Thyroid Hormone Resistance

History & Epidemiology

Thyroid hormone resistance (THR) describes a syndrome that causes impaired sensitivity to thyroid hormones, which exert a key role in postembryonic development and physiological homeostasis. Thyroid hormone resistance is a rare condition that has often been misdiagnosed and mistreated.

Because there is no therapy currently shown to completely correct the gene mutation causing THR, its management is tailored to the specific symptoms of thyroid hormone excess or deprivation experienced by the affected individual.1, 2

Etiology & Risk Factors for Thyroid Hormone Resistance

Impaired sensitivity is due to mutations in the thyroid hormone receptor. Thyroid hormone levels are determined by the concentrations of thyrotropin-releasing hormone (TRH), secreted by the hypothalamus, and thyroid-stimulating hormone (TSH), secreted by the anterior pituitary gland. The two types of thyroid hormone are 3,3’triiodo-L-thyronine (T3) and 3,3’,5,5’-tetraiodo-L-thyronine (T4) for which production is mediated by the hypothalamic-pituitary-thyroid axis.3

TSH is often characterized by elevated circulating levels of T4 and T3, elevated serum levels of thyroxine and triiodothyronine, and mutations of thyroid hormone receptor beta (TRβ), which is resistance to thyroid hormone beta (RTHβ).1 The mutant RTHβ protein has either reduced affinity for T3 or abnormal interaction with cofactors involved in thyroid hormone action, making the target tissues refractory to thyroid hormones.4

Another form of insensitivity to thyroid hormone has recently been identified as resistant, thyroid hormone alpha (RTHα), due to mutations in the thyroid hormone receptor alpha (TRα), which controls DNA damage and tissue repair.4

There are two main difficulties in addressing resistance to thyroid hormone (RTH): the many kinds of thyroid resistance mutations with different properties, and differences in the mechanism of RTH caused by these mutations. Researchers are currently only able to obtain a structure-based mechanistic explanation and classification for their mechanism of action.4

Prognosis of Thyroid Hormone Resistance

The prevalence of RTHβ is equal between the sexes but varies among ethnic groups. Genetic inheritance of RTHβ is often autosomal dominant. Dimers form between the mutant and normal (wild-type; WT) thyroid hormone receptors which interfere with the function of the WT TRβ. The molecular basis of generalized RTHβ in a consanguineous family is considered distinct for its autosomal recessive mode of inheritance.5

Thyroid resistance associated with hypothyroid Hashimoto thyroiditis (THRβ) is caused by gene mutations located in the functional areas of the ligand (T3)-binding domain and adjacent hinge region. Treatment for hypothyroid Hashimoto thyroiditis remains difficult due to the different sensitivity of different tissues to thyroid hormones.1

Because studies have found that 14% of individuals manifesting the RTHβ phenotype show no THRβ mutations, there is variability in phenotypic manifestation among RTH patients.3 Currently, approximately 170 mutated TRβ variants and over 20 mutated TRα variants have been reported in RTH patients.6

As a result, management is tailored to the specific symptoms of thyroid hormone excess or deprivation experienced by the patient. There is currently no available therapy to fully correct the TRβ defect.3,6

Thyroid Hormone Resistance Diagnosis & Presentation

Patients with RTH can present with symptoms of hyperthyroidism or hypothyroidism alongside the symptom complex of fibromyalgia. More specifically, patients with THR syndrome often present with variable degrees of mental and growth abnormalities due to mutations of TRβ responsible for T3-mediated feedback response.3

There are three categories for RTHβ: general RTHβ, pituitary RTHβ, and peripheral RTHβ.  With general RTHβ, patients tend to have normal thyroid function and skeletal development but may have a low IQ. For these patients, compensation for increased thyroid hormone production can help them achieve normal thyroid function.

With pituitary RTHβ, patients tend to have symptoms of hyperthyroidism with TSH secretion and increased levels of T4 and T3. With peripheral RTHβ, patients tend to have symptoms of hypothyroidism but with a normal TSH level, and the peripheral tissue is not sensitive to thyroid hormone when compared with the sensitivity of the pituitary gland.5 Researchers have reported that 48% to 83% of individuals with RTHβ, also have attention deficit hyperactivity disorder (ADHD), which can be treated using conventional drugs.4

More severe symptoms of thyroid hormone resistance may be caused by a nonclassical THR mechanism with loss of function of specific thyroid hormone membrane transporters and the resulting inability of hormones to enter targeted cells. The balance and circulation of thyroid hormones can be interrupted in several physiological steps including thyroid hormone synthesis, activation, transportation, and receptor-dependent transactivation. These steps can eventually lead to THR syndrome.7

Diagnostic Workup & Physical Examination Findings

Diagnostic and research-based genomic testing can sometimes identify pathogenic variants that are unrelated to the primary reason for testing. Hundreds of mutations have made this work complicated.1

Since the first description of a THRβ gene missense mutation causing RTHβ made by A Sakurai in 1989, 236 different mutations in 805 families have been identified.3 Mutations affecting thyroid hormone cell membrane transporters and thyroid hormone metabolism have now been described, and the concept of RTH syndrome is used to encompass any defect causing reduced effectiveness of the thyroid hormone.7

Patients tend to have elevated thyroid hormones and normal or elevated thyroid-stimulating hormone levels. These patients may receive a false diagnosis if the primary care doctor is unfamiliar with the condition due to its broad symptomatic presentation. This can result in frustration for the patient and sometimes unnecessary, invasive treatment.7

Differential Diagnosis of Thyroid Hormone Resistance

A serum TSH test is used to determine reduced sensitivity to thyroid hormone including when there is a blunted response to the peripheral thyroid hormone markers.8 The exact incidence of RTHβ is unknown because the majority of neonatal screening programs rely on TSH measurements made in dry blood spots.

Two different surveys, one including 80,884 and the other including 74,992 newborns, used TSH and T4 measurements to identify infants with THRβ gene mutations. The surveys found 2 and 4 infants with THRβ gene mutations indicating a prevalence of 1 in 40,000 and 1 in 19,000 live births, respectively.

Research shows the possibility of developing acquired reduced sensitivity to thyroid hormones through deiodinase-3 induced hormone inactivation. These patients don’t show signs of having a THRβ gene mutation.3

RTH can be difficult to differentiate from TSH-producing pituitary tumors, which present with a similar thyroid function profile. A case of the coexistence of both conditions has also been reported.8 TSH-producing pituitary tumors present elevated serum levels of T4, T3, and non-suppressed TSH. In contrast to patients with THR syndrome who may have a normally functioning thyroid, patients with TSH usually present with symptoms of mild to severe hyperthyroidism and compression symptoms resulting from tumor growth.7


1. Arsov T, Xie C, Shen N, Andrews D, Vinuesa CG, Vaskova O. Genomic test ends a long diagnostic odyssey in a patient with resistance to thyroid hormones. Thyroid Research. 2019;12(7):1-5.

2. Teixeira PD, dos Santos PB, Pazos-Moura CC. The role of thyroid hormone in metabolism and metabolic syndrome. Ther Adv Endocrinal Metab. 2020;11:1-33. doi:10.1177/2042018820917869.

3. Pappa T, Refetoff S. Resistance to thyroid hormone beta: a focused review. Front Endocrinol. 2021;12:1-8. doi:10.3389/fendo.2021.656551

4. Persani L, Campi I. Syndromes of resistance to thyroid hormone action. In Igaz P, Patócs A Genetics of Endocrine Diseases and Syndromes. Springer International Publishing; 2019:55-84.

5. Sun H, Cao L, Zheng R, Xie S, Liu C. Update on resistance to thyroid hormone syndromeβ. Ital J Pediatr. 2020;46(168):1-5.

6. Yao B, Yang C, Pan C, Li Y. Thyroid hormone resistance: Mechanisms and therapeutic development. Mol Cell Endocrinol. 2022;553(1):111679. doi:10.1016/j.mce.2022.111679

7. Rivas AM, Lado-Abeal J. Thyroid hormone resistance and its management. Proc (Bayl Univ Med Cent). 2016;29(2):209-211. doi:10.1080/08998280.2016.11929421

8. Teng X, Jin T, Brent GA, Wu A, Teng W, Shan Z. A patient with a thyrotropin-secreting microadenoma and resistance to thyroid hormone (P453T). J Clin Endocrinol Metab. 2015;100(7):2511-4. doi:10.1210/jc.2014-3994

Author Bio

Sydney Murphy is the Associate Editor of HealthDay Physicians Briefing and a freelance science writer based in New York City. You can follow her on Twitter @SydneyLiz_Murph.