ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Resistance to thyroid hormone and other defects in thyroid hormone action

Resistance to thyroid hormone and other defects in thyroid hormone action
Literature review current through: Jan 2024.
This topic last updated: Dec 07, 2023.

INTRODUCTION — Resistance to thyroid hormone (RTH) is a heritable defect in thyroid hormone sensitivity, usually caused by defects in one of the two the thyroid hormone receptors (TRs). It is characterized by tissue responsiveness to thyroid hormone that does not reflect the circulating thyroid hormone levels.

Three types of RTH have been identified, based on the underlying defect in TR [1-3]:

RTH-beta – Due to THRB gene defects

RTH-alpha – Due to THRA gene defects

RTH of unknown etiology (nonTR-RTH) – Likely due to an abnormality in a cofactor or interfering substance

These disorders will be discussed below. Other inherited disorders of thyroid hormone secretion, transport, and metabolism are discussed separately:

(See "Resistance to thyrotropin and thyrotropin-releasing hormone".)

(See "Genetic defects in thyroid hormone transport and metabolism".)

NORMAL THYROID HORMONE PHYSIOLOGY — Maintenance of thyroid hormone supply is ensured by a feedback control mechanism involving the hypothalamus, pituitary, and thyroid gland, as shown in panel A of the figure (figure 1). A decreased thyroid hormone supply stimulates secretion of thyrotropin-releasing hormone from the hypothalamus and thyroid-stimulating hormone (TSH) from the anterior pituitary thyrotrophs, which, in turn, stimulates thyroid follicular cells to synthesize and secrete thyroid hormone. Conversely, thyroid hormone excess shuts down the system through the same pathway until a steady state is restored.

Local requirements for thyroid hormone are adjusted through additional mechanisms. One such system is the control of thyroid hormone entry into the cell through active transmembrane transporters [4]. Activation of the prohormone thyroxine (T4) by removal of one of the outer ring iodine atoms (5'-deiodination) to form triiodothyronine (T3), or the inactivation of T4 and T3 by inner ring (5-deiodination) to form reverse T3 (rT3) and T2, respectively, provide an added level of control, as shown in panel B of the figure (figure 1) [5].

Finally, the presence and abundance of thyroid hormone receptors (TRs), through which thyroid hormone action is mediated, determine the type and degree of hormonal response. Action takes place in the nucleus as well as in the cytosol of the target cell [6,7]. TR action in the nucleus is known as a genomic effect and has been more extensively studied, as shown in panel C of the figure (figure 1) [8,9]. There are two TRs (TR-alpha and TR-beta), which are encoded by separate genes located on chromosomes 17 and 3, respectively. In addition, different isoforms are synthesized through alternative transcription and splicing. The receptors have structural and sequence similarities with DNA-binding and T3-binding domains (figure 2). Other regions of the molecules are involved in dimerization with another TR (homodimerization) or another type of nuclear receptor (heterodimerization), as well as in binding corepressor and coactivator protein cofactors [10,11].

In the nucleus, TRs act as transcription factors that regulate expression of specific genes, which are recognized through a DNA sequence known as the thyroid hormone response element (TRE). Dimers of unliganded (without T3) receptors bind to TREs and recruit corepressor proteins, resulting in inhibition of the expression of genes that are positively regulated by T3. When T3 binds to the receptors, the TR molecule undergoes a steric change that results in release of the corepressor protein, dissociation of the dimers, and formation of heterodimers of TR and retinoid X receptors that then bind coactivator proteins (figure 1). These changes promote expression of the target genes and ultimately increase the synthesis of specific proteins. Through this mechanism, genes such as that for type 1 iodothyronine deiodinase are upregulated and the gene for thyrotropin beta subunit is downregulated. (See "Thyroid hormone action".)

MECHANISMS OF IMPAIRED SENSITIVITY

History — In the late 1950s, blood tests that measure the amount of circulating thyroid hormone replaced the tedious and inaccurate determination of the basal metabolic rate as a means to define the thyroid status. High and low circulating thyroid hormone levels became the accepted standard for the diagnosis of hyper- and hypothyroidism, respectively.

This notion was first challenged in 1967 with the identification of inherited circulating thyroid hormone excess in the absence of hyperthyroidism, attributed to target organ refractoriness to thyroid hormone [12]. It took another 22 years before it was demonstrated that the syndrome was caused by defects in the thyroid hormone receptor (TR) beta [13,14]. This now relatively well-recognized condition is the main focus of this topic review.

In the early 2000s, additional disorders were identified that are caused by impaired transport or metabolism of thyroid hormone, resulting in reduced sensitivity to thyroid hormone in the target tissues. (See "Genetic defects in thyroid hormone transport and metabolism".)

These conditions are often grouped together as impaired sensitivity to thyroid hormone (table 1), although their causal mechanisms are quite distinct.

Classification and nomenclature — A classification and nomenclature for the forms of impaired sensitivity to thyroid hormone are outlined below (table 1) [1-3]. These defects should be considered in a patient with thyroid function tests that show a discordance of serum thyroid hormone and thyrotropin (thyroid-stimulating hormone [TSH]) concentrations, and each defect has its own constellation of test abnormalities and different clinical presentation.

The types of known and postulated defects are listed below according to the physiologic sequence of thyroid hormone cell transport, metabolism, and action rather than by clinical frequency.

Thyroid hormone cell membrane transport defect (THCMTD) – Abnormal intracellular levels of thyroid hormone can be caused by defects in one of the cell transport proteins that allow thyroid hormone to enter cells (figure 1). As an example, a mutation in the monocarboxylate transporter 8 (MCT8) gene causes elevated serum concentrations of triiodothyronine (T3) and low levels of thyroxine (T4) and reverse T3 (rT3) as well as a severe psychomotor deficit [15]. This disorder is discussed in a separate topic review. (See "Genetic defects in thyroid hormone transport and metabolism", section on 'Thyroid hormone cell membrane transport defect'.)

Thyroid hormone metabolism defect (THMD) – T4, the main hormone secreted by the thyroid gland, is a prohormone that must be activated by conversion to T3, as shown in panel B of the figure (figure 1). Defects in any of the factors involved in this enzymatic deiodination reaction can cause diminished production of T3 and thus reduced availability of active thyroid hormone in tissues that depend upon the circulating T4 for local generation of T3. Known defects include mutations in the SBP2 gene causing impaired synthesis of all selenoproteins including the deiodinases, as well as mutations in the DIO1 gene. (See "Genetic defects in thyroid hormone transport and metabolism", section on 'Thyroid hormone metabolism defect'.)

Thyroid hormone action defects – Several mechanisms cause resistance to thyroid hormone (RTH) in the target tissues; these are the focus of the remainder of this topic review.

Abnormal hormone transfer to the nucleus – Before it can exert its genomic effects, thyroid hormone must be transported into the nucleus, where it interacts with the TRs to regulate transcription of target genes, as shown in panel C of the figure (figure 1). Putative defects in transfer of hormone and/or its receptor to the nucleus are expected to reduce the hormonal action at the genomic level. However, no patients have been described to date whose thyroid hormone resistance is caused by this mechanism.

TR defect – Action of thyroid hormone is mediated through the TRs. Genomic or type 1 thyroid hormone action is mediated through TRs operating as transcription factors that activate or repress transcription of specific target genes, as shown in panel C of the figure (figure 1). Mutant TR proteins have reduced ability to bind cognate ligand or protein cofactors or to bind to DNA.

-RTH-beta – Mutation of the thyroid hormone receptor beta gene (THRB), which encodes the thyroid hormone receptor beta (TR-beta), is the most frequent cause of RTH and is known as RTH-beta; affected patients have persistent elevations of all three serum iodothyronines with nonsuppressed TSH. (See 'Resistance to thyroid hormone beta (RTH-beta and nonTR-RTH)' below.)

-RTH-alpha – In contrast, patients with mutations of the thyroid hormone receptor alpha gene (THRA) encoding thyroid hormone receptor alpha (TR-alpha) have low serum T4 and rT3, borderline high T3, and normal or slightly elevated TSH; this disorder is termed RTH-alpha. (See 'Resistance to thyroid hormone alpha (RTH-alpha)' below.)

Abnormal cofactors or interfering substances – Some individuals have a phenotype that mimics that of a TR-beta gene mutation but have no identifiable TR gene mutation. This disorder has been termed "nonTR-RTH" and is thought to be caused in some instances by defects in TR cofactors, although no such defect has been definitively identified. Putative defects in cofactors that normally stabilize the hormone receptor complex or cofactors that repress or activate function could be responsible for reduced hormone sensitivity. (See 'NonTR-RTH' below.)

RESISTANCE TO THYROID HORMONE BETA (RTH-beta and nonTR-RTH)

Prevalence and inheritance — Resistance to thyroid hormone beta (RTH-beta) is the most common type of defect in thyroid hormone action. It has been detected in 1 in 40,000 to 1 in 19,000 live births [16,17] and occurs with equal frequency in males and females. With the exception of a single family, all cases to date have shown an autosomal dominant pattern of inheritance.

More than 4000 individuals belonging to 805 families have been shown to have RTH-beta, harboring 236 different mutations [18]. Among 326 families investigated in the authors' institution, thyroid hormone receptor beta (TR-beta) gene mutations were identified in 85 percent and 28 percent occurred de novo (figure 2).

Categorization

RTH-beta — In approximately 85 percent of cases, RTH is due to mutations in the TR-beta gene (THRB). Most of the mutations are located in the triiodothyronine (T3)-binding domain of the THRB gene (figure 2). They interfere with the function of the normal THRB gene (dominant-negative effect). One family has been described in which the affected subjects had complete deletion of the THRB gene [19]. This was inherited in a recessive manner because the single normal allele in heterozygotes was sufficient for normal function. Somatic mutations in the THRB gene have been identified in two thyroid-stimulating hormone (TSH)-producing pituitary adenomas [20].

The severity of hormonal resistance varies among different subjects carrying the same gene mutation, such as affected siblings. The variation in phenotype is not fully understood but probably results from genetic variability of cofactors involved in thyroid hormone action [21]. The main clinical phenotypes were previously categorized as generalized RTH, isolated pituitary RTH, and isolated peripheral tissue RTH, but this classification is no longer used.

NonTR-RTH — In 15 percent of families with clinical and biochemical features that mimic RTH-beta, THRB gene mutations are not detected; this is known as "nonTR-RTH." It is clinically and biochemically indistinguishable from RTH-beta with THRB gene mutations (figure 3). Mosaicism should be excluded by sequencing the receptor in DNA obtained from different tissues or by in-depth sequencing. However, mosaicism has been ruled out in several of these families. Mutations in some of the cofactors that interact with the receptor cannot be excluded and may be responsible for the resistance in some of these families [22].

Mechanisms and biochemical features — In patients with RTH-beta, all tissues that express TR-beta have reduced sensitivity to action of T3. The severity of hormonal resistance varies among different tissues in an affected individual, probably due to differences in the relative expression of TR-beta and thyroid hormone receptor alpha (TR-alpha) in different tissues [23]. As an example, the tachycardia that occurs in patients with RTH-beta is probably caused by the high serum thyroxine (T4) and T3 concentrations in the heart, an organ expressing predominantly the alpha isoform of the TR [24,25]. Cardiac arrhythmias can be found in up to 20 percent of patients with RTH-beta; impaired cardiac systolic and diastolic functions can be also present, but heart failure has not been reported [26]. Reduced survival and increased cardiovascular morbidity has been reported in a cohort of patients with RTH-beta, possibly driven by lifelong cardiac exposure to thyroid hormone excess [27].

Effects on the hypothalamic-pituitary-thyroid axis – In RTH-beta, resistance of the pituitary thyrotrophs to thyroid hormone raises TSH secretion, which increases the synthesis and secretion of T4 and T3 from the thyroid gland. The elevated levels of these thyroid hormones fail to downregulate the hypothalamic-pituitary-thyroid axis as they would in an individual without RTH-beta, as shown in panel A of the figure (figure 1). As a result, these patients have high levels of T4 and T3 and normal or high levels of TSH. Because of this apparent dissociation between serum thyroid hormone and TSH concentrations, the syndrome has been called "inappropriate secretion of TSH." However, TSH secretion is not really inappropriate, because the response of the thyrotrophs to thyroid hormone is reduced; to the contrary, it is compensatory and appropriate for the level of thyroid hormone action mediated through the defective TR-beta.

The TSH secreted by these patients is rich in sialic acid and has increased bioactivity as compared with normal TSH [28]. This explains why patients with RTH have goiter and high serum T4 and T3 concentrations even though their serum immunoreactive TSH concentrations are normal or only slightly high. The relationship between serum TSH and T4 concentrations in patients remains negative log-linear, but the slope of serum TSH/free T4 is lower, and the slope appears to be characteristic of the specific mutation involved [28-30].

Effects on metabolism – Because increased thyroid hormone secretion compensates for thyroid hormone resistance, most patients with RTH-beta are clinically euthyroid, although the completeness of compensation varies in different patients and in different tissues in the same patient [31]. However, the level of tissue responses does not always correlate with the serum T4 and T3 concentrations, probably because of discordance between the hormonal effects on the pituitary and other body tissues [29]. For example, patients with RTH-beta have increased muscle-derived resting energy expenditure as a consequence of thyroid hormone-mediated mitochondrial uncoupling [32].

A study of individuals from a large family with RTH-beta due to the R243Q mutation assessed hepatic fat using controlled attenuation parameter (CAP) measured through transient elastography [33]. Family members with RTH-beta had increased hepatic fat compared with their unaffected relatives. CAP values correlated with age and body mass index in unaffected first-degree relatives, but this was not the case for individuals with RTH-beta, suggesting that the defect in TR-beta signaling was predominant over the effects of age and obesity. Circulating free fatty acid levels were also significantly higher in individuals with RTH-beta. There was no evidence of insulin resistance evaluated by the homeostatic model assessment of insulin resistance in either group.

The magnitude of the decrease in T3 binding by the mutant TR-beta is correlated with the clinical severity of RTH in most patients, which is usually determined by measuring the serum free T4 concentration needed to maintain normal TSH secretion [29]. However, some patients have a mild phenotype despite having mutations that result in marked impairment of T3 binding. In these individuals, the mutations are located in domains of the TR that, in addition to binding T3, also alter receptor dimerization or association with other proteins that mediate the dominant-negative effect of the mutant receptor [34-36].

Laboratory findings — RTH-beta is characterized by a high serum free T4 concentration and nonsuppressed (normal or slightly elevated) TSH; these features are essential requirements for the diagnosis. Serum levels of T3 and reverse T3 (rT3), if measured, are usually also high. The concentration of thyroglobulin (the protein within which T3 and T4 are synthesized and stored) tends to be high, reflecting the level of TSH-induced thyroid gland hyperactivity. If these abnormalities are found, they should be confirmed by repeat measurements several weeks later.

Clinical features — The hallmark of RTH-beta or nonTR-RTH is the paucity of symptoms and signs of thyroid dysfunction despite the presence of high serum T4 and T3 concentrations.

Among all clinical findings, goiter is by far the most common (65 to 95 percent), followed by hyperactivity (33 to 68 percent) and tachycardia (33 to 75 percent) (table 2). These abnormalities usually lead to evaluation of thyroid function. The subsequent finding of high serum T4 and T3 concentrations often results in the erroneous diagnosis of hyperthyroidism.

Patients with RTH-beta may have some symptoms or signs of hypothyroidism and hyperthyroidism, but these are variable and, when present, often reflect the relative significance of the THRB in the action of thyroid hormone in a particular tissue (table 2). If hypothyroid symptoms are present, clinical features may include growth retardation, delayed bone maturation, learning disabilities, intellectual disability, sensorineural deafness, and nystagmus. Patients with symptoms of hyperthyroidism may have tachycardia, hyperactivity, and increased basal metabolic rate. Overt clinical hypothyroidism is more common in patients who, because of erroneous diagnosis of hyperthyroidism, received ablative or antithyroid treatment to reduce their thyroid hormone level [31,37,38]. Severe THRB mutations manifest in childhood with a combination of the hypothyroid and hyperthyroid symptoms. Milder mutations can be identified in childhood or adulthood if thyroid function tests are performed, either routinely or in response to symptoms.

RTH-beta is associated with an increased risk for autoimmune thyroid disease [39]. Thus, the presence of antibodies to thyroperoxidase and thyroglobulin should not detract from the investigation of RTH-beta if thyroid function tests suggest this possibility. By contrast, the occasional co-occurrence of RTH-beta with somatic abnormalities and other congenital thyroid defects such as Pendred syndrome and lingual thyroid appears to be coincidental.

There is a high prevalence of attention deficit hyperactivity disorder (ADHD) and learning disabilities in patients with RTH-beta [31,37,40]. Hearing loss may be due, in part, to recurrent ear infections, which are more common in patients with RTH-beta [31]. However, sensorineural deafness is common among individuals with RTH due to THRB gene deletion [19]. In mice, absence of TR-beta-1 is sufficient to cause hearing loss [41]. Disrupted color vision due to retinal photoreceptor dysfunction has been reported in families with homozygous TR-beta deletions [12,15,37,42,43]. A study of 27 RTH-beta subjects described functional defects of medium-wavelength cones and rods leading to deranged color vision; this was independent of endogenous thyroid hormone levels or prenatal exposure to high or normal thyroid hormone [44]. High-resolution, three-dimensional, T1-weighted images acquired in 21 patients with RTH-beta in comparison with 21 healthy matched controls revealed alterations of the corticospinal tract, increased cortical thickness in the bilateral superior parietal cortex, and decreased grey matter volume in the bilateral inferior temporal cortex and thalamus [45]. It is unknown if these structural changes are linked to the behavioral changes seen in RTH-beta subjects.

Diagnosis — RTH-beta is suspected in a patient presenting with the following features:

High serum concentrations of free T4 and, usually, free T3, accompanied by normal or slightly high serum TSH concentrations [37,38].

Minimal signs and symptoms of thyroid dysfunction, although goiter and tachycardia are common.

Supraphysiologic doses of T4 or T3 are required to reduce the TSH secretion or to induce the appropriate responses in peripheral tissues, such as an increase in serum sex hormone-binding globulin and reduction in cholesterol concentrations.

No evidence of thyroid hormone binding abnormalities or pituitary adenoma. (See 'Differential diagnosis' below.)

A family history of thyroid disease or RTH-beta.

The diagnosis of RTH-beta is confirmed by genetic testing for mutations in the THRB gene by direct sequencing. Commercial laboratories that offer sequencing of THRB are listed on the Genetic Testing Registry website. This test provides a means to confirm the diagnosis, obtain prenatal diagnosis, and prevent inappropriate antithyroid treatment of patients with high serum levels of free thyroid hormone.

Differential diagnosis — Other causes of RTH are associated with low levels of at least one of these thyroid hormones (table 3). (See 'Resistance to thyroid hormone alpha (RTH-alpha)' below and "Genetic defects in thyroid hormone transport and metabolism".)

All causes of high serum T4 and T3 concentrations in association with normal to high serum TSH levels should be considered in the differential diagnosis (table 4). The following steps are appropriate to establish the diagnosis of RTH-beta; genetic analysis is very helpful in confirming the diagnosis:

Thyroid hormone binding abnormalities – To exclude abnormalities of thyroid hormone binding in serum, including familial dysalbuminemic hyperthyroxinemia, hereditary and acquired thyroxine-binding globulin (TBG) excess, and transthyretin excess, measure:

Serum free T4 and T3 by equilibrium dialysis

T4-binding panel, which measures T4 binding to serum albumin, TBG, and transthyretin as well as their respective levels

(See "Euthyroid hyperthyroxinemia and hypothyroxinemia".)

Pituitary adenoma – To exclude a TSH-producing pituitary adenoma, measure the alpha subunit of TSH. With the exception of postmenopausal women with increased serum gonadotropin levels, a high ratio of alpha subunit to whole TSH strongly suggests a TSH-secreting tumor. (See "TSH-secreting pituitary adenomas", section on 'Alpha subunit'.)

In one case series, all TSH-producing pituitary adenomas were successfully identified by a T3 suppression test (failure to suppress the TSH following the administration of 200 mcg of liothyronine) [46]. This disorder is associated with a similar thyroid hormone profile to RTH-beta, except that most, if not all, patients with a TSH-producing pituitary adenoma are clinically hyperthyroid [47]. A T3 suppression test is not necessary in patients with a familial pattern of RTH-beta. In families with established RTH-beta, evaluation of immediate family members (parents, siblings, children) by measurement of serum free T4 and TSH is sufficient to reach a diagnosis. (See "TSH-secreting pituitary adenomas", section on 'Resistance to thyroid hormone'.)

NonTR-TRH – Individuals without an identifiable THRB gene mutation but with thyroid function tests consistent with RTH-beta may have nonTR-RTH. (See 'NonTR-RTH' above.)

In this case, dynamic testing is required to confirm or exclude the diagnosis:

In patients with RTH-beta or nonTR-RTH, the response of TSH to TSH-releasing hormone (thyrotropin-releasing hormone) is normal or exaggerated, depending on the baseline TSH level. Thyrotropin-releasing hormone is not readily available in some countries, including the United States.

Supportive evidence for these disorders comes from observing a blunted suppressive effect of administered thyroid hormone on TSH, cholesterol, and creatine kinase (in contrast with the robust response seen in patients with hypothyroidism). Similarly, the stimulatory effect of thyroid hormone on sex hormone-binding globulin and ferritin is attenuated (figure 3).

The diagnosis of nonTR-RTH is also supported by the presence of the characteristic thyroid function tests in other family members, which distinguishes nonTR-RTH from TSH-secreting pituitary adenomas. (See 'NonTR-RTH' above.)

Treatment — There is no treatment that will correct the defect of TR-beta function in subjects with RTH-beta. Fortunately, treatment is not needed in most patients, because the hyposensitivity to thyroid hormone seems to be adequately compensated by the increase in secretion of T4 and generation of T3. This is not the case in patients with limited thyroid reserve due to prior destructive therapy directed to the thyroid gland or in association with congenital hypothyroidism. These patients should be treated with enough levothyroxine to reduce their serum TSH concentrations to normal or near-normal. Since the phenotype of patients with nonTR-RTH is identical to that of RTH-beta (subjects with known mutation in the THRB gene), management of these disorders is identical.

In general, treatments that ablate the thyroid gland should be avoided. Large glands have been successfully treated by the administration of a single high dose of liothyronine given every other day [48]. Patients with symptoms of thyrotoxicosis, more specifically tachycardia and tremor, usually respond to the administration of the beta adrenergic blocker atenolol. Another treatment, triiodothyroacetic acid, has limited beneficial effect and is not available in North America. Patients with symptoms of ADHD should be treated using standard regimens for ADHD, independently from the RTH-beta.

In some patients with RTH-beta, several peripheral tissues may be relatively more resistant than the thyrotrophs. Thus, the compensation for the hormonal resistance in these tissues is incomplete and judicious administration of a dose of T4 higher than that needed to restore TSH secretion to normal may be indicated. The dose must be individually determined by assessing tissue responses. In children, this should be done by regular assessment of growth, bone maturation, and mental development. Levothyroxine should be given in incremental doses, and serum thyroid function tests should be measured after treatment for four to six weeks before the dose is changed; bone age and growth should be followed on a longer-term basis.

Pregnancy — Management of thyroid hormone levels during pregnancy in a mother with RTH or a normal mother carrying a fetus with RTH is not straightforward. A fetus with a THRB gene mutation carried by a woman with RTH-beta is protected from adverse effects of the high maternal thyroid hormone levels, but fetal thyrotoxicosis may occur in offspring that do not carry the mutation.

A retrospective study of a large family with RTH-beta demonstrated that the adverse effect of high thyroid hormone on the unaffected fetus was independent of that on the pregnant woman [49]. The prevalence of early pregnancy loss was increased fivefold in affected mothers but not in couples with an affected father and unaffected mother. Two-thirds of their infants carried the THRB gene mutation, which suggests that nearly all miscarried fetuses had no mutation and thus a normal response to thyroid hormone. Furthermore, unaffected infants born to affected mothers had lower birth weights and suppressed serum TSH concentrations when compared with affected infants. These adverse pregnancy outcomes are similar to those for infants with excess thyroid hormone, caused by gain-of-function TSH receptor mutations, who are born prematurely and have low birth weights [50]. More recent findings showed that exposure to high thyroid hormone levels during embryonic life has a long-term effect, causing reduced sensitivity to thyroid hormone that persists during adulthood [51].

For mothers with RTH who are carrying unaffected fetuses (as determined by prenatal genetic analysis), antithyroid medication may be indicated, depending on the well-being of the fetus [52,53]. In such mothers, free T4 should be maintained not higher than 50 percent above the upper limit of normal. This can be achieved by judicious use of propylthiouracil, taking care to avoid inducing hypothyroidism. There is no basis for regular treatment of normal mothers carrying affected fetuses (from paternal source or de novo mutation) unless the fetus is found to have a large goiter or be in distress, in which case, the only treatment alternative is intraamniotic infusion of levothyroxine, which has been effective in the treatment of fetal goiter from other causes [13]. Further studies are needed before general recommendations can be made.

RESISTANCE TO THYROID HORMONE ALPHA (RTH-alpha)

Prevalence and genetics — Mutations in the thyroid hormone receptor alpha gene (THRA) were first reported in 2012 [54], more than two decades after discovery of a mutation in the thyroid hormone receptor beta gene (THRB). The reason is undoubtedly that thyroid hormone receptor alpha (TR-alpha) protein defects are associated with less obvious abnormalities in serum hormone tests, such that the latest-generation sequencing was required to identify this disorder. Since 2012, resistance to thyroid hormone alpha (RTH-alpha) in more than 32 individuals due to 18 different THRA gene mutations have been identified [18,55]. Mutations are of all varieties (frame shifts with early termination resulting in a truncated receptor, point mutations [missense and nonsense], inherited and de novo), and all are located in the ligand-binding domain. As with THRB gene mutations, this results in three different mechanisms causing functional impairment: (1) there is reduced affinity for triiodothyronine (T3); (2) the mutant TR-alpha interferes with the normal TR-alpha, resulting in a dominant-negative effect; and (3) coactivator recruitment to the liganded receptor is defective.

Laboratory findings — The most consistent laboratory findings in RTH-alpha are high ratios of T3 to thyroxine (T4) and T3 to reverse T3 (rT3). These are the consequences of borderline low serum T4, borderline high T3, and relatively low rT3, but most of these values overlap the normal range of these tests. Serum thyroid-stimulating hormone (TSH) concentrations are usually within the normal range.

These findings are distinct from the laboratory abnormalities in patients with RTH-beta, reflecting the fact that TR-alpha is not involved in the feedback regulation of the hypothalamic-pituitary-thyroid axis. The mechanism for these findings is unclear, but it may involve a reduction in type 3 deiodinase because absence of Thra in mice results in decreased clearance of thyroid hormone by type 3 deiodinase [56].

Clinical features — The phenotype of RTH-alpha is very variable but is consistent with some of the manifestations of untreated congenital hypothyroidism in peripheral tissues. Due to the main role of TR-alpha in mediating thyroid hormone action in bone, there are significant bony abnormalities in these patients, including reduced bone age, short stature, femoral epiphyseal dysgenesis, patent cranial sutures, and macrocephaly. Other major clinical findings are in the gastrointestinal tract (ranging from constipation to megacolon), heart (bradycardia), striated muscles, hematologic system (normocytic anemia), and central nervous system (ranging from autism to intellectual disability).

The phenotype may depend upon the type of THRA gene mutation. Clinical features were mild in one of the reported families with missense mutations [57]. However, THRA mutations that truncate the C-terminus of the TR-aplha-1 isoform result in a severe clinical phenotype and extreme RTH. THRA mutations in the C-terminus and corresponding mutations in the THRB gene impair ligand binding even at high concentrations, impair release of corepressors and recruitment of coactivators, and manifest a strong dominant-negative effect [58].

Treatment — The extent of clinical benefit from treatment with levothyroxine remains unclear. However, it has generally ameliorated constipation but not anemia. Clinical experience with this disorder is very limited, and optimal dosing and treatment targets are not known [58].

Treatment with levothyroxine was considered in several case reports [54,57-60]. In one of the cases, the hypothalamic-pituitary axis responded to exogenous thyroid hormone, but the skeletal, gastrointestinal, and myocardial tissues were resistant [54], consistent with the differential tissue expression of the TR-alpha subtype. In a third case report, liothyronine treatment was given, which reduced the TSH and consequently the T4 level, but an increase in heart rate was observed [59]. In a patient with a severe RTH-alpha phenotype, levothyroxine treatment was started in infancy. The improvements have been modest and, despite early aggressive treatment, bone and neurologic development have not normalized [58]. Because the long-term effects of high levothyroxine doses in the context of such a deleterious THRA mutation are not known, close monitoring is needed, taking into consideration all developmental parameters. It is notable that postnatal growth seems more delayed compared with the apparently normal intrauterine growth, potentially indicating that other mechanisms might be able to compensate in utero. The experience is too preliminary to make definitive recommendations regarding treatment in patients with THRA gene mutations.

SUMMARY AND RECOMMENDATIONS

Causes of impaired sensitivity to thyroid hormone – Resistance to thyroid hormone (RTH) is an inherited syndrome characterized by reduced responsiveness of target tissues to thyroid hormone. It usually is caused by a mutation in the genes encoding the thyroid hormone receptors beta and alpha. Other causes of reduced sensitivity to thyroid hormone include thyroid hormone cell membrane transport defect (THCMTD) and thyroid hormone metabolism defects (THMD). (See 'Mechanisms of impaired sensitivity' above.)

These disorders can be distinguished by their characteristic abnormalities of thyroid function (table 3). In each disorder, mutations in a single gene are responsible for most or all identified cases (table 1). THCMTD and THMD are discussed separately. (See "Genetic defects in thyroid hormone transport and metabolism".)

RTH-beta

Pathogenesis – RTH-beta is an inherited syndrome characterized by reduced responsiveness of target tissues to thyroid hormone. It is caused by mutations in the gene encoding the thyroid hormone receptor beta gene (THRB), which are inherited in an autosomal dominant fashion. (See 'Resistance to thyroid hormone beta (RTH-beta and nonTR-RTH)' above.)

Clinical and laboratory features – RTH-beta is characterized by high serum concentrations of free thyroxine (T4) and usually also free triiodothyronine (T3), with normal or slightly high serum thyroid-stimulating hormone (TSH) concentration and minimal symptoms and signs of thyroid dysfunction. Clinical features include goiter, hyperactivity, and tachycardia (table 2). The clinical disease is usually mild because the hyposensitivity to thyroid hormone is adequately compensated by the increase in secretion of T4 and generation of T3. (See 'Laboratory findings' above and 'Clinical features' above.)

Diagnosis – Diagnosis of RTH-beta depends on characteristic elevations in serum thyroid hormone concentrations and exclusion of other causes of hyperthyroxinemia (table 4). When RTH-beta is suspected, the diagnosis should be confirmed by direct sequencing of the THRB gene to identify mutations. (See 'Diagnosis' above and 'Differential diagnosis' above.)

Treatment – Treatment is not needed in most patients with RTH-beta, because the hyposensitivity to thyroid hormone seems to be adequately compensated by the increase in secretion of T4 and generation of T3. Treatment with levothyroxine is required for those patients with clinical hypothyroidism, which may be caused by limited thyroid reserve due to concurrent congenital primary hypothyroidism or prior destructive therapy directed to the thyroid gland. Other patients require interventions for goiter or symptoms of thyrotoxicosis. Management of pregnancies in mothers with RTH is complex. (See 'Treatment' above and 'Pregnancy' above.)

Non-thyroid hormone receptor RTH (nonTR-RTH) – In approximately 15 percent of cases, RTH-beta-like phenotype is caused by yet undetermined genetic abnormalities. This disorder is known as nonTR-RTH. (See 'NonTR-RTH' above and 'Differential diagnosis' above.)

RTH-alpha – A rare form of RTH (RTH-alpha) is due to mutations in the gene encoding the thyroid hormone receptor alpha gene (THRA). These patients are phenotypically different from patients with THRB gene mutations in both thyroid function tests and clinical features; thyroid hormone resistance is limited to those tissues in which thyroid hormone action is predominately mediated by the thyroid hormone receptor alpha (TR-alpha), ie, bone and gastrointestinal tract. THRA mutations that truncate the C-terminus of the TR-aplha-1 isoform can manifest a severe clinical phenotype and extreme RTH. (See 'Resistance to thyroid hormone alpha (RTH-alpha)' above.)

ACKNOWLEDGMENT — Support for this topic review was provided in part with funds from the National Institutes of Health (NIH) USA grant DK15070 and the Esformes Thyroid Research Fund.

  1. Refetoff S, Bassett JH, Beck-Peccoz P, et al. Classification and proposed nomenclature for inherited defects of thyroid hormone action, cell transport, and metabolism. Thyroid 2014; 24:407.
  2. Refetoff S, Bassett JH, Beck-Peccoz P, et al. Classification and proposed nomenclature for inherited defects of thyroid hormone action, cell transport, and metabolism. J Clin Endocrinol Metab 2014; 99:768.
  3. Refetoff S, Bassett JH, Beck-Peccoz P, et al. Classification and proposed nomenclature for inherited defects of thyroid hormone action, cell transport, and metabolism. Eur Thyroid J 2014; 3:7.
  4. Friesema EC, Jansen J, Milici C, Visser TJ. Thyroid hormone transporters. Vitam Horm 2005; 70:137.
  5. Gereben B, Zavacki AM, Ribich S, et al. Cellular and molecular basis of deiodinase-regulated thyroid hormone signaling. Endocr Rev 2008; 29:898.
  6. Bassett JH, Harvey CB, Williams GR. Mechanisms of thyroid hormone receptor-specific nuclear and extra nuclear actions. Mol Cell Endocrinol 2003; 213:1.
  7. Flamant F, Cheng SY, Hollenberg AN, et al. Thyroid Hormone Signaling Pathways: Time for a More Precise Nomenclature. Endocrinology 2017; 158:2052.
  8. Zhang J, Lazar MA. The mechanism of action of thyroid hormones. Annu Rev Physiol 2000; 62:439.
  9. Yen PM, Ando S, Feng X, et al. Thyroid hormone action at the cellular, genomic and target gene levels. Mol Cell Endocrinol 2006; 246:121.
  10. Koenig RJ. Thyroid hormone receptor coactivators and corepressors. Thyroid 1998; 8:703.
  11. Vella KR, Ramadoss P, Costa-E-Sousa RH, et al. Thyroid hormone signaling in vivo requires a balance between coactivators and corepressors. Mol Cell Biol 2014; 34:1564.
  12. Refetoff S, DeWind LT, DeGroot LJ. Familial syndrome combining deaf-mutism, stuppled epiphyses, goiter and abnormally high PBI: possible target organ refractoriness to thyroid hormone. J Clin Endocrinol Metab 1967; 27:279.
  13. Sakurai A, Takeda K, Ain K, et al. Generalized resistance to thyroid hormone associated with a mutation in the ligand-binding domain of the human thyroid hormone receptor beta. Proc Natl Acad Sci U S A 1989; 86:8977.
  14. Usala SJ, Tennyson GE, Bale AE, et al. A base mutation of the C-erbA beta thyroid hormone receptor in a kindred with generalized thyroid hormone resistance. Molecular heterogeneity in two other kindreds. J Clin Invest 1990; 85:93.
  15. Dumitrescu AM, Liao XH, Best TB, et al. A novel syndrome combining thyroid and neurological abnormalities is associated with mutations in a monocarboxylate transporter gene. Am J Hum Genet 2004; 74:168.
  16. Lafranchi SH, Snyder DB, Sesser DE, et al. Follow-up of newborns with elevated screening T4 concentrations. J Pediatr 2003; 143:296.
  17. Vela A, Pérez-Nanclares G, Ríos I, et al. Thyroid hormone resistance from newborns to adults: a Spanish experience. J Endocrinol Invest 2019; 42:941.
  18. Dumitrescu AM, Korwutthikulrangsri M, Refetoff S. Impaired sensitivity to thyroid hormone: defects of transport, metabolism, and action. In: Werner & Ingbar's The Thyroid: A Fundamental and Clinical Text, 11th ed, Braverman LE, Cooper DS, Kopp PA (Eds), Lippincott Williams & Wilkins, 2021. p.868.
  19. Takeda K, Sakurai A, DeGroot LJ, Refetoff S. Recessive inheritance of thyroid hormone resistance caused by complete deletion of the protein-coding region of the thyroid hormone receptor-beta gene. J Clin Endocrinol Metab 1992; 74:49.
  20. Ando S, Sarlis NJ, Oldfield EH, Yen PM. Somatic mutation of TRbeta can cause a defect in negative regulation of TSH in a TSH-secreting pituitary tumor. J Clin Endocrinol Metab 2001; 86:5572.
  21. Weiss RE, Marcocci C, Bruno-Bossio G, Refetoff S. Multiple genetic factors in the heterogeneity of thyroid hormone resistance. J Clin Endocrinol Metab 1993; 76:257.
  22. Reutrakul S, Sadow PM, Pannain S, et al. Search for abnormalities of nuclear corepressors, coactivators, and a coregulator in families with resistance to thyroid hormone without mutations in thyroid hormone receptor beta or alpha genes. J Clin Endocrinol Metab 2000; 85:3609.
  23. Flamant F, Samarut J. Thyroid hormone receptors: lessons from knockout and knock-in mutant mice. Trends Endocrinol Metab 2003; 14:85.
  24. Wikström L, Johansson C, Saltó C, et al. Abnormal heart rate and body temperature in mice lacking thyroid hormone receptor alpha 1. EMBO J 1998; 17:455.
  25. Weiss RE, Murata Y, Cua K, et al. Thyroid hormone action on liver, heart, and energy expenditure in thyroid hormone receptor beta-deficient mice. Endocrinology 1998; 139:4945.
  26. Illouz F, Briet C, Mirebeau-Prunier D, et al. Cardiac complications of thyroid hormone resistance syndromes. Ann Endocrinol (Paris) 2021; 82:167.
  27. Okosieme OE, Usman D, Taylor PN, et al. Cardiovascular morbidity and mortality in patients in Wales, UK with resistance to thyroid hormone β (RTHβ): a linked-record cohort study. Lancet Diabetes Endocrinol 2023; 11:657.
  28. Persani L, Borgato S, Romoli R, et al. Changes in the degree of sialylation of carbohydrate chains modify the biological properties of circulating thyrotropin isoforms in various physiological and pathological states. J Clin Endocrinol Metab 1998; 83:2486.
  29. Hayashi Y, Weiss RE, Sarne DH, et al. Do clinical manifestations of resistance to thyroid hormone correlate with the functional alteration of the corresponding mutant thyroid hormone-beta receptors? J Clin Endocrinol Metab 1995; 80:3246.
  30. Ercan-Fang S, Schwartz HL, Mariash CN, Oppenheimer JH. Quantitative assessment of pituitary resistance to thyroid hormone from plots of the logarithm of thyrotropin versus serum free thyroxine index. J Clin Endocrinol Metab 2000; 85:2299.
  31. Brucker-Davis F, Skarulis MC, Grace MB, et al. Genetic and clinical features of 42 kindreds with resistance to thyroid hormone. The National Institutes of Health Prospective Study. Ann Intern Med 1995; 123:572.
  32. Mitchell CS, Savage DB, Dufour S, et al. Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia. J Clin Invest 2010; 120:1345.
  33. Chaves C, Bruinstroop E, Refetoff S, et al. Increased Hepatic Fat Content in Patients with Resistance to Thyroid Hormone Beta. Thyroid 2021; 31:1127.
  34. Yagi H, Pohlenz J, Hayashi Y, et al. Resistance to thyroid hormone caused by two mutant thyroid hormone receptors beta, R243Q and R243W, with marked impairment of function that cannot be explained by altered in vitro 3,5,3'-triiodothyroinine binding affinity. J Clin Endocrinol Metab 1997; 82:1608.
  35. Yoh SM, Chatterjee VK, Privalsky ML. Thyroid hormone resistance syndrome manifests as an aberrant interaction between mutant T3 receptors and transcriptional corepressors. Mol Endocrinol 1997; 11:470.
  36. Tagami T, Gu WX, Peairs PT, et al. A novel natural mutation in the thyroid hormone receptor defines a dual functional domain that exchanges nuclear receptor corepressors and coactivators. Mol Endocrinol 1998; 12:1888.
  37. Refetoff S, Weiss RE, Usala SJ. The syndromes of resistance to thyroid hormone. Endocr Rev 1993; 14:348.
  38. Beck-Peccoz P, Chatterjee VK. The variable clinical phenotype in thyroid hormone resistance syndrome. Thyroid 1994; 4:225.
  39. Barkoff MS, Kocherginsky M, Anselmo J, et al. Autoimmunity in patients with resistance to thyroid hormone. J Clin Endocrinol Metab 2010; 95:3189.
  40. Hauser P, Zametkin AJ, Martinez P, et al. Attention deficit-hyperactivity disorder in people with generalized resistance to thyroid hormone. N Engl J Med 1993; 328:997.
  41. Abel ED, Boers ME, Pazos-Moura C, et al. Divergent roles for thyroid hormone receptor beta isoforms in the endocrine axis and auditory system. J Clin Invest 1999; 104:291.
  42. Friesema EC, Grueters A, Biebermann H, et al. Association between mutations in a thyroid hormone transporter and severe X-linked psychomotor retardation. Lancet 2004; 364:1435.
  43. Dumitrescu AM, Liao XH, Abdullah MS, et al. Mutations in SECISBP2 result in abnormal thyroid hormone metabolism. Nat Genet 2005; 37:1247.
  44. Campi I, Cammarata G, Bianchi Marzoli S, et al. Retinal photoreceptor functions are compromised in patients with resistance to thyroid hormone syndrome (RTHβ). J Clin Endocrinol Metab 2017.
  45. Rogge B, Heldmann M, Chatterjee K, et al. Changes in brain structure in subjects with resistance to thyroid hormone due to THRB mutations. Thyroid Res 2023; 16:34.
  46. Macchia E, Lombardi M, Raffaelli V, et al. Clinical and genetic characteristics of a large monocentric series of patients affected by thyroid hormone (Th) resistance and suggestions for differential diagnosis in patients without mutation of Th receptor β. Clin Endocrinol (Oxf) 2014; 81:921.
  47. Beck-Peccoz P, Brucker-Davis F, Persani L, et al. Thyrotropin-secreting pituitary tumors. Endocr Rev 1996; 17:610.
  48. Anselmo J, Refetoff S. Regression of a large goiter in a patient with resistance to thyroid hormone by every other day treatment with triiodothyronine. Thyroid 2004; 14:71.
  49. Anselmo J, Cao D, Karrison T, et al. Fetal loss associated with excess thyroid hormone exposure. JAMA 2004; 292:691.
  50. Vaidya B, Campbell V, Tripp JH, et al. Premature birth and low birth weight associated with nonautoimmune hyperthyroidism due to an activating thyrotropin receptor gene mutation. Clin Endocrinol (Oxf) 2004; 60:711.
  51. Srichomkwun P, Anselmo J, Liao XH, et al. Fetal Exposure to High Maternal Thyroid Hormone Levels Causes Central Resistance to Thyroid Hormone in Adult Humans and Mice. J Clin Endocrinol Metab 2017; 102:3234.
  52. Weiss RE, Dumitrescu A, Refetoff S. Approach to the patient with resistance to thyroid hormone and pregnancy. J Clin Endocrinol Metab 2010; 95:3094.
  53. Pappa T, Anselmo J, Mamanasiri S, et al. Prenatal Diagnosis of Resistance to Thyroid Hormone and Its Clinical Implications. J Clin Endocrinol Metab 2017; 102:3775.
  54. Bochukova E, Schoenmakers N, Agostini M, et al. A mutation in the thyroid hormone receptor alpha gene. N Engl J Med 2012; 366:243.
  55. Moran C, Chatterjee K. Resistance to thyroid hormone due to defective thyroid receptor alpha. Best Pract Res Clin Endocrinol Metab 2015; 29:647.
  56. Barca-Mayo O, Liao XH, Alonso M, et al. Thyroid hormone receptor α and regulation of type 3 deiodinase. Mol Endocrinol 2011; 25:575.
  57. Demir K, van Gucht AL, Büyükinan M, et al. Diverse Genotypes and Phenotypes of Three Novel Thyroid Hormone Receptor-α Mutations. J Clin Endocrinol Metab 2016; 101:2945.
  58. Furman AE, Dumitrescu AM, Refetoff S, Weiss RE. Early Diagnosis and Treatment of an Infant with a Novel Thyroid Hormone Receptor α Gene (pC380SfsX9) Mutation. Thyroid 2021; 31:1003.
  59. Espiard S, Savagner F, Flamant F, et al. A Novel Mutation in THRA Gene Associated With an Atypical Phenotype of Resistance to Thyroid Hormone. J Clin Endocrinol Metab 2015; 100:2841.
  60. van Gucht AL, Meima ME, Zwaveling-Soonawala N, et al. Resistance to Thyroid Hormone Alpha in an 18-Month-Old Girl: Clinical, Therapeutic, and Molecular Characteristics. Thyroid 2016; 26:338.
Topic 5827 Version 33.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟