TSH “can be very misleading” during thyroid therapy, say researchers

How many treated hypothyroid patients’ TSH has fallen below range even when both their thyroid hormones are in normal range and when they have no symptoms or signs of hyperactivity or hypermetabolism?

In my observation on thyroid patient forums, the answer is “too many.”

It’s common among thyroid patients to resort to such forums for peer support when their doctors lower their thyroid hormones based on the lower TSH alone.

This is an important blind spot in TSH-centered therapy guidelines that must be addressed in a series of posts that examine the topic of a low TSH’s uncertain relationship to the hypermetabolic state we know as “thyrotoxicosis.”

Yu and Farahani’s articles in 2014 and 2015 reviewed many years of research on antibodies in autoimmune thyroid disease.

They concluded, in their words, that “reliance on [TSH] for monitoring can be very misleading” when pituitary TSH secretion is suppressed by antibodies.

A common cause of thyrotoxicosis identified by Braverman & Cooper’s textbook is the “Circulating TSHR receptor antibody.”

They don’t discuss how TSH can be oversuppressed by this antibody when there is NO thyrotoxicosis, and therefore the research on this phenomenon should supplement their chapter.

HASHI’S PATIENTS CAN HAVE GRAVES’

Few people realize that the antibodies that lead to hypothyroidism and the antibodies that lead to hyperthyroidism can coexist in the same person.

• 100% of Graves’ Disease patients,
• up to 20% of Hashimoto’s Thyroiditis patients
• up to 75% of hypothyroid autoimmune Atrophic Thyroiditis patients. (Fröhlich & Wahl, 2017).

A person can’t be hyper- and hypothyroid at the same time, but autoimmune thyroid disease patients with or without thyroid therapy can have phases in which they transition between mild to extreme thyrotoxicosis, hypothyroidism, and euthyroidism. (Evans et al, 2010; Takasu & Matsushita, 2012; Takasu et al, 1992).

This is because anyone with autoimmune thyroid disease can have at least three different thyroid antibodies.

The two Hashimoto’s antibodies,

• 1) TPOab (Anti-Thyroid Peroxidase antibody) and
• 2) TGab (anti-Thyroglobulin antibody),

are indirect triggers of the pathology found in Hashimoto’s thryoiditis.

A third antibody,

• 3) TSAb, Thyroid Stimulating Antibody,

is responsible for overstimulating the thyroid gland to produce excess thyroid hormone, causing the state of hyperthyroidism and thyrotoxicosis in tissues throughout the body.

The Graves’ disease antibody, TSAb, is just one variant of a larger category, the TSHR antibody (Thyroid-stimulating Hormone Receptor antibody).

The three subtypes of the TSHR antibody are

1. Stimulating (TSAb)
2. Blocking  (TBAb)
3. Cleavage/neutral TRAb (Kahaly & Diana, 2017; Morshed & Davies, 2015).

Therefore, the TSAb is actually a “TSHR stimulating antibody.”

People who have the TSHR blocking antibody are far more likely to have the stimulating one as well (Takasu et al, 1992). This principle becomes important in clinical practice and research.

The Graves’ disease antibodies that block and cleave cause hypothyroidism by thyroid gland atrophy (Atrophic thyroiditis).

It is not contradictory to call manifestations of Graves disease within hypothyroidism “Graves’ HYPOthyroidism” (Christy & Morse, 1977; Lesho & Jones, 1997).  

In 2008, Takasu and Yoshimura reflected on this sharing of anti-thyroid antibodies across these populations and concluded “Hashimoto’s hypothyroidism and Graves’ hyperthyroidism could be the opposite spectrums of one disease.”

One disease, many antibodies, varying manifestations.

Autoimmune thyroid disease is not so simple.

HASHITOXICOSIS?

When Hashimoto’s patients become temporarily hyperthyroid, scientists have explained that their diseased gland is hypersecreting due to autoimmune attack and releasing stored hormone into the bloodstream. They have called this “Hashitoxicosis.”

According to a case study presented by Shahbaz et al 2018, some Hashimoto’s patients, 11.5% in one reviewed study, have TSAb antibodies when they are thyrotoxic.

Some Hashimoto’s patients can undergo long phases of thyrotoxicosis due to Graves’ antibodies before becoming hypothyroid.

Shahbaz and colleagues write “The presence of thyroid stimulation antibodies in our patient was intriguing. It may be due to the fact that both Hashimoto’s thyroiditis and Graves’s disease are manifestations of the same disease spectrum,” echoing Takasu and Yoshimura’s words without citing them.

The TSHR stimulating antibody has the same TSH-receptor affinity and binding sites regardless of whether it appears in a patient diagnosed with Graves’ disease or one diagnosed with autoimmune Hypothyroidism (Hashimoto’s and Atrophic thyroiditis). They also found that the TSHR blocking antibody works through a similar mechanism as the stimulating antibody (Morgenthaler et al, 2007).  

TSHR ANTIBODY COMPROMISES TSH

Here’s where the complexity gets even more interesting and explains the suffering of so many patients with Hashimoto’s as well as Graves’.

As of 2015, Scientists have concluded that the TSHR stimulating antibody doesn’t just affect the thyroid gland.

The antibody compromises pituitary TSH secretion.

The TSAb antibody interference with TSH can be extreme and long-lasting in some people.

Yu and Farahani wrote a 2014 review of “TSH suppression post-therapy in Graves’ Disease” in which they focused on poor “recovery” of TSH.  They write, “Studies examining the recovery of TSH levels illustrated more prolonged suppression despite achieving clinical and biochemical euthyroidism.”

Both “clinical” and “biochemical” euthyroidism meant they had no clinical signs and symptoms of thyrotoxicosis and their thyroid hormones were in normal reference range.

Yet their TSH was abnormally low or suppressed.

They write, “Data analysis illustrates that only 14.4% of patients had recovered their TSH less than 3 months after treatment. At 3 months, 47.5% of patients demonstrated TSH recovery, whereas 71% had recovered by 6 months (p<0.001).”

Yu and Farahani pointed their finger at the TSAb antibody as the main cause of this continued TSH suppression.

They mention the TBII test, Thyrotropin Binding Inhibition Immunoglobulin, which measures the activity of both stimulating and blocking TSH-receptor antibodies to interfere with TSH binding at the TSH receptor.

The TBII is different from some Graves’ disease TSAb tests that only measure the stimulating antibody, and perhaps the TBII is more predictive because it measures more of the same family of TSHR antibodies.

“TBII was a determinant of TSH recovery at 6 months. Analysis shows 58% of patients with positive TBII recovered their TSH compared with 76% of TBII-negative patients at 6 months (p=0.015).”

Another finding was the predictive value of the TBII test. “Also, TBII activity can be a predictor of prolonged TSH suppression, as analysis demonstrates a significant difference between the groups.”

They found two clinical applications:

1. “This may be helpful clinically to predict TSH recovery”

2. It may help to predict TSH’s “reliability when titrating thyroid supplements.”

In other words, TSH becomes UNreliable in the patients that do not experience normal TSH secretion during thyroid supplementation — thyroid replacement therapy.

Then, Yu and Farahani emphasized their conclusion further.

They updated and published their review again in 2015 in the Journal of Clinical and Investigation, where their abstract said the TSH test can become “misleading”:

“Clinical data suggests that TSH recovery is most likely to occur within the first 6 months after treatment, with recovery plateauing at approximately 70% of patients, suggesting that reliance on this assay for monitoring can be very misleading.”

Conversely, this means “TSH recovery” was incomplete in 30% of Graves’ disease patients. It plateaus there. No further recovery of TSH levels, or the degree of TSH suppression varied beyond the time-frame of the studies.

That’s a lot of people whose TSH secretion is compromised, long-term, indefinitely.

Therefore, even a hypothyroid patient may have antibodies suppressing their TSH inappropriately, when thyroid hormones are NOT elevated but rather normal or too low.

VARIABILITY AND LONG-TERM IMPACT

The impact of this delayed TSH recovery varies from person to person. It also varies within a patient over time. Antibody flares are unpredictable. You do not know when they will recur.

“Furthermore,” Yu and Farahani explain, “TBII positivity is associated with lower likelihood of TSH recovery. Pathophysiology behind suppressed TSH involves not only anatomical but also autoimmune mechanisms.”

The “anatomical” mechanism implies that the TSHR antibody has long-lasting structural impacts on the organs it targets, not just an effect that exists when the antibody disappears.

In fact, pituitary TSH-Receptors may be irreversibly damaged by TSHR antibody attack, just like the thyroid gland, eyes and skin can be permanently damaged after antibodies disappear. (Schwartz, et al, 2002; Tabasum et al, 2016)

An anatomical mechanism was found at the TSH receptor in 1984, when Kakita and colleagues found variable TSH suppression over time in their treated hyperthyroid rabbits. When they were rendered hypothyroid, injections of TSH (which would be similar in effect to TSHR antibody) had a TSH-oppressive effect for a few months, but after 2-3 months the effect declined. “as the duration of hypothyroidism increases, the sensitivity of the autoregulatory system to the suppressive effects of endogenous TSH changes.” The study was not as long term as human studies have been since then.

See Takasu and colleagues’ articles in 1992 and 2012, proving the TSHR antibody also has similar long-term effects over 10 years in both autoimmune Atrophic thyroiditis and Graves’ disease. 

In some patients, the presence of antibodies may not be necessary anymore to oversuppress this feedback loop — all they may require is a mutation in the TSHR gene to make their TSH oversensitive to suppression at normal concentrations of T4 and T3. (Gelwane et al, 2009) This research further proved the importance of TSH-receptor feedback on TSH secretion after the antibody is absent.

HARM DURING THERAPY

In very practical ways, the antibody can contradict and oversuppress TSH both during anti-thyroid therapy and during thyroid therapy for hypothyroidism, resulting in potential harm to the treated thyroid patient from misinterpretation of their TSH and ignorance or dismissal of Free T4 and Free T3.

DURING ANTI-THYROID THERAPY

While a Graves’ disease patient is being treated for hyperthyroidism, the TSHR stimulating antibody can stimulate synthesis & secretion while anti-thyroid therapies push them down. However, their anti-thyroid therapy may be so powerful that they become hypothyroid in thyroid hormone levels.

In this state, TSH could still remain oversuppressed by the TSHR antibody. The TSH will not rise to signal the patient’s hypothyroid state.

The patient can suffer from overdoses of anti-thyroid medication if they are not monitored by thyroid hormone levels instead of just TSH.

DURING HYPOTHYROID THERAPY

After a patient is on thyroid hormone, antibodies can oversuppress the TSH when the person is euthyroid or underdosed. 

In Hashimoto’s, if the patient also has this Graves TSHR stimulating antibody, the situation can be the same — a patient can be euthyroid or underdosed and the TSHR antibodies may flare up, or may have a long-lasting anatomical influence after antibodies disappear, making the TSH fall lower than it normally would.

When TSH alone drops, the doctor may be tempted to lower the thyroid dose. Clearly, reducing their thyroid hormones will render the patient hypothyroid.

CONCLUSION

When is the TSH level in an autoimmune thyroid disease patient untrustworthy? At all times.

TSH could be mildly or severely influenced at any time the TSHR antibody flares.

According to research, the TSHR antibody could have permanently damaged pituitary TSH receptors in the past.

Basically, the patient now has hypopituitarism, also known as secondary, or central, hypothyroidism, in which TSH secretion is compromised.

The potential harm of relying on TSH alone in any autoimmune thyroid disease patient should be obvious.

A hypothyroid Graves’ disease patient or a Hashimoto’s patient may have their thyroid medication reduced inappropriately because of an isolated, antibody-suppressed TSH that contradicts their clinical presentation and thyroid hormone levels.

Reducing doses of thyroid hormone based on an oversuppressed TSH is happening over and over again, every day.

It causes and worsens hypothyroidism. It ruins lives.

Autoimmune thyroid disease is lifelong. There’s no such thing as an antibody-ectomy.

Thyroid disease mismanagement can bankrupt medical systems by worsening other diseases and disorders, especially during the aging process.

The simplistic categories of Graves vs. Hashi’s have blinded many doctors to the fact that all thyroid antibodies can affect ANY autoimmune thyroid patient’s thyroid gland AND pituitary TSH.

It is shocking that TSH-centrism has blinded some doctors to the biological fact that excess thyroid hormones, specifically excess T3 and excess T4 conversion to T3, is the only possible cause of thyrotoxicosis in any tissue in the human body.

Medical systems must update TSH testing policies and flowcharts to emphasize Free T3 and Free T4 levels as ultimate confirmation of the causes of thyrotoxic symptoms observed in a patient.

When no thyrotoxic symptoms present and low TSH is the only anomaly, don’t doubt the patient or the thyroid hormone levels. Doubt the TSH!

REFERENCES

see References for Thyrotoxicosis vs. Low TSH series