Draft:TSH-T3 shunt

{{Short description|Direct TSH-dependent thyroidal pathway for triiodothyronine secretion}}

{{Infobox medical condition (new)

| name = TSH-T₃ shunt

| field = Endocrinology

| synonyms = Thyrotropin-T₃ shunt; thyroidal T₃ secretion pathway

| image =

| caption = Thyroid follicles where intrathyroidal conversion of T₄ → T₃ occurs

| complications= Instability of circulating T₃ when absent (e.g. athyreosis)

| causes = Physiological response to circulating TSH

| treatment =

}}

TSH-T₃ shunt is a feed-forward mechanism of the hypothalamic–pituitary–thyroid axis (HPT axis) in which pituitary thyroid-stimulating hormone (TSH) directly augments secretion of the biologically active thyroid hormone triiodothyronine (T₃) by the thyroid gland. Besides stimulating production of the pro-hormone thyroxine (T₄), TSH up-regulates intrathyroidal deiodination of T₄ to T₃ via type II iodothyronine deiodinase (DIO2), effectively “shunting” part of the gland’s T₄ output into active T₃ before release.{{cite journal |last1=Williams |first1=GR |last2=Bassett |first2=JHD |title=Local control of thyroid hormone action: role of type 2 deiodinase |journal=Journal of Endocrinology |volume=209 |issue=3 |pages=261–272 |year=2011 |doi=10.1530/JOE-11-0153 |doi-broken-date=20 May 2025 |pmid=21464387}}

The pathway buffers circulating free T₃ (FT₃) against fluctuations in thyroid output and contributes to the circadian rhythm of serum T₃.{{cite journal |last1=Fliers |first1=E |last2=Kalsbeek |first2=A |last3=Boelen |first3=A |title=Beyond the fixed set-point of the HPT axis |journal=European Journal of Endocrinology |volume=171 |issue=5 |pages=R197–R208 |year=2014 |doi=10.1530/EJE-14-0285 |pmid=25005935|url=https://pure.knaw.nl/portal/en/publications/63af7e0f-7872-4539-8ef7-663625da772e }} Recognition of a TSH-T₃ shunt has refined models of thyroid homeostasis and influences interpretation of thyroid function tests and the management of hypothyroidism.{{cite journal |last1=Hoermann |first1=R |last2=Midgley |first2=JE |last3=Giacobino |first3=A |title=Homeostatic equilibria between free thyroid hormones and pituitary thyrotropin |journal=Hormone and Metabolic Research |volume=47 |issue=9 |pages=674–680 |year=2015 |doi=10.1055/s-0034-1398616 |pmid=25750078}}

Background

In euthyroid adults about 80 % of circulating T₃ arises from peripheral deiodination of T₄, while ~20 % is secreted directly by the thyroid.{{cite journal |last=Pilo |first=A |title=Thyroidal and peripheral production of 3,5,3′-triiodothyronine in humans |journal=American Journal of Physiology |volume=258 |issue=5 |pages=E715–E726 |year=1990 |doi=10.1152/ajpendo.1990.258.5.E715 |doi-broken-date=20 May 2025 |pmid=2325880}} Under high TSH drive – for example in iodine deficiency or after exogenous TSH administration – the thyroidal fraction of T₃ secretion rises substantially.{{cite journal |last=Silva |first=JE |title=Type II iodothyronine deiodinase is highly expressed in human thyroid |journal=Journal of Clinical Investigation |volume=75 |issue=6 |pages=2291–2295 |year=1985 |doi=10.1172/JCI113934 |pmid=2989330}}

Mechanism

=Intrathyroidal deiodination=

TSH activates cAMP-dependent signalling that stimulates expression and activity of DIO2 (and to a lesser extent DIO1) in follicular cells, promoting rapid conversion of stored T₄ to T₃ and increasing the T₃:T₄ ratio of secreted hormone.{{cite journal |last1=Gereben |first1=B |last2=Zavacki |first2=AM |title=Cellular and molecular basis of deiodinase-regulated thyroid hormone signalling |journal=Endocrine Reviews |volume=29 |issue=7 |pages=898–938 |year=2008 |doi=10.1210/er.2008-0019 |pmid=18701647 |pmc=2647704}} TSH concurrently shortens thyroglobulin residence time, favouring release of newly formed T₃.

=Quantitative contribution=

Mathematical sensitivity analysis places the shunt gain (G_T) at 15–30 pmol s⁻¹ / 10⁹ thyrocytes, sufficient to stabilise FT₃ against ±30 % changes in T₄ output.{{cite journal |last1=Berberich |first1=J |last2=Dietrich |first2=JW |last3=Hoermann |first3=R |last4=Müller |first4=MA |title=Mathematical modelling of the pituitary–thyroid feedback loop: role of a TSH-T3 shunt and sensitivity analysis |journal=Frontiers in Endocrinology |volume=9 |pages=91 |year=2018 |doi=10.3389/fendo.2018.00091 |doi-access=free |pmid=29619006 |pmc=5871688}}

Physiological role

The shunt acts as a buffering, feed-forward element complementing negative feedback by thyroid hormones on TSH secretion.{{cite journal |last1=Chatzitomaris |first1=A |last2=Hoermann |first2=R |title=Thyroid allostasis – adaptive responses of thyrotropic feedback control |journal=Frontiers in Endocrinology |volume=8 |pages=163 |year=2017 |doi=10.3389/fendo.2017.00163 |doi-access=free |pmid=28775711}} In population studies FT₃ varies little across a six-fold range of TSH, whereas FT₄ shows a strong log-linear inverse relationship with TSH.{{cite journal |last1=Hoermann |first1=R |last2=Eckl |first2=WA |title=Complex relationship between FT₄ and TSH |journal=European Journal of Endocrinology |volume=162 |issue=6 |pages=1123–1129 |year=2010 |doi=10.1530/EJE-10-0106 |pmid=20299491}} The shunt therefore underlies the relative constancy of T₃ supply critical for metabolic stability.

Evidence

=Clinical studies=

In 1 768 euthyroid adults FT₃ remained normal across wide TSH and FT₄ ranges, whereas 287 athyreotic patients on levothyroxine (LT₄) displayed FT₃ proportional to exogenous T₄, indicating loss of thyroidal T₃ secretion.{{cite journal |last1=Hoermann |first1=R |last2=Midgley |first2=JE |title=Dual control of pituitary TSH secretion by thyroxine and triiodothyronine in athyreotic patients |journal=Therapeutic Advances in Endocrinology & Metabolism |volume=8 |issue=6 |pages=83–95 |year=2017 |doi=10.1177/2042018817716401 |pmid=28794850 |pmc=5524252}}
Serial measurements after recombinant human TSH injection showed a prompt, transient rise of FT₃ peaking ≈2 h after the TSH peak, with minimal FT₄ change.
Children in the upper TSH reference quartile had higher FT₃ but unchanged FT₄ compared with peers in the lower quartile, consistent with TSH-driven T₃ secretion.{{cite journal |last1=Wagner |first1=MS |last2=Maia |first2=AL |title=Regulation of Dio2 expression by thyroid hormones in mice |journal=Journal of Endocrinology |volume=193 |issue=3 |pages=435–444 |year=2007 |doi=10.1677/JOE-07-0176 |doi-broken-date=20 May 2025 |pmid=17616620}}

=Experimental studies=

Disruption of Dio2 in mice produced pituitary resistance to T₄ and reduced circulating T₃, demonstrating the importance of thyroidal DIO2 for systemic hormone balance.{{cite journal |last1=Schneider |first1=MJ |last2=St Germain |first2=DL |title=Pituitary resistance to T4 in Dio2 knockout mice |journal=Molecular Endocrinology |volume=15 |issue=12 |pages=2137–2148 |year=2001 |doi=10.1210/mend.15.12.0745 |pmid=11711423}}

Mathematical modelling

In silico models incorporating a TSH-dependent T₃ secretion term replicate the observed circadian FT₃ rhythm and the stability of FT₃ across variable gland capacities, whereas models without the shunt do not. Sensitivity analysis shows that shunt gain profoundly influences TSH responsiveness and FT₃ homeostasis.{{cite journal |last1=Dietrich |first1=JW |last2=Midgley |first2=JE |title=Dynamics of thyroid diseases and thyroid-axis gland masses |journal=Journal of Clinical Medicine |volume=10 |issue=16 |pages=3618 |year=2021 |doi=10.3390/jcm10163618 |doi-access=free |pmid=34442231}}

Clinical significance

=Implications for therapy=

Standard LT₄ monotherapy cannot replace the thyroidal component of T₃ secretion; a subset of treated patients have low-normal FT₃ and persistent symptoms despite normal TSH.{{cite journal |last1=Abdalla |first1=SM |last2=Bianco |first2=AC |title=Defending plasma T3 is a biological priority |journal=Clinical Endocrinology |volume=81 |issue=5 |pages=633–641 |year=2014 |doi=10.1111/cen.12416 |pmid=24548292}} Combination LT₄ + LT₃ or tailored TSH targets have been proposed to restore physiological FT₃ levels in these patients.{{cite journal |last=Mizukoshi |first=W |title=Serum thyroid hormone balance in LT4 monotherapy after radioiodine treatment |journal=Thyroid |volume=29 |issue=9 |pages=1309–1318 |year=2019 |doi=10.1089/thy.2019.0135 |pmid=31411123}}

History

Disproportionate thyroidal T₃ secretion under TSH stimulation was described in the 1960s,{{cite journal |last=Laurberg |first=P |title=Mechanisms governing the relative proportions of thyroxine and 3,5,3′-triiodothyronine in thyroid secretion |journal=Metabolism |volume=33 |issue=4 |pages=379–392 |year=1984 |doi=10.1016/0026-0495(84)90203-8 |pmid=6369072}} but the term “TSH-T3 shunt” and its formal cybernetic treatment were introduced in 2012–2018.{{cite journal |last=Dietrich |first=JW |title=TSH and thyrotropic agonists: key actors in thyroid homeostasis |journal=Journal of Thyroid Research |volume=2012 |pages=351864 |year=2012 |doi=10.1155/2012/351864 |doi-access=free |pmid=23365787 |pmc=3544290}}

References

External links

[https://www.frontiersin.org/articles/10.3389/fendo.2018.00091/ “Mathematical modelling of the pituitary–thyroid feedback loop”] – open-access article (Frontiers in Endocrinology)
[https://academic.oup.com/edrv/article/29/7/898/2354766 “Deiodinase-regulated thyroid hormone signalling”] – review (Endocrine Reviews)