Clinical Appraisal

Overview
Sensitivity, Specificity, Likelihood Ratios, ROC-Curves
References
Selection

SPINA Thyr has been evaluated in clinical trials covering more than 10,000 subjects. The results of all trials suggest calculated structure parameters to mirror thyroid biology probably better than levels of TSH, FT4 or FT3.

SPINA-GT correlates with thyroid volume and iodine supply, and it has a higher retest reliability than TSH, free T4 or free T3. SPINA-GD mirrors hypodeiodination in cases of NTIS (TACITUS syndrome), where it is significantly reduced, and it correlates with age, BNP concentration, PA-TDI inverval and serum concentration of 3,5-T2. Additionally, it is an independent predictor of L-T4 substitution dose.

Trial	Year	Included subjects	Main results
SPINA I	2002	228	SPINA-GT and SPINA-GD have highest specificity for diagnosis of various thyroid disorders. SPINA-GT correlates with thyroid volume and substitution therapy with iodide, SPINA-GD correlates with BMI.
Rosolowska-Huszcz et al.	2005	17	SPINA-GT correlates with creatinine clearance.
SPINA II	2012	20	SPINA-GT has higher reliability compared to TSH, FT4, FT3 and SPINA-GD.
Liu et al.	2012	44	SPINA-GD is significantly reduced in NTIS (TACITUS syndrome), SPINA-GT is not significantly elevated.
Han et al.	2013	226	SPINA-GD significantly reduced in NTIS.
Hoermann et al.	2013	1994	SPINA-GD correlates in untreated patients with TSH levels and is significantly reduced in patients under substitution therapy.
Midgley et al.	2013	6641	LS depends from state of thyroid homeostasis and interacts with GT.
Hoermann et al.	2014	1796	TSH, FT4 and FT3 each have their individual, but also interlocking roles to play in thyroid homeostasis. GD correlates with TSH and is significantly reduced after initiation of L-T4 substitution therapy.
Dietrich et al.	2015	39	SPINA-GD ist reduced in patients with NTIS, predicts postoperative atrial fibrillation and correlates to age, 3,5-T2 concentrations, BNP levels and PA-TDI interval.
Midgley et al.	2015	353	SPINA-GD is an inpedendent predictor for levothyroxine dose in patients on substitution therapy.
Fan et al.	2016	39	SPINA-GD significantly reduced in NTIS.
Wang et al.	2016	219	SPINA-GT significantly reduced in obesity with mild thyroid secretory insufficiency.
Hoermann et al.	2016	357	SPINA-GT correlates with thyroid volume in healthy controls, but not in cases with chronic autoimmune thyroiditis. Even after correction for spurious correlation nonlinear negative association between SPINA-GT and SPINA-GD.
Gürdal et al.	2017	56	SPINA-GT correlates to Tp-e interval, Tp-e/QT ratio and Tp-e/QTC ratio in healthy persons and patients with subclinical hypothyroidism.
Chan et al.	2017	3649	SPINA-GT predicts the incidence of prostate cancer in men.
Krysiak et al.	2017	37	Metformin therapy increases SPINA-GT in women.
Hoermann et al.	2017	502	In thyroid-healthy persons, SPINA-GD correlates to TSH concentration, but this effect is canceled under substitution therapy with levothyroxine. Here, SPINA-GD correlates to substitution dose.
Ruiz-Núñez	2018	197	SPINA-GT and SPINA-GD are significantly reduced in patients suffering from chronic fatigue syndrome (CFS) compared to healthy controls.
Kim et al.	2018	6	Resting respiratory expenditure (REE) positively corelates to SPINA-GT und SPINA-GD, which significantly decrease during treatment of Graves' disease.

Currently, the AQUA-FONTIS Study, the largest proxpective study on non-thyroidal illness syndrome, is investigating the utility of SPINA for diagnosing and predicting the outcome of non-thyroidal illness syndrome in crtically ill patients.

In 2016, two overview articles on clinical and research applications of calculated parameters of thyroid homeostasis have been published in the Research Topic Homeostasis and Allostasis of Thyroid Function of the journal Frontiers in Endocrinology.

References

Dietrich, J. W., U. Mitzdorf, R. Weitkunat und C. R. Pickardt (1997). "The pituitary-thyroid feedback control: stability and oscillations in a new nonlinear model." Journal of Endocrinological Investigation 20 (Suppl. to no. 5): 100.

Dietrich, J., M. Fischer, J. Jauch, E. Pantke, R. Gärtner und C. R. Pickardt (1999). "SPINA-THYR: A Novel Systems Theoretic Approach to Determine the Secretion Capacity of the Thyroid Gland." European Jounal of Internal Medicine 10, Suppl. 1 (5/1999): S34.

Dietrich, J. W., A. Tesche, C. R. Pickardt und U. Mitzdorf (2002). Fractal Properties of the Thyrotropic Feedback Control: Implications of a Nonlinear Model Compared with Empirical Data. In: Cybernetics and Systems 2002. R. Trappl (Hrsg). Vienna.

Dietrich JW, Tesche A, Pickardt CR, Mitzdorf U (2004). Thyrotropic Feedback Control: Evidence for an Additional Ultrashort Feedback Loop from Fractal Analysis. Cybernetics and Systems. 35(4):315-31.

Rosolowska-Huszcz D, Kozlowska L, Rydzewski A (2005). Influence of low protein diet on nonthyroidal illness syndrome in chronic renal failure. Endocrine. 27(3):283-8

Dietrich, J. W. und B. O. Boehm (2006). Equilibrium behaviour of feedback-coupled physiological saturation kinetics. In: Cybernetics and Systems 2006. R. Trappl (Hrsg). Vienna, Austrian Society for Cybernetic Studies. 1: 269-74.

Dietrich JW, Stachon A, Antic B, Klein HH, Hering S (2008). 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. 13;8(1):13.

Liu S, Ren J, Zhao Y, Han G, Hong Z, Yan D, Chen J, Gu G, Wang G, Wang X, Fan C, Li J. Nonthyroidal Illness Syndrome: Is it Far Away From Crohn's Disease? J Clin Gastroenterol. 2012 Aug 7. [Epub ahead of print] PMID 22874844

Dietrich, J. W., G. Landgrafe, E. H. Fotiadou (2012). TSH and thyrotropic agonists: Key actors in thyroid homeostasis. Journal of Thyroid Research, vol. 2012, Article ID 351864, 29 pages, 2012. PMID 23365787, doi:10.1155/2012/351864.

Hoermann, R., J. E. M. Midgley, R. Larisch, J. W. Dietrich (2013). Is Pituitary Thyrotropin an Adequate Measure Of Thyroid Hormone-Controlled Homeostasis During Thyroxine Treatment?. European Journal of Endocrinology 168(2):271-80. PMID 23184912, doi:10.1530/EJE-12-0819.

Midgley, J. E. M., R. Hoermann, R. Larisch, J. W. Dietrich (2013). 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. Journal of Clinical Pathology 66(4):335-42. PMID 23423518, doi:10.1136/jclinpath-2012-201213

Han G, Ren J, Liu S, Gu G, Ren H, Yan D, Chen J, Wang G, Zhou B, Wu X, Yuan Y, Li J. (2013) Nonthyroidal illness syndrome in enterocutaneous fistulas. Am J Surg. 2013 Sep;206(3):386-92. doi: 10.1016/j.amjsurg.2012.12.011. Epub 2013 Jun 27. PMID 23809674.

Hoermann R, Midgley JE, Giacobino A, Eckl WA, Wahl HG, Dietrich JW, Larisch R. (2014) 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 Dec;81(6):907-15. doi: 10.1111/cen.12527. Epub 2014 Jul 7. PMID 24953754.

Hoermann R, Midgley JE, Larisch R, Dietrich JW (2015). Integration of Peripheral and Glandular Regulation of Triiodothyronine Production by Thyrotropin in Untreated and Thyroxine-Treated Subjects. Hormone and Metabolic Research 2015; 47(9):674-80, PMID 25750078 doi: 10.1055/s-0034-1398616.

Dietrich JW, Müller P, Schiedat F, Schlömicher M, Strauch J, Chatzitomaris A, Klein HH, Mügge A, Köhrle J, Rijntjes E, Lehmphul I. (2015) Nonthyroidal Illness Syndrome in Cardiac Illness Involves Elevated Concentrations of 3,5-Diiodothyronine and Correlates with Atrial Remodeling. Eur Thyroid J. 2015 Jun;4(2):129-37. doi: 10.1159/000381543. Epub 2015 May 23. PMID 26279999, PMCID PMC4521060.

Midgley JE, Larisch R, Dietrich JW, Hoermann R. (2015) Variation in the Biochemical Response to L-Thyroxine Therapy and Relationship with Peripheral Thyroid Hormone Conversion. Endocr Connect. 2015 Aug 11. pii: EC-15-0056. [Epub ahead of print] PMID 26265111.

Fan S, Ni X, Wang J, Zhang Y, Tao S, Chen M, Li Y, Li J. (2016) Low Triiodothyronine Syndrome in Patients With Radiation Enteritis: Risk Factors and Clinical Outcomes an Observational Study. Medicine (Baltimore). 2016 Feb;95(6):e2640. doi: 10.1097/MD.0000000000002640. PubMed PMID 26871787.

Wang X, Liu H, Chen J, Huang Y, Li L, Rampersad S, Qu S. (2016) Metabolic Characteristics in Obese Patients Complicated by Mild Thyroid Hormone Deficiency. Horm Metab Res. 2016 May;48(5):331-7. doi: 10.1055/s-0042-105150. PMID 27101096.

Dietrich JW, Landgrafe-Mende G, Wiora E, Chatzitomaris A, Klein HH., Midgley JE, Hoermann R. (2016) Calculated parameters of thyroid homeostasis: Emerging tools for differential diagnosis and clinical research. Frontiers in Endocrinology. 2016; 7:00057. doi: 10.3389/fendo.2016.00057.

Hoermann R, Midgley JE, Larisch R, Dietrich JW (2016). Relational Stability of Thyroid Hormones in Euthyroid Subjects and Patients with Autoimmune Thyroid Disease. Eur Thyroid J. 2016 Sep;5(3):171-179. PMID 27843807. doi 10.1159/000447967.

Gürdal A, Eroğlu H, Helvaci F, Sümerkan MÇ, Kasali K, Çetin Ş, Aksan G, Kiliçkesmez K. Evaluation of Tp-e interval, Tp-e/QT ratio and Tp-e/QTc ratio in patients with subclinical hypothyroidism. Ther Adv Endocrinol Metab. 2017 Mar;8(3):25-32. doi 10.1177/2042018816684423. PMID 28377800.

Chan YX, Knuiman MW, Divitini ML, Brown SJ, Walsh J, Yeap BB. Lower TSH and higher free thyroxine predict incidence of prostate but not breast, colorectal or lung cancer. Eur J Endocrinol. 2017 Oct;177(4):297-308. doi 10.1530/EJE-17-0197. PMID 28684452.

Krysiak R, Szkróbka W, Okopień B. Sex-Dependent Effect of Metformin on Serum Prolactin Levels In Hyperprolactinemic Patients With Type 2 Diabetes: A Pilot Study. Exp Clin Endocrinol Diabetes. 2017 Nov 23. doi 10.1055/s-0043-122224. PMID 29169197.

Hoermann R, Midgley JEM, Larisch R, Dietrich JWC. Advances in applied homeostatic modelling of the relationship between thyrotropin and free thyroxine. PLoS One. 2017 Nov 20;12(11):e0187232. doi 10.1371/journal.pone.0187232. PMID 29155897.

Ruiz-Núñez B, Tarasse R, Vogelaar EF, Janneke Dijck-Brouwer DA, Muskiet FAJ. Higher Prevalence of "Low T3 Syndrome" in Patients With Chronic Fatigue Syndrome: A Case-Control Study. Front Endocrinol (Lausanne). 2018 Mar 20;9:97. doi 10.3389/fendo.2018.00097. PMID: 29615976

Kim MJ, Cho SW, Choi S, Ju DL, Park DJ, Park YJ. Changes in Body Compositions and Basal Metabolic Rates during Treatment of Graves’ Disease. International Journal of Endocrinology. 2018 9863050. doi 10.1155/2018/9863050.

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