scholarly journals Hypercholesterolemia in Two Siblings with Resistance to Thyroid Hormones Due to Disease-Causing Variant in Thyroid Hormone Receptor (THRB) Gene

Medicina ◽  
2020 ◽  
Vol 56 (12) ◽  
pp. 699
Author(s):  
Maja Pajek ◽  
Magdalena Avbelj Stefanija ◽  
Katarina Trebusak Podkrajsek ◽  
Jasna Suput Omladic ◽  
Mojca Zerjav Tansek ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Pathogenic Mutation ◽  
Laboratory Findings ◽  
Cholesterol Levels ◽  
Resistance To Thyroid Hormones ◽  
Hormonal Resistance ◽  
Disease Variant

Resistance to thyroid hormone beta (RTHβ) is a syndrome characterized by a reduced response of target tissues to thyroid hormones. In 85% of cases, a pathogenic mutation in the thyroid hormone receptor beta (THRB) gene is found. The clinical picture of RTHβ is very diverse; the most common findings are goiter and tachycardia, but the patients might be clinically euthyroid. The laboratory findings are almost pathognomonic with elevated free thyroxin (fT4) levels and high or normal thyrotropin (TSH) levels; free triiodothyronin (fT3) levels may also be elevated. We present three siblings with THRB mutation (heterozygous disease-variant c.727C>T, p.Arg243Trp); two of them also had hypercholesterolemia, while all three had several other clinical characteristics of RTHβ. This is the first description of the known Slovenian cases with RTHβ due to the pathogenic mutation in the THRB gene. Hypercholesterolemia might be etiologically related with RTHβ, since the severity of hormonal resistance varies among different tissues and hypercholesterolemia in patients with THRB variants might indicate the relatively hypothyroid state of the liver. We suggest that cholesterol levels are measured in all RTHβ patients.

scholarly journals Athyroid Pax8−/− Mice Cannot Be Rescued by the Inactivation of Thyroid Hormone Receptor α1

Endocrinology ◽  
2005 ◽  
Vol 146 (7) ◽  
pp. 3179-3184 ◽  
Author(s):  
Jens Mittag ◽  
Sönke Friedrichsen ◽  
Heike Heuer ◽  
Silke Polsfuss ◽  
Theo J. Visser ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Postnatal Life ◽  
Mrna Levels ◽  
Negative Effects ◽  
Double Knockout ◽  
Short Life Span ◽  
Knockout Animals

Abstract The Pax8−/− mouse provides an ideal animal model to study the consequences of congenital hypothyroidism, because its only known defect is the absence of thyroid follicular cells. Pax8−/− mice are, therefore, completely athyroid in postnatal life and die around weaning unless they are substituted with thyroid hormones. As reported recently, Pax8−/− mice can also be rescued and survive to adulthood by the additional elimination of the entire thyroid hormone receptor α (TRα) gene, yielding Pax8−/−TRαo/o double-knockout animals. This observation has led to the hypothesis that unliganded TRα1 might be responsible for the lethal phenotype observed in Pax8−/− animals. In this study we report the generation of Pax8−/−TRα1−/− double-knockout mice that still express the non-T3-binding TR isoforms α2 and Δα2. These animals closely resemble the phenotype of Pax8−/− mice, including growth retardation and a completely distorted appearance of the pituitary with thyrotroph hyperplasia and hypertrophy, extremely high TSH mRNA levels, reduced GH mRNA expression, and the almost complete absence of lactotrophs. Like Pax8−/− mice, Pax8−/−TRα1−/− compound mutants die around weaning unless they are substituted with thyroid hormones. These findings do not support the previous interpretation that the short life span of Pax8−/− mice is due to the negative effects of the TRα1 aporeceptor, but, rather, suggest a more complex mechanism involving TRα2 and an unliganded TR isoform.

scholarly journals Molecular cloning and characterization of thyroid hormone receptors in teleost fish

2001 ◽  
Vol 26 (1) ◽  
pp. 51-65 ◽  
Author(s):  
O Marchand ◽  
R Safi ◽  
H Escriva ◽  
E Van Rompaey ◽  
P Prunet ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Teleost Fish ◽  
Hormone Receptor ◽  
Hormone Receptors ◽  
Thyroid Hormone Receptor ◽  
Nuclear Hormone Receptor ◽  
Hormone Response Elements ◽  
Reverse Transcription Pcr ◽  
Wide Range

Thyroid hormones are pleiotropic factors important for many developmental and physiological functions in vertebrates. Their effects are mediated by two specific receptors (TRalpha and TRbeta) which are members of the nuclear hormone receptor superfamily. To clarify the function of these receptors, our laboratory has started a comparative study of their role in teleost fish. This type of approach has been hampered by the isolation of specific clones for each fish species studied. In this report, we describe an efficient reverse transcription/PCR procedure that allows the isolation of large fragments corresponding to TRalpha and TRbeta of a wide range of teleost fish. Phylogenetic analysis of these receptors revealed a placement consistent with their origin, sequences from teleost fish being clearly monophyletic for both TRalpha and TRbeta. Interestingly, this approach allowed us to isolate (from tilapia and salmon) several new TRalpha or TRbeta isoforms resulting from alternative splicing. These isoforms correspond to expressed transcripts and thus may have an important physiological function. In addition, we isolated a cDNA encoding TRbeta in the Atlantic salmon (Salmo salar) encoding a functional thyroid hormone receptor which binds specific thyroid hormone response elements and regulates transcription in response to thyroid hormones.

scholarly journals SUN-410 Reverse T3 in Patients with Hypothyroidism, Helpful or a Waste of Time?

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Theodore C Friedman ◽  
Julian B Wilson
Keyword(s):  
Thyroid Hormone ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Normal Range ◽  
Reverse T3 ◽  
Laboratory Findings ◽  
Inactive Form ◽  
Severe Fatigue ◽  
Hypothyroid Patients ◽  
Endocrinology Clinic

Abstract BACKGROUND: The normal thyroid secretes T4 (an inactive precursor), T3 (the active hormone) and reverse T3, a biologically inactive form of T3 that may block T3 from binding to the thyroid hormone receptor. As about 15% of patients on L-T4 replacement with a normalized TSH report continued fatigue and other hypothyroid symptoms, efforts are needed to understand this phenomenon. Decades ago, endocrinologists realized that in severe illnesses, rT3 is often high and T3 is often low and termed this “sick euthyroid syndrome”. However, more recently, alternative or functional doctors have argued that high rT3 is detrimental and can block T3 from binding to the thyroid hormone receptor. Without peer-reviewed publications, these functional doctors rely heavily on rT3 levels to treat patients that may have no other laboratory findings of hypothyroidism and often prescribe them L-T3-only preparations to try to lower the rT3. Hypothesis: Patients on L-T4 alone will more likely have an elevated rT3 compared to patients on desiccated thyroid or L-T4/L-T3 therapy. Methods rT3 was measured in 98 consecutive patients seen in a tertiary Endocrinology clinic with possible or confirmed hypothyroidism (all with severe fatigue) with many of them were already treated with different thyroid preparations. Results: The figure shows the 25%-75% quartiles, ranges and ratio of rT3 above the normal range/patients in that category. The cutoff of 24 ng/dL (upper limit of normal for rT3 at either Quest or LabCorp) is indicated by the line. Overall, 18 of the 98 patients had a rT3 above the normal range. Patients on L-T4 alone or desiccated thyroid plus L-T4 had the highest levels of rT3 and the highest % above the cut-off. Three of the patients with a high rT3 were not on any thyroid medicine, and in 2 of them, the rT3 normalized when repeated. The 8 patients with a high rT3 on L-T4 was a relatively high percentage (29%). Conclusion: Measuring rT3 may be helpful in patients who are already on T4-containing thyroid treatments who still have hypothyroid symptoms. Based on this data, measuring rT3 in most patients who are not taking thyroid medicine is not recommended, as only a very small percentage of them had an elevated rT3. Future studies are needed to determine if high rT3 levels correlate with hypothyroid symptoms and if adding L-T3 or desiccated thyroid to hypothyroid patients on L-T4 normalizes rT3 and improves hypothyroid symptoms.

Causes and laboratory investigation of hypothyroidism

2011 ◽  
pp. 530-537 ◽  
Author(s):  
Ferruccio Santini ◽  
Aldo Pinchera
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Gland ◽  
Thyroid Hormones ◽  
Thyroid Hormone Receptor ◽  
Hormone Secretion ◽  
Thyroid Tissue ◽  
Clinical Manifestations ◽  
Primary Hypothyroidism ◽  
Central Hypothyroidism ◽  
Resistance To Thyroid Hormones

Hypothyroidism is the clinical state that develops as a result of the lack of action of thyroid hormones on target tissues (1). Hypothyroidism is usually due to impaired hormone secretion by the thyroid, resulting in reduced concentrations of serum thyroxine (T4) and triiodothyronine (T3). The term primary hypothyroidism is applied to define the thyroid failure deriving from inherited or acquired causes that act directly on the thyroid gland by reducing the amount of functioning thyroid tissue or by inhibiting thyroid hormone production. The term central hypothyroidism is used when pituitary or hypothalamic abnormalities result in an insufficient stimulation of an otherwise normal thyroid gland. Both primary and central hypothyroidism may be transient, depending on the nature and the extent of the causal agent. Hypothyroidism following a minor loss of thyroid tissue can be recovered by compensatory hyperplasia of the residual gland. Similarly, hypothyroidism subsides when an exogenous inhibitor of thyroid function is removed. Peripheral hypothyroidism may also arise as a consequence of tissue resistance to thyroid hormones due to a mutation in the thyroid hormone receptor. Resistance to thyroid hormones is a heterogeneous clinical entity with most patients appearing to be clinically euthyroid while some of them have symptoms of thyrotoxicosis and others display selected signs of hypothyroidism. The common feature is represented by pituitary resistance to thyroid hormones, leading to increased secretion of thyrotropin that in turn stimulates thyroid growth and function. The variability in clinical manifestations depends on the severity of the hormonal resistance, the relative degree of tissue hyposensitivity, and the coexistence of associated genetic defects (see Chapter 3.4.8).

Developmental and regional expression of thyroid hormone receptor genes during Xenopus metamorphosis

Development ◽  
1991 ◽  
Vol 112 (4) ◽  
pp. 933-943 ◽  
Author(s):  
A. Kawahara ◽  
B.S. Baker ◽  
J.R. Tata
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Hormone Receptor ◽  
Thyroid Hormone Receptor ◽  
Head Region ◽  
Oocyte Growth ◽  
Obligatory Control ◽  
Metamorphic Climax ◽  
High Concentrations ◽  
Tail Tip

A characteristic feature of the obligatory control of amphibian metamorphosis by thyroid hormones is the early acquisition of response of tadpole tissues to these hormones well before the latter are secreted, with ‘exponentially’ increasing hormonal sensitivity upon the onset of metamorphosis. We have therefore analyzed the expression of the two thyroid hormone receptor genes (TR alpha and beta) before, during and after metamorphosis in Xenopus tadpoles and froglets. Using non-cross-hybridizing cRNA probes for 5′ and 3′ sequences of Xenopus TR alpha and beta transcripts for RNAase protection assays, the two mRNAs can be detected in tadpoles as early as stage 39. Their concentration increases abruptly at stage 44 and continues to increase differentially at the onset of metamorphosis (stage 55) and through metamorphic climax at stages 58–62, after which they decline upon completion of metamorphosis at stage 66. Quantitative densitometric scanning of autoradiograms showed that, although the concentration of TR beta transcripts is about 1/30th of that of TR alpha mRNA at stages 44–48, depending on the region, it accumulates 3–10 times more rapidly than does the alpha isoform during further development. A substantial proportion of the increase in TR beta mRNA is localized to the head region of tadpoles. Using the hormone-binding domain (HBD) and 3′ end of Xenopus TR alpha cRNA as probe for in situ hybridization, the highest concentration of TR transcripts in stage 44 tadpoles is seen in the brain and spinal cord. High concentrations of mRNA are also present in the intestinal epithelium and tail tip, tissues programmed for regression. At later stages (55 onwards), strong hybridization signals are also exhibited by hindlimb buds. This pattern persists through metamorphic climax, after which TR mRNAs decline in all tissues to low levels in froglets at stage 66. In developing froglets, TR transcripts were detected in large amounts in the cytoplasm of stage 1 and 2 oocytes but the rate of their accumulation did not increase with further oocyte growth. This observation raises the possibility that the response to thyroid hormones at early stages of tadpoles (42–44) may be due to TR synthesized on maternally derived mRNA. Exposure of tadpoles at premetamorphic stages (48–52) to exogenous thyroid hormone (T3) substantially enhanced the accumulation of TR mRNA, especially that of TR beta message, which could explain the accelerated increase in sensitivity of tadpoles to thyroid hormones at the onset of natural metamorphosis.(ABSTRACT TRUNCATED AT 400 WORDS)

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