Werner & Ingbar's The Thyroid: A Fundamental & Clinical Text, 9th Edition

81. Resistance to Thyroid Hormone

 Samuel Refetoff

Resistance to thyroid hormone (RTH) is a syndrome of reduced responsiveness of target tissues to thyroid hormone (TH). More than 1,000 cases have been described that appear to fit this definition. In practice, such patients are identified by their persistent elevation of circulating free thyroxine (FT4) and free triiodothyronine (FT3) levels in association with nonsuppressed serum thyrotropin (TSH), and in the absence of intercurrent illness, drugs, or alterations of TH transport serum proteins. More importantly, higher doses of exogenous TH are required to produce the expected suppressive effect on the secretion of pituitary TSH and on the metabolic responses in peripheral tissues.

Although the apparent resistance to TH may vary in severity, it is always partial. The variability in clinical manifestations may be due to the severity of the hormonal resistance, the effectiveness of compensatory mechanisms, the presence of modulating genetic factors, and the effects of prior therapy. The magnitude of the hormonal resistance is, in turn, dependent on the nature of the underlying genetic defect. The latter is usually, but not always, a mutation in the TH receptor (TR) β gene (1,2).

Despite a variable clinical presentation, the common features characteristic of the RTH syndrome are (a) elevated serum levels of free T4 and T3, (b) normal or slightly increased TSH level that responds to TRH, (c) absence of the usual symptoms and metabolic consequences of TH excess, and (d) goiter.

CLINICAL CLASSIFICATION

The diagnosis is based on the clinical findings and standard laboratory tests and, when possible, confirmed by genetic studies. Before TR gene defects were recognized, the proposed subclassification of RTH was based on symptoms, signs, and laboratory parameters of tissue responses to TH (3). Not withstanding the assessment of TSH feedback regulation by TH, the measurements of most other responses to the hormone are insensitive and relatively nonspecific. For this reason, all tissues other than the pituitary have been grouped together under the term , on which the impact of TH was roughly assessed by a combination of clinical observation and laboratory tests.peripheral tissues

The majority of patients appeared to be eumetabolic and maintained a near normal serum TSH concentration. They were classified as having generalized resistance to TH (GRTH). In such individuals, the defect seemed to be compensated by the high levels of TH. In contrast, patients with equally high levels of TH and nonsuppressed TSH that appeared to be hypermetabolic, because they were restless or had sinus tachycardia, were classified as having selective pituitary resistance to TH (PRTH). Finally, the occurrence of isolated peripheral tissue resistance to TH (PTRTH) was reported in a single patient studied in detail (4). In this individual with partial thyroid gland ablation, although serum TSH was suppressed with physiologic doses of liothironine (L-T3), supraphysiologic doses of this hormone failed to produce symptoms and signs of thyrotoxicosis or to increase oxygen consumption and pulse rate. No mutation in the TRβ gene of this patient was found (5) and no similar cases have been reported. More common in clinical practice is the apparent tolerance of some individuals to the ingestion of supraphysiologic doses of TH.

The earliest suggestion that PRTH may not constitute an entity distinct from GRTH can be found in a study by Beck-Peccoz et al. (6). In a group of 15 patients with PRTH, these investigators found that the serum level of the peripheral tissue marker of TH action, sex hormone–binding globulin (SHBG), was not increased as it should have been if the hormonal resistance were confined to the pituitary and hypothalamus. In a recent comprehensive study involving 312 patients with GRTH and 72 patients with PRTH, it was conclusively shown that the response of SHBG and other peripheral tissue markers of TH action were equally attenuated in GRTH and PRTH (7). The frequency of symptoms and signs were also similar in patients under both classifications. More importantly, identical mutations were found in individuals classified as having GRTH and PRTH, many of whom belonged to the same family (8). It was therefore concluded that these two forms of RTH are the product of the subjective nature of symptoms and poor specificity of signs (see later section on the Molecular Basis of the Defect). Thus, it is uncertain whether PRTH exists as a true TH resistance entity, except in association with TSH-producing pituitary adenomas (9,10).

INCIDENCE AND INHERITANCE

The precise incidence of RTH is unknown. Because routine neonatal screening programs are based on the determination of TSH, RTH is rarely identified by this means (11). A limited neonatal survey by measuring blood T4 concentration suggested the occurrence of 1 case per 40,000 live births (12). Currently published cases surpass 1,000, of which 349 have been previously reviewed in detail (1).

Although most thyroid diseases occur more commonly in women, RTH has been found with equal frequency in both genders. The condition appears to have wide geographic distribution and has been reported in Caucasians, Africans, and Asians. The prevalence may vary among different ethnic groups.

Familial occurrence of RTH has been documented in approximately 75% of cases. Taking into account only those families in whom both parents of the affected subjects have been studied, the true incidence of sporadic cases is 21.3%. This is in agreement with the current estimate of the frequency of  mutations of 22.5% (Table 81.1). The reports of acquired RTH are seriously questioned.de novo

TABLE 81.1. TYPES OF TRβ GENE MUTATIONS

 

 

No. of Occurrences at Different

No. of Families

 

Type

Sites

Total

Author's

Effect on TRβ

 

Substitution–single nucleotide

105

281

114

Single amino acid substitution

    3

   4

   0

Premature stop (C434X, C446X, E449X)

 

Substitution–dinucleotide

   1

   1

   0

Premature stop (F451X)

 

   1

   1

   0

 Single amino acid substitution (P453Y)

Deletion–single nucleotide

   1

   1

   1

Frameshift and premature stop (441X)

Deletion–trinucleotide

   5

   6

   1

Single amino acid deletion (T276D, T337D, M430D, G432D, P452D)

Deletion–all coding sequences

   1

   1

   1

Complete deletion

Insertion–single nucleotide

   3

   4

   2

Frameshift and two amino acid extension

Insertion–trinucleotide

   1

   1

   1

Single amino acid insertion

Duplication–seven nucleotides

   1

   1

   0

Frameshift and two amino acid extension

Mutations at CpG dinucleotides

   9

133a

  54

46.7% of 285 families with single nucleotide substitution and 47.4% of 114 similar families studied in the author's laboratory

De novo mutations Total

  29

  50

  27

16.7% of 301 families and 22.5% of 120bfamilies studied in the author's laboratory

 in CpGs

   6

  23

  12

46.0% and 44.4% of  mutations, respectivelyde novo

No TRβ gene mutations

   c

  23d

  21

14.9% of 141 families studied in the author's laboratory and in whom TRβ gene was sequenced

 

aNot included are seven families in which the mutation did not follow the rule of G to A or C to T transition.

bFamilies with TRβ gene mutations excluding those with a single affected individual when both parents were not tested.

cNot applicable.

dTotal number of families is grossly underestimated because usually they are not reported.

Inheritance is autosomal dominant. Transmission was clearly recessive in only one family (27,28). Consanguinity in a family with dominant inheritance of RTH has produced a homozygous child with severe resistance to the hormone (29) who died at the age of 7 years. There is only partial information on another patient with severe RTH, homozygote for a TRβ gene mutation (30).

ETIOLOGY AND GENETICS

Using the technique of restriction fragment length polymorphism (RFLP), Usala et al. (31) were first to demonstrate linkage between a TRβ locus on chromosome 3 and the RTH phenotype, 21 years after description of the syndrome (27). Subsequent studies at the University of Chicago and at the National Institutes of Health have identified distinct point mutations in the TRβ gene of two unrelated families with RTH (32,33). In both families only one of the two TRβ alleles was involved, compatible with the apparent dominant mode of inheritance. These mutations resulted in the substitutions of single amino acids in the T3-binding domain of the TRβ gene.

Mutations in the TRβ gene have now been identified in subjects with RTH belonging to 300 families (Table 81.1, Fig. 81.1). They comprise 122 different mutations. With the exception of the index family, found to have complete deletion of the TRβ gene (28), all others harbor minor alterations at the DNA level. The majority (285 families) have single nucleotide substitutions resulting in single amino acid replacements in 281 instances and stop codons in 4 others, producing truncated molecules of 433 to 448 amino acids in the TRβ1 protein. In two families, dinucleotide substitutions produce a single amino acid substitution and a premature stop, respectively. Six families have trinucleotide deletions producing the loss of single amino acid, while insertion of a trinucleotide produced the addition of a single amino acid in another family. A single nucleotide deletion in one family and an insertion in four others resulted in a frameshift, the latter producing a protein containing two extra amino acids.

 

FIGURE 81.1. Location of natural mutations in the TRβ molecule associated with resistance to thyroid hormone (RTH).  Schematic representation of the TRβ gene and its functional domains for interaction with TREs (DNA-binding), with hormone [triiodothyronine (TTop:3) binding], with activating (13), repressing (14,15,16) cofactors and with nuclear receptor partners (dimerization) (17,18,19,20). Their relationship to the three clusters of natural mutations is also indicated.  The TBottom:3-binding domain and distal end of the hinge region, which contain the three mutation clusters, are expanded and show the positions of CpG dinucleotide mutational “hot spots” in the corresponding RTβ gene. The location of the 121 different mutations detected in 299 unrelated families (published and our unpublished data) are each indicated by a symbol. Identical mutations in members of unrelated families are represented by the same shading pattern of vertically placed symbols. “Cold regions” are areas devoid of mutations associated with RTH. Amino acids are numbered consecutively starting at the amino terminus of the TRβ1 molecule according to the consensus statement of the First International Workshop on RTH (21). TRβ2 has 15 additional residues at the amino terminus. , hormone-dependent activation function (12th amphipatic helix) (22,23); , corepressor-binding enhancer; , corepressor-binding inhibitor (23); , silencing subdomain (16); , nuclear localization (24); , signature motif (25). (Modified from Refetoff S, Weiss RE. Resistance to thyroid hormone. In: Thakker TV, ed.  London: Chapman & Hill, 1997:85–122, with permission.)AF2RBERBISSDNucLSigMMolecular genetics of endocrine disorders.

Given that there are 178 more families than the number of different mutations, 45 of the mutations are shared by more than one family. Haplotyping of intragenic polymorphic markers showed that, in most instances, identical mutations have developed independently in different families (34). Eleven of these occur in more than six apparently unrelated families and, with the exception of two, all others occur in mutagenic CpG dinucleotide hot spots; the mutation R338W (CGG
→ TGG) has been identified in 25 different families. In agreement with this finding is the relatively high prevalence (16.7) of  mutations. In addition, different mutations producing more than one amino acid substitution at the same codon have been found at 37 different sites; mutations at codon 345 and 453 each produced five different amino acid replacements, G345R,S,A,V,D and P453T,S,A,Y,H.de novo

All TR β gene mutations are localized in the functionally relevant domain of T3 binding and its adjacent hinge region. Three mutational clusters have been identified with intervening cold regions (Fig. 81.1). With the exception of the family with TRβ gene deletion, in all others inheritance is autosomal dominant. No mutations have so far been detected in the TRα gene. Recent findings in mice with targeted mutations in the TRα gene (knock-in mice) indicate that such mutations do not produce the phenotype of RTH (35,36,37) (see later section on Animal Models of Resistance to Thyroid Hormone). The significance of somatic TRα gene mutations identified in nonfunctioning pituitary adenomas (38) is unclear.

Somatic mutations in the TRβ gene have been identified in some TSH-secreting pituitary tumors (9,10). These mutations can be identical to those occurring in the germ line. However, because their expression is limited to the thyrotrophs, the phenotype, as in other TSHomas, is that of TSH-induced thyrotoxicosis. It is postulated that defective TR interfering with the negative regulation of TSH by TH is responsible for the development of the pituitary tumor.

In a growing number of individuals, RTH occurs in the absence of mutations in the TRα or TRβ genes (non-TR-RTH) (39). They represent 15% of families and 7% of cases with RTH. Such individuals may have a defect in one of the cofactors involved in the mediation of TH action (see later section on Animal Models of Resistance to Thyroid Hormone).

MOLECULAR BASIS OF THE DEFECT

Thyroid Hormone Action at the Gene Level

Genes on chromosomes 17 and 3 each generate TRα and TRβ molecules, respectively, that have substantial structural and sequence similarities. Both genes produce two isoforms: α1 and α2 by alternative splicing and β1 and β2 by different transcription start points. TRα2 binds to TH response elements (TREs), but due to a sequence difference at the ligand-binding domain (LBD) site, it does not bind TH and thus does not function as a proper TR (40) and appears to have a weak antagonistic effect (41). Additional TR isoforms, including a TRβ with a shorter amino terminus (TRβ3) and truncated TRβ3, TRα1, and TRα2 [lacking the DNA-binding domain (DBD)], have been identified in different tissues of rodents (42,43). The latter three exhibit a dominant antagonistic effect, but their significance in humans remains unknown (44). Finally, a p43 protein, translated from a downstream AUG of TRα1, is believed to mediate the TH effect in mitochondria (45).

The relative expression of the two TR genes and the distribution of their products vary among tissues and during different stages of development (46,47,48). Recent studies have shown several splice variants involving the 5′-untranslated region of the human TRβ1 (49,50). Their relative abundance is developmentally and tissue regulated, thus potentially controlling the expression of the receptor protein. To a certain degree, TRβ and TRα are interchangeable (51,52). However, the resulting compensatory effects, observed in the absence of one of the receptors, do not represent functional equivalence during normal physiologic conditions. Some TH effects are absolutely TR isoform specific (see later section on Animal Models of Resistance to Thyroid Hormone). It is of interest that nuclear receptors, which arose from two waves of gene duplication during the evolution of metazoans, were initially orphan receptors that subsequently acquired ligand-binding ability (53).

TREs, located in TH regulated genes, consist of half-sites having the consensus sequence of AGGTCA and vary in number, spacing, and orientation (54,55). Each half-site usually binds a single TR molecule (monomer) and two half-sites bind two TRs (dimer) or one TR and a heterologous partner (heterodimer), the most prominent being the retinoid X receptor β (RXR). Dimer formation is facilitated by the presence of an intact “leucine zipper” motif located in the middle of the LBD of TRs. Occupation of TREs by unliganded (without hormone) TRs, also known as aporeceptors, inhibits the constitutive expression of genes that are positively regulated by TH (56) through association with corepressors such as the nuclear corepressor (NCoR) or the silencing mediator of retinoic acid and TH receptors (SMRT) (57). Transcriptional repression is mediated through the recruitment of the mammalian homologue of the  transcriptional corepressor (mSin3A) and histone deacetylases (HDAC) (58). This latter activity compacts nucleosomes into a tight and inaccessible structure, effectively shutting down gene expression. This effect is relieved by the addition of TH, which releases the corepressor, reduces the binding of TR dimers to TRE, enhances the occupation of TREs by TR/RXR heterodimers (59), and recruits coactivators (CoA) such as p/CAF (CREB binding protein-associated factor) and NCoA [steroid receptor coactivator-1 (SRC-1)] with HAT (histoneSaccharomyces acetylation) activity (57,60). This results in the loosening of the nucleosome structure, making the DNA more accessible to transcription factors. Actually, the ligand-dependent association with TR associated proteins (TRAP), in conjunction with the general coactivators PC2 and PC4, act to mediate transcription by RNA polymerase II and general initiation factors (61). TR dimerization is not required for hormone binding, and the latter does not induce dimerization. Furthermore, it is believed that T
3 exerts its effect by inducing conformational changes of the TR molecule and that TRAP stabilizes the association of TR with TRE.

Properties of Mutant TRβ Receptors and Dominant Negative Effect

TRβ gene mutations produce two forms of RTH. The less common, described in only one family (27), is caused by deletion of all coding sequences of the TRβ gene and is inherited as an autosomal-recessive trait (28). In addition to the hormonal and metabolic abnormalities typical of the syndrome of RTH, these individuals have severe deafness resulting in mutism (27), as well as monochromatic vision (62). This is caused by the complete lack of TRβ, which is required for the cochlear maturation and the development of cone photoreceptors that mediate color vision (63) (see later section on Animal Models of Resistance to Thyroid Hormone). Heterozygous individuals that express a single TRβ gene have no clinical or laboratory abnormalities. This is not due to compensatory overexpression of the single normal allele of the TRβ gene nor that of the TRα gene (64). However, because some responses to TH could be demonstrated in subjects homozygous for TRβ gene deletion, it is logical to conclude that TRα1 is capable of partially substituting for the function of TRβ (see later section on Animal Models of Resistance to Thyroid Hormone).

The more common form of RTH is inherited in a dominant fashion and is characterized by minor defects in one allele of the TRβ gene, principally missense mutations. This is in contrast to individuals that lack one allele of the TRβ that do not exhibit the RTH phenotype. These findings indicated that RTH is not simply the consequence of a reduced amount of a functional TR (haploinsufficiency) but is caused by the interference of the mutant TR (mTR) with the function of the wild-type (WT)-TR (dominant negative effect). This has been clearly demonstrated in experiments in which mTRs are coexpressed with WT-TRs (65,66). The most severe resistance to the action of TH observed in one child homozygous for a TRβ mutation (67) underscores the role of dominant negative effect exerted by the expression of two mTR alleles in the pathogenesis of RTH.

Studies conducted during the past decade have established two basic requirements for mTRs to exert a dominant negative effect. These include (a) preservation of binding to TREs on DNA and (b) the ability to dimerize with a homologous (68,69,70) or heterologous (20,71) partner. These criteria apply to mTRs with predominantly impaired T3-binding activity (Fig. 81.2). In addition, a dominant negative effect can be exerted through impaired association with a cofactor even in the absence of important impairment of T3 binding. Increased affinity of an mTR to a corepressor (CoR) (72,73), or reduced association with a coactivator (CoA) (74,75,76), have been found to play a role in the dominant expression of RTH. These conclusions are based on direct experimental evidence as well as observations that correlate the location of mutations on the receptor molecule and the clinical consequences. In the first instance, the introduction in an mTR of an additional artificial mutation that abolishes either DNA binding, dimerization, or the association with a CoR results in the abrogation of its dominant negative effect (71,77,78).

 

FIGURE 81.2. Mechanism of the dominant expression of RTH. In the absence of triiodothyronine (T3), occupancy of TRE by TR heterodimers (TR-TRAP) or dimers (TR-TR) suppresses transactivation through association with a corepressor (CoR).  TA:3-activated transcription mediated by TR-TRAP heterodimers involves the release of the CoR and association with coactivators () as well as  the removal of TR dimers from TRE releases their silencing effect and liberates TREs for the binding of active TR-TRAP heterodimers. The dominant negative effect of a mutant TR (), which does not bind TCoA(B)mTR3, can be explained by the inhibitory effect of mTR-containing dimers and heterodimers that occupy TRE. Thus, T3 is unable to activate the mTR-TRAP heterodimer (A′) or release TREs from the inactive mTR homodimers (B′). (Modified from Refetoff S, Weiss RE, Usala SJ. The syndromes of resistance to thyroid hormone.  1993;14:348–399, with permission.)Endocr Rev

Examination of the distribution of TRβ mutations associated with RTH reveals conspicuous absence of mutations in regions of the molecule that are important for dimerization, for the binding to DNA, and for the interaction with CoR (Fig. 81.1). These “cold regions” are not devoid of CpG hot spots, suggesting that these regions of the molecule may not be devoid of natural mutations. However, they would escape detection owing to their failure to produce clinically significant RTH in heterozygotes. This has been indirectly deduced from  studies with mTRβs harboring artificial mutations placed in the CpGs of the cold region 1 (79). Structural studies of the DBD and LBD have provided further understanding regarding the clustered distribution of mTRβ-associated RTH and defects in association with cofactors (80,81,82,83,84).in vitro

Based on the early finding that RTH is associated with mutations confined to the LBD of the TRβ, it was anticipated that the clinical severity of RTH will correlate with the degree of T3-binding impairment. In fact, some studies appeared to be in agreement with this hypothesis (85). Other investigators found a better correlation with the potency of the dominant negative effect of the mTR assessed  (70,86). Examination of 18 different mTRβs suggested that both opinions are correct (87). The serum free Tin vitro4 concentration, used as an indicator of thyrotroph hyposensitivity to TH, correlated with the degree of T3-binding impairment of the corresponding mutant receptor in 12 of these mTRβs, designated as group I. This correlation was not found in 6 of the mTRβs studied; a discrepancy explained in some of them by the demonstration of reduced dominant negative potency due to diminished ability to form homodimers (e.g., R316H and E338W) (70,87). Weakened association with DNA of CoR can produce the same effect.

Although a reduced dominant negative effect can explain a mild impairment of function in the heterozygote, despite severe impairment of T3-binding, the reason for the occurrence of the reverse situation was less readily apparent.

Indeed, more severe RTH and interference with the function of the WT-TRβ, despite mild impairment of T
3 binding or no binding defect at all, has been also observed (88). Two such mTRβs, R243Q and R243W, located in the hinge region of the receptor, have no significant impairment of T3 binding when tested in solution, yet both clinically and  manifested relatively severe RTH and impairment of transactivation function, respectively. The demonstration of normal nuclear translocation but reduced ability of Tin vitro3 to dissociate homodimers formed on TRE suggested that these mutant TRβs have reduced affinity for T3only after they bound to DNA (88). This has been confirmed by measurement of T3 binding after complexing to TRE (89). Another mTRβ, L454V located in the AF2 domain (Fig. 81.1) and with near normal T3 binding, exhibited altered transcriptional function and RTH because of attenuated interaction with the CoA (74). Finally, some mTRβs, such as R383H, exhibit a delay in CoR release despite minimal reduction of T3 binding (90).

In general the relative degree of impaired function among various mTRβs is similar whether tested using TRE-controlled reporter genes that are negatively or positively regulated by T3. Exceptions to this rule are the mTRβs R383H and R429Q, which show greater impairment of transactivation on negatively than positively regulated promoters (87,90,91). The reason for this discrepancy is a matter of conjecture. Given the fact that R429Q binds T3 normally, it is possible that T3 binding to these mTRβs is allosterically modulated by the different TREs and cofactors (92,93).

MOLECULAR BASIS OF THE VARIABLE PHENOTYPE OF RESISTANCE TO THYROID HORMONE

The extremes of the RTH phenotype have a clear molecular basis. Subjects heterozygous for a TRβ gene deletion are normal because the expression of a single TRβ allele is sufficient for normal function. RTH manifests in homozygotes completely lacking the TRβ gene and in heterozygotes that express an mTRβ with a dominant negative effect. The most severe form of RTH, with extremely high TH levels and signs of both hypothyroidism and thyrotoxicosis, occur in a homozygous individual expressing only mutant TRs (29,67). The severe hypothyroidism manifesting in bone and brain of this subject can be explained by the silencing effect of a double-dose mTR and its strong interference with the function of TRα (94), a situation that does not occur in homozygous subjects with TRβ deletion. In contrast, the manifestation of thyrotoxicosis in other tissues, such as the heart, may be explained by the effect that high TH levels have on tissues that normally express predominantly TRα1 (95,96) (see later section on Animal Models of Resistance to Thyroid Hormone). It is for the same reason that tachycardia is a relatively common finding in RTH (97).

Various mechanisms can be postulated to explain the tissue differences in TH resistance within the same subject and among individuals. The distribution of receptor isoforms varies from tissue to tissue (46,98,99). This likely accounts for greater hormonal resistance of the liver as compared with the heart. Differences in the degree of resistance among individuals harboring the same mTRβ could be explained by the relative level of mutant and WT-RT expression. Such differences have been found in one study (100) but not in another (64).

Although in a subset of mTRβs a correlation was found between their functional impairment and the degree of thyrotroph hyposensitivity to TH, it is surprising that this correlation was not maintained with regard to the hormonal resistance of peripheral tissues (87). Subjects with the same mutations, even belonging to the same family, showed different degrees of RTH. A most striking example is that of family G.H., in which the mTRβ R316H did not cosegregate with the RTH phenotype in all family members (101). This variability of clinical and laboratory findings was not observed in affected members of two other families with the same mutation (7,102). A study in a large family with the mTRβ R320H suggests that genetic variability of factors other than TR may modulate the phenotype of RTH (103).

RESISTANCE TO THYROID HORMONE WITHOUT THYROID HORMONE RECEPTOR GENE MUTATIONS

The molecular basis of non-TR-RTH remains unknown. Since the first demonstration of non-TR-linked RTH (2), 29 subjects belonging to 23 different families have been identified (39,104,105). The phenotype is indistinguishable from that in subjects harboring TRβ gene mutations (see later section on Differential Diagnosis). Distinct features are an increased female:male ratio of 2.5:1 and the high prevalence of sporadic cases. Of the 21 families in whom both parents, all siblings, and progeny were examined, the occurrence of RTH in another family member was documented in only 4. In those instances, and as in the case of TRβ-linked RTH, the inheritance pattern is dominant. Although it has been postulated that non-TR-RTH is likely caused by a defect in one of the cofactors involved in the mediation of TH action, proof supporting this contention is lacking. Indeed a search for abnormalities in several corepressors, coactivators, coregulators, and a TH membrane transporter yielded negative results (106,107).

ANIMAL MODELS OF RESISTANCE TO THYROID HORMONE

TRβ Gene Manipulations

 Understanding of TH action , particularly the mechanisms underlying abnormalities observed in patients with RTH, has been bolstered by observations made in genetically manipulated mice. Three types of genetic manipulations have been applied: (a) transgenic mice that overexpress a receptor; (b) deletion of the receptor (knockout or KO mice); and (c) introduction of mutations in the receptor (knock-in or KI mice). The latter two types of gene manipulation, species differences notwithstanding, have yielded true models of the recessively and dominantly inherited forms of RTH, respectively (108).in vivo

The features of RTH found in patients homozygous for TRβ deletion also manifest in the TRβ-deficient mouse (109,110,111) (Table 81.2). Special features, such as sensorineural deafness and monochromatic vision, are characteristic and shared by mice (112,113) and humans (27,62). This indicates that the lack of TRβ per se, rather than deletion of other genetic material, is responsible for the deaf mutism and color blindness in affected members of the family (28). The mouse model allowed for investigations in greater depth into the mechanisms responsible for the development of these abnormalities. Thus, TRβ1 deficiency retards the expression of fast-activating potassium conductance in inner hair cells of the cochlea that transforms the immature cells from spiking pacemaker to high-frequency signal transmitters (114). TRβ2 interacts with transcription factors involved in photoreceptor development to provide timed and spatial order for cone differentiation, resulting in the selective loss off M-opsin (113). The down-regulation of hypothalamic TRH is also TRβ2 specific (115). Mice deficient in TRβ have an increased heart rate that can be decreased to the level of the WT mouse by reduction on the TH level (111). This finding, together with the lower heart rate in mice selectively deficient in TRα1 (116), indicates that TH-dependent changes in heart rate are mediated through TRα, and explains the tachycardia observed in some patients with RTH. TRβ is also required for the T3-mediated regulation of hepatic cholesterol metabolism, which cannot be compensated by TRα1 (117).

TABLE 81.2. TESTS OF THYROID FUNCTION IN MICE AND HUMANS WITH RESISTANCE TO THYROID HORMONE CAUSED BY TRβ GENE MUTATIONS

 

 T4

 

 

T3

 

TSH

 

Genotype

 µg/dL

%WT

ng/dL

%WT

µU/mL

%WT

 

WT

Mouse

3.8 ± 0.7

84 ± 11

25 ± 20

Human

7.8 ± 0.9

119 ± 32

3.1 ± 2.2

Hetorozygous KO

Mouse

4.3 ± 0.7

113

98 ± 14

117

19 ± 21

76

Human

7.6 ± 1.5

97

102 ± 11

86

3.5 ± 2.5

113

Homozygous KO

Mouse

7.8 ± 2.0

205

142 ± 43

169

136 ± 116

544

Human

15.6 ± 4.5

203

209 ± 21

176

5.5 ± 2.6

177

WT

Mouse

3.0 ± 0.8

147 ± 46

—-

58 ± 41

Human

8.0 ± 0.7

115 ± 30

2.1 ± 1.0

Heterozygous KI

Mouse

6.3 ± 1.2

210

283 ± 83

193

129 ± 140

230

Human

18.3 ± 4.6

230

286 ± 87

250

3.5 ± 3.4

0

Homozygous KI

Mouse

36 ± 14

1210

1, 257 ± 507

855

19, 485 ± 6, 520

34, 790

Human

54

680

850

740

840

40, 000

 

KI, knock-in; KO, knockout; WT, wild-type; T3, triiodothyronine; T4, thyroxine; TSH, thyrotropin.

The combined deletion of TRα1 and α2 produces no important alterations in TH or TSH concentrations in serum (51). However, expression of the carboxyl-terminal fragment of the TRα, due to the presence of a natural promoter and a transcription start site in intron 5, produces in the context of deficient intact TRα severe neonatal hypothyroidism that is lethal but can be rescued by short-term treatment with TH (118). The complete lack of TRs, both α and β, is compatible with life (51,52). This contrasts with the complete lack of TH, which in the athyreotic Pax8-deficient mouse results in death prior to weaning, unless rescued by TH treatment (119). The survival of combined TR-deficient mice is not due to expression of a yet unidentified TR but to the absence of the noxious effect of aporeceptors. Indeed, removal of the TRα gene rescues Pax8 KO mice from death (120). The combined TRβ- and TRα-deficient mice have serum TSH levels that are 500-fold higher than those of WT mice and T4 concentrations 12-fold above the average normal mean (51). Thus, in this instance, the presence of an aporeceptor does not seem to be required for the up-regulation of TSH.

The first, partial model of the dominantly inherited RTH used somatic gene transfer of a mutant TRβ1, G345R, by means of a recombinant adenovirus (121). The liver of these mice was resistant to TH, as demonstrated by the reduced responsiveness of TH controlled genes to the administration of L-T3. Overexpression of the WT TRβ increased the severity of hypothyroidism in the TH-deprived mouse, confirming that the unliganded TR has a constitutive effect  as  Similarly, the response to TH is enhanced in animals that overexpress the WT TR. Transgenic mice have also been developed that express mTRβ1 genes (122). True mouse models of dominantly inherited RTH were recently generated by targeted mutations in the TRβ gene (123,124). Mutations were modeled on those formerly identified in humans with RTH [frame-shift resulting in 16 carboxyl-terminal nonsense amino acids (PV mouse) and T337Δ]. As in humans, the phenotype manifested in the heterozygous KI animals, and many of the abnormalities observed in humans were reproduced in these mice (Table 81.2).in vivoin vitro.

Recent work has shown that NcoA (SRC-1) deficient mice have RTH manifesting with elevated T4, T3, and TSH concentrations (125). A more mild form of RTH was identified in mice deficient in RXRγ (126). Animals show reduced sensitivity to T3 in terms of TSH down-regulation but not metabolic rate. These data indicate that abnormalities in cofactors can produce RTH.

The Phenotype of TRα Gene Mutation in the Mouse

The question of why mutations in the TRα gene have not been identified in humans was partially answered by the study of mice with targeted gene manipulations. As stated in the preceding section, TRα gene deletions, total or only α1, failed to produce an RTH phenotype. Similarly, mice with targeted TRα gene mutations failed to manifest the phenotype of RTH. Human mutations known to occur in the TRβ gene were targeted in homologous regions of the TRα gene of the mouse. These were the PV frameshift mutation in the carboxyl-terminus of TRα1 (35), TRα1 R348C [equivalent to TRβ R438C (36)] and P398H [equivalent to TRβ P453H (37)]. The resulting phenotypes were variable but did not exhibit RTH. In the heterozygous state, the former two show severe retardation in postnatal development and growth, while the latter has an increase in body fat and insulin resistance. Decreased heart rate and cold-induced thermogenesis, as well as reduced fertility, were also observed. The TRαPV KI mice exhibited severe reduction in brain glucose utilization and synaptic density (127,128). All three TRα KIs were lethal in the homozygous state, recapitulating the noxious effect of unliganded TRα1.

PATHOGENESIS

The reduced sensitivity to TH in subjects with RTH is shared to a variable extent by all tissues. The hyposensitivity of the pituitary thyrotrophs results in nonsuppressed serum TSH, which in turn increases the synthesis and secretion of TH. The persistence of TSH secretion in the face of high levels of free TH contrasts with the low TSH levels in the more common forms of TH hypersecretion that are TSH independent. This apparent paradoxic dissociation between TH and TSH is responsible for the wide use of the term “inappropriate secretion of TSH” to designate the syndrome. However, TSH hypersecretion is not at all inappropriate, given the fact that the response to TH is reduced. It is compensatory and appropriate for the level of TH action mediated through a defective TR. As a consequence, most patients are eumetabolic, although the compensation is variable among affected individuals and tissues in the same individual. However, the level of tissue responses do not correlate with the level of TH, probably owing to a discordance between the hormonal effect on the pituitary and other body tissues. Thyroid gland enlargement occurs with chronic, though minimal, TSH hypersecretion due to increased biologic potency of this glycoprotein through increased sialylation (129). Administration of supraphysiologic doses of TH are required to suppress TSH secretion without induction of thyrotoxic changes in peripheral tissues.

When sought, TSH-binding antibodies could not be detected (130,131). Thyroid-stimulating antibodies, which are responsible for the thyroid gland hyperactivity in Graves' disease, have been conspicuously absent in patients with RTH. Another potential thyroid stimulator, human chorionic gonadotropin, is also not involved (132,133).

The selectivity of the resistance to TH has been convincingly demonstrated. When tested at the pituitary level, both thyrotrophs and lactotrophs were less sensitive only to TH. Thyrotrophs responded normally to the suppressive effects of the dopaminergic drugs L-dopa and bromocriptine (131,134) as well as to glucocorticoids (131,135,136). Studies conducted in cultured fibroblasts confirm the  findings of selective resistance to TH. The responsiveness to dexamethasone, measured in terms of glycosaminoglycan (137) and fibronectin synthesis (138), was preserved in the presence of Tin vivo3 insensitivity (Fig. 81.3).

 

FIGURE 81.3. The inhibitory effect of triiodothyronine (T3) and dexamethasone on glycosaminoglycan synthesis in fibroblasts from subjects with TH and glucocorticoid resistance compared with that in fibroblasts from a normal (nonresistant) subject. Note that fibroblasts from the patient with RTH had an attenuated response to T3 but not to dexamethasone, while those from the patient with glucocorticoid resistance showed an attenuated response to dexamethasone only. (Modified from Refetoff S, Weiss RE, Usala SJ. The syndromes of resistance to thyroid hormone.  1993;14:348–399, with permission.)Endocr Rev

Several of the clinical features encountered in some patients with RTH may be the manifestation of selective tissue deprivation of TH during early stages of development. These clinical features include retarded bone age, stunted growth, mental retardation or learning disability, emotional disturbances, attention deficit/hyperactivity disorder (ADHD), hearing defects, and nystagmus (1). A variety of associated somatic abnormalities appear to be unrelated pathogenically and may be the result of involvement of other genes such as in major deletions of DNA sequences (28). However, no gross chromosomal abnormalities have been detected on karyotyping (27,139).

PATHOLOGY

Little can be said about the pathologic findings in tissues other than the thyroid gland because of unavailability of autopsy data from patients with RTH. Electron microscopic examination of striated muscle obtained by biopsy from one patient revealed mitochondrial swelling, also known to be encountered in thyrotoxicosis (27). This is compatible with the predominant expression of TRα in muscle (140), resulting in a low level of expression of the mutant TRβ and unobstructed action of the excessive amount of circulating TH available to this tissue. Light microscopy of skin fibroblasts stained with toluidine blue showed moderate to intense metachromasia (141) as described in myxedema and is probably a manifestation of a decreased TH action in this tissue. However, in contrast to patients with myxedema due to TH deficiency, treatment with the hormone failed to induce a disappearance of the metachromasia in fibroblasts from patients with RTH.

Thyroid tissue, obtained by biopsy or at surgery, revealed various degrees of hyperplasia of the follicular epithelium (130,131,142,143). The follicles may vary in size, from small to large. Some specimens have been described as “adenomatous goiters,” others as “colloid goiters,” and still others as normal thyroid tissue. Occasional lymphocytic infiltration, a finding not related to the syndrome, is due to the fortuitous coexistence of thyroiditis (144).

CLINICAL FEATURES

Characteristic of the RTH syndrome is the paucity of specific clinical manifestations. When present, manifestations are variable from one patient to another. Investigation leading to the diagnosis has been undertaken because of the presence of goiter, hyperactive behavior or learning disabilities, developmental delay, and sinus tachycardia (Fig. 81.4). The finding of elevated serum TH levels in association with nonsuppressed TSH is usually responsible for the pursuit of further studies leading to the diagnosis.

 

FIGURE 81.4. The reasons prompting further investigation of the key member of each family with resistance to thyroid hormone.

The majority of untreated subjects maintain a normal metabolic state at the expense of high levels of TH. The degree of this compensation of tissue hyposensitivity to the hormone is, however, variable among individuals as well as in different tissues. As a consequence, clinical and laboratory evidence of TH deficiency and excess often coexist. For example, RTH can present with a mild to moderate growth retardation, delayed bone maturation, and learning disabilities suggestive of hypothyroidism, along with hyperactivity and tachycardia, compatible with thyrotoxicosis. The more common clinical features and their frequency are given in Table 81.3. Frank symptoms of hypothyroidism are more common in those individuals who, because of erroneous diagnosis, have received treatment to normalize their circulating TH levels. In such patients, symptoms of fatigue, somnolence, depression, weight gain, and bradycardia were noted. In children, inappropriate treatment has aggravated the delay in growth and development (1).

TABLE 81.3. CLINICAL FEATURES

 

Findings

Frequency (%)

 

Thyroid gland

Goiter

66–95

Heart

Tachycardia

33–75

Nervous system

Emotional disturbances

60

Hyperkinetic behavior

33–68

Attention deficit hyperactivity disorder

40–60

Learning disability

30

Mental retardation (IQ < 70)

4–16

Hearing loss (sensorineural)

10–22

Growth and development

Short stature (< 5%)

18–25

Delayed bone age >2 SD

29–47

Low body mass index (in children)

33

Recurrent ear and throat infections

55

 

Data derived from references 1, 7, and 145.

On physical examination, goiter is by far the most common abnormality. It has been reported in 66% to 95% of cases. In some patients without clinically obvious thyroid gland enlargement, goiter could be detected by ultrasonography, was absent due to prior surgery, or was present in other affected members of the family. Gland enlargement is usually diffuse; nodular changes and gross asymmetry are found in recurrent goiters after surgery.

Sinus tachycardia is also common, with some studies reporting frequency as high as 80% (7). Palpitations often bring the patient to the physician, and the finding of tachycardia is the most common reason for the erroneous diagnosis of autoimmune thyrotoxicosis or the suspicion of PRTH.

Careful evaluation of subjects with RTH has shown that about half have some degree of learning disability with or without ADHD (1,146). One fourth have intellectual quotients (IQs) of less than 85, but frank mental retardation (IQ < 60) has been found only in 3% of cases. Impaired mental function was found to be associated with impaired or delayed growth (< 5th percentile) in 20% of subjects, although growth retardation alone is rare (4%) (1). Despite the high prevalence of ADHD in patients with RTH, the occurrence of RTH in children with ADHD must be rare, none having been detected in 330 such children studied (147,148). Current data do not support a genetic linkage of RTH with ADHD. Rather, the higher prevalence of low IQ scores may confer a higher likelihood for subjects with RTH to exhibit ADHD symptoms (102).

A variety of physical defects that cannot be explained on the basis of TH deprivation or excess have been recorded. These include major or minor somatic defects, such as winged scapulae, vertebral anomalies, pigeon breast, prominent pectoralis, birdlike facies, scaphocephaly, craniosynostosis, short fourth metacarpals, as well as Besnier's prurigo, congenital ichthyosis, and bull's eye type macular atrophy (1). No particular defect appears to be prevalent in RTH. A distinct body habitus and deaf-mutism occurred in all three affected members of a single family with TRβ gene deletion (27).

COURSE OF THE DISEASE

The course of the disease is as variable as is its presentation. Some subjects have normal growth and development, and lead a normal life at the expense of high TH levels and a small goiter. Others have variable degrees of mental and growth retardation. Symptoms of hyperactivity tend to improve with age, but this is not characteristic of RTH since it has been also observed in subjects with ADHD only.

Goiter has recurred in every patient who underwent thyroid surgery. As a consequence, some subjects have been submitted to several consecutive thyroidectomies or treatments with radioiodide (143,149,150,151).

Only in one patient is RTH believed to have contributed to his demise. This child, homozygous for a dominantly inherited TRβ mutation and a resting heart rate of 190 beats/minute (29), died from cardiogenic shock complicating staphyloccocal pneumonia (B.B. Bercu, personal communication).

LABORATORY FINDINGS

Thyroid Hormone and Its Metabolites in Serum

In the untreated patient, elevation in the concentration of serum free T4 is a sine qua non requirement for the diagnosis of RTH. It is accompanied by high serum levels of T3. Serum TBG and TTR concentrations are normal. The resin T3 uptake is usually high, as is the case in patients with thyrotoxicosis.

Serum T4 and T3 values vary from just above to severalfold the upper limit of normal. Although the levels may vary in the course of time in the same patient (7), the degree of T4 and T3 elevation is usually congruent, resulting in a normal T3:T4 ratio (1). This is in contrast to the disproportionate increase in serum T3 concentration relative to that of T4, characteristic of autoimmune thyrotoxicosis (152). This observation has led some investigators to consider the possibility of reduced extrathyroidal conversion of T4 to T3 in patients with RTH (143).

Reverse T3 concentration is also high in patients with RTH, as is that of another product of T4 degradation, 3,3′-T2 (130). Serum thyroglobulin concentration also tends to be high, and the degree of its elevation reflects the level of TSH-induced thyroid gland hyperactivity.

Thyrotropin and Other Thyroid Stimulators

A characteristic, if not pathognomonic, feature of the syndrome is the presence of TSH in serum and preservation of its response to TRH despite an elevated TH level (153). In most cases, the basal serum TSH concentration is normal and the circadian rhythm is unaltered (154,155). TSH values above 10 mU/L occur in subjects that have received treatment aimed at reducing their high level of TH. The TSH response to TRH is either normal or exaggerated.

Thyrotropin has increased biologic activity (129,156), and the concentration of its free α subunit is not disproportionately high. Except for the rare occurrence of coincidental autoimmune thyroiditis (157), serum is free of thyroid-stimulating immunoglobulins as well as antibodies against thyroglobulin and thyroid peroxidases.

Thyroid Gland Activity and Integrity of Hormone Synthesis

The fractional uptake of radioiodide by the thyroid gland is high, as is the absolute amount of accumulated iodide. The latter is normally organified, since no discharge of trapped iodide has been observed following the administration of perchlorate (27,149,158). No abnormal iodide-containing compounds have been detected in the circulation (27,141).

Turnover of Thyroid Hormone

In vivo turnover kinetics of T4 showed a normal or slightly increased volume of distribution and fractional disappearance rate of the hormone. However, because of the high concentration of T4 in serum, the extrathyroidal pool and absolute daily production of T4 are increased, up to twofold the upper limit of normal, and that of T3 is increased by about two- to fourfold (133,141,149,159,160). However, the extrathyroidal conversion of T4 to T3 is normal (160).

In Vivo Effects of Thyroid Hormone

The impact of TH on peripheral tissues has been assessed  by a variety of tests. By and large, results have been normal and, given the high serum levels of TH, suggest a reduced biologic response to the hormone (1,7). The metabolic status has been evaluated by measurements of the basal metabolic rate (BMR), serum cholesterol, carotene, triglycerides, creatine kinase, alkaline phosphatase, angiotensin-converting enzyme, SHBG, ferritin, and osteocalcin, all of which usually have been within the normal range. Urinary excretion of magnesium, hydroxyproline, creatine, creatinine, carnitine, and cyclic adenosine monophosphate (cAMP), all found to be elevated in thyrotoxicosis, have been normal or low, suggesting normal or slightly reduced TH effect. With the exception of an increased resting pulse rate in about half of the patients with RTH, the cardiac function is only minimally altered. Two-dimensional and Doppler echocardiography showed mild hyperthyroid effect on cardiac systolic and diastolic function of the myocardium, whereas other parameters, such as ejection and shortening fractions of the left ventricle, systolic diameter, and left ventricle wall thickness, were normal (97). The Achilles tendon reflex relaxation time has also been normal or slightly prolonged. The PRL response to TRH was not blunted as it is in patients with thyrotoxicosis. In fact, the PRL hyperresponsiveness in some patients with RTH may be due to the functional TH deprivation at the level of the lactotrophs (153).in vivo

Other Endocrine Tests

Evaluation of endocrine function by a variety of tests has failed to reveal significant defects other than those related to the thyroid. The following laboratory analyses have been conducted in patients with RTH and were found to be within the normal range: serum levels of cortisol and its diurnal rhythm; testosterone, estrogens, and progesterone; gonadotropins and their response to gonadotropin-releasing hormone; adrenocorticotropic hormone; insulin; prolactin and its response to TRH, L-dopa and glucocorticoids; growth hormone and its response to insulin hypoglycemia, arginine, and pyrogen; as well as the urinary excretion of 17-hydroxycorticoids, 17-ketosteroids, vanillylmandelic acid, adrenaline, and noradrenaline. Radiologic and magnetic resonance examinations of the pituitary gland and sella turcica have shown no anatomic abnormalities.

Bone Age

Radiologic evidence of delayed bone maturation has been observed in one half of patients with RTH diagnosed during infancy or childhood (1). However, the majority achieve normal adult stature. It is unclear whether the presence, in some cases, of stippled epiphyses is also the consequence of reduced TH action.

IN VITRO TESTS OF THYROID HORMONE ACTION

The normal stimulatory effect of T3 on the degradation rate of low-density lipoproteins was reduced in cultured skin fibroblasts obtained from three affected members of one family (151). Similarly, T3 and T4, but not dexamethasone, failed to produce the normal inhibitory effect on the synthesis of glycosaminoglycans in fibroblasts from four of six patients with RTH (137) (Fig. 87.3). In contrast, T3 normally stimulated glucose consumption by cultured fibroblasts from a patient with RTH (136,161).  demonstration of TH resistance has been most consistent by measurement of the normal inhibitory effect of TIn vitro3 on the synthesis of fibronectin and its mRNA in skin fibroblasts maintained in culture. Of 12 patients with RTH who were studied, 11 showed either an attenuated or paradoxic response (138).

Responses to the Administration of Thyroid Hormone

Because reduced responsiveness to TH is central in the pathogenesis of the syndrome, patients have been given TH in order to observe their responses and thereby establish the presence of hyposensitivity to the hormone. Unfortunately, data generated have been discrepant, not only because of differences in the relative degree of resistance to TH among patients, but also because of lack of uniformity in the manner the hormone trials have been performed. These include differences in hormonal preparations, dosages, duration of treatment, and the type of observations and measurements performed, not to mention the conspicuous lack of adequate control studies.

Administration of TH ultimately suppresses TSH secretion, resulting in a decrease and eventually the abolition of the TSH response to TRH. The amount of TH necessary to produce such an effect has been variable, as has been the relative effectiveness of L-T3 as compared with L-T4. Such observations have led to earlier speculations that some patients may have an abnormality in conversion of T4 to T3 (142,143). The decreased TSH secretion during the administration of supraphysiologic doses of TH is accompanied by a reduction in the thyroidal radioiodide uptake and, when exogenous T3 is given, a reduction in the pretreatment level of serum T4 (132,133,143,149,151).

Various responses of peripheral tissues to the administration of TH have been quantitated. Most notable are measurements of the BMR, pulse rate, reflex relaxation time, serum cholesterol, lipids, enzymes, osteocalcin and SHBG, and urinary excretion of hydroxyproline, creatine, and carnitine. Either no significant changes were observed, or they were much reduced relative to the amount of TH given (1).

Of great importance are observations on the catabolic effect of exogenous TH. In some subjects with RTH, L-T4 given in doses of up to 1,000 µg/day, and L-T3up to 400 µg/day, failed to produce weight loss without a change in calorie intake, nor did they induce a negative nitrogen balance (131,132,141). In contrast, administration of these large doses of TH over a prolonged period of time was apparently anabolic, as evidenced by a dramatic increase in growth rate and accelerated bone maturation (11,131).

Effects of Other Drugs

As expected, administration of the TH analogue 3,5,3′-triiodo-L-thyroacetic acid (TRIAC) to patients with RTH produced attenuated responses (141,155,162).

Administration of glucocorticoids promptly reduced the TSH response to TRH and the serum T4 concentration (131,132,135,142,159).

Administration of L-dopa and bromocriptine produced a prompt suppression of TSH secretion, as well as a diminution of the thyroidal radioiodide uptake and serum T3 level (131,134,142). Domperidone, a dopamine antagonist, caused an increase in the serum TSH level when given to patients with RTH (155). These observations indicate that, in this syndrome, the normal inhibitory effect of dopamine on TSH is intact.

The response to antithyroid drugs has shown some variability. Methimazole and propylthiouracil, in doses usually effective in reducing the high serum TH level of hyperthyroidism of autoimmune etiology, had no effect in two patients (141). However, in other cases of RTH, antithyroid drugs induced some decrease in the circulating level of TH, producing a reciprocal change in the TSH concentration (32,139,158,163). Administration of 100 mg of iodine daily had a similar effect in one patient (133), but 4 mg potassium iodide per day produced no changes in another (141).

Observations on the effect of other drugs such as diazepam and chlorpromazine are limited. With one exception (141), propranolol and atenolol caused a significant reduction in heart rate.

DIFFERENTIAL DIAGNOSIS

Because the clinical presentation of RTH is variable, detection requires a high degree of suspicion. The differential diagnosis includes all possible causes of hyperthyroxinemia. The sequence of diagnostic procedures listed in Table 81.4 is suggested.

TABLE 81.4. SUGGESTED SEQUENCE OF DIAGNOSTIC PROCEDURES IN SUSPECTED RESISTANCE TO THYROID HORMONE

 

1. Usual presentation: high serum levels of free T4 and T3 with nonsuppressed TSH.

2. Confirm the elevated serum levels of free thyroid hormone (T4 and T3) and exclude TH transport defects.

3. Obtain tests of thyroid function in first-degree relatives: parents, siblings, and children.

4. In the absence of similar TH test abnormalities in other family members, exclude the presence of a pituitary adenoma by measurement of α subunit in serum.

5. Demonstrate a blunted TSH suppression and metabolic response to the administration of supraphysiologic doses of TH (see L-T3 suppression protocol, Fig. 87.5).

6. Perform linkage analysis and demonstrate a TH receptor gene defect.

 

T3, triiodothyronine; T4, thyroxine; TH, thyroid hormone; TSH, thyrotropin.

The presence of elevated serum T4 concentration with nonsuppressed TSH needs to be confirmed by repeated testing. The possibility of an inherited or acquired increase in serum TBG must be excluded by direct measurement and by estimation of the circulating free T4 level. The presence of a high serum T3level must also be documented because reduced conversion of T4 to T3 by peripheral tissues may occasionally give rise to the elevation of total and free T4 but not T3 levels. This may occur transiently in a variety of nonthyroidal illnesses or during the administration of some drugs (see Chapter 11). A familial form of hyperthyroxinemia, presumably due to a defective T4 monodeiodination, has been also described (164). The inherited abnormality of T4 binding to an albumin presents with high serum T4 but normal T3 concentration (See Chapters 6 and 13).

A rare cause of elevated serum T4 and T3 level is the endogenous production of antibodies directed against these hormones, which can be excluded by direct testing

Most useful is the measurement of the serum TSH. Under most circumstances, patients with high concentrations of circulating free TH have virtually undetectable serum TSH levels, which characteristically fail to increase in response to TRH. This is true even when the magnitude of TH excess is minimal and therefore subclinical both on physical examination or by other laboratory tests (See Chapters 13 and 79). The combination of elevated serum levels of TH and nonsuppressed TSH narrows the differential diagnosis to RTH and autonomous hypersecretion of TSH associated with pituitary tumors. The latter should be suspected when other members of the family, particularly the parents of the patient, fail to exhibit thyroid test abnormalities. Rarely, endogenous antibodies to TSH or some of the test components can give rise to false increases in serum TSH values.

In addition to symptoms and signs of thyrotoxicosis, some patients with TSH-producing (thyrotroph) pituitary adenomas may present with acromegaly due to the concomitant hypersecretion of growth hormone by the tumor. Galactorrhea and amenorrhea in association with hyperprolactinemia have also been reported (see Chapter 24). The tumors may be demonstrated by computed tomography or by magnetic resonance imaging of the pituitary. A typical finding in patients with TSH-producing pituitary adenomas is a disproportionate abundance in serum of free α subunit of TSH relative to whole TSH (165). Moreover, with rare exceptions (166), serum TSH fails to increase above the basal level in response to TRH or to decrease during the administration of TH. Ectopic production of TSH has not been unequivocally demonstrated (see Chapter 26). It is uncertain that endogenous TRH hypersecretion could maintain high TSH levels and induce hyperthyroidism.

Because the etiology of PRTH is not distinct from that of RTH, failure to demonstrate an anatomic defect in the pituitary gland by imaging does not exclude the presence of a small adenoma or thyrotroph hyperplasia. Furthermore, absence of conspicuous signs and symptoms of hypermetabolism are not sufficient to rule out thyrotoxicosis. The occurrence of an apparent selective hyposensitivity to T4, but not T3, has been reported in one family (167). Initially attributed to a putative defect in type II 5′-deiodinase, it was recently shown that affected family members had the TRβ R320L mutation (D. Gross, P.R. Larsen, and W.W. Chin, personal communication).

Proving the existence of peripheral tissue resistance to TH is not simple. Lack of clinical symptoms and signs of hypermetabolism are not sufficient to establish the diagnosis of RTH, and no single test objectively proves the existence of eumetabolism. Because resistance to the hormone is variable in different tissues, no single test measuring a particular response to TH is diagnostic. Furthermore, results of most tests that measure the effect of TH on peripheral tissues show considerable overlap among thyrotoxic, euthyroid, and hypothyroid subjects. The value of these tests is enhanced if measurements are obtained before and following the administration of supraphysiologic doses of TH.

Although the demonstration of TRβ gene mutation is sufficient to establish the diagnosis of RTH,  demonstration of tissue resistance to TH is required when RTH is not associated with a TR gene mutation (2). A standardized diagnostic protocol, using short-term administration of incremental doses of L-Tin vivo3 and outlined in Fig. 81.5, is recommended. It is designed to assess several parameters of central and peripheral tissue effects of TH in the basal state and in comparison with those elicited following the administration of L-T3. The three doses given in sequence are a replacement dose of 50 µg/day and two supraphysiologic doses of 100 and 200 µg/day. The hormone is administered in a split dose every 12 hours, and each incremental dose is given for the period of 3 days. Doses are adjusted in children and in adults of unusual size to achieve the same level of serum T3. L-T3, rather than L-T4, is used because of its direct effect on tissues, bypassing potential defects of T4 transport and metabolism, which may also produce attenuated responses. In addition, the more rapid onset and shorter duration of T3 action reduces the period required to complete the evaluation and shortens the duration of symptoms that may arise in individuals with normal responses to the hormone. Responses to each incremental dose of L-T3 are expressed as increments and decrements or as a percentage of the value measured at baseline. The results of such a study are shown in Figs. 81.6 and 81.7.

 

FIGURE 81.5. Schematic representation of a protocol for the assessment of the sensitivity to thyroid hormone using incremental doses of liothyronine (L-T3). (Adapted from Refetoff S, Weiss RE, Usala SJ. The syndromes of resistance to thyroid hormone.  1993;14: 348–399, with permission.)Endocr Rev

 

FIGURE 81.6. Thyrotroph responses to thyrotropin stimulation at baseline and after the administration of graded doses of liothyronine (L-T3). The hormone was given in three incremental doses, each for 3 days as depicted in Fig. 81.5. Results are shown for patients with resistance to thyroid hormone (RTH) in the presence (left) or absence (right) of a TRβ gene mutation, together with the unaffected mother of the patient with non-TR-RTH (center).

 

FIGURE 81.7. Responses of peripheral tissues to the administration of liothyronine (L-T3) in the presence or absence of mutations in the TRβ gene. The hormone was given as described in Fig. 81.6. Note the stimulation of ferritin and sex hormone binding globulin () and the suppression of cholesterol and creatine kinase () in the normal subject. Responses in affected subjects, with or without a TRβ gene mutation, were blunted or paradoxic.SHBGCK

Failure to differentiate RTH from ordinary thyrotoxicosis has resulted in the inappropriate treatment of nearly one third of patients. The diagnosis requires awareness of the possible presence of RTH, usually suspected when high levels of circulating TH are not accompanied by a suppressed TSH.

TREATMENT

Although no specific treatment is available to fully and specifically correct the defect, the ability to identify specific mutations in the TRs provides a means for prenatal diagnosis and appropriate family counseling. This is particularly important in families whose affected members show evidence of growth or mental retardation. Fortunately, in most cases of RTH, the partial tissue resistance to TH appears to be adequately compensated for by an increase in the endogenous supply of TH. Thus, treatment need not be given to such patients. This is not the case in patients with limited thyroidal reserve due to prior ablative therapy. In these patients, the serum TSH level can be used as a guideline for hormone dosage.

Not infrequently, some peripheral tissues in patients with RTH appear to be relatively more resistant than the pituitary. Thus, compensation for the defect at the level of peripheral tissues is incomplete. In such instances, judicious administration of supraphysiologic doses of the hormone is indicated. Because the dose varies greatly among cases, it should be individually determined by assessing tissue responses. In childhood, particular attention must be directed to growth, bone maturation, and mental development. It is suggested that TH be given in incremental doses and that the BMR, nitrogen balance, and serum SHBG be monitored at each dose, and bone age and growth on a longer term. Development of a catabolic state is an indication of overtreatment.

The exact criteria for treatment of RTH in infancy have not been established. This is often an issue when the diagnosis is made at birth or in early infancy. In infants with elevated serum TSH levels, subclinical hypothyroidism may be more harmful than treatment with TH. Indications for treatment may include a TSH level above the upper limit of normal, retarded bone development and failure to thrive. The outcome of affected older members of the family who did not receive treatment may serve as a guideline. Longer follow-up and psychological testing of infants who have been given treatment will determine the efficacy of early intervention.

A recent survey has shown an increased miscarriage rate and low birth weight of normal infants born to mothers with RTH (168). It is unclear at this time whether intervention during early gestation is appropriate. However, mothers with RTH should be followed carefully during pregnancy and not allowed to have low serum TSH values. The wisdom of  treatment is questionable (169,170).in utero

Patients with more severe thyrotroph resistance and symptoms of thyrotoxicosis may require therapy. Symptomatic treatment with an adrenergic β-blocking agent, preferably atenolol, usually suffices. Treatment with antithyroid drugs or thyroid gland ablation increase TSH secretion and may result in thyrotroph hyperplasia. Development of true pituitary tumors, even after long periods of thyrotroph overactivity, is extremely rare (171).

It has been shown recently that treatment with supraphysiologic doses of L-T3, given as a single dose every other day, is successful in reducing goiter size with remarkable cosmetic benefits and without causing side effects (172). This appears to be the treatment of choice considering that postoperative recurrence of goiter is the rule. The L-T3 dose must be adjusted in increments until TSH and TG are suppressed and reduction of goiter size is observed.

Patients with presumed isolated peripheral tissue resistance to TH present a most difficult therapeutic dilemma. The problem is, in reality, diagnostic rather than therapeutic. Many, if not most, patients falling into this category are habitual TH users. Gradual reduction of the TH dose and psychotherapy is recommended.

ACKNOWLEDGMENTS

This work was supported in part by U.S. Public Health Grants DK15070 and RR00055.

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