An overview of thyroid function tests in subjects with resistance to thyroid hormone and related disorders

Abstract

Confirmation of sustained syndrome of inappropriate secretion of thyrotropin (SITSH) is a milestone in diagnosis of β type of resistance to thyroid hormone (RTHβ). The differential diagnoses of RTHβ include TSH-producing pituitary adenoma (TSHoma) and familial dysalbuminemic hyperthyroxinemia (FDH), which also present SITSH. Recently, patients with RTHα caused by a mutation in thyroid hormone receptor α were reported and they did not present SITSH but a decline in the serum T4/T3 ratio. This review was aimed to overview thyroid function tests in RTH and related disorders. First, the characteristics of the thyroid function in RTHβ, TSHoma, and FDH obtained from a Japanese database are summarized. Second, the degrees of SITSH in patients with truncations and frameshifts were compared with those in patients with single amino acid deletions and single amino acid substitutions obtained from the literature. Third, the degrees of SITSH in homozygous patients were compared with those in heterozygous patients with cognate mutations. Finally, the FT3/FT4 ratios in RTHα are summarized. In principle, the TSH values in FDH were within the normal range and apparent FT4 values in FDH were much higher than in RTHβ and TSHoma. The FT3/FT4 values in RTHβ were significantly lower than in TSHoma. The degrees of SITSH in patients with truncations and frameshifts were more severe than those in patients with single amino acid deletions and single amino acid substitutions, and those in homozygous patients were more severe than those in heterozygous patients with cognate mutations. The FT3/FT4 ratios in RTHα were higher than 1.0.

Introduction

The effects of the thyroid hormone are mediated by thyroid hormone receptors (TRs). There are two different subtypes of TR, TRα, and TRβ. Therefore, the syndrome of resistance to thyroid hormone (RTH), which is characterized by the reduced response to thyroid hormone in various tissues, should include RTH due to TRα mutation (RTHα) in addition to RTH due to TRβ mutation (RTHβ). However, because a family with RTH first reported by Refetoff et al. in 1967 [1] presented elevated thyroid hormone levels with non-suppressed thyrotropin (also known as thyroid-stimulating hormone [TSH]), so called syndrome of inappropriate secretion of TSH (SITSH), SITSH has become a hallmark of RTH. Since a germline mutation in the TRβ gene in a patient with RTH was first found in 1989 [2], hundreds of RTH have been reported due to TRβ mutations. Beside them, no mutations in TRβ as well as in TRα were found in some patients with SITSH (called nonTR-RTH) [3]. RTHα was reported in 2012 [4] using whole-exome sequencing, but it did not present SITSH. Given that TRβ, but not TRα, mediates the negative feedback regulation of TSH by the thyroid hormone in the anterior pituitary [5], it is reasonable that RTHα does not present SITSH. The committee for formulating the diagnostic guideline of RTHβ in the Japan Thyroid Association (JTA) has defined the guideline and the algorism, which starts at SITSH, a hallmark of RTHβ [6]. The differential diseases of RTHβ are TSH-producing pituitary adenoma (TSHoma) and familial dysalbuminemic hyperthyroxinemia (FDH) because all three of them present SITSH, while true FT4 and/or FT3 values are not high in subjects with FDH [7]. To date, over 3,000 affected individuals belonging to approximately 1,000 families have been identified [8], harboring mutations in the TRβ gene. Most mutations in this gene are substitutions of a single amino acid in the ligand binding domain (LBD) [9]. Recently, we found a familial case of heterozygous p.R316C who manifested occasional SITSH [10]. In contrast, Ferrara et al. [11] reported a patient with severe RTH homozygous for the p.R316C mutation. In addition, RTHα does not present the phenotype of SITSH [4] but rather a decline in the serum T4/T3 ratio. Here I compared and summarized the characteristics of thyroid function in order to differentiate RTH-related diseases, such as RTHβ, TSHoma, FDH, and RTHα, by conducting literature searches.

Methods

Thyroid function tests in Japanese cases of RTHβ, TSHoma and FDH—from JMAS database—

Because JTA has listed TSHoma and FDH as the differential diagnoses of RTHβ, as mentioned above, RTHβ, TSHoma, and FDH patients were searched using the Japan Medical Abstract Society (JMAS [https://search.jamas.or.jp/]) database to compare the degrees of SITSH. The last date when the search was done was February 18, 2021. The mean values were adopted when multiple measurements for one patient were described at different times in the literature. However, the values measured under transient inappropriate treatments (for example, ablative therapy under misdiagnosed as Grave’s disease) were excluded. In addition, the values measured under special complications such as Grave’s disease and painless thyroiditis, which affect the thyroid function, were also excluded.

Thyroid function tests in RTHβ patients with an insertion, deletion or truncation in TRβ

Because the degree of SITSH among RTHβ patients caused by a single amino acid substitution in TRβ is relatively mild according to our previous study [9], RTHβ patients were searched caused by an insertion, deletion, or truncation in TRβ. Because there was only a limited number of reports regarding patients with an insertion, deletion, truncation in JMAS, PubMed (http://www.ncbi.nlm.nih.gov/pubmed/) database was used in this study. The key words for PubMed search were ‘thyroid hormone resistance beta’ and ‘insertion, deletion, or truncation’.

Thyroid function tests in homozygous RTHβ patients

Homozygous mutants for RTHβ patients were searched to compare with their heterozygous counterparts. Because no patient with homozygous mutation was reported in Japan before the search day, PubMed database was used. The key words for PubMed search were ‘thyroid hormone resistance beta’ and ‘homozygous’.

Thyroid function tests in RTHα patients

RTHα patients were searched to clarify the characteristics of their thyroid function. Because no RTHα patient was reported in Japan before the search day, PubMed database was used. The key words for PubMed search were ‘thyroid hormone resistance alpha’.

Statistical analysis

Data are expressed as the mean ± SD. Data between two groups were compared using the Games-Howell test because the variances were not equal. A p value of <0.05 was considered statistically significant.

Results and Discussion

This review is an overview of thyroid function tests in RTH/SITSH derived from literature databases, and there are no other reports assessed from this viewpoint [12, 13]. We searched case reports in Japanese in JMAS database using the words «thyroid hormone resistance» for RTHβ, «TSH-producing» for TSHoma, and «dysalbuminemic hyperthyroxinemia» for FDH in Japanese. JMAS includes not only published reports but also the abstracts of presentations in scientific meetings. The articles found in PubMed were confirmed to cover all Japanese cases identified in JMAS. After deduplication, 103, 152, and 14 abstracts/articles were identified for RTHβ, TSHoma, and FDH, respectively. Number of abstracts picked up in each year derived from JMAS database is shown in Table 1. For RTHβ, 56 different point mutations with 41 different amino acid positions were reported in Japan, as shown in Table 2. In detail, 12 different point mutations in THRB for clusters #1 (429–460), 20 for #2 (310–353), and 21 for #3 (234–283) [14] in addition to three variants for R383 were reported. In contrast, the patients with FDH in Japan harbored only a p.R218P mutation in the albumin gene, which was first reported by Wada et al. [15]. After the values measured under inappropriate treatments and under special complications as mentioned in Methods were excluded, 101 samples of thyroid function for RTHβ, 160 for TSHoma, and 25 for FDH were obtained because some reports contained two or more patients’ data. In this series, the absolute values of FT4 in the literature were plotted against their TSH values. The distributions of FT4 against TSH in RTHβ, TSHoma, and FDH are shown in Fig. 1A. The reference ranges of two representative different kits, i.e., Architect (Abbott Laboratories, Japan) and ECLusys (Roche Diagnostics, Japan) were represented by squares. There were no significant differences in the distribution among the three clusters of RTHβ (data not shown; see also reference #10). Although the distributions in RTHβ and TSHoma were overlapped, that of FDH was different from the others, and many points of FDH distributed the area with higher FT4 and lower TSH values than the others. Namely, TSH values of FDH were fundamentally within normal range. Accordingly, FT4/TSH values were significantly higher in FDH (9.59 ± 9.54) than in RTHβ (1.46 ± 1.61, p < 0.0005) and TSHoma (1.02 ± 1.17, p < 0.0005) (Fig. 1B). FT4/TSH values were also significantly higher in RTHβ than in TSHoma (p < 0.05). The distributions of FT3 against TSH in RTHβ, TSHoma, and FDH were more overlapping among the three diseases (Fig. 2A). FT3/TSH values were also significantly higher in FDH (9.75 ± 5.85) than in RTHβ (3.06 ± 3.55, p < 0.0001) and TSHoma (2.51 ± 2.18, p < 0.0001), but there was no significant difference between RTHβ and TSHoma (Fig. 2B). The distributions of FT3 (pg/mL)/FT4 (ng/dL) values were more characteristic (Fig. 3A). FT3/FT4 values in FDH (1.29 ± 0.65) were significantly lower than in RTHβ (2.23 ± 0.63, p < 0.0001) and TSHoma (2.72 ± 0.71, p < 0.0001) and those were also significantly lower in RTHβ than in TSHoma (p < 0.0001) (Fig. 3B). Namely, the proportion of FT3/FT4 values higher than the average level of 2.65, which was calculated from the reference range, was 66% in TSHoma but 29% in RTHβ. In contrast, the average level of these values in FDH was as low as approximately 1.0. The reason for the low FT3/FT4 values in FDH could be that the effect of dysalbumin on T4 is larger than that on T3. In contrast, the reason that FT3/FT4 ratios are different between RTHβ and TSHoma is unclear. However, potential mechanisms can be presented. The increment of thyroidal deiodinase activities in the patients with T3-predominant Graves’ disease [16] suggests that peripheral T3 production may switch from Type 2 (D2) to type 1 (D1) iodothyronine deiodinase dependency in thyrotoxic patients [17] because T3 increases D1 but not D2 activity [18-20]. Therefore, FT3/FT4 ratio can be increased in TSHoma, which is a central hyperthyroidism. In the case of RTHβ, the increment of deiodinase activities might be blunted because TR is mutated.

Table 1 Number of abstracts/articles picked up in each year derived from JMAS database

year	RTHβ	TSHoma	FDH
1990		1
1991	1	2
1992		2
1993		4
1994	1	3
1995		3
1996		3
1997	1	3	1
1998		2
1999	1	3
2000	2	4	1
2001	5	2
2002	1	5
2003	1	2
2004		5
2005	7	4
2006	1	5	1
2007	5	14
2008	3	5
2009	3	5	1
2010		7
2011	2	4	1
2012	8	4	1
2013	8	6
2014	6	9	1
2015	7	7	1
2016	12	6	2
2017	13	14	3
2018	7	9	1
2019	3	3
2020	5	6
Total	103	152	14

Table 2 Single amino acid substitutions in RTHβ found in Japan

Cluster #3 (234–283)	A234T/V, R243Q/W, F245L, I250F, D256G, A268D, F269L, T277I, R282G/S
Cluster #2 (310–353)	M310V, M313T, R316C, A317T, R320C, Y321C, T329A, L330S, G332E, E333K, M334T, R338H/Q/W, Q340H, K342I, G345D, G347A/R, D351E
	R383C/H/S
Cluster #1 (429–460)	R429Q, I431T, H435L, R438C/H, F439L, K443E, P447L, F451L/I, P452L, P453A/H/R/S/T, L454F/V, F455S, L456C, E460K

Fig. 1

Distribution of FT4 against TSH and FT4/TSH values in RTHβ, TSHoma, and FDH reported in Japan.

In total, 101 samples of thyroid function for RTHβ, 160 for TSHoma, and 25 for FDH were obtained. (A) Absolute values of FT4 in the literature are plotted against their TSH values, and the reference ranges of two different representative kits, i.e., Architect and ECLusys, are represented by squares. (B) FT4/TSH values in RTHβ, TSHoma, and FDH are plotted with the mean ± SD.

Fig. 2

Distribution of FT3 against TSH and FT3/TSH values in RTHβ, TSHoma, and FDH reported from Japan.

(A) The absolute values of FT3 in the literature are plotted against their TSH values, and the reference ranges of representative two different kits, i.e., Architect and ECLusys, are represented by squares. (B) FT4/TSH values in RTHβ, TSHoma, and FDH are plotted with the mean ± SD.

Fig. 3

Distribution of FT3/FT4 against TSH and FT3/FT4 values in RTHβ, TSHoma, and FDH reported from Japan.

(A) FT3/FT4 values are plotted against their TSH values, and the reference values of FT3/FT4 are calculated from their reference ranges of two different representative kits, i.e., Architect and ECLusys, are represented by squares. (B) FT3/FT4 values in RTHβ, TSHoma, and FDH are plotted with the mean ± SD, and the reference values of FT3/FT4 calculated using two different representative kits, i.e., Architect and ECLusys, are represented by a square.

Next, we searched for RTHβ caused by a deletion, truncation, or frameshift of TRβ to compare with RTHβ caused by a single amino acid substitution on PubMed (http://www.ncbi.nlm.nih.gov/pubmed/). In this series, the values of FT4 reported in the literature were expressed as the percentage to the upper limit of the reference range in each institution. Four different single amino acid deletions, five different premature stop codons, and six different frameshifts were found (Table 3) [21-39]. The degrees of SITSH in truncations and frameshifts were more severe than those in single amino acid deletions and single amino acid substitutions that were obtained in our previous study [10] (Fig. 4A).

Table 3 Deletions, premature stop codons, and frameshifts identified in RTHβ

Single amino acid deletion	Δ276I (21), Δ337T (22), Δ430M, Δ432G (23)
Premature stop codon	C443X (24), E445X (25), C446X (26), E449X (27, 28), F451X (29)
Frameshift	A433CfsX29 (30), A436CfsX29 (31), R438AfsX5 (32), T448HfsX17 (33), E449DfsX11 (34), L454FfsX11 (31, 35–39)

Numbers in parenthesis indicate the reference number.

Fig. 4

Distribution of FT4 against TSH in RTHβ caused by a deletion, truncation, or frameshift of TRβ collected from the literature.

The reported values of FT4 in the literature were expressed as the percentage to the upper limit of the reference range in each institution. (A) Four different single amino acid deletions (green circles), five different premature stop codons (red circles), and six different frameshifts (blue circles) were obtained from the case reports through a PubMed search and compared with single amino acid deletions and single amino acid substitutions (open circles), which were collected from the literature in our previous study. The values for FT4 are plotted against their absolute values of TSH (log scale), and the reference ranges are represented by a gray square. The two truncations with an asterisk are plotted using the total T4 values. (B) The homozygous patients of RTHβ (closed circles) with one single amino acid deletion (Δ337T), five different single amino acid substitutions, and one complete deletion (exons 4–10) were obtained through a PubMed search and compared with heterozygous patients with the cognate mutations (open circles). CD, complete deletion

We also searched for homozygous patients for RTHβ on PubMed. One single amino acid deletion (Δ337T), five different single amino acid substitutions, and one complete deletion (exons 4–10) were obtained as shown in Table 4 [22, 40-45]. The degrees of SITSH in homozygous patients were more severe than those in heterozygous patients with cognate mutations (Fig. 4B). In addition, the SITSH in the patients with complete deletion became apparent only in homozygous patients, as previously reported [40].

Table 4 Homozygous mutations identified in RTHβ

Deletion of exon	Deletion of exons 4–10 (40)
Single amino acid deletion	Δ337T (22, 41)
Single amino acid substitution	R243Q (42), I280S (43), E311K (44), R316C, G347E (45)

Numbers in parenthesis indicate the reference number.

Finally, we searched for patients with RTHα on PubMed. Twenty different mutations were reported to date as shown in Table 5 [4, 46-59]. Nine were single amino acid substitutions in the LBD of TRα common to TRα1 and TRα2. In the region of TRα1 specific, five were single amino acid substitutions, three were frameshifts, and three were premature stop codons. As shown in Fig. 5, the FT3/FT4 ratios were higher than 1.0, and there were no apparent differences among mutations; however, these ratios were a little higher in patients with frameshifts and truncations than in those with single amino acid substitutions, with some exceptions.

Table 5 Mutations identified in RTHα

Common to TRα1 and TRα2	Single amino acid substitution	D211G (46, 47), M256T, (48), M259T, A263S (49), A263V (50), T273A (51), L274P (52), H351Q (53), N359Y (54)
TRα1 specific		R384C (55), R384H (49), P398R (56), F401S (47), E403K (56)
	Frameshift	C380fs387X (50), A382fs388X (57), F397fs406X (58)
	Premature stop codon	C392X (56), E395X (59), E403X (4,56)

Numbers in parenthesis indicate the reference number.

Fig. 5

Distribution of FT3 against FT4 in RTHα collected from the literature.

The lower limit and the upper limit of reference ranges of FT3 or FT4 in the literature were expressed as 100% and 200%, respectively. Then, the reported values of FT3 and FT4 were converted to the percentages against the reference ranges, respectively. The values of FT3 (%) were plotted against the values of FT4 (%). Single amino acid substitutions in the LBD of TRα common to TRα1 and TRα2 (blue circles), single amino acid substitutions (green circles), frameshifts (red circles), and premature stop codons (black circles) in the region of TRα1-specific are shown. The reference ranges are represented by a gray square. A solid line and a dotted line indicate 1.0 and 2.0 of FT3 (%)/FT4 (%), respectively.

There are some limitations in this study. First, the distinct normal ranges due to distinct methods among multiple reports might reduce the accuracy of the data. However, it is conceivable that the effects are minor as shown by the reference ranges of two different assay kits in Figs. 1–3. In addition, the reported values in the literature were expressed as the percentage to the upper limit of the reference range in each institution in Figs. 4 and 5. Second, the mean values of multiple measurements for the applicable patients adopted in some patients might reduce the reality of the data because some reports provided two or more data sets of thyroid function measured at different times for a patient. Alternatively, thyroid function may fluctuate [10] and some epigenetic factors may influence thyroid function among family members with the same mutation [60]. In addition, there is a case of TSH-secreting pituitary adenoma with cyclic fluctuations in serum TSH levels [61]. Third, the mechanisms that FT3/FT4 ratio may distinguish RTHβ and TSHoma remain to be clarified.

Summary

SITSH in RTHβ, TSHoma, and FDH in Japan

1. The TSH values in FDH are, in principle, within the normal range, while those in RTHβ and TSHoma are often distributed higher than the normal range. Specifically, the percentages of patients with the TSH value higher than 5.0 mU/L in FDH, RTHβ and TSHoma were 0.0%, 18.8% and 39.1%, respectively.

2. The distributions of FT4 and FT3 against TSH in RTHβ and TSHoma overlapped, and values for FT4/TSH and FT3/TSH were similar between RTHβ and TSHoma.

3. The distributions of FT4 and FT3 against TSH in FDH were different from those in RTHβ and TSHoma; the points of FDH distributed the area with higher FT4 and FT3, and lower TSH values than the others and values for FT4/TSH and FT3/TSH were significantly higher in FDH than in RTHβ and TSHoma.

4. FT3/FT4 values in FDH (0.90–1.45) were significantly lower than in RTHβ (1.71–2.52) and TSHoma (2.30–3.11). In addition, FT3/FT4 values in RTHβ were significantly lower than in TSHoma.

SITSH in RTHβ

1. The degrees of SITSH in patients with truncations and frameshifts were more severe than those in patients with single amino acid deletions and single amino acid substitutions.

2. The degrees of SITSH in homozygous patients were more severe than those in heterozygous patients with cognate mutations, but SITSH in patients with complete deletion become apparent only in homozygous patients.

FT3/FT4 ratio in RTHα

1. The FT3/FT4 ratios in RTHα were higher than 1.0.

2. There were no significant differences in the FT3/FT4 ratios among single amino acid substitutions in the LBD of TRα common to TRα1 and TRα2, single amino acid substitutions, frameshifts, and premature stop codons in the TRα1-specific region.

Financial Support

This work was partially supported by the Japan Society for the Promotion of Science KAKENHI Grants JP18K11093.

Disclosure

The author has no conflicts of interest to declare.

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