Johannes W. Dietrich
John E. M. Midgley
Rudolf Hoermann- 1Medical Department 1, Endocrinology and Diabetology, Bergmannsheil University Hospitals, Ruhr University of Bochum, Bochum, North Rhine-Westphalia, Germany
- 2Ruhr Centre of Rare Diseases (CeSER), Ruhr University of Bochum, Bochum, North Rhine-Westphalia, Germany
- 3Ruhr Centre of Rare Diseases (CeSER), Witten/Herdecke University, Bochum, North Rhine-Westphalia, Germany
- 4North Lakes Clinical, Ilkley, United Kingdom
- 5Private Consultancy, Research and Development, Yandina, QLD, Australia
Editorial on the Research Topic
Homeostasis and Allostasis of Thyroid Function
Current Challenges in Thyroidology
A basic understanding of thyroid control involving pituitary thyrotropin (TSH) has become a cornerstone for the contemporary diagnosis of thyroid disorders. However, long-held simplistic interpretations of the classical feedback concept fall short of the elusive goal of a universally applicable and reliable diagnostic test. Diagnostic ambiguities may arise from the dynamic nature of thyroid homeostasis. Concentrations of TSH and T3 are governed by circadian (1) and, additionally for TSH, ultradian rhythms (2). Plasticity of the hypothalamic–pituitary–thyroid axis in form of adaptive responses may promote misdiagnosis, especially in pregnancy and critical illness (3, 4). Diagnosis of subclinical dysfunction is also dependent on the mode of statistical analysis (5–9).
Consequently, the clinical care of thyroid patients faces major challenges, foremost ill-defined reference ranges for TSH and thyroid hormones (THs), and persistently poor quality of life in a substantial subset of treated hypothyroid patients (10). Divergent criteria by guidelines for defining thyroid disease and guiding therapeutic intervention have further added to the confusion. It remains unclear, if patients with subclinical hypothyroidism benefit from treatment and which are sensible targets of substitution therapy (11, 12).
By addressing predictive adaptation, the rather new theory of allostasis complements the established concept of homeostasis. In situations of strain and stress, allostasis ensures stability through change by modifying setpoints and parameters of feedback control (13–15). Despite being a basically beneficial reaction allostasis may also expose the organism to a new kind of strain referred to as allostatic load, which may result in even life-threatening diseases.
This research topic focusing on homeostasis and—still understudied—allostasis of thyroid function was initiated with the goal that deeper physiological insights in pituitary–thyroid feedback control may aid in solving the aforementioned problems. A series of articles summarizes the state of current scientific knowledge, and delivers new perspectives, as significant progress has been made in that regard.
Thyroid Homeostasis—Unexpected Complexities in a Classic Endocrine Feedback Loop
A review article by the editors (Hoermann et al.) provides an overview of homeostatic mechanisms in the light of recent research. The classical “short feedback” structure (Astwood-Hoskins loop) (16) is now complemented by additional motifs, an “ultrashort” autocrine loop, where TSH inhibits its own secretion, and a TSH-T3 shunt relaying stimulation from pituitary to intrathyroidal step-up deiodinases. Although documented for decades on a biochemical level (17, 18), the clinical importance of the TSH-T3 shunt has only recently been recognized (19–23).
Newly identified non-classical processing structures add to the complexity of the control system. They explain both pulsatile thyrotropin release and significant deviations from a log-linear relationship between FT4 and TSH concentrations [Hoermann et al.; (24–26)]. In onset hypothyroidism, rising TSH concentrations stimulate T3 formation (22), thereby maintaining thyroid signaling and unburdening the thyroid from T4 synthesis (Hoermann et al.).
A balancing concept for TSH, FT4, and FT3 is introduced under the term relational stability [Hoermann et al.; (22)]. Importantly, it is lacking in athyreotic patients and suspended when treatment with L-T4 reduces TSH concentration—an important argument against universal L-T4 substitution in subclinical hypothyroidism.
The novel clinical concepts feed back to theory. Berberich et al. describe an expanded physiology-based mathematical model of thyroid homeostasis that incorporates the rediscovered TSH-T3 shunt. This model extends a rich tradition of related “parametrically isomorphic” models (27–35), demonstrating that circadian variations of FT3 concentrations are well explained by TSH action and shedding a fresh light on the evolution of subclinical thyroid diseases (Berberich et al.).
Interpretation of thyroid function tests can be severely affected by homeostatic time constants resulting in hysteresis effects (36), as reviewed by Leow, extending implications to antithyroid treatment and LT4 substitution.
Technological Advancements and Novel Diagnostic Tools
Although sensitive for primary hypothyroidism, TSH measurement has low specificity and is unable to detect dysfunctions of central origin. Isolated TSH measurements may be misleading in certain physiological (37) and allostatic conditions (38), including non-thyroidal illness (39).
In a short perspective article, we summarize methodological principles and clinical trial results (Dietrich et al.) for novel diagnostic approaches based on mathematical modeling, such as functional thyroid reserve capacity and step-up deiodinase activity. These calculated parameters deliver estimates for “hidden” structure parameters of thyroid homeostasis and provide early indicators of thyroid failure. Reconstructing the individual equilibrium point (the so-called set point) of thyroid homeostasis is facilitated by new tools and may prove useful as a personal target for L-T4 dosage titration (40, 41). Mathematical modeling can further improve interpretation of L-T4 absorption tests (42).
The Enigmatic Role of Non-Classical TH
The world of THs is composed of more than T4 and T3. Today, we know 27 metabolites derived from the thyronine skeleton, some of them being hormonally active [Hoermann et al.; (43)]. Thyronamines have received special attention, binding to trace amine-associated receptors (44) and acting as functional antagonists of iodothyronines (45, 46).
Glossmann et al. critically appraise suggested pharmacological uses of 3-monoiodothyronamine (3-T1AM), e.g., for therapy of stroke or in long-lasting space flights. Based on its pleiotropic effects they question if 3-T1AM can be a safe cryogenic drug. Some of the inconsistencies in reported serum concentrations may result from plasma protein binding, potential role of gut microbiota in the formation of thyronamines from iodothyronines or conversion of 3-T1AM to 3-iodothyroacetic acid (3-TA1), a possible major mediator of thyronaminergic signaling (47).
Hypothalamus–Pituitary–Thyroid Axis—an Open and Dynamic System
The traditional view of pituitary–thyroid feedback control holding T4 plasma concentration constant close to a fixed set point (48) has been challenged by variable concentrations of TSH and THs in certain physiological situations beyond thyroid disease (38, 49–55). Thyroid allostasis delivers a unified theory for a plethora of adaptive processes spanning from fetal life, pregnancy, starvation, exercise, obesity, aging, and general severe illness to psychiatric disorders. In strain and stress, type 1 and type 2 allostasis affect thyroid function in different ways, creating each distinctly recognizable patterns (Chatzitomaris et al.).
Prospectus
Deeper insights in the physiology of thyroid function and its homeostatic control warrant a rethinking of diagnostic practice. The old paradigm employing TSH in the center of diagnostic work-up has to be replaced by a relational concept, where TSH is interlocked with FT4 and FT3, and multivariable distributions represent homeostatic equilibria (9, 30). This new approach allows for personalized interpretation of thyroid function and understands physiological influences as constituents of homeostatic/allostatic control modes (Hoermann et al.).
Author Contributions
JD, JM, and RH wrote some of the papers in this Research Topic and participated as guest editors for manuscripts, where they were not coauthors themselves. All authors listed have made a substantial, direct, and intellectual contribution to this editorial and approved it for publication.
Conflict of Interest Statement
JD received funding and personal fees by Sanofi-Henning, Hexal AG, Bristol-Myers Squibb, and Pfizer and is co-owner of the intellectual property rights for the patent “System and Method for Deriving Parameters for Homeostatic Feedback Control of an Individual” (Singapore Institute for Clinical Sciences, Biomedical Sciences Institutes, Application Number 201208940-5, WIPO number WO/2014/088516). All other authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
Acknowledgments
JD, JM, and RH thank all authors, reviewers, and external editors for their valuable contributions to this Research Topic.
References
1. Weeke J, Gundersen HJ. Circadian and 30 minutes variations in serum TSH and thyroid hormones in normal subjects. Acta Endocrinol (Copenh) (1978) 89:659–72. doi:10.1530/acta.0.0890659
2. Brabant G, Prank K, Ranft U, Bergmann P, Schuermeyer T, Hesch RD, et al. Circadian and pulsatile TSH secretion under physiological and pathophysiological conditions. Horm Metab Res Suppl (1990) 23:12–7.
3. Dietrich JW, Stachon A, Antic B, Klein HH, Hering S. The AQUA-FONTIS study: protocol of a multidisciplinary, cross-sectional and prospective longitudinal study for developing standardized diagnostics and classification of non-thyroidal illness syndrome. BMC Endocr Disord (2008) 8:13. doi:10.1186/1472-6823-8-13
4. Dietrich JW, Landgrafe G, Fotiadou EH. TSH and thyrotropic agonists: key actors in thyroid homeostasis. J Thyroid Res (2012) 2012:351864. doi:10.1155/2012/351864
5. Dickey RA, Wartofsky L, Feld S. Optimal thyrotropin level: normal ranges and reference intervals are not equivalent. Thyroid (2005) 15:1035–9. doi:10.1089/thy.2005.15.1035
6. Inal TC, Serteser M, Coşkun A, Özpinar A, Ünsal I. Indirect reference intervals estimated from hospitalized population for thyrotropin and free thyroxine. Croat Med J (2010) 51:124–30. doi:10.3325/cmj.2010.51.124
7. Arzideh F, Wosniok W, Haeckel R. Indirect reference intervals of plasma and serum thyrotropin (TSH) concentrations from intra-laboratory data bases from several German and Italian medical centres. Clin Chem Lab Med (2011) 49:659–64. doi:10.1515/CCLM.2011.114
8. Larisch R, Giacobino A, Eckl W, Wahl H-G, Midgley JEM, Hoermann R. Reference range for thyrotropin. Nuklearmedizin (2015) 54:112–7. doi:10.3413/Nukmed-0671-14-06
9. Hoermann R, Larisch R, Dietrich JW, Midgley JEM. Derivation of a multivariate reference range for pituitary thyrotropin and thyroid hormones: diagnostic efficiency compared to conventional single reference method. Eur J Endocrinol (2016) 174(6):735–43. doi:10.1530/EJE-16-0031
10. Peterson SJ, Cappola AR, Castro MR, Dayan CM, Farwell AP, Hennessey JV, et al. An online survey of hypothyroid patients demonstrates prominent dissatisfaction. Thyroid (2018). doi:10.1089/thy.2017.0681
11. Waise A, Price HC. The upper limit of the reference range for thyroid-stimulating hormone should not be confused with a cut-off to define subclinical hypothyroidism. Ann Clin Biochem (2009) 46:93–8. doi:10.1258/acb.2008.008113
12. Portillo-Sanchez P, Rodriguez-Gutierrez R, Brito JP. Subclinical hypothyroidism in elderly individuals – overdiagnosis and overtreatment? JAMA Intern Med (2016) 176:1741. doi:10.1001/jamainternmed.2016.5756
13. Sterling P, Eyer J. Allostasis: a new paradigm to explain arousal pathology. In: Fisher S, Reason J, editors. Handbook of Life Stress, Cognition and Health. Oxford, England: John Wiley & Sons (1988). p. 629–49.
14. McEwen BS. Stress, adaptation, and disease: allostasis and allostatic load. Ann N Y Acad Sci (1998) 840:33–44. doi:10.1111/j.1749-6632.1998.tb09546.x
15. Schulkin J. Allostasis, Homeostasis, and the Costs of Physiological Adaptation. Cambridge, UK: Cambridge University Press (2015).
16. Ortiga-Carvalho TM, Chiamolera MI, Pazos-Moura CC, Wondisford FE. Hypothalamus-pituitary-thyroid axis. Compr Physiol (2016) 6(3):1387–428. doi:10.1002/cphy.c150027
17. Celi FS, Coppotelli G, Chidakel A, Kelly M, Brillante BA, Shawker T, et al. The role of type 1 and type 2 5′-deiodinase in the pathophysiology of the 3,5,3′-triiodothyronine toxicosis of McCune-Albright syndrome. J Clin Endocrinol Metab (2008) 93:2383–9. doi:10.1210/jc.2007-2237
18. Köhrle J. Thyrotropin (TSH) action on thyroid hormone deiodinaton and secretion: one aspect of thyrotropin regulation of thyroid cell biology. Horm Metab Res (1990) 23:18–28.
19. Midgley JEM, Larisch R, Dietrich JW, Hoermann R. Variation in the biochemical response to L-thyroxine therapy and relationship with peripheral thyroid hormone conversion. Endocr Connect (2015) 4(4):196–205. doi:10.1530/EC-15-0056
20. Hoermann R, Midgley J, Larisch R, Dietrich J. Integration of peripheral and glandular regulation of triiodothyronine production by thyrotropin in untreated and thyroxine-treated subjects. Horm Metab Res (2015) 47:674–80. doi:10.1055/s-0034-1398616
21. Hoermann R, Midgley JEM, Giacobino A, Eckl WA, Wahl HG, Dietrich JW, et al. Homeostatic equilibria between free thyroid hormones and pituitary thyrotropin are modulated by various influences including age, body mass index and treatment. Clin Endocrinol (Oxf) (2014) 81:907–15. doi:10.1111/cen.12527
22. Hoermann R, Midgley JEM, Larisch R, Dietrich JW. Relational stability of thyroid hormones in euthyroid subjects and patients with autoimmune thyroid disease. Eur Thyroid J (2016) 5:171–9. doi:10.1159/000447967
23. Midgley JEM, Hoermann R, Larisch R, Dietrich JW. Physiological states and functional relation between thyrotropin and free thyroxine in thyroid health and disease: in vivo and in silico data suggest a hierarchical model. J Clin Pathol (2013) 66:335–42. doi:10.1136/jclinpath-2012-201213
24. Clark PM, Holder RL, Haque SM, Hobbs FDR, Roberts LM, Franklyn JA. The relationship between serum TSH and free T4 in older people. J Clin Pathol (2012) 65:463–5. doi:10.1136/jclinpath-2011-200433
25. Hadlow NC, Rothacker KM, Wardrop R, Brown SJ, Lim EM, Walsh JP. The relationship between TSH and free T4 in a large population is complex and nonlinear and differs by age and sex. J Clin Endocrinol Metab (2013) 98:2936–43. doi:10.1210/jc.2012-4223
26. Fitzgerald SP, Bean NG. The relationship between population T4/TSH set point data and T4/TSH physiology. J Thyroid Res (2016) 2016:6351473. doi:10.1155/2016/6351473
27. DiStefano JJ, Stear EB. On identification of hypothalamo-hypophysial control and feedback relationships with the thyroid gland. J Theor Biol (1968) 19:29–50. doi:10.1016/0022-5193(68)90003-9
28. Dietrich JW, Tesche A, Pickardt CR, Mitzdorf U. Thyrotropic feedback control: evidence for an additional ultrashort feedback loop from fractal analysis. Cybern Syst (2004) 35:315–31. doi:10.1080/01969720490443354
29. Han SX, Eisenberg M, Larsen PR, DiStefano J. THYROSIM app for education and research predicts potential health risks of over-the-counter thyroid supplements. Thyroid (2016) 26:489–98. doi:10.1089/thy.2015.0373
30. Hoermann R, Midgley JEM, Larisch R, Dietrich JWC. Advances in applied homeostatic modelling of the relationship between thyrotropin and free thyroxine. PLoS One (2017) 12:e0187232. doi:10.1371/journal.pone.0187232
31. Goede SL, Leow MK-S, Smit JWA, Klein HH, Dietrich JW. Hypothalamus-pituitary-thyroid feedback control: implications of mathematical modeling and consequences for thyrotropin (TSH) and free thyroxine (FT4) reference ranges. Bull Math Biol (2014) 76:1270–87. doi:10.1007/s11538-014-9955-5
32. Lumen A, McNally K, George N, Fisher JW, Loizou GD. Quantitative global sensitivity analysis of a biologically based dose-response pregnancy model for the thyroid endocrine system. Front Pharmacol (2015) 6:107. doi:10.3389/fphar.2015.00107
33. Lumen A, Mattie DR, Fisher JW. Evaluation of perturbations in serum thyroid hormones during human pregnancy due to dietary iodide and perchlorate exposure using a biologically based dose-response model. Toxicol Sci (2013) 133:320–41. doi:10.1093/toxsci/kft078
34. Degon M, Chipkin SR, Hollot CV, Zoeller RT, Chait Y. A computational model of the human thyroid. Math Biosci (2008) 212:22–53. doi:10.1016/j.mbs.2007.10.009
35. McLanahan ED, Andersen ME, Fisher JW. A biologically based dose-response model for dietary iodide and the hypothalamic-pituitary-thyroid axis in the adult rat: evaluation of iodide deficiency. Toxicol Sci (2008) 102:241–53. doi:10.1093/toxsci/kfm312
36. Leow MKS. A mathematical model of pituitary-thyroid interaction to provide an insight into the nature of the thyrotropin-thyroid hormone relationship. J Theor Biol (2007) 248:275–87. doi:10.1016/j.jtbi.2007.05.016
37. Benvenga S, Di Bari F, Granese R, Antonelli A. Serum Thyrotropin and Phase of the Menstrual Cycle. Front Endocrinol (2017) 8:250. doi:10.3389/fendo.2017.00250
38. Petrosyan L. Relationship between high normal TSH levels and metabolic syndrome components in type 2 diabetic subjects with euthyroidism. J Clin Transl Endocrinol (2015) 2:110–3. doi:10.1016/j.jcte.2015.02.004
39. Papi G, Corsello SM, Pontecorvi A. Clinical concepts on thyroid emergencies. Front Endocrinol (2014) 5:102. doi:10.3389/fendo.2014.00102
40. Leow MKS, Goede SL. The homeostatic set point of the hypothalamus-pituitary-thyroid axis – maximum curvature theory for personalized euthyroid targets. Theor Biol Med Model (2014) 11:35. doi:10.1186/1742-4682-11-35
41. Goede SL, Leow MKS, Smit JWA, Dietrich JW. A novel minimal mathematical model of the hypothalamus-pituitary-thyroid axis validated for individualized clinical applications. Math Biosci (2014) 249:1–7. doi:10.1016/j.mbs.2014.01.001
42. Eisenberg M, Distefano JJ III. TSH-based protocol, tablet instability, and absorption effects on L-T4 bioequivalence. Thyroid (2009) 19:103–10. doi:10.1089/thy.2008.0148
43. Senese R, Cioffi F, de Lange P, Goglia F, Lanni A. Thyroid: biological actions of “nonclassical” thyroid hormones. J Endocrinol (2014) 221:R1–12. doi:10.1530/JOE-13-0573
44. Qatato M, Szumska J, Skripnik V, Rijntjes E, Köhrle J, Brix K. Canonical TSH Regulation of Cathepsin-Mediated Thyroglobulin Processing in the Thyroid Gland of Male Mice Requires Taar1 Expression. Front Pharmacol (2018) 9:221. doi:10.3389/fphar.2018.00221
45. Hoefig CS, Zucchi R, Köhrle J. Thyronamines and derivatives: physiological relevance, pharmacological actions, and future research directions. Thyroid (2016) 26:1656–73. doi:10.1089/thy.2016.0178
46. Piehl S, Hoefig CS, Scanlan TS, Köhrle J. Thyronamines – past, present, and future. Endocr Rev (2011) 32:64–80. doi:10.1210/er.2009-0040
47. Laurino A, Raimondi L. Commentary: Torpor: The Rise and Fall of 3-Monoiodothyronamine from Brain to Gut—From Gut to Brain? Front Endocrinol (2017) 8:206. doi:10.3389/fendo.2017.00206
48. Reichlin S, Utiger RD. Regulation of the pituitary-thyroid axis in man: relationship of TSH concentration to concentration of free and total thyroxine in plasma. J Clin Endocrinol Metab (1967) 27:251–5. doi:10.1210/jcem-27-2-251
49. Sterling K, Lazarus JH. The thyroid and its control. Annu Rev Physiol (1977) 39:349–71. doi:10.1146/annurev.ph.39.030177.002025
50. Fontes KN, Cabanelas A, Bloise FF, Andrade CBV, Souza LL, Wilieman M, et al. Differential Regulation of Thyroid Hormone Metabolism Target Genes during Non-thyroidal Illness Syndrome Triggered by Fasting or Sepsis in Adult Mice. Front Physiol (2017) 8:828. doi:10.3389/fphys.2017.00828
51. Lesmana R, Iwasaki T, Iizuka Y, Amano I, Shimokawa N, Koibuchi N. The change in thyroid hormone signaling by altered training intensity in male rat skeletal muscle. Endocr J (2016) 63:727–38. doi:10.1507/endocrj.EJ16-0126
52. Wajner SM, Maia AL. New insights toward the acute non-thyroidal illness syndrome. Front Endocrinol (2012) 3:8. doi:10.3389/fendo.2012.00008
53. Van den Berghe G. Non-thyroidal illness in the ICU: a syndrome with different faces. Thyroid (2014) 24:1456–65. doi:10.1089/thy.2014.0201
54. Dietrich JW, Müller P, Schiedat F, Schlömicher M, Strauch J, Chatzitomaris A, et al. Nonthyroidal illness syndrome in cardiac illness involves elevated concentrations of 3,5-diiodothyronine and correlates with atrial remodeling. Eur Thyroid J (2015) 4:129–37. doi:10.1159/000381543
Keywords: thyroid hormones, thyronamines, homeostasis, allostasis, feedback regulation, hysteresis, TACITUS syndrome, syndrome T
Citation: Dietrich JW, Midgley JEM and Hoermann R (2018) Editorial: “Homeostasis and Allostasis of Thyroid Function”. Front. Endocrinol. 9:287. doi: 10.3389/fendo.2018.00287
Received: 12 April 2018; Accepted: 15 May 2018;
Published: 05 June 2018
Edited by:
Douglas Forrest, National Institute of Diabetes and Digestive and Kidney Diseases (NIH), United StatesReviewed by:
Yun-Bo Shi, High-Performance Computing (NIH), United StatesCopyright: © 2018 Dietrich, Midgley and Hoermann. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Johannes W. Dietrich, am9oYW5uZXMuZGlldHJpY2gmI3gwMDA0MDtydWhyLXVuaS1ib2NodW0uZGU=