Are you sure the patient has thyroid hormone resistance?

The diagnosis of thyroid hormone resistant syndromes (THRS) is based on abnormal thyroid hormone (TH) laboratory tests. This class of conditions is due to a defect in TH action (Resistance to thyroid hormone, RTH), T4 transport into the cell (thyroid hormone Cell Transport Defect, THCTD) or metabolism of T4 to the active hormone, T3 (Thyroid Hormone Metabolism Defect, THMD). Clinical findings of hyperthyroidism or hypothyroidism (and some aspects of both in the same patient) usually prompt the initial thyroid screening tests. However, the results reveal elevated free TH levels and normal or slightly elevated thyroid stimulating hormone (TSH).

Resistance to thyroid hormone (RTH)

RTH is inherited in an autosomal dominant manner and usually caused by a mutation in the thyroid hormone receptor beta (TRb). The mutant TRb is unable to bind T3 or interact with other factors that are necessary for TH-induced gene transcription. Since most patients are heterozygous for the mutant TRb, a dominant negative interaction with normal allele occurs. Patients with RTH present with goiter (65-95% of known cases), hyperactivity (33-68%) and tachycardia (33-75%). Variably present is growth retardation, delayed bone maturation, learning disabilities [such as Attention Deficient Hyperactivity Disorder (40-60%)], and sensorineural deafness.

Depending on whether a particular tissue predominately expresses the TRb or the other TR, TRa (which is not mutated), will depend on the clinical manifestations. For example, the heart is predominately regulated by TRa and in RTH the heart may appear to be hyperthyroid, while the liver that responds to TH via TRb is relatively hypothyroid. Some investigators have distinguished between Pituitary Resistance to Thyroid Hormone (PRTH) and more generalized RTH.

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Subjects with PRTH have a clinical phenotype predominately related to impaired TH feedback to the pituitary and manifest frank hyperthyroidism in other tissues. Given the variability in clinical presentation in all patients with RTH, it is difficult to classify patients as having purely PRTH or RTH, as some patients with the identical Tr beta mutation may present with either PRTH or RTH.

Thyroid Hormone Cell Transport Defect (THCTD)

THCTD is another form of THRS that presents usually in infancy or young childhood with a characteristic progressive and severe neurologic phenotype. The earliest signs are poor feeding and hypotonia. Neurologic deterioration is noticed with advancing age as progressive hypotonia with spastic quadriplegia. Most affected children are unable to sit by themselves or walk and have no speech. The condition is caused by a mutation in the monocarboxylate transporter (MCT) 8 gene and results in failure of T4 to enter the cell despite sufficient blood levels of TH. MCT8 is on the X-chromosome.

Therefore, generally only males manifest the disease, and females are usually carriers. As in RTH, patients with THCTD present with stigmata of both TH deficiency (neurological) as well as excess, such as a hypermetabolic state and difficulty to maintain weight. The aspects of the clinical presentation depend on whether the particular organ is dependent on MCT8 for transport of TH (as in brain, but not in liver). Patients with THCTD present with elevated levels of serum free T3 and low reverse T3. T4 has the tendency to be low (unlike RTH) and TSH levels are normal or slightly elevated. A common feature on brain magnetic resonance imaging (MRI) is dysmyelination.

Thyroid Hormone Metabolism Defect (THMD)

THMD has been described in 5 kindreds. The propositi came to medical attention during childhood because of short stature and delayed bone age, which prompted thyroid testing. Contrary to RTH and THCTD, THMD presents with elevated levels of T4 and reverse T3, but low levels of T3 and normal or slightly elevated levels of TSH. The condition is caused by a deficiency in the deiodinase gene, a selenocysteine-containing protein, which is necessary for the de-iodination of T4 into the active hormone T3. The mutated gene codes for the selenocysteine insertion sequence-binding protein (SECISBP2 or SBP2) which is essential for the insertion of selenocysteine in the protein structure, without which the enzyme is unable to function.

Table I. Thyroid function tests in thyroid hormone resistant syndromes

Table I.
THRS TYPE FT4 FT3 reverse T3 TSH
RTH Inc Inc Inc Nl or Inc
THCTD Dec Inc Dec Nl or slight Inc
THMD Inc Dec Dec Nl or Inc

What else could the patient have?

THRS are most commonly misdiagnosed, as the clinician does not consider all the laboratory data. For example, RTH is commonly diagnosed as Graves’ disease, as the patient presents with elevated T4 and T3 levels and a goiter. Patients with RTH also have a high incidence of autoimmune thyroid disease as in Graves’ Disease. However, failure to recognize that the TSH is not suppressed despite high levels of free thyroid hormone, leads the physician to the incorrect diagnosis and ultimately to the incorrect treatment, usually with antithyroid drugs or surgical thyroidectomy.

Abnormal protein binding is a likely cause of euthyroid hyperthyroxinemia, such as thyroxine binding globulin (TBG) excess or familial dysalbuminemic hyperthyroxinemia (FDH). These are important to distinguish from the THRS, as no treatment is required for binding protein abnormalities, since these patients are usually euthyroid with normal TSH range levels. Confirmation of a binding protein abnormality can be obtained by measurement of free T4 and/or T3 levels by equilibrium dialysis assays. Free hormone levels are always normal in FDH and TBG excess, although may be abnormal when measured by some analog 1-step FT4 assays.

The possibility of a TSH-secreting pituitary tumor should be considered in all patients with elevated TH levels and a non-suppressed TSH level. TSHomas are usually excluded by: (1) the presence of multiple family members with the same thyroid function tests which would not be seen with pituitary tumors; (2) the absence of an elevated serum alpha-subunit; (3) unresponsive TSH to thyrotropin releasing hormone (TRH) stimulation. The presence or absence of a tumor on MRI of the pituitary is usually not helpful, as such a structural lesion may be seen if the tumor is small. Alternatively, it may be incidentally present in up to 10% of the population and unrelated to the thyroid tests.

Key laboratory and imaging tests

Diagnosis of the syndromes of thyroid hormone resistance relies mainly on thyroid function tests and in most cases, confirmation with genetic testing.

RTH: RTH is caused by mutations in the TRb gene located on chromosome 3. Tissues in patients with RTH are resistant to the action of T3 to the extent this gene is expressed in cells involved. In 80% of cases, mutations have been found in the carboxyl terminus of the TRb covering the ligand-binding domain and adjacent hinge domain. They are contained within three clusters rich in CG “hot spots”, separated by areas devoid of mutations (cold regions). In 15% of families with thyroid tests and clinical presentation identical to RTH, there is no identifiable TRb gene mutation. This is known as “nonTR-RTH”. It is clinically and biochemically indistinguishable from RTH with TRb gene mutations.

Mutations of one of the cofactors that interact with the receptors may be responsible for the resistance in these families. Rarely nonTR-RTH may actually be a mosaicism in which the TRb mutation is not present in all tissues. For example, peripheral white blood cell DNA is commonly used; however, skin fibroblasts or buccal swab may demonstrate a TRb mutation in a patient with RTH, but it may be absent in the WBC.

THCTD: Diagnosis of THCTD is confirmed by the presence of a mutation in the MCT8 gene. The severity of disease is related to the degree of disruption of the gene. Hemizygous females with the mutation are clinically unaffected. MRI of the brain in affected males before the age of 2 years may show delayed myelination.

THMD: here is limited experience with defects in the conversion of T4 to T3. However, all patients to date have had mutations in the selenocysteine binding protein (SBP)-2 gene. Severity of disease is dependent on the degree of expression of SBP-2. Total deletion of the gene has profound neurologic and metabolic defects, while partial deficiency results in a mild phenotype.

Other tests that may prove helpful diagnostically

Recognition of the abnormal thyroid function tests and confirmation by mutation analysis is usually sufficient in the diagnosis of the different forms of THRS. However, since these diseases are relatively rare, it is possible that a mutation may not be found. For example, in RTH, 15% of subjects have no identifiable mutation in the TR beta gene.

In larger kindreds with the RTH phenotype, there is absence of linkage with the TR beta gene. It becomes necessary to demonstrate resistance to exogenous administration of thyroid hormone. Similarly, in THMD, while all subjects to date have had SBP-2 mutations, it is possible that other genes may be involved in similar defects of de-iodination. Therefore additional tests may be required. These tests are based on in vivo clinical studies and in vitro studies of cultured skin fibroblasts from the affected subject.

In Vivo Studies of TH Action

RTH: Administration of graded doses of L-T3 (q 12 hours) in 3 day increments, with measurements at the end of each dose of response, can confirm the diagnosis of RTH. Central activity of TH is measured by TSH response to TRH stimulation. Peripheral tissue response to TH is measured by changes in sleeping pulse, basal metabolic rate and peripheral markers of thyroid hormone action (serum cholesterol, sex hormone binding globulin, creatinine kinase and ferritin) in response to the graded doses of T3. Failure to respond to the increasing doses of T3 would suggest generalized RTH1.

THMD: Administration of graded doses of L-T4 can demonstrate failure to suppress TSH at a given blood concentration of T4 in THMD subjects compared to unaffected relatives. However, administration of L-T3 results in similar suppression of TSH in affected and unaffected relatives. Furthermore, the increase in reverse T3 in response to T4 administration would be greater in patients with THMD than normal. Similar changes in peripheral blood markers of thyroid hormone action have been demonstrated in THMD subjects.

THCTD: Cultured skin fibroblasts from subjects with THCTD demonstrated failure to transport radiolabeled T3 into cells of affected individuals.

Management and treatment of the disease


General Principles: The key to “treatment” of RTH is to recognize that elevated serum thyroid hormone levels are compensatory for the degree of resistance. Failure to recognize this may incorrectly result in antithyroid treatment. The latter results in a more difficult clinical problem, i.e. thyroid hormone replacement therapy in light of even greater serum TSH values, goiter, and hypothyroidism at the tissue level. Not all tissues are equally resistant to TH, depending on the predominance of TRb gene versus TRa expression for the defect; the high levels of serum TH are appropriate for the resistance. Therefore, the heart, which is predominately TRa, will show “signs” of hyperthyroidism, such as tachycardia. However, to lower the thyroid hormone levels would result in relative hypothyroidism elsewhere.

Patients with symptomatic tachycardia are usually treated with atenolol to decrease the effect on the heart and not inhibit T4 to T3 conversion, as has been reported for large doses of propranolol. Furthermore, patients with RTH may complain of diarrhea which is symptomatically treated. Other patients complain of symptoms associated with obstruction from goiter. In such patients, treatment with more thyroid hormone would be indicated to bring the serum TSH to the upper limit of normal.

TH Analogues: Thyroid hormone analogues, such as TRIAC and TETRAC, have been variably successful in abating some of the symptoms with the intention of providing drugs with increased affinity for the TH receptor.

Pregnancy: Guidelines on management of RTH during pregnancy is limited by insufficient data. Several studies have shown that when mothers with RTH give birth to unaffected newborns (non-RTH), these newborns have smaller birth weights and there is a higher incidence of miscarriages. Furthermore, RTH children (where the mutant allele was inherited by the fetus from the father) born to unaffected mothers are of normal weight, and there is no increase incidence of miscarriages.

If there is a history of other family members with RTH and neurocognitive problems, then RTH mothers giving birth to RTH fetuses may benefit from supplemental thyroid hormone during pregnancy to keep the FT4 levels approximately 25% above the upper limit of normal. It has therefore been suggested that RTH mothers have amniocentesis to rapidly diagnose the TRb genotype of their offspring. If the fetus is without RTH, the maternal TH levels should be titrated down to a maximum of 25% above the upper limit of normal for a non-pregnant normal subject.


Protocols are currently being evaluated for treatment of MCT8 defects. Ideally, the aim is to find a drug that will be able to bypass the MCT8 transporter and deliver T3 into the cells that require it for normal development and function. Preliminary data has been proposed that a combination of T4 and propylthiouracil may be beneficial to reduce serum T3 and increase serum T4 and reduce the hypermetabolism in the liver. An analogue of T3, DITPA, has been used in an MCT8 mutant mouse model which holds promise as a treatment in humans with MCT8 defects.


In THMD the defect is in the inability of the cells to metabolism T4 into the active hormone T3 which then binds to the TH receptors. Administration of T3 can circumvent the defect, titrating the T3 dose to the desired level of TSH. Limited studies with selenium treatment have been unsuccessful in correcting the defect.

What’s the Evidence?/References

Refetoff, S, Weiss, RE, Usala, SJ. “The syndromes of resistance to thyroid hormone”. Endocr Rev. vol. 14. 1993. pp. 348-99. (An extensive review of the signs, symptoms and laboratory tests of subjects with RTH.)

Refetoff, S, DeWind, LT, DeGroot, LJ. “Familial syndrome combining deaf-mutism, stippled epiphyses, goiter and abnormally high PBI: possible target organ refractoriness to thyroid hormone”. J Clin Endocrinol Metab. vol. 27. 1967. pp. 279-94. (A classic paper describing the first family with RTH. This case was ultimately found to be the only one to date with deletion of the TR-beta.)

Dumitrescu, AM, Liao, XH, Best, TB, Brockmann, K, Refetoff, S. “A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene”. Am J Hum Genet. vol. 74. 2004. pp. 168-75.

Friesema, EC, Ganguly, S, Abdalla, A, Manning Fox, JE, Halestrap, AP, Visser, TJ. “Identification of monocarboxylate transporter 8 as a specific thyroid hormone transporter”. J Biol Chem. vol. 278. 2003. pp. 40128-35. (The above 2 papers present the index cases and mutations for MCT8. The clinical and laboratory findings are documented in these reports.)

Dumitrescu, AM, Di Cosmo, C, Liao, XH, Weiss, RE, Refetoff, S. “The syndrome of inherited partial SBP2 deficiency in humans”. Antioxid Redox Signal. vol. 12. 2010. pp. 905-20. (A review of the known clinical signs and symptoms as well as molecular pathogenesis of thyroid hormone metabolism defect.)

Dumitrescu, AM, Liao, XH, Abdullah, MS. “Mutations in SECISBP2 result in abnormal thyroid hormone metabolism”. Nat Genet. vol. 37. 2005. pp. 1247-52. (The first paper describing the family with an SBP-2 mutation resulting in THMD.)

Barkoff, MS, Kocherginsky, M, Anselmo, J, Weiss, RE, Refetoff, S. “Autoimmunity in patients with resistance to thyroid hormone”. J Clin Endocrinol Metab. vol. 95. 2010. pp. 3189-93. (Demonstration of the incidence of antibodies associated with RTH.)

Refetoff, S. “Inherited thyroxine-binding globulin abnormalities in man”. Endocr Rev. vol. 10. 1989. pp. 275-93. (Thyroxine binding globulin excess as a cause for euthyroid hyperthyroxinemia.)

Xie, J, Pannain, S, Pohlenz, J. “Resistance to thyrotropin (TSH) in three families is not associated with mutations in the TSH receptor or TSH”. J Clin Endocrinol Metab. vol. 82. Dec 1997. pp. 3933-40. (Clinical characteristics of non-TR RTH.)

Anselmo, J, Cao, D, Karrison, T, Weiss, RE, Refetoff, S. “Fetal loss associated with excess thyroid hormone exposure”. JAMA. vol. 292. 2004. pp. 691-5. (Review of pregnancy outcome in a large kindred with RTH.)