Thyrotroph Thyroid Hormone Sensitivity Index

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Thyrotroph Thyroid Hormone Sensitivity Index
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Reference Range 100-150
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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]

How to determine TTSI[edit | edit source]

Universal form[edit | edit source]

The TTSI can be calculated with

<math>TTSI = {100 \cdot TSH \cdot FT4 \over l_u}</math>

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[edit | edit source]

Parameter Lower limit Upper limit Unit
TTSI 100 150

Short form[edit | edit source]

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

<math>TTSI = {100 \cdot TSH \cdot FT4}</math>.

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[edit | edit source]

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[edit | edit source]

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].

See also[edit | edit source]

References[edit | edit source]

  1. ↑ , 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., 1997, Vol. 82(Issue: 5), pp. 1608–14, DOI: 10.1210/jcem.82.5.3945, PMID: 9141558,
  2. ↑ , Five new families with resistance to thyroid hormone not caused by mutations in the thyroid hormone receptor beta gene, J. Clin. Endocrinol. Metab., 1999, Vol. 84(Issue: 11), pp. 3919–28, DOI: 10.1210/jcem.84.11.6080, PMID: 10566629,
  3. ↑ 3.0 3.1 , Metabolic syndrome prevalence is increased with increasing thyroid hormone resistance levels among normothyroid subjects, Atherosclerosis, Vol. 275, pp. e18, DOI: 10.1016/j.atherosclerosis.2018.06.038,
  4. ↑ 4.0 4.1 4.2 , Calculated Parameters of Thyroid Homeostasis: Emerging Tools for Differential Diagnosis and Clinical Research., Frontiers in Endocrinology, Vol. 7, pp. 57, DOI: 10.3389/fendo.2016.00057, PMID: 27375554, PMC: 4899439,
  5. ↑ , 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, Vol. 150(Issue: 8), pp. 3927–3934, DOI: 10.1210/en.2009-0093, PMID: 19406944, PMC: 2717870,
  6. ↑ , Impaired Sensitivity to Thyroid Hormone: Defects of Transport, Metabolism and Action, , PMID: 25905294,
  7. ↑ , 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, Vol. 97(Issue: 4), pp. 1328–1336, DOI: 10.1210/jc.2011-2642, PMID: 22319036, PMC: 3319181,
  8. ↑ , A novel de novo mutation in the thyroid hormone receptor-beta gene, Experimental and Clinical Endocrinology & Diabetes, Vol. 122(Issue: 3), DOI: 10.1055/s-0035-1547617,
  9. ↑ , The role of functional thyroid capacity in pituitary thyroid feedback regulation., European Journal of Clinical Investigation, Vol. 48(Issue: 10), pp. e13003, DOI: 10.1111/eci.13003, PMID: 30022470,
  10. ↑ , Heritability of serum TSH, free T4 and free T3 concentrations: a study of a large UK twin cohort, Clinical Endocrinology, Vol. 68(Issue: 4), pp. 652–659, DOI: 10.1111/j.1365-2265.2007.03079.x, PMID: 17970774,
  11. ↑ , Human longevity is characterised by high thyroid stimulating hormone secretion without altered energy metabolism., Scientific Reports, Vol. 5, pp. 11525, DOI: 10.1038/srep11525, PMID: 26089239, PMC: 4473605,
  12. ↑ , Impaired Sensitivity to Thyroid Hormones Is Associated With Diabetes and Metabolic Syndrome, Diabetes Care, Vol. 42(Issue: 2), pp. 303–310, DOI: 10.2337/dc18-1410, PMID: 30552134,
  13. ↑ , Mild Acquired Thyroid Hormone Resistance Is Associated with Diabetes-Related Morbidity and Mortality in the General Population, Clinical Thyroidology, Vol. 31(Issue: 4), pp. 138–140, DOI: 10.1089/ct.2019;31.138-140,
  14. ↑ , Adaptive Veränderungen des Schilddrüsenstoffwechsels als Risikoindikatoren bei Traumata, Trauma und Berufskrankheit, DOI: 10.1007/s10039-019-00438-z,
  15. ↑ , Inhibition of the hypothalamic-pituitary-thyroid axis in response to lipopolysaccharide is independent of changes in circulating corticosteroids., Neuroimmunomodulation, 1997, Vol. 4(Issue: 4), pp. 188–94, DOI: 10.1159/000097337, PMID: 9524963,
  16. ↑ , Lipopolysaccharide modulation of thyrotropin-releasing hormone (TRH) and TRH-like peptide levels in rat brain and endocrine organs., Journal of Molecular Neuroscience, Vol. 31(Issue: 3), pp. 245–59, PMID: 17726229,
  17. ↑ , Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions., Endocrine Reviews, Vol. 35(Issue: 2), pp. 159–94, DOI: 10.1210/er.2013-1087, PMID: 24423980, PMC: 3963261,
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Contributors: Prab R. Tumpati, MD