Resistance to thyroid hormone ß in autoimmune thyroid disease: a case report and review of literature.

BACKGROUND: Resistance to thyroid hormone beta (RTHß) results in symptoms of both increased and decreased thyroid hormone action. The effect of thyroid hormone changes in different types of autoimmune thyroid disease (AITD) in RTHß is dynamic. CASE PRESENTATION: A 25-year-old Asian female had a RTHß Y321C mutation with Hashimoto's thyroiditis and type 2 diabetes mellitus. She was followed-up through gestation and two years postpartum, revealing development of postpartum thyroiditis (PPT) with characteristic wide fluctuations in serum thyrotropin levels, and of spontaneous recovery from an episode of transient hypothyroidism. The presence of RTHß did not prolong thyroiditis duration nor progressed toward permanent hypothyroidism. Prenatal genetic analysis was not performed on the unaffected fetus, and did not result in congenital hypothyroidism, possibly because maternal free thyroxine (FT4) levels were mildly elevated at less than 50% above the reference range in early gestation and gradually decreased to less than 20% after the 28th gestational week. CONCLUSION: In RTHß patients with autoimmune thyroid disease, episodes of thyroid dysfunction can significantly alter thyrotropin levels. During pregnancy, mildly elevated maternal free thyroxine levels less than 20% above the upper limit may not be harmful to unaffected fetuses. Unnecessary thyroid hormone control and fetal genetic testing was avoided during the gestational period with monthly follow-up.

[Impaired sensitivity to thyroid hormone]. / Nedsatt følsomhet for thyreoideahormon.

BACKGROUND: In conditions with impaired sensitivity to thyroid hormone, reduced effect of thyroid hormone is attributable to various defects. The purpose of this article is to give an overview of these conditions, as well as to provide updated knowledge on impaired sensitivity to thyroid hormone, also known as thyroid hormone resistance, with mutations in thyroid hormone receptor ß (TRß). MATERIAL AND METHOD: This article is based on a selection of English-language articles, and Norwegian original and review articles found in PubMed, and the authors' own experiences with this patient group. RESULTS: Thyroid hormone resistance has long been a recognised cause of the reduced effect of thyroid hormone. Several other conditions that involve impaired sensitivity to thyroid hormone have been described in recent decades, and mutations have been identified in genes that code for thyroid hormone receptor α (TRα), a cell membrane transporter, as well as in the deiodinases that metabolise thyroxine (T4) to the bioactive form triiodothyronine (T3). The conditions vary in terms of their clinical picture and biochemical profile. INTERPRETATION: Based on clinical and biochemical findings, thyroid hormone resistance may be erroneously interpreted as hyperthyroidism. In patients with thyroid hormone resistance, the condition may be exacerbated if it is treated as hyperthyroidism. It is therefore essential to recognise the conditions and their differential diagnoses.

Resistance to thyroid hormone mediated by defective thyroid hormone receptor alpha.

BACKGROUND: Thyroid hormone acts via receptor subtypes (TRα1, TRß1, TRß2) with differing tissue distributions, encoded by distinct genes (THRA, THRB). THRB mutations cause a disorder with central (hypothalamic-pituitary) resistance to thyroid hormone action with markedly elevated thyroid hormone and normal TSH levels. SCOPE OF REVIEW: This review describes the clinical features, genetic and molecular pathogenesis of a homologous human disorder mediated by defective THRA. Clinical features include growth retardation, skeletal dysplasia and constipation associated with low-normal T4 and high-normal T3 levels and a low T4/T3 ratio, together with subnormal reverse T3 levels. Heterozygous TRa1 mutations in affected individuals generate defective mutant receptors which inhibit wild-type receptor action in a dominant negative manner. MAJOR CONCLUSIONS: Mutations in human TRα1 mediate RTH with features of hypothyroidism in particular tissues (e.g. skeleton, gastrointestinal tract), but are not associated with a markedly dysregulated pituitary-thyroid axis. GENERAL SIGNIFICANCE: Human THRA mutations could be more common but may have eluded discovery due to the absence of overt thyroid dysfunction. Nevertheless, in the appropriate clinical context, a thyroid biochemical signature (low T4/T3 ratio, subnormal reverse T3 levels), may enable future identification of cases. This article is part of a Special Issue entitled Thyroid hormone signalling.

The syndromes of reduced sensitivity to thyroid hormone.

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 ß 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 novel p.E311K mutation of thyroid receptor beta gene in resistance to thyroid hormone syndrome, inherited in autosomal recessive trait.

Resistance to thyroid hormone (RTH) syndrome is caused by mutations in THRB gene and is inherited mainly as an autosomal dominant trait with dominant negative effect. Most of up-to-now described RTH cases were heterozygous. We studied a 19-year-old woman presenting severe mental impairment, hyperkinetic behavior, learning disability, hearing loss, tachycardia, goiter, strabismus, nystagmus, and normal stature. The laboratory findings revealed elevated TSH, T3, and T4 serum levels. Her parents were healthy with normal serum level of TSH, fT3, and fT4. Sequence based prediction of a substitution was analyzed by SDM, PolPhen, and SNAP software whereas structural visualizations were performed in UCSF Chimera. We found a novel mutation in THRB gene in position 1216 (G to A transition, codon 311) resulting in novel Glu-311-Lys (p.E311K) substitution, homozygous in proband presenting with severe symptoms of RTH and heterozygous in both of her healthy parents, thus suggesting autosomal recessive mode of inheritance. p.E311K substitution was not found in 50 healthy, unrelated individuals. p.E311K was shown to be deleterious by SDM, PolPhen, and SNAP software. Structural visualizations of mutated protein performed by UCSF Chimera software disclosed a loss of hydrogen bonds between E311, R383, and R429 along with abnormal residue-residue contact between K311 and L377. This is a very rare case of a homozygous mutation in a patient with severe symptoms of RTH and lack of symptoms in both heterozygous parents. Although, computational analyses have provided the evidence that p.E311K substitution may affect THRB function, lack of dominant negative effect typical for THRB mutations could not be explained by structure-based modeling. Further in vitro analysis is required to assess the functional consequences of this substitution.

A thyroid hormone receptor mutation that dissociates thyroid hormone regulation of gene expression in vivo.

Resistance to thyroid hormone (RTH) is most often due to point mutations in the beta-isoform of the thyroid hormone (TH) receptor (TR-beta). The majority of mutations involve the ligand-binding domain, where they block TH binding and receptor function on both stimulatory and inhibitory TH response elements. In contrast, a few mutations in the ligand-binding domain are reported to maintain TH binding and yet cause RTH in certain tissues. We introduced one such naturally occurring human RTH mutation (R429Q) into the germline of mice at the TR-beta locus. R429Q knock-in (KI) mice demonstrated elevated serum TH and inappropriately normal thyroid-stimulating hormone (TSH) levels, consistent with hypothalamic-pituitary RTH. In contrast, 3 hepatic genes positively regulated by TH (Dio1, Gpd1, and Thrsp) were increased in R429Q KI animals. Mice were then rendered hypothyroid, followed by graded T(3) replacement. Hypothyroid R429Q KI mice displayed elevated TSH subunit mRNA levels, and T(3) treatment failed to normally suppress these levels. T(3) treatment, however, stimulated pituitary Gh levels to a greater degree in R429Q KI than in control mice. Gsta, a hepatic gene negatively regulated by TH, was not suppressed in R429Q KI mice after T(3) treatment, but hepatic Dio1 and Thrsp mRNA levels increased in response to TH. Cardiac myosin heavy chain isoform gene expression also showed a specific defect in TH inhibition. In summary, the R429Q mutation is associated with selective impairment of TH-mediated gene repression, suggesting that the affected domain, necessary for TR homodimerization and corepressor binding, has a critical role in negative gene regulation by TH.

Reduced Sensitivity to Thyroid Hormone Is Associated with Diabetes and Hypertension.

CONTEXT: Recently, reduced sensitivity to thyroid hormone as a more common finding in the general population and its possible association with metabolic parameters has been the focus of attention. OBJECTIVE: The objective was to evaluate the cross-sectional association of thyroid hormone sensitivity with diabetes, metabolic syndrome (MetS), and its components. METHODS: The study included a Tehranian representative sample of 5124 subjects aged ≥20 years participating in the Tehran Thyroid Study (2008-2011). Body weight, waist circumference, and blood pressure (BP) were measured, and serum concentrations of lipids and lipoproteins, fasting blood glucose, insulin, free thyroxine (fT4), and thyrotropin (TSH) were assayed. Thyroid hormone resistance was calculated by the Thyroid Feedback Quantile-based Index (TFQI) and Iranian-referenced Parametric TFQI (PTFQI) and compared with 2 other indices: Thyrotroph T4 Resistance Index (TT4RI) and TSH Index. RESULTS: TFQI was significantly associated with high BP MetS criterion (OR = 1.14, 95% CI: 1.06, 1.23) and diabetes mellitus (OR = 1.16, 95% CI: 1.04, 1. 30, P = .009) in euthyroid subjects after adjusting for age, sex, smoking, physical activity, body mass index, and Homeostasis Model Assessment Index for Insulin Resistance. TFQI was not associated with new-onset diabetes contrary to known diabetes in subgroup analysis. The results were similar for PTFQI. TSHI (OR = 1.22, 95% CI: 1.08, 1.38, P = .001) and TT4RI (OR = 1.08, 95% CI: 1.01, 1.16, P < .001) were associated only with high BP in euthyroid subjects. CONCLUSION: The new TFQI index seems to be the indicator of reduced sensitivity to thyroid hormone most suitable to associate its population variations with diabetes and hypertension in euthyroid subjects; however, interpretation for diabetes should be concerned with cautions, necessitating future studies.

Resistance to Thyroid Hormone Beta: A Focused Review.

Resistance to thyroid hormone (RTH) is a clinical syndrome defined by impaired sensitivity to thyroid hormone (TH) and its more common form is caused by mutations in the thyroid hormone receptor beta (THRB) gene, termed RTHß. The characteristic biochemical profile is that of elevated serum TH levels in absence of thyrotropin suppression. Although most individuals are considered clinically euthyroid, there is variability in phenotypic manifestation among individuals harboring different THRB mutations and among tissue types in the same individual due in part to differential expression of the mutant TRß protein. As a result, management is tailored to the specific symptoms of TH excess or deprivation encountered in the affected individual as currently there is no available therapy to fully correct the TRß defect. This focused review aims to provide a concise update on RTHß, discuss less well recognized associations with other thyroid disorders, such as thyroid dysgenesis and autoimmune thyroid disease, and summarize existing evidence and controversies regarding the phenotypic variability of the syndrome. Review of management addresses goiter, attention deficit disorder and "foggy brain". Lastly, this work covers emerging areas of interest, such as the relevance of variants of unknown significance and novel data on the epigenetic effect resulting from intrauterine exposure to high TH levels and its transgenerational inheritance.

Resistance to thyroid hormone caused by a mutation of the thyroid ß receptor gene in a family over three generations.

Not required for Clinical Vignette.

Inherited Disorders of Thyroid Hormone Metabolism Defect Caused by the Dysregulation of Selenoprotein Expression.

Consistent activation and functioning of thyroid hormones are essential to the human body as a whole, especially in controlling the metabolic rate of all organs and systems. Impaired sensitivity to thyroid hormones describes any process that interferes with the effectiveness of thyroid hormones. The genetic origin of inherited thyroid hormone defects and the investigation of genetic defects upon the processing of thyroid hormones are of utmost importance. Impaired sensitivity to thyroid hormone can be categorized into three conditions: thyroid hormone cell membrane transport defect (THCMTD), thyroid hormone metabolism defect (THMD), and thyroid hormone action defect (THAD). THMD is caused by defects in the synthesis and processing of deiodinases that convert the prohormone thyroxine (T4) to the active hormone triiodothyronine (T3). Deiodinase, a selenoprotein, requires unique translation machinery that is collectively composed of the selenocysteine (Sec) insertion sequence (SECIS) elements, Sec-insertion sequence-binding protein 2 (SECISBP2), Sec-specific eukaryotic elongation factor (EEFSEC), and Sec-specific tRNA (TRU-TCA1-1), which leads to the recognition of the UGA codon as a Sec codon for translation into the growing polypeptide. In addition, THMD could be expanded to the defects of enzymes that are involved in thyroid hormone conjugation, such as glucuronidation and sulphation. Paucity of inherited disorders in this category leaves them beyond the scope of this review. This review attempts to specifically explore the genomic causes and effects that result in a significant deficiency of T3 hormones due to inadequate function of deiodinases. Moreover, along with SECISBP2, TRU-TCA1-1, and deiodinase type-1 (DIO1) mutations, this review describes the variants in DIO2 single nucleotide polymorphism (SNP) and thyroid stimulating hormone receptor (TSHR) that result in the reduced activity of DIO2 and subsequent abnormal conversion of T3 from T4. Finally, this review provides additional insight into the general functionality of selenium supplementation and T3/T4 combination treatment in patients with hypothyroidism, suggesting the steps that need to be taken in the future.

Persistent COUP-TFII expression underlies the myopathy and impaired muscle regeneration observed in resistance to thyroid hormone-alpha.

Thyroid hormone signaling plays an essential role in muscle development and function, in the maintenance of muscle mass, and in regeneration after injury, via activation of thyroid nuclear receptor alpha (THRA). A mouse model of resistance to thyroid hormone carrying a frame-shift mutation in the THRA gene (THRA-PV) is associated with accelerated skeletal muscle loss with aging and impaired regeneration after injury. The expression of nuclear orphan receptor chicken ovalbumin upstream promoter-factor II (COUP-TFII, or Nr2f2) persists during myogenic differentiation in THRA-PV myoblasts and skeletal muscle of aged THRA-PV mice and it is known to negatively regulate myogenesis. Here, we report that in murine myoblasts COUP-TFII interacts with THRA and modulates THRA binding to thyroid response elements (TREs). Silencing of COUP-TFII expression restores in vitro myogenic potential of THRA-PV myoblasts and shifts the mRNA expression profile closer to WT myoblasts. Moreover, COUP-TFII silencing reverses the transcriptomic profile of THRA-PV myoblasts and results in reactivation of pathways involved in muscle function and extracellular matrix remodeling/deposition. These findings indicate that the persistent COUP-TFII expression in THRA-PV mice is responsible for the abnormal muscle phenotype. In conclusion, COUP-TFII and THRA cooperate during post-natal myogenesis, and COUP-TFII is critical for the accelerated skeletal muscle loss with aging and impaired muscle regeneration after injury in THRA-PV mice.

Increased Hepatic Fat Content in Patients with Resistance to Thyroid Hormone Beta.

Background: Thyroid hormone (TH) has important functions in controlling hepatic lipid metabolism. Individuals with resistance to thyroid hormone beta (RTHß) who harbor mutations in the THRB gene experience loss-of-function of thyroid hormone receptor beta (TRß), which is the predominant TR isoform expressed in the liver. We hypothesized that individuals with RTHß may have increased hepatic steatosis. Methods: Controlled attenuation parameter (CAP) was assessed in individuals harboring the R243Q mutation of the THRB gene (n = 21) and in their wild-type (WT) first-degree relatives (n = 22) using the ultrasound-based transient elastography (TE) device (FibroScan). All participants belonged to the same family, lived on the same small island, and were therefore exposed to similar environmental conditions. CAP measurements and blood samples were obtained after an overnight fast. The observers were blinded to the status of the patients. Results: The hepatic fat content was increased in RTHß individuals compared with their WT relatives (CAP values of 263 ± 21 and 218.7 ± 43 dB/m, respectively, p = 0.007). The CAP values correlated with age and body mass index (BMI) (age: r = 0.55, p = 0.011; BMI: r = 0.51, p = 0.022) in the WT first-degree relatives but not in RTHß individuals, suggesting that the defect in TRß signaling was predominant over the effects of age and obesity. Circulating free fatty acid levels were significantly higher in RTHß individuals (0.29 ± 0.033 vs. 0.17 ± 0.025 mmol/L, p = 0.02). There was no evidence of insulin resistance evaluated by the homeostatic model assessment of insulin resistance in both groups studied. Conclusions: Our findings provide evidence that impairments in intrahepatic TRß signaling due to mutations of the THRB gene can lead to hepatic steatosis, which emphasizes the influence of TH in the liver metabolism of lipids and provides a rationale for the development TRß-selective thyromimetics. Consequently, new molecules with a very high TRß affinity and hepatic selectivity have been developed for the treatment of lipid-associated hepatic disorders, particularly nonalcoholic fatty liver disease.

Generation of Novel Genetic Models to Dissect Resistance to Thyroid Hormone Receptor α in Zebrafish.

Background: Patients with mutations of the thyroid hormone receptor alpha (THRA) gene show resistance to thyroid hormone alpha (RTHα). No amendable mouse models are currently available to elucidate deleterious effects of TRα1 mutants during early development. Zebrafish with transient suppressed expression by morpholino knockdown and ectopic expression of TRα1 mutants in the embryos have been reported. However, zebrafish with germline transmittable mutations have not been reported. The stable expression of thra mutants from embryos to adulthood facilitated the study of molecular actions of TRα1 mutants during development. Methods: In contrast to human and mice, the thra gene is duplicated in zebrafish, thraa, and thrab. Using CRISPR/Cas9-mediated targeted mutagenesis, we created dominant negative mutations in the two duplicated thra genes. We comprehensively analyzed the molecular and phenotypic characteristics of mutant fish during development. Results: Adult and juvenile homozygous thrab 1-bp ins (m/m) mutants exhibited severe growth retardation, but adult homozygous thraa 8-bp ins (m/m) mutants had very mild growth impairment. Expression of the growth hormone (gh1) and insulin-like growth factor 1 was markedly suppressed in homozygous thrab 1-bp ins (m/m) mutants. Decreased messenger RNA and protein levels of triiodothyronine-regulated keratin genes and inhibited keratinocyte proliferation resulted in hypoplasia of the epidermis in adult and juvenile homozygous thrab 1-bp ins (m/m) mutants, but not homozygous thraa 8-bp ins (m/m) mutants. RNA-seq analysis showed that homozygous thrab 1-bp ins (m/m) mutation had global impact on the functions of the adult pituitary. However, no morphological defects nor any changes in the expression of gh1 and keratin genes were observed in the embryos and early larvae. Thus, mutations of either the thraa or thrab gene did not affect initiation of embryogenesis. But the mutation of the thrab gene, but not the thraa gene, is detrimental in postlarval growth and skin development. Conclusions: The thra duplicated genes are essential to control temporal coordination in postlarval growth and development in a tissue-specific manner. We uncovered novel functions of the duplicated thra genes in zebrafish in development. These mutant zebrafish could be used as a model for further analysis of TRα1 mutant actions and for rapid screening of therapeutics for RTHα.

Thyroid hormone transport in and out of cells.

Thyroid hormone (TH) is essential for the proper development of numerous tissues, notably the brain. TH acts mostly intracellularly, which requires transport by TH transporters across the plasma membrane. Although several transporter families have been identified, only monocarboxylate transporter (MCT)8, MCT10 and organic anion-transporting polypeptide (OATP)1C1 demonstrate a high degree of specificity towards TH. Recently, the biological importance of MCT8 has been elucidated. Mutations in MCT8 are associated with elevated serum T(3) levels and severe psychomotor retardation, indicating a pivotal role for MCT8 in brain development. MCT8 knockout mice lack neurological damage, but mimic TH abnormalities of MCT8 patients. The exact pathophysiological mechanisms in MCT8 patients remain to be elucidated fully. Future research will probably identify novel TH transporters and disorders based on TH transporter defects.

Resistance to thyroid hormone with a mutation of the thyroid ß receptor gene in an eight-month-old infant - a case report.

INTRODUCTION: Resistance to thyroid hormone (RTHß) is a rare syndrome of impaired tissue responsiveness to thyroid hormones (THs). The disorder has an autosomal dominant or recessive pattern of inheritance. Most of the reported mutations have been detected in the thyroid hormone receptorß gene (THRß). CASE REPORT: Authors present an eight-month-old infant with poor linear growth, decreased body weight, tachycardia, positive family history, and neonatal features suggestive of RTHß. Both our patient and his mother had elevated free thyroxine, free triiodothyronine, and non-suppressed thyrotropin (TSH) concentration. The fluorescent sequencing analysis showed a heterozygous mutation c.728G>A in TRß gene. This pathogenic variant is known to be associated with THR. CONCLUSIONS: The clinical presentation of RTHb is variable, ranging from isolated biochemical abnormalities to symptoms of thyrotoxicosis or hypothyroidism. The syndrome should be suspected in patients with increased serum TH level, accompanied by a normal or elevated TSH concentration. The affected patients require individualised management.

Mutational Landscape of Resistance to Thyroid Hormone Beta (RTHß).

Resistance to thyroid hormone beta (RTHß) is a syndrome characterized by reduced responsiveness of peripheral tissues to thyroid hormone (TH). In most cases, the disorder is associated with germline pathogenic variants in the thyroid hormone receptor beta (THRB) gene. This paper summarizes the clinical and biochemical presentation of the disease, providing a comprehensive overview on molecular genetic features. Particular care is given in reporting all identified THRB variants with an assessed or unknown clinical significance. Our aim is to offer a useful tool for clinical and genetic specialists in order to ease clinical diagnosis and genetic counseling.

Challenging diagnosis of thyroid hormone resistance initially as Hashimoto's thyroiditis.

Background Resistance to thyroid hormone (RTH) commonly presents with goiter, attention deficit hyperactivity disorder (ADHD), short stature and tachycardia. However, due to its variable presentation with subtle clinical features, a third of the cases are mistreated, typically as hyperthyroidism. Case presentation A 15-year-old female with ADHD and oligomenorrhea was initially diagnosed as Hashimoto's thyroiditis but found to have a rare heterozygous mutation in c803 C>G (p Ala 268 Gly) in the THRß gene, confirming resistance to thyroid hormone. Conclusions Fluctuating thyroid function tests in addition to thyroid peroxidase antibody (TPO Ab) positivity complicated the diagnosis of RTH, initially diagnosed as Hashimoto's thyroiditis. A high index of suspicion is needed to prevent misdiagnosis and mistreatment.

Very Severe Resistance to Thyroid Hormone ß in One of Three Affected Members of a Family with a Novel Mutation in the THRB Gene.

A 13-year-old female with a novel THRB gene mutation (c.1033G>T, p.G345C) presented with 3- to 6-fold higher serum iodothyronine levels and more severe clinical manifestation than 2 other family members carrying the same mutation. The leukocytes of the proband expressed both wild-type and mutant THRB mRNAs, excluding the possibility of a partial deletion of the allele not carrying the mutation. The proband's fibroblasts showed reduced responsiveness to triiodothyronine compared with those of another affected family member. The more severe clinical and biochemical phenotype suggest a modifier-mediated worsening of the resistance to thyroid hormone.

Think globally: act locally. New insights into the local regulation of thyroid hormone availability challenge long accepted dogmas.

Recent evidence derived from transgenic mouse models and findings in humans with mutations affecting thyroid hormone (TH) metabolism have convincingly supported a model of TH signalling in which regulated local adjustment of active TH concentrations is far more important than circulating plasma hormone levels. Although this theory was put forward several years ago and has been supported by significant, but inherently indirect evidence, recent insights from targeted deletion of the genes encoding deiodinase (Dio) isozymes have revived this model and greatly increased our understanding of TH metabolism. However, gene targeting proved to be a double edged sword, since the overall model was supported, but several predictions are apparently not consistent with the new experimental evidence. Human genetics further provided additional exciting data on the physiological role of Dio isozymes that need to be incorporated into any model of TH biology. The recent identification of mutations in the T3 plasma membrane transporter MCT8 has sparked new interest in the role of TH in brain function, since affected patients suffered from psychomotor retardation. Moreover, selenium (Se) and TH physiology have finally been unequivocally connected by newly identified inherited defects in a gene involved in selenoprotein biosynthesis. Finally, a link between Dio expression and energy metabolism has been delineated in mice that may hold great promise for the management of the adiposity pandemic.

Proposing a causal link between thyroid hormone resistance and primary autoimmune hypothyroidism.

Resistance to thyroid hormone (RTH) is a rare, inherited condition. It is characterised by raised circulating fT4 and TSH levels. The literature contains a number of descriptions of the finding of thyroid autoantibodies in patients with RTH. Until now, this has been attributed to the coincidental development of primary autoimmune thyroiditis as a second unrelated pathology. Our hypothesis is that the chronic TSH elevation in RTH stimulates lymphocytes to produce the pro-inflammatory cytokine TNF-alpha. TNF-alpha, in turn mediates thyroid cell destruction by binding to its receptors on thyrocytes, or indirectly by potentiating antibody formation or cytotoxic T lymphocyte production.