This post takes a closer look at the “ultrashort feedback loop,” the biological mechanism by which the TSHR stimulating antibody (TSAb) can oversuppress or inflate TSH in any autoimmune hypothyroid patient.
The antibody’s effect alters the normal TSH-FT4 relationship. It may look like the patient has another thyroid condition:
- It may mimic “Resistance to thyroid hormone” (RTH) with a mid-range or higher FT4 or FT3 alongside an elevated TSH, or a high FT4 with an unsuppressed TSH.
- It may mimic “Central hypothyroidism” (CeH), with a mid-range or lower FT4 and FT3 alongside a low or suppressed TSH.
ULTRASHORT FEEDBACK LOOP
This feedback loop was first discovered in 1984 in rabbits (Kakita et al, 1984, 1986).
It is sometimes called the “Brokken, Wiersinga, and Prummel” feedback loop, since it was explored by these three scientists in a series of three articles 2001-2004. It was further discussed in 2004 by Johannes Dietrich and colleagues.
This loop is often omitted from simplistic images showing the HPT axis (hypothalamus-pituitary-thyroid axis), but it does appear on complete visual models (Chatzitomaris et al, 2017).
How does it work?
The TSH ultrashort feedback loop is important to a normal HPT axis.
The pituitary gland uses this ultrashort feedback loop to adjust its TSH secretion.
As a rough analogy, think about how your ears help regulate your speech volume in various situations in life.
The pituitary gland uses its own TSH receptors to sense how much TSH it is secreting, just like we use our hearing to adjust how loudly we are speaking.
We speak more softly in a conversation, compared to shouting to a friend across a busy street.
TSH “speaks” very softly or not at all when it hears its own voice amplified in its “ears” (its TSH-Receptors).
TSHR antibody effects beyond the thyroid
As most people know, in Graves’ disease, when TSH receptors on the thyroid gland are overstimulated by TSH-Receptor antibodies (TSAb), the thyroid gland may produce too much hormone.
Powerful antibody-driven thyroid stimulation continues long after TSH stimulation is suppressed by excess thyroid hormone.
That’s why the TSH receptor-stimulating antibody used to be called the “Long-Acting Thyroid Stimulator” (LATS), until science realized it was an antibody acting on the TSH receptor.
But TSH receptors are located throughout the body, not just on the thyroid gland.
Therefore, this antibody doesn’t just stimulate the thyroid gland; it can and does attack other organs and tissues, too, and it’s “long-acting” on them as well:
1. SKIN: When TSH receptors on the skin are overstimulated by TSHR antibody, “Graves dermopathy” or Graves’ skin disease is the result, and the effect of this antibody can persist long after the patient is euthyroid or hypothyroid, as shown in a study with a 14 year follow-up (Schwartz, et al, 2002).
2. EYES: When TSH receptors in the eyes are stimulated by TSHR antibody, “Graves’ ophthalmopathy,” or Graves’ eye disease is the result. As in the case of thyroid skin disease, elevated thyroid hormones are not necessary for Graves’ eye disease.
The TSHR antibodies can trigger eye disease long after the Graves’ patient has had a total thyroidectomy and is in a hypothyroid or euthyroid state.
Once triggered by this antibody, Graves’ eye disease can happen even when TSAb antibody is not detectable in serum and thyroid hormone levels are normal. (Tabasum et al, 2016).
3. PITUITARY: When TSH receptors on the pituitary gland itself get overstimulated by these antibodies, what happens?
Not only TSH hormone, but also TSH-Receptor antibodies act directly on the TSH receptors on the pituitary gland through the ultrashort feedback loop.
TSH-Receptor antibodies mimic TSH and confuse the pituitary gland about how much it is currently secreting. As a result, TSH can be independently oversuppressed or amplified by this antibody attack.
TSHR ANTIBODY MEASUREMENT
Researchers have been explaining the clinical relevance of TRAb testing in autoimmune thyroid diagnosis and therapy. (Diana et al, 2016).
The degree and direction to which TSH is warped by antibody interference depends on which variants of the antibody is or have been dominant (suppressing vs. blocking), the antibody’s current concentration in blood, and the degree to which the antibody may have already resulted in permanent damage to its target organs.
Historically, the first test that measured both blocking and stimulating antibodies at the same time was called the TBII test (thyrotropin-binding inhibitor immunoglobulin).
The old TBII test has now been replaced by the “TRAb” test.
Although the TRAb is technically capable of measuring both types of TSH receptor antibodies — stimulating and blocking — the TRAb antibody tests are marketed and developed largely for the detection of the stimulating antibody variant, TSAb.
Another test, the TSI test, focuses only on the Thyroid Stimulating Immunoglobulins, and it uses another method, so it may yield slightly different results.
While a positive result is strongly conclusive of TRAb activity, a negative result does not rule out the antibody’s activity in the past or the present.
Sometimes a thryoid uptake scan (scintigraphy) will reveal that the thyroid is being diffusely overstimulated when no TSH is present (TSAb is likely), or that there is little to no activity despite high levels of TSH in blood and little sign of damage to the thyroid (transient TBAb blocking hypothyroidism, without thyroid atrophy, is likely).
Antibody measurements are only a snapshot, and antibody levels fluctuate and can disappear. The most important thing to know is that they CAN be there and can return in any autoimmune thyroid patient.
The research proving the long-acting effects of TSH-Receptor antibody interference with TSH results is discussed in more depth in the post “TSH “can be very misleading” during thyroid therapy, say researchers.”
THE VIGILANT, YET VULNERABLE TSH
We can learn from this research on the ultrashort feedback loop that the pituitary gland’s secretion of TSH is at the center of more than one feedback loop.
Even beyond these two feedback loops, the pituitary has to be vigilant. Hypersensitive. It must attend to factors that indicate the biological need for adjustments in TSH-stimulation of thyroid secretion.
In human biology, pituitary adjustment of TSH is an ACTIVE force that initiates changes in thyroid secretion rates and ratios, not just a PASSIVE element that responds to thyroid hormone levels. The TSH responds to “feed-forward” stimulation, not just “feedback” signalling.
The hypothalamus and pituitary’s complex regulation of TSH has to receive more input than just thyroid hormone levels so that it can have a regulatory role in health.
Therefore the TSH response, both in theory and in reality, as shown in research, is not always “specific” to thyroid hormone levels. It is sensitive to leptin, to glucocorticoids, and dopamine receptor activation, and it is sensitive to TSH levels in blood.
Beyond the ultrashort feedback loop, the many common health factors and substances can lower the TSH beyond what it should be given thyroid hormone levels and clinical presentation — see a list and citations in our post Thyrotoxicosis? Many factors can lower TSH.
It’s unfortunate, but doctors are being indoctrinated to believe something false and illogical about the exclusivity of TSH response only to thyroid hormones.
Pituitary TSH would be irresponsible if it exclusively responded only to T3 and T4 in blood and ignored other important metabolic signals that may require it to drive an increase or decrease in thyroid hormone.
Pituitary TSH has to listen. It has to be “nonspecific” to thyroid hormones. Vigilant to valid metabolic signals . Attentive to a wide range of _relevant_ inputs.
But we also learn from research that the ultrashort loop is vulnerable. It is vulnerable to irrelevant, foreign, confusing or contradictory inputs — such interference by an antibody that mimics or blocks TSH action on receptors.
Direct measurement of both major thyroid hormone levels (Free T3 and Free T4) can always give the most accurate data on the degree to which the entire human body beyond the pituitary gland exchanges its T3 and T4 thyroid hormone supply with bloodstream.
In addition, during thyroid therapy, listening to the patient’s body and symptoms can tell you a lot about how far away from that desirable point B they are, the ideal euthyroid metabolic state.