Thyroid hormone resistance

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Thyroid hormone resistance
Other namesResistance to thyroid hormone
Thyroid system.svg
Regulation of thyroid hormone
Specialty Endocrinology

Thyroid hormone resistance (also resistance to thyroid hormone (RTH), and sometimes Refetoff syndrome) describes a rare syndrome in which the thyroid hormone levels are elevated but the thyroid stimulating hormone (TSH) level is not suppressed, or not completely suppressed as would be expected. The first report of the condition appeared in 1967. [1] Essentially this is decreased end organ responsiveness to thyroid hormones. [2] A new term "impaired sensitivity to thyroid hormone" has been suggested in March 2014 by Refetoff et al. [3]

Contents

Presentation

The syndrome can present with variable symptoms, even between members of the same family harboring the same mutation. [1] Typically most or all tissues are resistant to thyroid hormone, so despite raised measures of serum thyroid hormone the individual may appear euthyroid (have no symptoms of over- or underactivity of the thyroid gland). The most common symptoms are goiter and tachycardia. It has also been linked to some cases of attention deficit hyperactivity disorder (ADHD), although the majority of people with that diagnosis have no thyroid problems. [4] An association with depression has been proposed. [5]

Causes

Normal thyroid hormone function requires normal thyroid hormone transport across cell membrane, appropriate deiodination, thyroid hormone nuclear receptor, thyroid hormone response elements, co-activators, co-repressors, and normal histone acetylation. Any abnormalities in this chain can result in thyroid hormone resistance and it has not been as well studied as the various forms of insulin resistance.[ citation needed ]

The most well known cause of the syndrome are mutations of the β (beta) form ( THRB gene) of the thyroid hormone receptor, of which over 100 different mutations have been documented. [6] Mutations in MCT8 and SECISBP2 have also been associated with this condition. [7]

Regulation of thyroid hormone secretion

Hypothalamus secretes a hormone called thyrotropin releasing hormone (TRH) which in turn release thyroid stimulating hormone (TSH). TSH signals thyroid to secrete thyroid hormones thyroxine (T4) and triiodothyronine (T3). T4 gets converted to active T3 in peripheral tissues with the help of deiodinase enzymes. T3 negatively feedback on the pituitary and decreases TSH secretion.[ citation needed ]

Diagnosis

The characteristic blood test results for this disorder can also be found in other disorders (for example TSH-oma (pituitary adenoma), or other pituitary disorders). The diagnosis may involve identifying a mutation of the thyroid receptor, which is present in approximately 85% of cases. [8]

Management

Beta blockers, like metoprolol, are sometimes used to help suppress symptoms.[ citation needed ]

Incidence

Thyroid hormone resistance syndrome is rare, incidence is variously quoted as 1 in 50,000 or 1 in 40,000 live births. [9] More than 1000 individuals have been identified with thyroid hormone resistance, of which 85% had thyroid hormone beta receptor mutation. [7]

Related Research Articles

Thyroid-stimulating hormone (also known as thyrotropin, thyrotropic hormone, or abbreviated TSH) is a pituitary hormone that stimulates the thyroid gland to produce thyroxine (T4), and then triiodothyronine (T3) which stimulates the metabolism of almost every tissue in the body. It is a glycoprotein hormone produced by thyrotrope cells in the anterior pituitary gland, which regulates the endocrine function of the thyroid.

Thyroxine-binding globulin mammalian protein found in Homo sapiens

Thyroxine-binding globulin (TBG) is a globulin protein that in humans is encoded by the SERPINA7 gene. TBG binds thyroid hormones in circulation. It is one of three transport proteins (along with transthyretin and serum albumin) responsible for carrying the thyroid hormones thyroxine (T4) and triiodothyronine (T3) in the bloodstream. Of these three proteins, TBG has the highest affinity for T4 and T3 but is present in the lowest concentration relative to transthyretin and albumin, which also bind T3 and T4 in circulation. Despite its low concentration, TBG carries the majority of T4 in the blood plasma. Due to the very low concentration of T4 and T3 in the blood, TBG is rarely more than 25% saturated with its ligand. Unlike transthyretin and albumin, TBG has a single binding site for T4/T3. TBG is synthesized primarily in the liver as a 54-kDa protein. In terms of genomics, TBG is a serpin; however, it has no inhibitory function like many other members of this class of proteins.

Triiodothyronine chemical compound

Triiodothyronine, also known as T3, is a thyroid hormone. It affects almost every physiological process in the body, including growth and development, metabolism, body temperature, and heart rate.

Levothyroxine chemical compound

Levothyroxine, also known as L-thyroxine, is a manufactured form of the thyroid hormone thyroxine (T4). It is used to treat thyroid hormone deficiency, including the severe form known as myxedema coma. It may also be used to treat and prevent certain types of thyroid tumors. It is not indicated for weight loss. Levothyroxine is taken by mouth or given by injection into a vein. Maximum effect from a specific dose can take up to six weeks to occur.

Thyroid disease type of endocrine disease

Thyroid disease is a medical condition that affects the function of the thyroid gland. The thyroid gland is located at the front of the neck and produces thyroid hormones that travel through the blood to help regulate many other organs, meaning that it is an endocrine organ. These hormones normally act in the body to regulate energy use, infant development, and childhood development.

Thyroid function tests (TFTs) is a collective term for blood tests used to check the function of the thyroid.

The thyroid hormone receptor (TR) is a type of nuclear receptor that is activated by binding thyroid hormone. TRs act as transcription factors, ultimately affecting the regulation of gene transcription and translation. These receptors also have non-genomic effects that lead to second messenger activation, and corresponding cellular response.

Desiccated thyroid, also known as thyroid extract, is thyroid gland that has been dried and powdered for medical use. It is used to treat hypothyroidism. It is less preferred than levothyroxine. It is taken by mouth. Maximal effects may take up to 3 weeks to occur.

Hypothalamic–pituitary–thyroid axis part of the neuroendocrine system responsible for the regulation of metabolism.

The hypothalamic–pituitary–thyroid axis is part of the neuroendocrine system responsible for the regulation of metabolism and also responds to stress.

Euthyroid sick syndrome (ESS) is a state of adaptation or dysregulation of thyrotropic feedback control wherein the levels of T3 and/or T4 are abnormal, but the thyroid gland does not appear to be dysfunctional. This condition may result from allostatic responses of hypothalamus-pituitary-thyroid feedback control, dyshomeostatic disorders, drug interferences and impaired assay characteristics in critical illness.

GNRHR protein-coding gene in the species Homo sapiens

Gonadotropin-releasing hormone receptor is a protein that in humans is encoded by the GNRHR gene.

Tiratricol chemical compound

Tiratricol is a thyroid hormone analogue. Triiodothyroacetic acid is also a physiologic thyroid hormone that is present in the normal organism in low concentrations.

Thyroid hormone receptor beta protein-coding gene in the species Homo sapiens

Thyroid hormone receptor beta (TR-beta) also known as nuclear receptor subfamily 1, group A, member 2 (NR1A2), is a nuclear receptor protein that in humans is encoded by the THRB gene.

PROP1 protein-coding gene in the species Homo sapiens

Homeobox protein prophet of PIT-1 is a protein that in humans is encoded by the PROP1 gene.

Autoimmune hypophysitis is defined as inflammation of the pituitary gland due to autoimmunity.

TSHB protein-coding gene in the species Homo sapiens

Thyroid stimulating hormone, beta also known as TSHB is a protein which in humans is encoded by the TSHB gene.

Mild androgen insensitivity syndrome

Mild androgen insensitivity syndrome (MAIS) is a condition that results in a mild impairment of the cell's ability to respond to androgens. The degree of impairment is sufficient to impair spermatogenesis and / or the development of secondary sexual characteristics at puberty in males, but does not affect genital differentiation or development. Female genital and sexual development is not significantly affected by the insensitivity to androgens; as such, MAIS is only diagnosed in males. The clinical phenotype associated with MAIS is a normal male habitus with mild spermatogenic defect and / or reduced secondary terminal hair.

The fetal endocrine system is one of the first systems to develop during prenatal development.

Jostel's TSH index, also referred to as Jostel's thyrotropin index or Thyroid Function index (TFI) is a method for estimating the thyrotropic function of the anterior pituitary lobe in a quantitative way. The equation has been derived from the logarithmic standard model of thyroid homeostasis. In a paper from 2014 further study was suggested to show if it is useful, but the 2018 guideline by the European Thyroid Association for the diagnosis of uncertain cases of central hypothyroidism regarded it as beneficial.

The Thyrotroph Thyroid Hormone Sensitivity Index is a calculated structure parameter of thyroid homeostasis. It was originally developed to deliver a method for fast screening for resistance to thyroid hormone. Today it is also used to get an estimate for the set point of thyroid homeostasis, especially to assess dynamic thyrotropic adaptation of the anterior pituitary gland, including non-thyroidal illnesses.

References

  1. 1 2 Refetoff S, DeWind LT, DeGroot LJ (1967). "Familial syndrome combining deaf-mutism, stuppled epiphyses, goiter and abnormally high PBI: possible target organ refractoriness to thyroid hormone". J. Clin. Endocrinol. Metab. 27 (2): 279–94. doi:10.1210/jcem-27-2-279. PMID   4163616.
  2. Weiss RE, Dumitrescu A, Refetoff S (2010). "Approach to the patient with resistance to thyroid hormone and pregnancy". J. Clin. Endocrinol. Metab. 95 (7): 3094–102. doi:10.1210/jc.2010-0409. PMC   2928892 . PMID   20610605.
  3. Refetoff S, Bassett JH, Beck-Peccoz P, Bernal J, Brent G, Chatterjee K, et al. (March 2014). "Classification and proposed nomenclature for inherited defects of thyroid hormone action, cell transport, and metabolism". Eur Thyroid J. 3 (1): 7–9. doi:10.1159/000358180. PMC   4005262 . PMID   24847459.
  4. Hauser P, Zametkin AJ, Martinez P, et al. (1993). "Attention deficit-hyperactivity disorder in people with generalized resistance to thyroid hormone" (PDF). N. Engl. J. Med. 328 (14): 997–1001. doi:10.1056/NEJM199304083281403. hdl:2318/1646358. PMID   8450877.
  5. Fardella CE, Artigas RA, Gloger S, Jiménez M, Carvajal CA, Krall PM, Quiroz D, Campino C, Mosso LM (June 2007). "Refractory depression in a patient with peripheral resistance to thyroid hormone (RTH) and the effect of triiodothyronine treatment". Endocrine. 31 (3): 272–8. doi:10.1007/s12020-007-0042-7. PMID   17906375. S2CID   19503692.
  6. Beato-Víbora P, Arroyo-Díez J, Rodríguez-López R (March 2013). "Thyroid hormone resistance caused by a novel deleterious variant of the thyroid hormone receptor beta gene". Eur. J. Obstet. Gynecol. Reprod. Biol. 167 (1): 118–9. doi:10.1016/j.ejogrb.2012.11.001. PMID   23195042.
  7. 1 2 Refetoff S, Dumitrescu AM (2007). "Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination". Best Pract. Res. Clin. Endocrinol. Metab. 21 (2): 277–305. doi:10.1016/j.beem.2007.03.005. PMID   17574009.
  8. Bottcher Y, Paufler T, Stehr T, Bertschat FL, Paschke R, Koch CA (2007). "Thyroid hormone resistance without mutations in thyroid hormone receptor beta". Med. Sci. Monit. 13 (6): CS67–70. doi:10.12659/MSM.484143. PMID   17534237.
  9. Lafranchi SH, Snyder DB, Sesser DE, Skeels MR, Singh N, Brent GA, Nelson JC (September 2003). "Follow-up of newborns with elevated screening T4 concentrations". J. Pediatr. 143 (3): 296–301. doi:10.1067/S0022-3476(03)00184-7. PMID   14517508.
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