Thyrotroph Thyroid Hormone Sensitivity Index

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Thyrotroph Thyroid Hormone Sensitivity Index
Synonyms TTSI, Thyrotroph T4 Resistance Index, TT4RI
Reference range 100-150
Test ofSensitivity of TSH-producing pituitary cells to thyroid hormones; also a marker for the set point of thyroid homeostasis

The Thyrotroph Thyroid Hormone Sensitivity Index (abbreviated TTSI, also referred to as Thyrotroph T4 Resistance Index or TT4RI) is a calculated structure parameter of thyroid homeostasis. It was originally developed to deliver a method for fast screening for resistance to thyroid hormone. [1] [2] Today it is also used to get an estimate for the set point of thyroid homeostasis, [3] especially to assess dynamic thyrotropic adaptation of the anterior pituitary gland, including non-thyroidal illnesses. [4]

Contents

How to determine TTSI

Universal form

The TTSI can be calculated with

from equilibrium serum or plasma concentrations of thyrotropin (TSH), free T4 (FT4) and the assay-specific upper limit of the reference interval for FT4 concentration (lu). [4]

Reference ranges

ParameterLower limitUpper limitUnit
TTSI100150

Short form

Some publications use a simpler form of this equation that doesn't correct for the reference range of free T4. It is calculated with

.

The disadvantage of this uncorrected version is that its numeric results are highly dependent on the used assays and their units of measurement.[ citation needed ]

Biochemical associations

In case of resistance to thyroid hormone, the magnitude of TTSI depends on which nucleotide in the THRB gene is mutated, but also on the genotype of coactivators. A systematic investigation in mice demonstrated a strong association of TT4RI to the genotypes of THRB and the steroid receptor coactivator (SRC-1) gene. [5]

Clinical significance

The TTSI is used as a screening parameter for resistance to thyroid hormone due to mutations in the THRB gene, where it is elevated. [4] It is also beneficial for assessing the severity of already confirmed thyroid hormone resistance, [6] even on replacement therapy with L-T4, [7] and for monitoring the pituitary response to substitution therapy with thyromimetics (e.g. TRIAC) in RTH Beta. [8]

In autoimmune thyroiditis the TTSI is moderately elevated. [9]

A large cohort study demonstrated TTSI to be strongly influenced by genetic factors. [10] A variant of the TTSI that is not corrected for the upper limit of the FT4 reference range was shown to be significantly increased in offspring from long-lived siblings compared to their partners. [11]

Conversely, an elevated set point of thyroid homeostasis, as quantified by the TT4RI, is associated to higher prevalence of metabolic syndrome [3] and several harmonized criteria by the International Diabetes Federation, including triglyceride and HDL concentration and blood pressure. [12] [13]

In certain phenotypes of non-thyroidal illness syndrome, especially in cases with concomitant sepsis, the TTSI is reduced. [14] This reflects a reduced set point of thyroid homeostasis, as also experimentally predicted in rodent models of inflammation and sepsis. [15] [16] [17]

Negative correlation of the TTSI with the urinary excretion of certain phthalates suggests that endocrine disruptors may affect the central set point of thyroid homeostasis. [18]

See also

Related Research Articles

<span class="mw-page-title-main">Hypothyroidism</span> Endocrine disease

Hypothyroidism is a disorder of the endocrine system in which the thyroid gland does not produce enough thyroid hormone. It can cause a number of symptoms, such as poor ability to tolerate cold, a feeling of tiredness, constipation, slow heart rate, depression, and weight gain. Occasionally there may be swelling of the front part of the neck due to goiter. Untreated cases of hypothyroidism during pregnancy can lead to delays in growth and intellectual development in the baby or congenital iodine deficiency syndrome.

Proopiomelanocortin Mammalian protein found in Homo sapiens

Pro-opiomelanocortin (POMC) is a precursor polypeptide with 241 amino acid residues. POMC is synthesized in corticotrophs of the anterior pituitary from the 267-amino-acid-long polypeptide precursor pre-pro-opiomelanocortin (pre-POMC), by the removal of a 26-amino-acid-long signal peptide sequence during translation. POMC is part of the central melanocortin system.

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.

Thyroid hormone resistance Medical condition

Thyroid hormone resistance 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. Essentially this is decreased end organ responsiveness to thyroid hormones. A new term "impaired sensitivity to thyroid hormone" has been suggested in March 2014 by Refetoff et al.

Thyroid function tests (TFTs) is a collective term for blood tests used to check the function of the thyroid. TFTs may be requested if a patient is thought to suffer from hyperthyroidism or hypothyroidism, or to monitor the effectiveness of either thyroid-suppression or hormone replacement therapy. It is also requested routinely in conditions linked to thyroid disease, such as atrial fibrillation and anxiety disorder.

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.

Thyrotropin receptor Mammalian protein found in Homo sapiens

The thyrotropin receptor is a receptor that responds to thyroid-stimulating hormone and stimulates the production of thyroxine (T4) and triiodothyronine (T3). The TSH receptor is a member of the G protein-coupled receptor superfamily of integral membrane proteins and is coupled to the Gs protein.

Thyrotropin-releasing hormone receptor

Thyrotropin-releasing hormone receptor (TRHR) is a G protein-coupled receptor which binds thyrotropin-releasing hormone.

Hypothalamic–pituitary–thyroid axis Part of the neuroendocrine system

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.

Nuclear receptor co-repressor 2

The nuclear receptor co-repressor 2 (NCOR2) is a transcriptional coregulatory protein that contains several nuclear receptor-interacting domains. In addition, NCOR2 appears to recruit histone deacetylases to DNA promoter regions. Hence NCOR2 assists nuclear receptors in the down regulation of target gene expression. NCOR2 is also referred to as a silencing mediator for retinoid or thyroid-hormone receptors (SMRT) or T3 receptor-associating cofactor 1 (TRAC-1).

<span class="mw-page-title-main">Thyroid hormone receptor alpha</span> Protein-coding gene in the species Homo sapiens

Thyroid hormone receptor alpha (TR-alpha) also known as nuclear receptor subfamily 1, group A, member 1 (NR1A1), is a nuclear receptor protein that in humans is encoded by the THRA gene.

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.

<span class="mw-page-title-main">Thyroid hormones</span> Hormones produced by the thyroid gland

Thyroid hormones are two hormones produced and released by the thyroid gland, namely triiodothyronine (T3) and thyroxine (T4). They are tyrosine-based hormones that are primarily responsible for regulation of metabolism. T3 and T4 are partially composed of iodine. A deficiency of iodine leads to decreased production of T3 and T4, enlarges the thyroid tissue and will cause the disease known as simple goitre.

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.

<span class="mw-page-title-main">Thyroid's secretory capacity</span>

Thyroid's secretory capacity is the maximum stimulated amount of thyroxine that the thyroid can produce in a given time-unit.

The sum activity of peripheral deiodinases is the maximum amount of triiodothyronine produced per time-unit under conditions of substrate saturation. It is assumed to reflect the activity of deiodinases outside the central nervous system and other isolated compartments. GD is therefore expected to reflect predominantly the activity of type I deiodinase.

Pulsatile secretion is a biochemical phenomenon observed in a wide variety of cell and tissue types, in which chemical products are secreted in a regular temporal pattern. The most common cellular products observed to be released in this manner are intercellular signaling molecules such as hormones or neurotransmitters. Examples of hormones that are secreted pulsatilely include insulin, thyrotropin, TRH, gonadotropin-releasing hormone (GnRH) and growth hormone (GH). In the nervous system, pulsatility is observed in oscillatory activity from central pattern generators. In the heart, pacemakers are able to work and secrete in a pulsatile manner. A pulsatile secretion pattern is critical to the function of many hormones in order to maintain the delicate homeostatic balance necessary for essential life processes, such as development and reproduction. Variations of the concentration in a certain frequency can be critical to hormone function, as evidenced by the case of GnRH agonists, which cause functional inhibition of the receptor for GnRH due to profound downregulation in response to constant (tonic) stimulation. Pulsatility may function to sensitize target tissues to the hormone of interest and upregulate receptors, leading to improved responses. This heightened response may have served to improve the animal's fitness in its environment and promote its evolutionary retention.

Jostels TSH index

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. It is also recommended for purposes of differential diagnosis in the sociomedical expert assessment.

The Thyroid Feedback Quantile-based Index (TFQI) is a calculated parameter for thyrotropic pituitary function. It was defined to be more robust to distorted data than established markers including Jostel's TSH index (JTI) and the thyrotroph thyroid hormone sensitivity index (TTSI).

References

  1. ↑ Yagi H, Pohlenz J, Hayashi Y, Sakurai A, Refetoff S (1997). "Resistance to thyroid hormone caused by two mutant thyroid hormone receptors beta, R243Q and R243W, with marked impairment of function that cannot be explained by altered in vitro 3,5,3'-triiodothyroinine binding affinity". J. Clin. Endocrinol. Metab. 82 (5): 1608–14. doi: 10.1210/jcem.82.5.3945 . PMID   9141558.
  2. ↑ Pohlenz J, Weiss RE, Macchia PE, Pannain S, Lau IT, Ho H, Refetoff S (1999). "Five new families with resistance to thyroid hormone not caused by mutations in the thyroid hormone receptor beta gene". J. Clin. Endocrinol. Metab. 84 (11): 3919–28. doi: 10.1210/jcem.84.11.6080 . PMID   10566629.
  3. 1 2 Laclaustra, M.; Moreno-Franco, B.; Mateo-Gallego, R.; Perez-Calahorra, S.; Lamiquiz-Moneo, I.; Marco-Benedi, V.; Cenarro, A.; Casasnovas, J.A.; Civeira, F. (August 2018). "Metabolic syndrome prevalence is increased with increasing thyroid hormone resistance levels among normothyroid subjects". Atherosclerosis. 275: e18. doi:10.1016/j.atherosclerosis.2018.06.038. S2CID   81721947.
  4. 1 2 3 Dietrich, JW; Landgrafe-Mende, G; Wiora, E; Chatzitomaris, A; Klein, HH; Midgley, JE; Hoermann, R (2016). "Calculated Parameters of Thyroid Homeostasis: Emerging Tools for Differential Diagnosis and Clinical Research". Frontiers in Endocrinology. 7: 57. doi: 10.3389/fendo.2016.00057 . PMC   4899439 . PMID   27375554.
  5. ↑ Alonso, Manuela; Goodwin, Charles; Liao, XiaoHui; Ortiga-Carvalho, Tania; Machado, Danielle S.; Wondisford, Fredric E.; Refetoff, Samuel; Weiss, Roy E. (August 2009). "Interaction of Steroid Receptor Coactivator (SRC)-1 and the Activation Function-2 Domain of the Thyroid Hormone Receptor (TR) β in TRβ E457A Knock-In and SRC-1 Knockout mice". Endocrinology. 150 (8): 3927–3934. doi:10.1210/en.2009-0093. PMC   2717870 . PMID   19406944.
  6. ↑ Dumitrescu, AM; Refetoff, S; Feingold, KR; Anawalt, B; Boyce, A; Chrousos, G; Dungan, K; Grossman, A; Hershman, JM; Kaltsas, G; Koch, C; Kopp, P; Korbonits, M; McLachlan, R; Morley, JE; New, M; Perreault, L; Purnell, J; Rebar, R; Singer, F; Trence, DL; Vinik, A; Wilson, DP (2000). "Impaired Sensitivity to Thyroid Hormone: Defects of Transport, Metabolism and Action". PMID   25905294.{{cite journal}}: Cite journal requires |journal= (help)
  7. ↑ Ferrara, Alfonso Massimiliano; Onigata, Kazumichi; Ercan, Oya; Woodhead, Helen; Weiss, Roy E.; Refetoff, Samuel (April 2012). "Homozygous Thyroid Hormone Receptor β-Gene Mutations in Resistance to Thyroid Hormone: Three New Cases and Review of the Literature". The Journal of Clinical Endocrinology & Metabolism. 97 (4): 1328–1336. doi:10.1210/jc.2011-2642. PMC   3319181 . PMID   22319036.
  8. ↑ Chatzitomaris, A; Köditz, R; Höppner, W; Peters, S; Klein, HH; Dietrich, JW (12 March 2015). "A novel de novo mutation in the thyroid hormone receptor-beta gene". Experimental and Clinical Endocrinology & Diabetes. 122 (3). doi:10.1055/s-0035-1547617.
  9. ↑ Hoermann, R; Midgley, JEM; Larisch, R; Dietrich, JW (October 2018). "The role of functional thyroid capacity in pituitary thyroid feedback regulation". European Journal of Clinical Investigation. 48 (10): e13003. doi:10.1111/eci.13003. PMID   30022470. S2CID   51698223.
  10. ↑ Panicker, V.; Wilson, S. G.; Spector, T. D.; Brown, S. J.; Falchi, M.; Richards, J. B.; Surdulescu, G. L.; Lim, E. M.; Fletcher, S. J.; Walsh, J. P. (April 2008). "Heritability of serum TSH, free T4 and free T3 concentrations: a study of a large UK twin cohort". Clinical Endocrinology. 68 (4): 652–659. doi:10.1111/j.1365-2265.2007.03079.x. PMID   17970774. S2CID   21809978.
  11. ↑ Jansen, SW; Akintola, AA; Roelfsema, F; van der Spoel, E; Cobbaert, CM; Ballieux, BE; Egri, P; Kvarta-Papp, Z; Gereben, B; Fekete, C; Slagboom, PE; van der Grond, J; Demeneix, BA; Pijl, H; Westendorp, RG; van Heemst, D (19 June 2015). "Human longevity is characterised by high thyroid stimulating hormone secretion without altered energy metabolism". Scientific Reports. 5: 11525. Bibcode:2015NatSR...511525J. doi:10.1038/srep11525. PMC   4473605 . PMID   26089239.
  12. ↑ Laclaustra, Martin; Moreno-Franco, Belen; Lou-Bonafonte, Jose Manuel; Mateo-Gallego, Rocio; Casasnovas, Jose Antonio; Guallar-Castillon, Pilar; Cenarro, Ana; Civeira, Fernando (February 2019). "Impaired Sensitivity to Thyroid Hormones Is Associated With Diabetes and Metabolic Syndrome". Diabetes Care. 42 (2): 303–310. doi: 10.2337/dc18-1410 . PMID   30552134. S2CID   54632324.
  13. ↑ Guan, Haixia (April 2019). "Mild Acquired Thyroid Hormone Resistance Is Associated with Diabetes-Related Morbidity and Mortality in the General Population". Clinical Thyroidology. 31 (4): 138–140. doi:10.1089/ct.2019;31.138-140. S2CID   145947179.
  14. ↑ Dietrich, J. W.; Ackermann, A.; Kasippillai, A.; Kanthasamy, Y.; Tharmalingam, T.; Urban, A.; Vasileva, S.; Schildhauer, T. A.; Klein, H. H.; Stachon, A.; Hering, S. (19 September 2019). "Adaptive Veränderungen des Schilddrüsenstoffwechsels als Risikoindikatoren bei Traumata". Trauma und Berufskrankheit. 21 (4): 260–267. doi:10.1007/s10039-019-00438-z. S2CID   202673793.
  15. ↑ Kondo, K; Harbuz, MS; Levy, A; Lightman, SL (1997). "Inhibition of the hypothalamic-pituitary-thyroid axis in response to lipopolysaccharide is independent of changes in circulating corticosteroids". Neuroimmunomodulation. 4 (4): 188–94. doi:10.1159/000097337. PMID   9524963.
  16. ↑ Pekary, AE; Stevens, SA; Sattin, A (2007). "Lipopolysaccharide modulation of thyrotropin-releasing hormone (TRH) and TRH-like peptide levels in rat brain and endocrine organs". Journal of Molecular Neuroscience. 31 (3): 245–59. doi:10.1385/jmn:31:03:245. PMID   17726229. S2CID   11463905.
  17. ↑ Fekete, C; Lechan, RM (April 2014). "Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions". Endocrine Reviews. 35 (2): 159–94. doi:10.1210/er.2013-1087. PMC   3963261 . PMID   24423980.
  18. ↑ Chen, Y; Zhang, W; Chen, J; Wang, N; Chen, C; Wang, Y; Wan, H; Chen, B; Lu, Y (2021). "Association of Phthalate Exposure with Thyroid Function and Thyroid Homeostasis Parameters in Type 2 Diabetes". Journal of Diabetes Research. 2021: 4027380. doi: 10.1155/2021/4027380 . PMC   8566079 . PMID   34746318.
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