Do you know about the THIRD type of autoimmune thyroid disease?
Atrophic thyroiditis may coexist with Hashimoto’s and can occur in people with Graves’ disease.
Atrophic Thyroiditis is an extreme form of primary hypothyroidism in which the thyroid gland is severely atrophied (shrunken, shrivelled) by antibody attack.
In some estimates, approximately 10% of Hashimoto’s patients carry the blocking antibodies associated with Atrophic Thyroiditis (AT) (Fröhlich & Wahl, 2017). See the statistics of how many people are affected by this form of thyroid autoimmunity in “Overlooked: How many Hashimoto’s patients with TSH-Receptor antibodies?“
But Atrophic Thyroiditis is not simply a subtype of Hashimoto’s. Paradoxically, it’s more related to Graves’ disease, even though Graves’ disease causes the opposite clinical presentation, hyperthyroidism. Atrophic Thyroiditis is caused by a different set of antibodies than Hashimoto’s and Graves, but it is genetically and immunologically related to Graves disease.
As I explain in this article, many myths and general ignorance exists regarding this form of thyroid disease because thyroid autoimmunity is not as simple as it seems.
Atrophic Thyroiditis has a different prognosis than Hashimoto’s.
- It involves TSH-blocking antibodies that act instantly on thyroid lab results.
- It often leads to far swifter process of thyroid gland destruction if certain antibodies coexist in a susceptible person.
- It can affect both maternal and fetal health during pregnancy.
- It can occur at any age, even in early childhood.
Despite its severity and influence on health, atrophic thyroiditis not easy to diagnose.
This is because of widespread medical ignorance and myths, the absence of goiter, the frequency of antibody fluctuations, and problems with testing technologies and test ordering practices.
You may often hear the mantra that “thyroid antibodies don’t affect treatment,” but that’s false with regard to Graves’ disease antibodies, and it’s also false with regard to Atrophic Thyroiditis antibodies.
The antibodies that are part of this thyroid disease can significantly interfere with lifelong thyroid therapy, if or when the antibody persists, or reappears long after thyroid atrophy has decimated the thyroid gland.
Myths and ignorance of atrophic thyroiditis
The current level of ignorance and the widespread myths about this thyroid disease entity is astounding.
Atrophic thyroiditis used to be better known more than 20 years ago when hypothyroidism was classified into either of two presentations based on there being thyroid swelling (goiter) or not, prior to thyroid hormone treatment:
- atrophic (or non-goitrous)
- vs. goitrous (Hashimoto’s) (See Bogner et al, 1992).
Today, most doctors and patients have never heard about Atrophic Thyroiditis (AT). That’s because it’s not usually taught in medical school anymore, and most thyroid blogs, books, and websites don’t mention it.
One reason why AT has been overlooked is that it simplifies diagnosis to pretend that it does not exist.
Real thyroid autoimmunity is not simple, but a complex overlapping web of antibodies and clinical presentations. The blocking and cleavage antibodies can occur in people who also have Hashimoto’s or Graves’ disease. The full spectrum of thyroid autoimmunity involves overlapping antibodies in some patients.
The drive to oversimplify thyroid diagnosis has been going on for decades. Some thyroid scientists and textbook writers appear to find the scientific fact of complex thyroid “multi-autoimmunity” too confusing for their students or readers. The large number of people with autoimmune hypothyroidism makes it too tempting to simplify the autoimmune hypothyroid category and treat it as if it’s homogenous.
As a result of these myths and lack of knowledge, many people with Atrophic Thyroiditis (such as myself) have been misclassified as Hashimoto’s thyroiditis.
This mistake is based on the false assumption that ALL autoimmune hypothyroidism is Hashimoto’s.
Most of the science on thyroid atrophy is buried in archives. I’ve discovered more than 100 articles on thyroid gland atrophy going back to the 1800s, and every decade there appear new publications on it. But scientists tend to review only the most recent 10 years of research. (See the bibliography I shared back in early 2019 when I first published this article). This common practice of looking only at recent publications causes medical and scientific amnesia.
Based on medical amnesia and the shortcomings of thyroid antibody testing systems, some patients are even left as unclassified cases of hypothyroidism of unknown or “idiopathic” cause just because the Hashimoto’s TPO antibodies are absent or (as in my case) present but not elevated.
Most forms of autoimmune thyroid disease are associated with the thyroid peroxidase (TPO) antibody known to be involved in Hashimoto’s. Therefore, many diagnostic algorithms stop after measuring TPOAb, and some stop after measuring both TPOAb and thyroglobulin (TG) antibodies.
However, neither thyroid gland atrophy nor TSH-blocking antibody activity require the presence of the TPO antibody or TG antibody.
The TPO antibody is in fact incapable of causing thyroid gland atrophy (Fröhlich & Wahl, 2017). Instead, TPO antibody is implicated in lymphocytic infiltration of thyroid cells without thyroid volume loss. Only in cases where a person has both Hashimoto’s AND TSH receptor blocking / cleavage antibodies will you find thyroid atrophy occur in a Hashimoto’s patient.
Therefore, it is false to claim that an atrophied thyroid is “end-stage” Hashimoto’s ! That’s a common myth. It’s still perpetuated by research publications that perform incomplete literature reviews, misinterpret their sources, don’t fact check their sources’ claims, and don’t understand the various subtypes and mechanisms of the TSH receptor antibody.
- How can it be the “end stage” of Hashimoto’s if it occurs even in a five-year-old child? (Inamo et al, 2011)
To add to the invisibility of this disease, both Graves’ stimulating antibodies and AT blocking antibodies are known to completely disappear (go into remission) and to occasionally return (relapse).
If you want to test for the blocking antibodies, another major barrier today is that most Graves’ hyperthyroidism tests available at laboratories do not focus on the blocking antibody but rather the stimulating antibody alone, and they are usually only ordered if a person’s thyroid hormones are high and TSH is low.
Therefore, testing for the blocking antibody is not a reliable way to diagnose Atrophic Thyroiditis due to the high likelihood of a false negative or remission. (See the section below for practical tips on AT signs and diagnosis).
What causes Atrophic Thyroiditis?
Atrophic thyroiditis is defined in various ways, but in this article, I consider atrophic thyroiditis as autoimmune-caused severe thyroid gland atrophy necessitating lifelong thyroid hormone replacement. (An antibody-related phenomenon is temporary autoimmune “blocking hypothyroidism” that need not always cause a lifelong disabling state of thyroid gland atrophy. See Tagami et al, 2019.)
Atrophic Thyroiditis is a HYPOthyroid form of Graves’ disease. Jara, et al, 2008, explains that Atrophic Thyroiditis patients usually have a Graves’ disease genetic profile, which is quite distinct genetically from Hashimoto’s.
The normal form of Graves’ HYPERthyroidism is caused by TSH-Receptor *stimulating* antibodies that overstimulate the thyroid gland to produce hormone, even in the absence of TSH.
But Atrophic Thyroiditis is associated with the presence of TSH-Receptor *blocking* antibodies that cause HYPOthyroidism.
The blocking antibody prevents TSH from stimulating TSH receptors in the thyroid gland and other tissues where the receptor is expressed. Therefore, even in patients with extremely high TSH levels over 100 can have no TSH stimulation of their thyroid gland when the antibody is strong enough to block the receptors.
- As demonstration that the blocking antibody is a Graves’ disease-associated antibody, according to Fröhlich & Wahl, 2017, “Thyroid Autoimmunity,” blocking anti-TSH-Receptor antibodies occur in 25–75% of Graves’ Disease patients.
It is now known that *cleavage* (formerly called “neutral”) TSH-receptor antibodies that can cause thyroid cell apoptosis in the absence of the stimulating antibody, and that the presence of the stimulating antibody protects the gland from apoptosis (Morshed et al, 2013, 2015).
- Like the blocking antibody, the cleavage antibody is also a Graves’ disease-associated antibody. Morshed et al, 2010, mentioned that 59% of Graves patients in a study had the neutral/cleavage TSH-receptor antibodies in circulation.
Merely the absence or suppression of TSH, or the presence of blocking antibodies with TSH receptor antagonism (or inverse agonism), cannot cause thyroid gland atrophy. A TSH suppressed by thyroid hormone treatment does not cause thyroid atrophy. As demonstration of this principle,
- In patients with pituitary dysfunction (central hypothyroidsm), many of whom cannot secrete any TSH during adequate thyroid treatment, thyroid gland volume and function is usually maintained despite TSH deficiency (Persani et al, 2019).
- Patients who experience severe TSH-blocking hypothyroidism caused by the blocking antibody can experience full remission because the blocking antibody alone does not always result in disabling thyroid atrophy. After the blocking antibody disappears from blood, a person can revert to a state that requires no thyroid therapy if enough thyroid tissue remains to support normal TSH-driven thyroid function. (Takasu et al, 2000)
Therefore, current science points to the copresence of both “blocking” and “cleavage” TSH receptor antibodies as the likely cause of thyroid gland atrophy (severe shrinkage).
AT patients with incomplete atrophy can flip between hypo and hyper status
According to Takasu et al, 2012, a small percentage of hypothyroid patients with the blocking antibody, as well as Graves’ disease patients, can flip between hypothyroid, hyperthyroid and euthyroid status over many years, depending on whether the blocking antibody predominates over the stimulating antibody, or whether the two antibodies are in balance with each other, and whether there is enough thyroid tissue to overstimulate.
TSHR antibody levels can fluctuate wildly and can also completely disappear or resurface over time.
A real example — My thyroid and failed therapy
A normal female gland is about 12-15 mL volume. My gland is 0.5 mL, a size that is found in less than 2% of autoimmune thyroid patients, according to Carle et al, 2009.
I was without hypothyroid symptoms until my late 20s. In my early 30s I presented with a TSH over 150 without any goiter, which should have been a clear diagnostic sign to my doctor.
Because of my lack of goiter, my severe hypothyroidism went undiagnosed until I was in a severe state of mental and physical distress that interfered with daily life and work. I misattributed my health problems to my other autoimmune disease (ankylosing spondylitis). Finally, after looking up my many symptoms online, I was the one who asked for a TSH test.
Because the TSH was so clearly elevated, I was put on therapy with no further antibody tests, and no ultrasound was ordered to explain the lack of goiter which is usually present with an elevated TSH.
In my final 3 years of therapy on Synthroid, I had a TSH receptor blocking antibody attack. Previously, records show I had a TSH that ranged from low-normal to almost suppressed by a FT4 at top of reference range and a FT3 level in the lower half of reference.
When the antibody attack arrived (or returned after many years), after a small dose reduction, my TSH suddenly rose to 18.8 mU/L while my FT4 was still in the upper part of reference. I continued to have a high and variable TSH level despite a high-normal FT4. Meanwhile, the Total and Free T3 level remained almost flatlined below reference range over three years and many thyroid tests.
T4 monotherapy finally became unsustainable after I fell into a severe health crisis for three months including random daily and nightly chest pain and tachycardia that triggered a numb or weak arm, legs, or severe lightheadedness. Walking, standing, and normal cognitive tasks became difficult. T3 levels fell even lower. Reverse T3 elevated far above reference, demonstrating the presence of a severe yet undiagnosed illness. Reducing T4 dose offered temporary relief from chest pain but worsened the hypothyroidism. Several attempts to return the T4 dose back to normal levels ended in severe pain and hospital emergency visits.
An ultrasound was finally ordered and revealed the atrophied thyroid gland. A TRAb antibody test completed in Alberta was negative, but a positive result was unnecessary in light of the clear ultrasound, the history of elevated TSH on diagnosis without goiter, and the recent laboratory history.
Transition to therapy with T3 hormone finally resolved the health crisis.
How the antibody warps TSH-FT4-FT3 relationships
What I experienced is a fluctuating pattern seen in others with active blocking antibodies during thyroid therapy (Tagami et al, 2019).
The loss of normal T4 feedback on TSH happens partly because the antibody blocks the ultrashort feedback loop at the pituitary gland. The “ultrashort feedback loop” has also been called the “Brokken-Prummel-Wiersinga” feedback loop after the team that published a few articles about it in the early 2000s. This pituitary TSH feedback loop has been more extensively studied in hyperthyroid Graves’ disease, but the inverse happens at the same receptor in patients with blocking antibodies.
As with cases of fluctuating Graves’ disease during treatment, as the antibody varies, TSH can be variable, unrelated to FT4 and FT3 levels, fluctuating mainly with the antibody level (Alzahrani et al, 2005). TSH becomes a distraction, not a useful measure of treatment effectiveness.
The TSH receptor blocking antibody may even function as an “inverse agonist” of TSH receptor signaling (McLachlan & Rapoport, 2013). The baseline TSH-receptor signaling could be cut off during a severe blocking antibody attack, and high levels of circulating TSH in blood would not signal at the blocked receptors in the thyroid and elsewhere across the entire body.
TSH signaling, by means elevating cAMP signaling in cells, usually upregulates Deiodinase type 2, an important deiodinase that performs T4-T3 conversion in the thyroid gland and throughout the body (Canettieri et al, 2000). Without even the basal signal produced by an empty TSH receptor, the T4-T3 conversion rate drops throughout the body, even in the pituitary and hypothalamus.
The downregulation of D2 in the pituitary could be the second reason why the TSH can become abnormally elevated in relationship to FT4 during therapy — the pituitary and hypothalamus could not convert enough T4 to T3 locally, and my circulating T3 levels were very low.
AT and Blocking hypothyroidism in pregnancy
In Graves’ disease and in Atrophic Thyroiditis, maternal TSAb (stimulating) and TBAb (blocking) antibodies can be transferred to the fetus during pregnancy.
As explained by the 2017 ATA guidelines for thyroid disease in pregnancy (Alexander et al, 2017),
“In mothers with autoimmune thyroid disease, autoantibodies to TPO, Tg, and the TSH receptor can be transmitted to the fetus. …
Whereas TPO antibodies and Tg antibodies do not significantly affect fetal or neonatal thyroid function, antibodies to the TSH receptor can stimulate or block thyroid hormonogenesis.”
Bucci et al in 2017 reviewed several studies showing how fetal and maternal health can be affected by the TSH receptor blocking antibody. In one US study of 788 neonates with congenital hypothyroidism,
“the neonatal screening program in US demonstrated potent TSHR-blocking activity in 11 cases.
The 11 babies were born to 9 mothers, all of whom were receiving thyroid replacement because of autoimmune hypothyroidism, and 3 had been treated initially for Graves’ disease.
TPO antibodies, although detectable in all mothers, did not predict the neonatal thyroid dysfunction, while the presence of TBAbs was confirmed in the serum of eight mothers: all newborns had transient congenital hypothyroidism.”
Bucci also summarized another study:
“In a large series of newborns screened for congenital hypothyroidism in Wales (375 cases identified over 966,969 infants screened), 6 (1.6%) were found to have transient congenital hypothyroidism due to maternal TBAbs.
All the mothers were hypothyroid on levothyroxine replacement therapy or were diagnosed with hypothyroidism after the reported elevation of TSH in their infants.”
Unfortunately, in both cases, the low incidence rates are biased by the fact that the case-finding was done as part of screening for congenital hypothyroidism or high TSH in the child after its birth. Even Bucci’s article examines the TBAb antibody within the context of screening for Graves disease during pregnancy.
But the danger to the fetus is extreme. It is possible that the transfer of blocking antibodies to the fetus can occur before a mother’s diagnosis and treatment. Atrophic Thyroiditis and Blocking hypothyroidism are often not diagnosed early enough because of a lack of goiter as TSH elevates. The symptoms of hypothyroidism may be misattributed to the pregnancy itself. Very severe intellectual disability can occur in a fetus who is hypothyroid during gestation because of TBAb antibodies, since their hypothyroidism may be deep and prolonged even past the first trimester. The ATA guidelines give this caution:
“Affected infants may have significantly impaired cognitive outcomes despite early and adequate postnatal treatment if maternal hypothyroidism was present and untreated during gestation.”(Alexander et al, 2017)
The low incidence rates of TBAb, partly a result of medical ignorance, make it unlikely that screening hypothyroid pregnant women for TBAb antibodies will occur anytime soon.
Therefore, the doctor or patient need to be aware of this diagnosis and its risks during pregnancy.
Common signs and diagnosis
Jara et al, offered a diagnostic pathway in 2008, in a chapter titled “Atrophic Thyroiditis”:
“we propose the following bases for AT diagnosis:
1. Clinic[al] or subclinic[al] hypothyroidism: Clinical picture of overt hypothyroidism or increase of TSH and TRH values without symptoms.
2. Positive thyroid autoantibodies: Positive thyroid stimulation blocking antibodies (TRBAb).
3. Thyroid ultrasonographic characteristic: Abnormal thyroid echographic pattern characterized by diffuse low thyroid echogenicity associated with a reduced
However, Criterion #2, the antibody test, is difficult, as explained below, and the “clinical picture” involves more than TSH and symptoms. TRH is not routinely tested.
The best antibody test is (or was) the TBII test — Thyrotropin-Binding Inhibitory Immunoglobulin (Khoo et al, 1999), even though the test does not reveal the blocking antibody alone. TBII tests measure both stimulating and blocking TSHR antibodies and add them together to yield a single number. The number is higher in Atrophic Thyroiditis when blocking antibodies are active than when only a mild attack of stimulating antibody antibodies is present. The presence of blocking antibodies can be interpreted in the context of thyroid hormone and TSH laboratory results.
Unfortunately, the old technology TBII test is being replaced by newer TRAb (thyroid receptor antibody) tests. Some of these “third generation” TRAb tests falsely claim to offer exactly what the TBII test used to provide (Ehlers et al, 2019).
It seems that most of these test developers have decided that the hypothyroid form of the TRAb antibody is not important to diagnose, from a test marketing perspective. Most of them simply measure the net difference between stimulating and blocking, giving a number only for the stimulating effect (McLachlan & Rapoport, 2013).
Criterion #3, a thyroid ultrasound, is important, since gland atrophy remains even after the antibody has disappeared. “Reduced thyroid volume” is relative, so it needs to be assessed by sex (thyroids are smaller in women) and body surface area. Glands will show abnormal shrinkage in relationship to the person’s sex and body surface area, and sometimes an abnormal pattern of shrinkage in which the lobe that is usually larger in populations is smaller in the individual. (Vitti et al, 1994; Carle et al, 2009; Turicos et al, 2015).
The TSH and absence of goiter is significant in diagnosis. In my review of the literature, I see that a very high TSH (over 50 mU/L, often over 100 mU/L) at diagnosis, prior to treatment, with no goiter (no thyroid swelling) is a common finding in studies of Atrophic Thyroiditis.
The scientific literature also gives case studies with examples of the thyroid hormone fluctuations and TSH/T4 inconsistencies that occur in people who experience remissions and relapses of the blocking and/or stimulating TSH receptor antibody. See Fan et al, 2014, and the examples on page 2 of my article “Remissions and fluctuations in autoimmune thyroid disease: TRAb.”
Spread the knowledge
With so much at stake for the people who have Atrophic Thyroiditis, we ought to do our part in spreading the knowledge among patients and doctors.
“The prevalence and functional significance of TSHR blocking autoantibodies (TBAb) in autoimmune hypothyroidism has been less well investigated compared to TSHR stimulating Ab.
There is an increasing body of data, however, that demonstrate the clinical utility and relevance of TBAb, and thus the importance of TBAb bioassays, in the diagnosis and management of patients with AITD.”
For doctors and scientists interested in an introduction to the newest research, I highly recommend the article “Thyrotropin Receptor Blocking Antibodies” by Diana et al, 2018.
As further explanation, I recommend McLachlan & Rapoport’s article, alongside Takasu et al’s 2012 study of patients. Jara et al’s article is also very good (2008).
Read more recent articles that cover the TSH-receptor blocking antibody and Atrophic Thyroiditis:
- The Spectrum of Thyroid Autoimmunity
- Remissions and fluctuations in autoimmune thyroid disease: TRAb
- Infographics for Antibody testing
- Overlooked: How many Hashimoto’s patients with TSH-Receptor antibodies?