TSH-T3 shunt
| TSH-T3 shunt | |
|---|---|
| Other names | Thyrotropin-T3 shunt; thyroidal T3 secretion pathway |
| Specialty | Lua error in Module:WikidataIB at line 665: attempt to index field 'wikibase' (a nil value). |
| Complications | Instability of circulating T3 when absent (e.g. athyreosis) |
| Causes | Physiological response to circulating TSH |
| Frequency | Lua error in Module:PrevalenceData at line 12: attempt to index field 'wikibase' (a nil value). |
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.[1] 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.[2][3]
The pathway buffers circulating free T3 (FT3) against fluctuations in thyroid output and contributes to the circadian rhythm of serum T3.[4] Recognition of a TSH-T3 shunt has refined models of thyroid homeostasis and influences interpretation of thyroid function tests and the management of hypothyroidism.[5]
Background
In euthyroid adults about 80 % of circulating T3 arises from peripheral deiodination of T4, while ~20 % is secreted directly by the thyroid.[6] Under high TSH drive – for example in iodine deficiency or after exogenous TSH administration – the thyroidal fraction of T3 secretion rises substantially.[7]
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.[2] TSH concurrently shortens thyroglobulin residence time, favouring release of newly formed T3.[3]
Quantitative contribution
Mathematical sensitivity analysis places the shunt gain (GT) at 15–30 pmol s−1 / 109 thyrocytes, sufficient to stabilise FT3 against ±30 % changes in T4 output.[1]
Physiological role
The shunt acts as a buffering, feed-forward element complementing negative feedback by thyroid hormones on TSH secretion.[8] In population studies FT3 varies little across a six-fold range of TSH, whereas FT4 shows a strong log-linear inverse relationship with TSH.[9] 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.[10]
- 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.[4]
- 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.[11]
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.[12]
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.[1] Sensitivity analysis shows that shunt gain profoundly influences TSH responsiveness and FT3 homeostasis.[13]
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.[14] Combination LT4 + LT3 or tailored TSH targets have been proposed to restore physiological FT3 levels in these patients.[15]
History
Disproportionate thyroidal T3 secretion under TSH stimulation was described in the 1960s,[16] but the term “TSH-T3 shunt” and its formal cybernetic treatment were introduced in 2012–2018.[17][1]
See also
References
- ↑ 1.0 1.1 1.2 1.3 Berberich, J; Dietrich, JW; Hoermann, R; Müller, MA (2018). "Mathematical modelling of the pituitary–thyroid feedback loop: role of a TSH-T3 shunt and sensitivity analysis". Frontiers in Endocrinology. 9. doi:10.3389/fendo.2018.00091. PMC 5871688. PMID 29619006. Unknown parameter
|article-number=ignored (help) - ↑ 2.0 2.1 Gereben, B; Zavacki, AM (2008). "Cellular and molecular basis of deiodinase-regulated thyroid hormone signalling". Endocrine Reviews. 29 (7): 898–938. doi:10.1210/er.2008-0019. PMC 2647704. PMID 18701647.
- ↑ 3.0 3.1 Williams, GR; Bassett, JHD (2011). "Local control of thyroid hormone action: role of type 2 deiodinase". Journal of Endocrinology. 209 (3): 261–272. doi:10.1001/archpediatrics.2011.21. PMID 21464387.
- ↑ 4.0 4.1 Fliers, E; Kalsbeek, A; Boelen, A (2014). "Beyond the fixed set-point of the HPT axis". European Journal of Endocrinology. 171 (5): R197–R208. doi:10.1530/EJE-14-0285. PMID 25005935.
- ↑ Hoermann, R; Midgley, JE; Giacobino, A (2015). "Homeostatic equilibria between free thyroid hormones and pituitary thyrotropin". Hormone and Metabolic Research. 47 (9): 674–680. doi:10.1055/s-0034-1398616. PMID 25750078.
- ↑ Pilo, A (1990). "Thyroidal and peripheral production of 3,5,3′-triiodothyronine in humans". American Journal of Physiology. 258 (5): E715–E726. doi:10.1016/0304-3940(90)90800-o. PMID 2325880.
- ↑ Silva, JE (1985). "Type II iodothyronine deiodinase is highly expressed in human thyroid". Journal of Clinical Investigation. 75 (6): 2291–2295. doi:10.1172/JCI113934. PMC 425529. PMID 2989330.
- ↑ Chatzitomaris, A; Hoermann, R (2017). "Thyroid allostasis – adaptive responses of thyrotropic feedback control". Frontiers in Endocrinology. 8: 163. doi:10.3389/fendo.2017.00163. PMC 5517413. PMID 28775711.
- ↑ Hoermann, R; Eckl, WA (2010). "Complex relationship between FT4 and TSH". European Journal of Endocrinology. 162 (6): 1123–1129. doi:10.1530/EJE-10-0106. PMID 20299491.
- ↑ Hoermann, R; Midgley, JE (2017). "Dual control of pituitary TSH secretion by thyroxine and triiodothyronine in athyreotic patients". Therapeutic Advances in Endocrinology & Metabolism. 8 (6): 83–95. doi:10.1177/2042018817716401. PMC 5524252. PMID 28794850.
- ↑ Wagner, MS; Maia, AL (2007). "Regulation of Dio2 expression by thyroid hormones in mice". Journal of Endocrinology. 193 (3): 435–444. doi:10.1128/AEM.00052-07. PMC 2042094. PMID 17616620.
- ↑ Schneider, MJ; St Germain, DL (2001). "Pituitary resistance to T4 in Dio2 knockout mice". Molecular Endocrinology. 15 (12): 2137–2148. doi:10.1210/mend.15.12.0745. PMC 1121662. PMID 11711423.
- ↑ Dietrich, JW; Midgley, JE (2021). "Dynamics of thyroid diseases and thyroid-axis gland masses". Journal of Clinical Medicine. 10 (16): 3618. doi:10.3390/jcm10163618. PMC 8396428 Check
|pmc=value (help). PMID 34442231 Check|pmid=value (help). - ↑ Abdalla, SM; Bianco, AC (2014). "Defending plasma T3 is a biological priority". Clinical Endocrinology. 81 (5): 633–641. doi:10.1111/cen.12416. PMID 24548292.
- ↑ Mizukoshi, W (2019). "Serum thyroid hormone balance in LT4 monotherapy after radioiodine treatment". Thyroid. 29 (9): 1309–1318. doi:10.1089/thy.2019.0135. PMC 6797065 Check
|pmc=value (help). PMID 31411123. - ↑ Laurberg, P (1984). "Mechanisms governing the relative proportions of thyroxine and 3,5,3′-triiodothyronine in thyroid secretion". Metabolism. 33 (4): 379–392. doi:10.1016/0026-0495(84)90203-8. PMID 6369072.
- ↑ Dietrich, JW (2012). "TSH and thyrotropic agonists: key actors in thyroid homeostasis". Journal of Thyroid Research. 2012: 351864. doi:10.1155/2012/351864. PMC 3544290. PMID 23365787.
External links
- “Mathematical modelling of the pituitary–thyroid feedback loop” – open-access article (Frontiers in Endocrinology)
- “Deiodinase-regulated thyroid hormone signalling” – review (Endocrine Reviews)
Further reading
- Hoermann, R; Midgley, J E M; Larisch, R; Dietrich, J W (22 December 2017). "Recent Advances in Thyroid Hormone Regulation: Toward a New Paradigm for Optimal Diagnosis and Treatment". Frontiers in Endocrinology. 8. doi:10.3389/fendo.2017.00364. PMC 5763098. PMID 29375474. Unknown parameter
|article-number=ignored (help) - Berberich, J; Dietrich, J W; Hoermann, R; Müller, M A (21 March 2018). "Mathematical Modeling of the Pituitary–Thyroid Feedback Loop: Role of a TSH-T3-Shunt and Sensitivity Analysis". Frontiers in Endocrinology. 9. doi:10.3389/fendo.2018.00091. PMC 5871688. PMID 29619006. Unknown parameter
|article-number=ignored (help) - Hoermann, R; Pekker, M J; Midgley, J E M; Dietrich, J W (14 March 2023). "The Role of Supporting and Disruptive Mechanisms of FT3 Homeostasis in Regulating the Hypothalamic–Pituitary–Thyroid Axis". Therapeutic Advances in Endocrinology and Metabolism. 14. doi:10.1177/20420188231158163. PMC 10017955 Check
|pmc=value (help). PMID 36936128 Check|pmid=value (help). Unknown parameter|article-number=ignored (help)
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