[SPINA] Year in Review: 2020

Fr Jan 1 18:16:00 CET 2021

Dear subscribers of the SPINA list,

you all know that 2020 was a difficult year, and, of course, you are aware of all the details. With respect to the SPINA methodology, 2020 was, however, a successful year again. Multiple scientific projects could make use of SPINA, thereby gaining new insights.

A group from Katowice in Poland demonstrated an interesting interaction of oral contraceptives, metformin and thyroid function. Although thyroid’s secretory capacity (SPINA-GT) decreases under contraception, the well-known increase under metformin is more pronounced in probands on contraceptives. Similar considerations apply to Jostel’s TSH index (JTI) mirroring the central set point of the feedback loop [1]. This may be one of the reasons why the positive effects of metformin on life expectancy and cognitive performance depend on a complex pattern including age, sex and comorbidity matrix [2].

A Chinese working group observed a fascinating relationship between thyroid function and the phenotype of Parkinsonian disease. In tremor-dominant and mixed types, SPINA-GT proved to be higher than in the akinetic-rigid type. Conversely, the sum activity of peripheral step-up deiodinases (SPINA-GD) was elevated in the akinetic type. Progressive severity of the disease was associated with a decreased set point of the homeostatic system, as measured with JTI and the thyrotroph thyroid hormone sensitivity index (TTSI) [3].

In diabetic nephropathy, SPINA-GD predicted both a reduced glomerular filtration rate (GFR, Odds Ratio 0.754–0.852) and albuminuria (OR 0.926–0.977), as demonstrated by another Chinese group in the METAL study. The conclusions apply to a subgroup of euthyroid subjects, too. These results underscore type 1 thyroid allostasis (TACITUS syndrome) to be of significance in chronic disease, too [4]. This as well extends to another study from China that described reduced SPINA-GD and slightly increased SPINA-GT in subjects with short bowel syndrome [5].

For a long time, a strong influence of endocrine disruptors on thyroid function has been suspected. Recently, a group from South Korea demonstrated that this applies to early and subtle alterations, too. They found a positive correlation of SPINA-GD and the urinary concentration of phthalate metabolites and a negative correlation of bisphenol A excretion and deiodinase capacity [6]. In a second study, the same group described a positive correlation of mercury excretion with SPINA-GT and of cadmium excretion with SPINA-GD. Conversely, SPINA-GD was negatively correlated to mercury excretion [7]. These results provide clues for potential mechanisms linking endocrine disruptors and other environmental pollutants with thyroid function.

For some time, a (positive) influence of vitamin D and selenium on the biology of the thyroid is being discussed as well. Now, a study from Poland demonstrated that combination therapy of 25-hydroxy vitamin D and selenomethionine is able to raise both SPINA-GT and SPINA-GD. Confirming earlier studies (see our review of 2019), this fits well the physiological roles played by vitamin D and especially selenium. Interestingly, this effect is mitigated by prolactinemia [8]. The same group observed in men with hypothyroidism thyroid's secretory capacity to be increased under therapy with dehydroepiandrosterone [9].

A strong influence of thyroid hormones on the heart is well known. Now, a group from Austria and Germany found a significant association between SPINA-GT and resting heart rate [10]. The results suggest that the thyrocardiac axis is more active than previously assumed and that some effects may be observed well before free hormones or even the TSH concentration change (vide infra for our own studies).

In an own study, we could demonstrate that in patients receiving TSH-suppressive therapy due to thyroid cancer, SPINA-GD was significantly lower than in true hyperthyroidism resulting from Graves's disease, toxic adenoma or toxic multinodular goitre [11]. The difference was for SPINA-GD more pronounced than for FT3 and more unambiguous than for FT4. TSH didn't differ at all among the groups. Unlike FT4 and FT3, SPINA-GD was independent of the TSH category. If these results get confirmed, SPINA-GD could be utilised for the differential diagnosis of hyperthyroidism and factitious thyrotoxicosis.

In another project (THORACAL study) we observed that increased SPINA-GT is a significant risk factor for malignant cardiac arrhythmia. Here, we included patients with heart disease that underwent supply with an implantable cardioverter/defibrillator (ICD). Immediately before implant TSH, FT4 and FT3 were determined and from the results, we calculated SPINA-GT, SPINA-GD and JTI. All included subjects were euthyroid according to the reference ranges for TSH, FT4 and FT3. What we found was that both SPINA-GT and JTI in the upper tertile of their respective reference range were associated with increased risk for adequate shock due to ventricular fibrillation or ventricular tachycardia. Additionally, subjects with SPINA-GT of 4.2 pmol/s or higher or with JTI of 2.8 or higher were faced with a significantly lower chance of shock-free survival. This observation suggests thyrogenic arrhythmia to have a dual aetiology, viz. early primary hyperthyroidism (even before the onset of subclinical dysfunction) and increased set point of the feedback loop, which may be explained by genetic or epigenetic effects or by chronic psychosocial stress representing type 2 allostatic load [12].

For the first time, these results might provide a convincing explanatory model for the up to now poorly understood and debated observations of the Rotterdam study that showed within-reference range high-normal FT4 concentration to be associated with significantly increased risk of sudden cardiac death [13].

Similar conclusions may apply to the Takotsubo syndrome (TTS, aka stress cardiomyopathy). In a cohort of patients with TTS, we measured thyroid hormones and calculated structural parameters. We compared the results with those of normal subjects from the NHANES cohort and of patients with acute coronary syndrome from the AQUA FONTIS study. Using machine learning, we could identify two clusters (stress type and endocrine type of TTS). As in the THORACAL study, the two types mirror type 2 allostatic load and ensuing primary hyperthyroidism, representing two alternative ways to heart disease. This is reflected by significantly increased thyroid's secretory capacity (SPINA-GT) in TTS [14].

In general, allostatic load (AL) might be an understudied but strong influencing factor for thyroid function. Obviously, this applies to both patients and normal subjects: By calculating the SIQALS 2 score, quantifying allostatic load, we could detect a strong correlation of AL and several markers of thyroid function (including SPINA-GT and JTI) in the NHANES collective. Instrumental variable regression suggests this to represent a causal relationship. A parallel meta-analysis revealed similar changes in post-traumatic stress disorder [15]. These results underscore the previously underestimated role of psychoendocrine relations.

Due to this continuously growing number of important results, it may perhaps not be surprising that calculated parameters of thyroid homeostasis are now increasingly covered in recommendations and guidelines [16, 17, 18].

On January 25th, 2020, we could publish SPINA Thyr 4.1.1, an update of version 4.1 fixing several minor bugs. The software runs on macOS, Windows and Linux and is, as always, available from  http://spina.sf.net <http://spina.sf.net/> or via the DOI https://doi.org/10.5281/zenodo.3596049 <https://doi.org/10.5281/zenodo.3596049>. On March 31st, 2020, we published version 4.0.2 and on September 1st version 4.0.3 of the "sister program" SimThyr. This software, which covers the theoretical foundations of the SPINA methodology, is available from http://simthyr.sf.net <http://simthyr.sf.net/> or https://doi.org/10.5281/zenodo.1303822 <https://doi.org/10.5281/zenodo.1303822>.

This list of references may, as always, be incomplete, the more as the methodology is increasingly used all over the planet. I will be grateful for any hint on missing papers.

You may find current news on SPINA on our Twitter channel at https://twitter.com/SPINATeam <https://twitter.com/SPINATeam>.

With best wishes for 2021,
JWD

References

1. Krysiak R, Kowalcze K, Wolnowska M, Okopień B. The impact of oral hormonal contraception on metformin action on hypothalamic-pituitary-thyroid axis activity in women with diabetes and prediabetes: A pilot study. J Clin Pharm Ther. 2020 Oct;45(5):937-945. doi: 10.1111/jcpt.13105. Epub 2020 Jan 5. PMID: 31903641. https://pubmed.ncbi.nlm.nih.gov/31903641/ <https://pubmed.ncbi.nlm.nih.gov/31903641/> https://doi.org/10.1111/jcpt.13105 <https://doi.org/10.1111/jcpt.13105>

2. Chaudhari K, Reynolds CD, Yang SH. Metformin and cognition from the perspectives of sex, age, and disease. Geroscience. 2020 Feb;42(1):97-116. doi: 10.1007/s11357-019-00146-3. Epub 2020 Jan 2. PMID: 31897861; PMCID: PMC7031469. https://pubmed.ncbi.nlm.nih.gov/31897861/ <https://pubmed.ncbi.nlm.nih.gov/31897861/> https://doi.org/10.1007/s11357-019-00146-3 <https://doi.org/10.1007/s11357-019-00146-3>

3. Tan Y, Gao L, Yin Q, Sun Z, Man X, Du Y, Chen Y. Thyroid hormone levels and structural parameters of thyroid homeostasis are correlated with motor subtype and disease severity in euthyroid patients with Parkinson's disease. Int J Neurosci. 2020 Mar 24:1-11. doi: 10.1080/00207454.2020.1744595. Epub ahead of print. PMID: 32186220. https://pubmed.ncbi.nlm.nih.gov/32186220/ <https://pubmed.ncbi.nlm.nih.gov/32186220/> https://doi.org/10.1080/00207454.2020.1744595 <https://doi.org/10.1080/00207454.2020.1744595>

4. Chen Y, Zhang W, Wang N, Wang Y, Wang C, Wan H, Lu Y. Thyroid Parameters and Kidney Disorder in Type 2 Diabetes: Results from the METAL Study. J Diabetes Res. 2020 Mar 28;2020:4798947. doi: 10.1155/2020/4798947. PMID: 32337292; PMCID: PMC7149438. https://pubmed.ncbi.nlm.nih.gov/32337292/ <https://pubmed.ncbi.nlm.nih.gov/32337292/> https://doi.org/10.1155/2020/4798947 <https://doi.org/10.1155/2020/4798947>

5. Wan S, Yang J, Gao X, Zhang L, Wang X. Nonthyroidal Illness Syndrome in Patients With Short-Bowel Syndrome. JPEN J Parenter Enteral Nutr. 2020 Jul 22. doi: 10.1002/jpen.1967. Epub ahead of print. PMID: 32697347. https://pubmed.ncbi.nlm.nih.gov/32697347/ <https://pubmed.ncbi.nlm.nih.gov/32697347/> https://doi.org/10.1002/jpen.1967 <https://doi.org/10.1002/jpen.1967>

6. Choi S, Kim MJ, Park YJ, Kim S, Choi K, Cheon GJ, Cho YH, Jeon HL, Yoo J, Park J. Thyroxine-binding globulin, peripheral deiodinase activity, and thyroid autoantibody status in association of phthalates and phenolic compounds with thyroid hormones in adult population. Environ Int. 2020 Jul;140:105783. doi: 10.1016/j.envint.2020.105783. Epub 2020 May 25. PMID: 32464474. https://pubmed.ncbi.nlm.nih.gov/32464474/ <https://pubmed.ncbi.nlm.nih.gov/32464474/> https://doi.org/10.1016/j.envint.2020.105783 <https://doi.org/10.1016/j.envint.2020.105783>

7. Kim, M. J., Kim, S., Choi, S., Lee, I., Moon, M. K., Choi, K., … Park, J. (2021). Association of exposure to polycyclic aromatic hydrocarbons and heavy metals with thyroid hormones in general adult population and potential mechanisms. Science of The Total Environment, 762, 144227. https://doi.org/https://doi.org/10.1016/j.scitotenv.2020.144227

8. Krysiak R, Kowalcze K, Okopień B. Hyperprolactinaemia attenuates the inhibitory effect of vitamin D/selenomethionine combination therapy on thyroid autoimmunity in euthyroid women with Hashimoto's thyroiditis: A pilot study. J Clin Pharm Ther. 2020 Dec;45(6):1334-1341. doi: 10.1111/jcpt.13214. Epub 2020 Jul 10. PMID: 32649802. https://pubmed.ncbi.nlm.nih.gov/32649802/ <https://pubmed.ncbi.nlm.nih.gov/32649802/> https://doi.org/10.1111/jcpt.13214 <https://doi.org/10.1111/jcpt.13214>

9. Krysiak R, Szkróbka W, Okopień B. Impact of dehydroepiandrosterone on thyroid autoimmunity and function in men with autoimmune hypothyroidism. Int J Clin Pharm. 2020 Nov 27. doi: 10.1007/s11096-020-01207-w. Epub ahead of print. PMID: 33245519. https://pubmed.ncbi.nlm.nih.gov/33245519/ <https://pubmed.ncbi.nlm.nih.gov/33245519/> https://doi.org/10.1007/s11096-020-01207-w <https://doi.org/10.1007/s11096-020-01207-w>

10. Steinberger E, Pilz S, Trummer C, Theiler-Schwetz V, Reichhartinger M, Benninger T, Pandis M, Malle O, Keppel MH, Verheyen N, Grübler MR, Voelkl J, Meinitzer A, März W. Associations of Thyroid Hormones and Resting Heart Rate in Patients Referred to Coronary Angiography. Horm Metab Res. 2020 Dec;52(12):850-855. doi: 10.1055/a-1232-7292. Epub 2020 Sep 4. Erratum in: Horm Metab Res. 2020 Sep 14;: PMID: 32886945. https://pubmed.ncbi.nlm.nih.gov/32886945/ <https://pubmed.ncbi.nlm.nih.gov/32886945/> https://doi.org/10.1055/a-1232-7292 <https://doi.org/10.1055/a-1232-7292>

11. Hoermann R, Midgley JEM, Larisch R, Dietrich JW. Heterogenous biochemical expression of hormone activity in subclinical/overt hyperthyroidism and exogenous thyrotoxicosis. J Clin Transl Endocrinol. 2020 Feb 8;19:100219. doi: 10.1016/j.jcte.2020.100219. PMID: 32099819; PMCID: PMC7031309. https://pubmed.ncbi.nlm.nih.gov/32099819/ <https://pubmed.ncbi.nlm.nih.gov/32099819/> https://doi.org/10.1016/j.jcte.2020.100219 <https://doi.org/10.1016/j.jcte.2020.100219> 

12. Müller P, Dietrich JW, Lin T, Bejinariu A, Binnebößel S, Bergen F, Schmidt J, Müller SK, Chatzitomaris A, Kurt M, Gerguri S, Clasen L, Klein HH, Kelm M, Makimoto H. Usefulness of Serum Free Thyroxine Concentration to Predict Ventricular Arrhythmia Risk in Euthyroid Patients With Structural Heart Disease. Am J Cardiol. 2020 Apr 15;125(8):1162-1169. doi: 10.1016/j.amjcard.2020.01.019. Epub 2020 Jan 29. PMID: 32087999. https://pubmed.ncbi.nlm.nih.gov/32087999/ <https://pubmed.ncbi.nlm.nih.gov/32087999/> https://doi.org/10.1016/j.amjcard.2020.01.019 <https://doi.org/10.1016/j.amjcard.2020.01.019> 

13. Chaker L, van den Berg ME, Niemeijer MN, Franco OH, Dehghan A, Hofman A, Rijnbeek PR, Deckers JW, Eijgelsheim M, Stricker BH, Peeters RP. Thyroid Function and Sudden Cardiac Death: A Prospective Population-Based Cohort Study. Circulation. 2016 Sep 6;134(10):713-22. doi: 10.1161/CIRCULATIONAHA.115.020789. PMID: 27601558. https://pubmed.ncbi.nlm.nih.gov/27601558/ <https://pubmed.ncbi.nlm.nih.gov/27601558/> https://doi.org/10.1161/circulationaha.115.020789 <https://doi.org/10.1161/circulationaha.115.020789>

14. Aweimer A, El-Battrawy I, Akin I, Borggrefe M, Mügge A, Patsalis PC, Urban A, Kummer M, Vasileva S, Stachon A, Hering S, Dietrich JW. Abnormal thyroid function is common in takotsubo syndrome and depends on two distinct mechanisms: results of a multicentre observational study. J Intern Med. 2020 Nov 12. doi: 10.1111/joim.13189. Epub ahead of print. PMID: 33179374. https://pubmed.ncbi.nlm.nih.gov/33179374/ <https://pubmed.ncbi.nlm.nih.gov/33179374/> https://doi.org/10.1111/joim.13189 <https://doi.org/10.1111/joim.13189>

15. Dietrich JW, Hoermann R, Midgley JEM, Bergen F, Müller P. The Two Faces of Janus: Why Thyrotropin as a Cardiovascular Risk Factor May Be an Ambiguous Target. Front Endocrinol (Lausanne). 2020 Oct 26;11:542710. doi: 10.3389/fendo.2020.542710. PMID: 33193077; PMCID: PMC7649136. https://pubmed.ncbi.nlm.nih.gov/33193077/ <https://pubmed.ncbi.nlm.nih.gov/33193077/> https://doi.org/10.3389/fendo.2020.542710 <https://doi.org/10.3389/fendo.2020.542710>

16. Persani L, Brabant G, Dattani M, Bonomi M, Feldt-Rasmussen U, Fliers E, Gruters A, Maiter D, Schoenmakers N, van Trotsenburg ASP. 2018 European Thyroid Association (ETA) Guidelines on the Diagnosis and Management of Central Hypothyroidism. Eur Thyroid J. 2018 Oct;7(5):225-237. doi: 10.1159/000491388. Epub 2018 Jul 19. PMID: 30374425; PMCID: PMC6198777. https://pubmed.ncbi.nlm.nih.gov/30374425/ <https://pubmed.ncbi.nlm.nih.gov/30374425/> https://doi.org/10.1159/000491388 <https://doi.org/10.1159/000491388> 

17. Pilz, S., Theiler-Schwetz, V., Malle, O. et al. Hypothyreose: Guidelines, neue Erkenntnisse und klinische Praxis. J. Klin. Endokrinol. Stoffw. 13, 88–95 (2020). https://doi.org/10.1007/s41969-020-00114-9 <https://doi.org/10.1007/s41969-020-00114-9>

18. Monzani, M.L., Piccinini, F., Simoni, M. et al. Terapia sostitutiva tiroidea e risposta tissutale: quando il TSH non basta. L'Endocrinologo 21, 319–324 (2020). https://doi.org/10.1007/s40619-020-00775-3 <https://doi.org/10.1007/s40619-020-00775-3>

-- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- --
-- PD Dr. med. Johannes W. Dietrich
-- Laboratory XU44, Endocrine Research
-- Medical Hospital I, Bergmannsheil University Hospitals
-- Ruhr University of Bochum
-- Buerkle-de-la-Camp-Platz 1, D-44789 Bochum, NRW, Germany
-- Phone: +49:234:302-6400, Fax: +49:234:302-6403
-- eMail: "johannes.dietrich at ruhr-uni-bochum.de"
-- http://www.thyreologie.com.de
-- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- -- --

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