Thyroid Resistance Abstracts 1

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Thyroid hormone resistance.
            (Agrawal et al., 2008) Download
Thyroid hormone resistance (THR) is a rare syndrome of reduced end organ sensitivity. Patients with THR have elevated serum free thyroxine (FT4), free triiodothyronine (FT3), but normal or slightly elevated serum thyrotropin values. The characteristic clinical feature is goitre without symptoms and metabolic consequences of thyroid hormone excess. THR can be classified on the basis of tissue resistance into pituitary, peripheral or generalised (both pituitary and peripheral) types. Mutations in the TRbeta gene, cell membrane transporter and genes controlling intracellular metabolism of thyroid hormone have been implicated. THR is differentiated from thyroid stimulating hormone (TSH) secreting pituitary adenoma by history of THR in the family. No specific treatment is often required for THR; patients with features of hypo- or hyperthyroidism are appropriately treated with levo-triiodothyronine (L-T3), levo-thyroxine (L-T4), dextro-thyroxine(D-T4) or 3,3,5 triiodo-thyroacetic acid (TRIAC). The diagnosis helps in appropriate genetic counselling of the family.

Function of pituitary-thyroid axis in copper-deficient rats.
            (Allen et al., 1982) Download
Thirty male weanling Sprague-Dawley rats were fed either a copper deficient diet (0.85 mg Cu/kg) or a copper-adequate diet (8 mg Cu/kg). After 7 weeks, the rats were fasted for 12 hours, and injected intravenously with thyrotropin-releasing hormone (TRH, 30 ng/100 g body weight). Six rats from each treatment were killed at 0, 0.5, 1, 2 and 4 hours after TRH injection. Sera obtained at 0, 0.5 and 1 hour, and at 0.2 and 4 hours were used for the radioimmunoassay of thyroid-stimulating hormone (TSH) and thyroxine (T4), respectively. Reduction in liver copper content confirmed that the rats fed the test diet were copper-deficient. Serum TSH levels appeared to have peaked at 30 minutes but declined to a level higher than basal at 1 hour. No difference in TSH response was observed between the 2 treatments. Serum T4 response to TRH was reduced in the copper-deficient as compared to the adequate rats at all time intervals. After 2 hours a slight elevation was observed in the controls, but marked elevations in T4 were observed in both treatments at 4 hours. This reduction in T4 levels could be due to an impaired T4 synthesis or release in copper-deficient rats.


 

The syndromes of reduced sensitivity to thyroid hormone.
            (Dumitrescu and Refetoff, 2013) Download
BACKGROUND: Six known steps are required for the circulating thyroid hormone (TH) to exert its action on target tissues. For three of these steps, human mutations and distinct phenotypes have been identified. SCOPE OF REVIEW: The clinical, laboratory, genetic and molecular characteristics of these three defects of TH action are the subject of this review. The first defect, recognized 45years ago, produces resistance to TH and carries the acronym, RTH. In the majority of cases it is caused by TH receptor beta gene mutations. It has been found in over 3000 individuals belonging to approximately 1000 families. Two relatively novel syndromes presenting reduced sensitivity to TH involve membrane transport and metabolism of TH. One of them, caused by mutations in the TH cell-membrane transporter MCT8, produces severe psychomotor defects. It has been identified in more than 170 males from 90 families. A defect of the intracellular metabolism of TH in 10 individuals from 8 families is caused by mutations in the SECISBP2 gene required for the synthesis of selenoproteins, including TH deiodinases. MAJOR CONCLUSIONS: Defects at different steps along the pathway leading to TH action at cellular level can manifest as reduced sensitivity to TH. GENERAL SIGNIFICANCE: Knowledge of the molecular mechanisms involved in TH action allows the recognition of the phenotypes caused by defects of TH action. Once previously known defects have been ruled out, new molecular defects could be sought, thus opening the avenue for novel insights in thyroid physiology. This article is part of a Special Issue entitled Thyroid hormone signaling.

A metabolic basis for fibromyalgia and its related disorders: the possible role of resistance to thyroid hormone.
            (Garrison and Breeding, 2003) Download
It has long been recognized that the symptom complex of fibromyalgia can be seen with hypothyroidism. Hypothyroidism may been categorized, like diabetes, into type I (hormone deficient) and type II (hormone resistant). Most cases of fibromyalgia fall into the latter category. The syndrome is reversible with treatment, and is usually of late onset. It is likely more often acquired than due to mutated receptors. Now that there is evidence to support the hypothesis that fibromyalgia may be due to thyroid hormone resistance, four major questions appear addressable. First, can a simple biomarker be found to help diagnose it? Second, what other syndromes similar to Fibromyalgia may share a thyroid-resistant nature? Third, in non-genetic cases, how is resistance acquired? Fourth, what other methods of treatment become available through this new understanding? Preliminary evidence suggests that serum hyaluronic acid is a simple, inexpensive, sensitive, and specific test that identifies fibromyalgia. Overlapping symptom complexes suggest that chronic fatigue syndrome, Gulf war syndrome, premenstrual syndrome, post traumatic stress disorder, breast implant silicone sensitivity syndrome, bipolar affective disorder, systemic candidiasis, myofascial pain syndrome, and idiopathic environmental intolerance are similar enough to fibromyalgia to merit investigation for possible thyroid resistance. Acquired resistance may be due most often to a recently recognized chronic consumptive coagulopathy, which itself may be most often associated with chronic infections with mycoplasmids and related microbes or parasites. Other precipitants of thyroid resistance may use this or other paths as well. In addition to experimentally proven treatment with supraphysiologic doses of thyroid hormone, the thyroid-resistant disorders might be treatable with anti-hypercoagulant, anti-infective, insulin-sensitizing, and hyaluronolytic strategies.

What should be done when thyroid function tests do not make sense?
            (Gurnell et al., 2011) Download
Interpretation of thyroid function tests (TFTs) is generally straightforward. However, in a minority of contexts the results of thyroid hormone and thyrotropin measurements either conflict with the clinical picture or form an unusual pattern. In many such cases, reassessment of the clinical context provides an explanation for the discrepant TFTs; in other instances, interference in one or other laboratory assays can be shown to account for divergent results; uncommonly, genetic defects in the hypothalamic-pituitary-thyroid axis are associated with anomalous TFTs. Failure to recognize these potential 'pitfalls' can lead to misdiagnosis and inappropriate management. Here, focusing particularly on the combination of hyperthyroxinaemia with nonsuppressed thyrotropin, we show how a structured approach to investigation can help make sense of atypical TFTs.

Case report: thyroid hormone resistance and its therapeutic challenges.
            (Kim and Travers, 2008) Download
Thyroid hormone resistance occurs when a genetic mutation in the thyroid hormone receptor leads to reduced hormone binding affinity; the concentration of free thyroid hormone in the circulation is inversely correlated with the hormone binding affinity of the mutant receptor. Thyroid hormone resistance mutations are associated with a wide variety of phenotypes and subsequent treatment challenges. Among the more common symptoms are hyperactivity, emotional lability, a below average intelligence quotient, and short stature. We report here a patient who presented with thyroid hormone resistance at an early age, providing an opportunity to optimize her overall growth and development. We review the limited information currently available in the literature addressing the treatment of thyroid hormone resistance in children and describe the approach used to determine the treatment plan in this young child.


 

Pitfalls in the measurement and interpretation of thyroid function tests.
            (Koulouri et al., 2013) Download
Thyroid function tests (TFTs) are amongst the most commonly requested laboratory investigations in both primary and secondary care. Fortunately, most TFTs are straightforward to interpret and confirm the clinical impression of euthyroidism, hypothyroidism or hyperthyroidism. However, in an important subgroup of patients the results of TFTs can seem confusing, either by virtue of being discordant with the clinical picture or because they appear incongruent with each other [e.g. raised thyroid hormones (TH), but with non-suppressed thyrotropin (TSH); raised TSH, but with normal TH]. In such cases, it is important first to revisit the clinical context, and to consider potential confounding factors, including alterations in normal physiology (e.g. pregnancy), intercurrent (non-thyroidal) illness, and medication usage (e.g. thyroxine, amiodarone, heparin). Once these have been excluded, laboratory artefacts in commonly used TSH or TH immunoassays should be screened for, thus avoiding unnecessary further investigation and/or treatment in cases where there is assay interference. In the remainder, consideration should be given to screening for rare genetic and acquired disorders of the hypothalamic-pituitary-thyroid (HPT) axis [e.g. resistance to thyroid hormone (RTH), thyrotropinoma (TSHoma)]. Here, we discuss the main pitfalls in the measurement and interpretation of TFTs, and propose a structured algorithm for the investigation and management of patients with anomalous/discordant TFTs.

Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia.
            (Mitchell et al., 2010) Download
Resistance to thyroid hormone (RTH), a dominantly inherited disorder usually associated with mutations in thyroid hormone receptor beta (THRB), is characterized by elevated levels of circulating thyroid hormones (including thyroxine), failure of feedback suppression of thyrotropin, and variable tissue refractoriness to thyroid hormone action. Raised energy expenditure and hyperphagia are recognized features of hyperthyroidism, but the effects of comparable hyperthyroxinemia in RTH patients are unknown. Here, we show that resting energy expenditure (REE) was substantially increased in adults and children with THRB mutations. Energy intake in RTH subjects was increased by 40%, with marked hyperphagia particularly evident in children. Rates of muscle TCA cycle flux were increased by 75% in adults with RTH, whereas rates of ATP synthesis were unchanged, as determined by 13C/31P magnetic resonance spectroscopy. Mitochondrial coupling index between ATP synthesis and mitochondrial rates of oxidation (as estimated by the ratio of ATP synthesis to TCA cycle flux) was significantly decreased in RTH patients. These data demonstrate that basal mitochondrial substrate oxidation is increased and energy production in the form of ATP synthesis is decreased in the muscle of RTH patients and that resting oxidative phosphorylation is uncoupled in this disorder. Furthermore, these observations suggest that mitochondrial uncoupling in skeletal muscle is a major contributor to increased REE in patients with RTH, due to tissue selective retention of thyroid hormone receptor alpha sensitivity to elevated thyroid hormone levels.

Physiological consequences of the TRalpha1 aporeceptor state.
            (Mittag et al., 2010a) Download
Many patients have been characterized harboring a mutation in thyroid hormone receptor (TR) beta. Surprisingly none has yet been identified carrying a mutation in TRalpha1. To facilitate the identification of such patients, several animal models with a mutant TRalpha1 have been generated. While some phenotypic characteristics, such as an adult euthyroidism, are similar in the mutant mice, other aspects such as metabolism are quite variable. This review summarizes the most important consequences of a mutation in TRalpha1 in mice focusing on the TRalpha1-R384C mutation, and projects the insights from the animal models to a putative phenotype of patients with a mutated TRalpha1.

Thyroid hormones regulate selenoprotein expression and selenium status in mice.
            (Mittag et al., 2010b) Download
Impaired expression of selenium-containing proteins leads to perturbed thyroid hormone (TH) levels, indicating the central importance of selenium for TH homeostasis. Moreover, critically ill patients with declining serum selenium develop a syndrome of low circulating TH and a central downregulation of the hypothalamus-pituitary-thyroid axis. This prompted us to test the reciprocal effect, i.e., if TH status would also regulate selenoprotein expression and selenium levels. To investigate the TH dependency of selenium metabolism, we analyzed mice expressing a mutant TH receptor α1 (TRα1+m) that confers a receptor-mediated hypothyroidism. Serum selenium was reduced in these animals, which was a direct consequence of the mutant TRα1 and not related to their metabolic alterations. Accordingly, hyperthyroidism, genetically caused by the inactivation of TRβ or by oral TH treatment of adult mice, increased serum selenium levels in TRα1+m and controls, thus demonstrating a novel and specific role for TRα1 in selenium metabolism. Furthermore, TH affected the mRNA levels for several enzymes involved in selenoprotein biosynthesis as well as serum selenoprotein P concentrations and the expression of other antioxidative selenoproteins. Taken together, our results show that TH positively affects the serum selenium status and regulates the expression of several selenoproteins. This demonstrates that selenium and TH metabolism are interconnected through a feed-forward regulation, which can in part explain the rapid parallel downregulation of both systems in critical illness.


 

Serum copper as a novel biomarker for resistance to thyroid hormone.
            (Mittag et al., 2012) Download
Thyroid hormone action is mediated by the thyroid hormone receptors TRalpha1 and TRbeta. Defects in TRbeta lead to RTH (resistance to thyroid hormone) beta, a syndrome characterized by high levels of thyroid hormone and non-suppressed TSH (thyroid-stimulating hormone). However, a correct diagnosis of RTHbeta patients is difficult as the clinical picture varies. A biochemical serum marker indicative of defects in TRbeta signalling is needed and could simplify the diagnosis of RTHbeta, in particular the differentiation to TSH-secreting pituitary adenomas, which present with clinically similar symptoms. In the present paper we show that serum copper levels are regulated by thyroid hormone, which stimulates the synthesis and the export of the hepatic copper-transport protein ceruloplasmin into the serum. This is accompanied by a concerted reduction in the mRNA levels of other copper-containing proteins such as metallothioneins 1 and 2 or superoxide dismutase 1. The induction of serum copper is abolished in genetically hyperthyroid mice lacking TRbeta and human RTHbeta patients, demonstrating an important role of TRbeta for this process. Together with a previously reported TRalpha1 specific regulation of serum selenium, we show that the ratio of serum copper and selenium, which is largely independent of thyroid hormone levels, volume changes or sample degradation, can constitute a valuable novel biomarker for RTHbeta. Moreover, it could also provide a suitable large-scale screening parameter to identify RTHalpha patients, which have not been identified to date.

Resistance to thyroid hormone: an historical overview.
            (Refetoff, 1994) Download
Resistance to thyroid hormone (RTH) is an inherited syndrome characterized by reduced tissue responsiveness to thyroid hormone. Subjects have elevated serum thyroid hormone levels in association with a nonsuppressed TSH. Goiter and thyroid test abnormalities have most often led to further investigation, underscoring the paucity of specific clinical manifestations of RTH. Hypothyroidism has been considered when growth or mental retardation was the presenting symptom and thyrotoxicosis when dealing with attention deficit or hyperactivity. Failure to recognize the inappropriate persistence of TSH secretion, in spite of elevated thyroid hormone levels, has commonly resulted in erroneous diagnosis leading to treatment aimed to normalize the thyroid hormone level. More than 400 subjects with this syndrome have been identified. The mode of inheritance appears to be autosomal dominant in the majority of families. It has long been suspected that RTH is most likely caused by an abnormal thyroid hormone receptor (TR), but this hypothesis could not be directly tested until the isolation of two TR genes, TR alpha and TR beta, located in chromosomes 17 and 3, respectively. TR beta gene mutations have been recently identified in 68 families with RTH. All mutations are located in the T3-binding domain, straddling the putative TR-dimerization region. Mutant TRs exhibit hormone-binding impairment, the degree of which does not correlate with the severity of clinical manifestations. This finding, and the fact that heterozygous subjects with complete TR deletion are not affected, while those with point mutations are, indicated that interactions of the mutant TRs with normal TRs and with other factors, are responsible for the dominant inheritance of RTH and its clinical heterogeneity.(ABSTRACT TRUNCATED AT 250 WORDS)

Resistance to thyroid hormone accompanied by Graves' disease.
            (Shiwa et al., 2011) Download
Resistance to thyroid hormone (RTH) is characterized by elevated serum levels of thyroid hormones and normal or slightly increased serum thyrotropin (TSH) levels. Recently it has been suggested that chronic TSH stimulation in RTH activates intrathyroidal lymphocytes, leading to thyroid damage and autoimmune thyroid disease (AITD). Therefore, individuals with RTH have an increased likelihood of AITD compared to unaffected relatives. We here report a 33-year-old woman in whom we diagnosed Graves' disease and treated her with thiamazole (MMI). For two years, her TSH levels were suppressed when thyroid hormones were elevated and conversely they were increased when thyroid hormones levels were decreased. These findings were common for a clinical course during treatment for Graves' disease with anti-thyroid drug. However, three years after the initiation of MMI therapy, she had a normal or gradually elevated serum TSH level even though the level of thyroid hormones never decreased, indicating inappropriate secretion of TSH. We concluded she had RTH clinically, and we demonstrated by direct sequence analysis a mutation of the TRbeta gene, causing replacement of a glycine (G) with arginine (R) at codon 251. The finding of an elevated TSH level without decreased thyroid hormones should suggest the presence of RTH during therapy of Graves' disease.

Severe psychomotor and metabolic damages caused by a mutant thyroid hormone receptor alpha 1 in mice: can patients with a similar mutation be found and treated
            (Vennström et al., 2008) Download
UNLABELLED:  Individuals suffering from the resistance to thyroid hormone syndrome (RTH) have a mutation in thyroid hormone receptor (TR) beta. Surprisingly, no patient with a mutation in TRalpha1 has been found. To facilitate their identification, animal models with a RTH-like mutation in TRalpha1 have been generated. The mutations introduced into the mouse decrease affinity to ligand, resulting in a 'receptor-mediated hypothyroidism' in tissues expressing the mutant receptor: brain, heart and bone. The mice present minor perturbances in thyroid hormone homeostasis, but show major aberrancies in postnatal development, psychomotor behaviour and metabolism. These parameters are akin to those seen in endemic cretinism and untreated congenital hypothyroidism. Treatment of the mice with high doses of triiodothyronine leads to normalization or amelioration of the dysfunctions when applied at adequate developmental periods. CONCLUSION:  Our studies on mice suggest the existence of a potentially debilitating disease caused by a mutant TRalpha1, and provide insights for identification and treatment of corresponding patients.

 


References

Agrawal, NK, et al. (2008), ‘Thyroid hormone resistance.’, Postgrad Med J, 84 (995), 473-77. PubMed: 18940949
Allen, DK, CA Hassel, and KY Lei (1982), ‘Function of pituitary-thyroid axis in copper-deficient rats.’, J Nutr, 112 (11), 2043-46. PubMed: 6813435
Dumitrescu, AM and S Refetoff (2013), ‘The syndromes of reduced sensitivity to thyroid hormone.’, Biochim Biophys Acta, 1830 (7), 3987-4003. PubMed: 22986150
Garrison, RL and PC Breeding (2003), ‘A metabolic basis for fibromyalgia and its related disorders: the possible role of resistance to thyroid hormone.’, Med Hypotheses, 61 (2), 182-89. PubMed: 12888300
Gurnell, M, DJ Halsall, and VK Chatterjee (2011), ‘What should be done when thyroid function tests do not make sense?’, Clin Endocrinol (Oxf), 74 (6), 673-78. PubMed: 21521292
Kim, TJ and S Travers (2008), ‘Case report: thyroid hormone resistance and its therapeutic challenges.’, Curr Opin Pediatr, 20 (4), 490-93. PubMed: 18622209
Koulouri, O, et al. (2013), ‘Pitfalls in the measurement and interpretation of thyroid function tests.’, Best Pract Res Clin Endocrinol Metab, 27 (6), 745-62. PubMed: 24275187
Mitchell, CS, et al. (2010), ‘Resistance to thyroid hormone is associated with raised energy expenditure, muscle mitochondrial uncoupling, and hyperphagia.’, J Clin Invest, 120 (4), 1345-54. PubMed: 20237409
Mittag, J, et al. (2010b), ‘Thyroid hormones regulate selenoprotein expression and selenium status in mice.’, PLoS One, 5 (9), e12931. PubMed: 20877559
Mittag, J, et al. (2012), ‘Serum copper as a novel biomarker for resistance to thyroid hormone.’, Biochem J, 443 (1), 103-9. PubMed: 22220593
Mittag, J, K Wallis, and B Vennström (2010a), ‘Physiological consequences of the TRalpha1 aporeceptor state.’, Heart Fail Rev, 15 (2), 111-15. PubMed: 19009345
Refetoff, S (1994), ‘Resistance to thyroid hormone: an historical overview.’, Thyroid, 4 (3), 345-49. PubMed: 7833674
Shiwa, T, et al. (2011), ‘Resistance to thyroid hormone accompanied by Graves’ disease.’, Intern Med, 50 (18), 1977-80. PubMed: 21921380
Vennström, B, J Mittag, and K Wallis (2008), ‘Severe psychomotor and metabolic damages caused by a mutant thyroid hormone receptor alpha 1 in mice: can patients with a similar mutation be found and treated’, Acta Paediatr, 97 (12), 1605-10. PubMed: 18795907