Brokken, Wiersinga and Prummel (2003-2004) studied only the TSH-receptor stimulating antibody, not the blocking antibody. But they found that when the antibody binds to TSH receptors located in pituitary tissue, it interferes with the pituitary’s self-regulatory system, the TSHR-TSH ultrashort feedback loop (they called it “ultra short-loop feedback”). Both TRAb antibodies can be present at the same time, playing a cruel game of tug-of-war with TSH receptors and TSH secretion rates, falsely normalizing the TSH. They theorized that this would have a minimal effect on TSH, but in fact, they did not study how distorted TSH-FT4 relationships could become if either stimulating OR blocking TRAb — or both — manipulated TSH receptor signaling in the pituitary gland after the thyroid gland had been damaged and while thyroid hormone is being administered. The TSH distortion can also occur while anti-thyroid medication is administered to patients with Graves’ hyperthyroidism.

Thirdly, anti-pituitary antibodies can damage the TSH-secreting pituitary gland, as well. The disorder is called autoimmune hypophysitis (“hypophysis” is the Greek name for the pituitary gland). These antibodies damage pituitary tissue and may cause various degrees of TSH secretion inhibition, leading to central hypothyroidism. This pituitary disorder may present with a normal TSH concurrent with a low-normal or low FT4.

When a patient has thyroid autoimmunity, other types of autoimmunity may coexist. Other antibodies may potentially distort TSH since the signaling pathways that lead to TSH synthesis and secretion are so complex. We must remain humble and open-minded to what scientists have not yet examined about TSH-distorting autoimmunity.

Main lesson: Antibodies can interfere with thyroid diagnosis

One reason why Hashimoto’s thyroiditis is the most prevalent form of hypothyroidism is that the antibody involved elevates the TSH so that its presence comes to the attention of physicians.

Other people without elevated TPOAb may be equally hypothyroid as a Hashimoto’s patient, but their TSH may not rise as high per unit of FT4 reduced.

Another reason for the dominance of Hashimoto’s diagnoses is that TBAb-induced blocking hypothyroidism and atrophic thyroiditis are often misdiagnosed as “late-stage Hashimoto’s,” even though TPOAb have no known power to block TSH receptor signaling or induce thyroid atrophy.

If a hypothyroid person is TPOAb negative, but neither blocking nor stimulating TRAb antibodies have been tested, and no thyroid ultrasound has been performed to look for characteristic signs of autoimmune thyroid damage, they may be misdiagnosed as non-autoimmune, or reinterpreted with a misleading diagnosis, “seronegative chronic autoimmune thyroiditis” (Baker et al, 1988; Takamatsu et al, 1998; Koca & Seber, 2023).

Despite the scientific articles that discuss TRAb and the articles that describe TSH-FT4 or TSH-FT3-FT4 distortions (TSH-TH distortions) within people diagnosed with thyroid autoimunity, ignorance persists regarding the power of unmeasured blocking and stimulating TRAb. Ignorance is partly due to the sheer complexity of thyroid autoimmunity and TSH-receptor autoimmunity.

But most of all, ignorance is held in place by TSH idolatry. Too many pepople have become resistant to the fact that TSH responds to more than just thyroid hormone signaling. Therefore, TSH is “sensitive” to thyroid hormones, but TSH is not “specific” to thyroid hormones. TSH is not a perfect proxy for thyroid hormone status. The TSH-TH relationship can be distorted by antibodies. Antibodies can make a normal TSH cloak the correct diagnosis. Antibodies can make “TSH normalization” a very deceptive treatment target.

References