Thyrotroph Thyroid Hormone Sensitivity Index

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| name = Thyrotroph Thyroid Hormone Sensitivity Index

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| test of = Sensitivity of TSH-producing pituitary cells to thyroid hormones; also a marker for the set point of thyroid homeostasis

| synonyms = TTSI, Thyrotroph T4 Resistance Index, TT4RI

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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.{{cite journal | pmid = 9141558 | doi=10.1210/jcem.82.5.3945 | volume=82 | issue=5 | title=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 | year=1997 | journal=J. Clin. Endocrinol. Metab. | pages=1608–14 | vauthors=Yagi H, Pohlenz J, Hayashi Y, Sakurai A, Refetoff S| doi-access=free }}{{cite journal | pmid = 10566629 | doi=10.1210/jcem.84.11.6080 | volume=84 | issue=11 | title=Five new families with resistance to thyroid hormone not caused by mutations in the thyroid hormone receptor beta gene | year=1999 | journal=J. Clin. Endocrinol. Metab. | pages=3919–28 | vauthors=Pohlenz J, Weiss RE, Macchia PE, Pannain S, Lau IT, Ho H, Refetoff S| doi-access=free }} Today it is also used to get an estimate for the set point of thyroid homeostasis,{{cite journal |last1=Laclaustra |first1=M. |last2=Moreno-Franco |first2=B. |last3=Mateo-Gallego |first3=R. |last4=Perez-Calahorra |first4=S. |last5=Lamiquiz-Moneo |first5=I. |last6=Marco-Benedi |first6=V. |last7=Cenarro |first7=A. |last8=Casasnovas |first8=J.A. |last9=Civeira |first9=F. |title=Metabolic syndrome prevalence is increased with increasing thyroid hormone resistance levels among normothyroid subjects |journal=Atherosclerosis |date=August 2018 |volume=275 |pages=e18 |doi=10.1016/j.atherosclerosis.2018.06.038|s2cid=81721947 }} especially to assess dynamic thyrotropic adaptation of the anterior pituitary gland, including non-thyroidal illnesses.{{cite journal |last1=Dietrich |first1=JW |last2=Landgrafe-Mende |first2=G |last3=Wiora |first3=E |last4=Chatzitomaris |first4=A |last5=Klein |first5=HH |last6=Midgley |first6=JE |last7=Hoermann |first7=R |title=Calculated Parameters of Thyroid Homeostasis: Emerging Tools for Differential Diagnosis and Clinical Research. |journal=Frontiers in Endocrinology |date=2016 |volume=7 |pages=57 |doi=10.3389/fendo.2016.00057 |pmid=27375554|pmc=4899439 |doi-access=free }}

How to determine TTSI

=Universal form=

The TTSI can be calculated with

: $TTSI = {100 \cdot TSH \cdot FT4 \over l_u}$

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 (l_u).

==Reference ranges==

class="wikitable"

|Parameter

Lower limit

Upper limit

Unit

TTSI

100

150

=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

: $TTSI = {100 \cdot TSH \cdot FT4}$ .

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|date=July 2020}}

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.{{cite journal |last1=Alonso |first1=Manuela |last2=Goodwin |first2=Charles |last3=Liao |first3=XiaoHui |last4=Ortiga-Carvalho |first4=Tania |last5=Machado |first5=Danielle S. |last6=Wondisford |first6=Fredric E. |last7=Refetoff |first7=Samuel |last8=Weiss |first8=Roy E. |title=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 |journal=Endocrinology |date=August 2009 |volume=150 |issue=8 |pages=3927–3934 |doi=10.1210/en.2009-0093 |pmid=19406944|pmc=2717870 }}

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. It is also beneficial for assessing the severity of already confirmed thyroid hormone resistance,{{cite journal |last1=Dumitrescu |first1=AM |last2=Refetoff |first2=S |last3=Feingold |first3=KR |last4=Anawalt |first4=B |last5=Boyce |first5=A |last6=Chrousos |first6=G |last7=Dungan |first7=K |last8=Grossman |first8=A |last9=Hershman |first9=JM |last10=Kaltsas |first10=G |last11=Koch |first11=C |last12=Kopp |first12=P |last13=Korbonits |first13=M |last14=McLachlan |first14=R |last15=Morley |first15=JE |last16=New |first16=M |last17=Perreault |first17=L |last18=Purnell |first18=J |last19=Rebar |first19=R |last20=Singer |first20=F |last21=Trence |first21=DL |last22=Vinik |first22=A |last23=Wilson |first23=DP |title=Impaired Sensitivity to Thyroid Hormone: Defects of Transport, Metabolism and Action |date=2000 |pmid=25905294}} even on replacement therapy with L-T4,{{cite journal |last1=Ferrara |first1=Alfonso Massimiliano |last2=Onigata |first2=Kazumichi |last3=Ercan |first3=Oya |last4=Woodhead |first4=Helen |last5=Weiss |first5=Roy E. |last6=Refetoff |first6=Samuel |title=Homozygous Thyroid Hormone Receptor β-Gene Mutations in Resistance to Thyroid Hormone: Three New Cases and Review of the Literature |journal=The Journal of Clinical Endocrinology & Metabolism |date=April 2012 |volume=97 |issue=4 |pages=1328–1336 |doi=10.1210/jc.2011-2642 |pmid=22319036|pmc=3319181 }} and for monitoring the pituitary response to substitution therapy with thyromimetics (e.g. TRIAC) in RTH Beta.{{cite journal |last1=Chatzitomaris |first1=A |last2=Köditz |first2=R |last3=Höppner |first3=W |last4=Peters |first4=S |last5=Klein |first5=HH |last6=Dietrich |first6=JW |title=A novel de novo mutation in the thyroid hormone receptor-beta gene |journal=Experimental and Clinical Endocrinology & Diabetes |date=12 March 2015 |volume=122 |issue=3 |doi=10.1055/s-0035-1547617}}

In autoimmune thyroiditis the TTSI is moderately elevated.{{cite journal |last1=Hoermann |first1=R |last2=Midgley |first2=JEM |last3=Larisch |first3=R |last4=Dietrich |first4=JW |title=The role of functional thyroid capacity in pituitary thyroid feedback regulation. |journal=European Journal of Clinical Investigation |date=October 2018 |volume=48 |issue=10 |pages=e13003 |doi=10.1111/eci.13003 |pmid=30022470|s2cid=51698223 }}

A large cohort study demonstrated TTSI to be strongly influenced by genetic factors.{{cite journal |last1=Panicker |first1=V. |last2=Wilson |first2=S. G. |last3=Spector |first3=T. D. |last4=Brown |first4=S. J. |last5=Falchi |first5=M. |last6=Richards |first6=J. B. |last7=Surdulescu |first7=G. L. |last8=Lim |first8=E. M. |last9=Fletcher |first9=S. J. |last10=Walsh |first10=J. P. |title=Heritability of serum TSH, free T4 and free T3 concentrations: a study of a large UK twin cohort |journal=Clinical Endocrinology |date=April 2008 |volume=68 |issue=4 |pages=652–659 |doi=10.1111/j.1365-2265.2007.03079.x |pmid=17970774|s2cid=21809978 }} 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.{{cite journal |last1=Jansen |first1=SW |last2=Akintola |first2=AA |last3=Roelfsema |first3=F |last4=van der Spoel |first4=E |last5=Cobbaert |first5=CM |last6=Ballieux |first6=BE |last7=Egri |first7=P |last8=Kvarta-Papp |first8=Z |last9=Gereben |first9=B |last10=Fekete |first10=C |last11=Slagboom |first11=PE |last12=van der Grond |first12=J |last13=Demeneix |first13=BA |last14=Pijl |first14=H |last15=Westendorp |first15=RG |last16=van Heemst |first16=D |title=Human longevity is characterised by high thyroid stimulating hormone secretion without altered energy metabolism. |journal=Scientific Reports |date=19 June 2015 |volume=5 |pages=11525 |doi=10.1038/srep11525 |pmid=26089239|pmc=4473605 |bibcode=2015NatSR...511525J }}

Conversely, an elevated set point of thyroid homeostasis, as quantified by the TT4RI, is associated to higher prevalence of metabolic syndrome and several harmonized criteria by the International Diabetes Federation, including triglyceride and HDL concentration and blood pressure.{{cite journal |last1=Laclaustra |first1=Martin |last2=Moreno-Franco |first2=Belen |last3=Lou-Bonafonte |first3=Jose Manuel |last4=Mateo-Gallego |first4=Rocio |last5=Casasnovas |first5=Jose Antonio |last6=Guallar-Castillon |first6=Pilar |last7=Cenarro |first7=Ana |last8=Civeira |first8=Fernando |title=Impaired Sensitivity to Thyroid Hormones Is Associated With Diabetes and Metabolic Syndrome |journal=Diabetes Care |date=February 2019 |volume=42 |issue=2 |pages=303–310 |doi=10.2337/dc18-1410 |pmid=30552134|s2cid=54632324 |doi-access=free }}{{cite journal |last1=Guan |first1=Haixia |title=Mild Acquired Thyroid Hormone Resistance Is Associated with Diabetes-Related Morbidity and Mortality in the General Population |journal=Clinical Thyroidology |date=April 2019 |volume=31 |issue=4 |pages=138–140 |doi=10.1089/ct.2019;31.138-140|s2cid=145947179 }}

In certain phenotypes of non-thyroidal illness syndrome, especially in cases with concomitant sepsis, the TTSI is reduced.{{cite journal |last1=Dietrich |first1=J. W. |last2=Ackermann |first2=A. |last3=Kasippillai |first3=A. |last4=Kanthasamy |first4=Y. |last5=Tharmalingam |first5=T. |last6=Urban |first6=A. |last7=Vasileva |first7=S. |last8=Schildhauer |first8=T. A. |last9=Klein |first9=H. H. |last10=Stachon |first10=A. |last11=Hering |first11=S. |title=Adaptive Veränderungen des Schilddrüsenstoffwechsels als Risikoindikatoren bei Traumata |journal=Trauma und Berufskrankheit |volume=21 |issue=4 |pages=260–267 |date=19 September 2019 |doi=10.1007/s10039-019-00438-z|s2cid=202673793 }} This reflects a reduced set point of thyroid homeostasis, as also experimentally predicted in rodent models of inflammation and sepsis.{{cite journal |last1=Kondo |first1=K |last2=Harbuz |first2=MS |last3=Levy |first3=A |last4=Lightman |first4=SL |title=Inhibition of the hypothalamic-pituitary-thyroid axis in response to lipopolysaccharide is independent of changes in circulating corticosteroids. |journal=Neuroimmunomodulation |volume=4 |issue=4 |pages=188–94 |doi=10.1159/000097337 |pmid=9524963|year=1997 }}{{cite journal |last1=Pekary |first1=AE |last2=Stevens |first2=SA |last3=Sattin |first3=A |title=Lipopolysaccharide modulation of thyrotropin-releasing hormone (TRH) and TRH-like peptide levels in rat brain and endocrine organs. |journal=Journal of Molecular Neuroscience |date=2007 |volume=31 |issue=3 |pages=245–59 |pmid=17726229|doi=10.1385/jmn:31:03:245 |s2cid=11463905 }}{{cite journal |last1=Fekete |first1=C |last2=Lechan |first2=RM |title=Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions. |journal=Endocrine Reviews |date=April 2014 |volume=35 |issue=2 |pages=159–94 |doi=10.1210/er.2013-1087 |pmid=24423980|pmc=3963261 }}

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.{{cite journal |last1=Chen |first1=Y |last2=Zhang |first2=W |last3=Chen |first3=J |last4=Wang |first4=N |last5=Chen |first5=C |last6=Wang |first6=Y |last7=Wan |first7=H |last8=Chen |first8=B |last9=Lu |first9=Y |title=Association of Phthalate Exposure with Thyroid Function and Thyroid Homeostasis Parameters in Type 2 Diabetes. |journal=Journal of Diabetes Research |date=2021 |volume=2021 |pages=4027380 |doi=10.1155/2021/4027380 |pmid=34746318|pmc=8566079 |doi-access=free }}