When it comes to diseases and conditions affecting the butterfly-shaped gland hypothyroidism and hyperthyroidism are widely known, but what about others?
The reality is that your thyroid is prone to various problems that affect the production and concentration of hormones T3 and T4. For example, thyroid hormone resistance is yet another problem, but it's not discussed as often as it should.
In this post, we’re going to talk about thyroid hormone resistance and everything you need to know about it. Read on to learn more.
What is thyroid hormone resistance?
Thyroid hormone resistance is defined as a disorder wherein the body's tissues, and organs are resistant to the effects of thyroid hormone.
Sometimes this condition is referred to as Refetoff syndrome after a man who released the first report of thyroid hormone resistance in 1967. In his report, Refetoff wrote about thyroid hormone resistance affecting an infant of eight weeks while siblings and parents were okay.
His hypothesis revolved around the possibility of inhibition of thyroid hormone transport into a tissue or end-organ resistance to the hormone in view of the metabolic states of the participants in the presence of high levels of circulating blood thyroxine (T4) and normal thyroxine binding capacity[i].
It's important to mention that thyroid hormone resistance is a rare problem, but it still requires more research in order to analyze all its aspects. Refetoff et al. suggested, in 2014, that the condition should go under a different term – impaired sensitivity to thyroid hormone.
The same study describes thyroid hormone resistance as a disorder where serum levels of thyroid hormone are elevated, but TSH is unsuppressed often with various symptoms including goiter[ii]. You’ll learn more about symptoms further in the article.
How common is thyroid hormone resistance?
Thyroid hormone resistance is considered a rare condition. Evidence shows that the disorder occurs in one out of 40,000 live births. One in 40,000 to 50,000 people have this condition[iii].
However, keeping in mind that thyroid hormone resistance isn't studied enough and it's often misdiagnosed, the number could be higher. This is why it's important to investigate this condition in greater detail.
More studies would also give us an in-depth insight into the prevalence and incidence of thyroid hormone resistance.
In most cases, thyroid hormone resistance is an inherited disorder. In fact, 80% of individuals with this condition have inherited it from one of their parents.
Man or a woman with thyroid hormone resistance has about 50% chance to pass it on to their child.
Causes of thyroid hormone resistance
In order to understand the causes behind thyroid hormone resistance, it’s crucial to elaborate on the normal function of the thyroid and its hormones.
The butterfly-shaped gland’s function is to take iodine and convert it into thyroid hormones triiodothyronine (T3) and thyroxine (T4). Thyroid cells are the only cells in your body which are able to absorb iodine. They combine amino acid tyrosine and iodine in order to produce T3 and T4 hormones. Thyroid hormones are vital for the proper function of your body, and they carry out their role by interacting with a thyroid receptor in target cells in the body.
The selective actions of thyroid hormone receptors are influenced by various factors including the relative expression and distribution of thyroid receptor isoforms, transport of thyroid hormone into the cell, just to name a few[iv].
As you can see receptors are crucial for the effects of thyroid hormones. But, in thyroid hormone resistance they don’t work properly. As a result, thyroid hormones are unable to act to act normally on cells and exhibit their effects. There are two types of thyroid hormone receptors: alpha and beta. Tissues and organs in the body contain different amounts of these two types of thyroid receptors, i.e. presence of both alpha and beta isn't the same.
In thyroid hormone resistance genetic mutation of the beta receptor is the most common cause, but some studies show that defective alpha receptor[v] can also be the problem.
In thyroid hormone resistance levels of T3 and T4 are elevated (because receptors don’t work properly), but the tissues respond to this occurrence differently depending on the relative amount of alpha versus beta receptors in that particular tissue.
For instance, tissues with predominantly defective beta receptors are resistant to the action of thyroid hormone and can manifest themselves through symptoms similar to hypothyroidism, while tissues with mainly defective alpha receptors can exhibit features of thyroid overactivity or hyperthyroidism.
Although more research on this topic is necessary, because there’s a lot of science still doesn’t know about thyroid hormone resistance, a growing body of evidence confirms the condition is inherited. For instance, Guo et al. found that heterozygous A317T mutation in THRβ gene could cause thyroid resistance[vi]. Of course, in some cases alpha receptors are defective, but gene mutation isn’t involved here. The exact cause of thyroid hormone resistance, in this case, hasn’t been determined yet.
Types of thyroid hormone resistance
Not all cases of thyroid hormone resistance are equal. In fact, we can divide this disorder into three different types: generalized resistance to thyroid hormone (GRTH), selective pituitary resistance to thyroid hormone (PRTH), and selective peripheral resistance to thyroid hormone (PerRTH). So, what’s the difference between the two?
McDermott et al. explain that GRTH is indicated by resistance in the pituitary gland and in most or all peripheral tissues. People with GRTH have elevated levels of thyroid hormones and inappropriately normal or elevated concentration of TSH, but they are usually euthyroid and require no treatment.
On the other hand, PRTH is characterized by resistance in the pituitary gland, but not in the peripheral tissues. Persons with this type of thyroid hormone resistance tend to have higher serum thyroid hormone levels and normal or elevated TSH, and they’re usually thyrotoxic.
The term thyrotoxic refers to an occurrence when thyroid hormone concentration is high due to any cause and therefore includes hyperthyroidism. In this case, the treatment is necessary, but current options aren't effective enough.
PerRTH is indicated by resistance in peripheral tissues, but not in the pituitary gland. It appears that people with this condition have normal thyroid levels and TSH, but are clinically hypothyroid. The condition improved with administration of thyroid hormone. McDermott and his team suggest that thyroid hormone resistance disorders are probably more common than we think, they’re just misdiagnosed and inadequately treated[vii].
When discussing types of thyroid hormone resistance, it's also important to mention the following[viii]:
- Thyroid hormone cell transport defect (THCTD) – another form of thyroid hormone resistance syndrome that develops “in infancy or young childhood with a characteristic progressive and severe” phenotype. Only males manifest this disease while females are usually the carriers. People with THCTD have elevated levels of serum free T3 (fT3) and low reverse T3 (rT3) while T4 is low and TSH is normal or higher
- Thyroid hormone metabolism defect (THMD) – patients with this condition have higher T4 levels and rT3, “but low levels of T3 and normal or slightly” higher TSH concentration. This disorder “is caused by a deficiency in the deiodinase gene” which is crucial for de-iodination of T4 into an active thyroid hormone T3
Symptoms of thyroid hormone resistance
Some people with thyroid hormone resistance have no symptoms at all, but others do. Symptoms depend on the severity of the abnormality with the hormone receptor. For instance, in some patients, signs, and symptoms of these disorders can be relatively mild, but there's also someone with symptoms that are severe.
As mentioned above, in some cases thyroid hormone resistance may manifest itself through symptoms that are similar to hypo- or hyperthyroidism depending on the type of receptors affected.
So, a person can gain weight, experience hair loss, high cholesterol, and other signs of hypothyroidism, or lose weight and deal with other symptoms of hyperthyroidism.
Below, you can see some of the most common signs and symptoms of thyroid hormone resistance identified in the studies mentioned in this post:
- Memory loss
- Gastrointestinal problems with alternating diarrhea and constipation
- Heat intolerance
- Increased appetite
- Growth retardation
- Intellectual deficit
- Skeletal dysplasia (dwarfism)
- Dysmorphic facies (dysmorphic feature, a difference in body structure)
- Hypotonia (floppy baby syndrome)
- Poor feeding (baby)
- The child is unable to sit or walk, but himself/herself, or they're unable to speak
- Severe fatigue
Bear in mind it doesn’t mean a person with thyroid hormone resistance will have all above-mentioned symptoms. Signs of the condition can vary from one person to another, and the disorder needs to be evaluated more thoroughly in order to uncover other symptoms.
This would also prevent the current problem when thyroid hormone resistance is misdiagnosed, probably due to the similarity of symptoms to hypo- and hyperthyroidism.
How is thyroid hormone resistance diagnosed?
The main reason why thyroid hormone resistance is misdiagnosed is that sometimes we overlook the symptoms we experience (or our child). After all, symptoms can be similar to other conditions. When you're stressed out and gain weight, you won't think anything of it. It is only when serious symptoms occur that people schedule an appointment to see their doctor or they take their child to the pediatrics.
The first step toward a diagnosis of the problem is through a regular blood test. Results usually show high T3 and T4 levels along with normal or slightly elevated TSH.
These abnormal results are also observed in patients with thyroid hormone resistance who don’t experience symptoms of the condition. Based on the results of this test the doctor will determine the next step. For example, laboratory workers may check the test results carefully in order to exclude interference with measurement or other factors that would interfere with the analysis.
To differentiate between thyroid hormone resistance and TSH-secreting pituitary adenoma the doctor may order thyrotropin-releasing hormone test. Triiodothyronine suppression test may also serve for diagnostic purposes. Further research of the subject would allow scientists and doctors to develop new and more accurate diagnostic methods.
How is thyroid hormone resistance managed?
In order to treat the condition effectively, it's crucial to determine those hormone concentrations, and symptoms in a patient are a consequence of thyroid hormone resistance. Failure to diagnose the condition properly results in the wrong treatment and, thereby, unsatisfactory results. It's needless to mention this could pave the way for other complications.
When treating patients with thyroid hormone resistance, it is critical for a doctor to focus on the patient’s symptoms and clinical picture instead of trying to normalize thyroid hormone levels at first. Most patients can adequately overcome resistance by increased secretion of thyroid hormone and don’t even require treatment.
Treating persons with elevated TSH can be tricky as administration of thyroid hormone may be required. Patients who experience hyperthyroidism-like symptoms should be treated symptomatically with anti-anxiety medications or beta blockers, depending on the symptoms they experience.
Some patients who experience hypothyroidism-like signs and symptoms may need levothyroxine therapy, but it depends on the severity of the symptoms they experience.
Thyroid hormone resistance is a rare disorder where tissues and organs are resistant to the effects of thyroid hormones due to genetic mutations and defective receptors.
Symptoms are, in some cases, nonexistent, but they can also be similar to hyperthyroidism, hypothyroidism, and other potentially serious problems can occur. More research is absolutely vital to develop new diagnostic methods and treatment approaches.
[i] Refetoff S, Dewind DT, Degroot LJ. Familial syndrome combining deaf-mutism, stippled epiphyses, goiter, and abnormally high PBI: possible target organ refractoriness to thyroid hormone. Journal of Clinical and Endocrinology and Metabolism 1967 Feb;27(2):279-94. Doi: 10.1210/jcem-27-2-279 https://academic.oup.com/jcem/article-abstract/27/2/279/2715353?redirectedFrom=fulltext
[ii] Refetoff S, Bassett JHD, Beck-Peccoz P, et al. Classification and proposed nomenclature for inherited defects of thyroid hormone action, cell transport, and metabolism. European Thyroid Journal 2014;3:7-9. Doi: 10.1159/000358180 https://www.karger.com/Article/FullText/358180
[iii] Rivas AM, Lado-Abeal J. Thyroid hormone resistance and its management. Proc (Bayl Univ Med Cent). 2016;29(2):209-11. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4790576/
[iv] Brent GA. Mechanisms of thyroid hormone action. J Clin Invest. 2012;122(9):3035-43. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3433956/
[v] Moran C, Chatterjee K. Resistance to thyroid hormone due to defective thyroid receptor alpha. Best Pract Res Clin Endocrinol Metab. 2015;29(4):647-57. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4559105/
[vi] Guo QH, Wang BA, Wang CZ, et al. Thyroid hormone resistance syndrome caused by heterozygous A317T mutation in thyroid hormone receptor β gene: Report of one Chinese pedigree and review of the literature. Medicine (Baltimore). 2016;95(33):e4415. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5370793/
[viii] Weiss R, Thyroid hormone resistance. Endocrinology Advisor https://www.endocrinologyadvisor.com/endocrinology-metabolism/thyroid-hormone-resistance/article/595557/