Thyrotroph Thyroid Hormone Sensitivity Index

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]

Thyrotroph Thyroid Hormone Sensitivity Index
SynonymsTTSI, Thyrotroph T4 Resistance Index, TT4RI
Reference range100-150
Test ofSensitivity of TSH-producing pituitary cells to thyroid hormones; also a marker for the set point of thyroid homeostasis

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.

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

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. 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. 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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