Clinical Thyroidology / Original Paper
Nonthyroidal Illness Syndrome in Cardiac Illness Involves Elevated Concentrations of 3,5-Diiodothyronine and Correlates with Atrial RemodelingDietrich J.W.a · Müller P.b, d · Schiedat F.b · Schlömicher M.c · Strauch J.c · Chatzitomaris A.a · Klein H.H.a · Mügge A.b · Köhrle J.e · Rijntjes E.e · Lehmphul I.e
aDepartment of Endocrinology and Diabetes, Medical Hospital I, bDepartment of Cardiology and Angiology, Medical Hospital II, and cDepartment of Cardiac Surgery, Bergmannsheil University Hospitals, Ruhr University of Bochum, Bochum, dHeart Center Bad Neustadt, Clinic for Interventional Electrophysiology, Bad Neustadt an der Saale, and eInstitut für Experimentelle Endokrinologie, Charité-Universitätsmedizin Berlin, Berlin, Germany
Dr. Johannes W. Dietrich
Department of Endocrinology and Diabetes, Medical Hospital I
Bergmannsheil University Hospitals, Ruhr University of Bochum
Bürkle-de-la-Camp-Platz 1, DE-44789 Bochum (Germany)
Do you have an account?
Background: Although hyperthyroidism predisposes to atrial fibrillation, previous trials have suggested decreased triiodothyronine (T3) concentrations to be associated with postoperative atrial fibrillation (POAF). Therapy with thyroid hormones (TH), however, did not reduce the risk of POAF. This study reevaluates the relation between thyroid hormone status, atrial electromechanical function and POAF. Methods: Thirty-nine patients with sinus rhythm and no history of atrial fibrillation or thyroid disease undergoing cardiac surgery were prospectively enrolled. Serum concentrations of thyrotropin, free (F) and total (T) thyroxine (T4) and T3, reverse (r)T3, 3-iodothyronamine (3-T1AM) and 3,5-diiodothyronine (3,5-T2) were measured preoperatively, complemented by evaluation of echocardiographic and electrophysiological parameters of cardiac function. Holter-ECG and telemetry were used to screen for POAF for 10 days following cardiac surgery. Results: Seven of 17 patients who developed POAF demonstrated nonthyroidal illness syndrome (NTIS; defined as low T3 and/or low T4 syndrome), compared to 2 of 22 (p < 0.05) patients who maintained sinus rhythm. In patients with POAF, serum FT3 concentrations were significantly decreased, but still within their reference ranges. 3,5-T2 concentrations directly correlated with rT3 concentrations and inversely correlated with FT3 concentrations. Furthermore, 3,5-T2 concentrations were significantly elevated in patients with NTIS and in subjects who eventually developed POAF. In multivariable logistic regression FT3, 3,5-T2, total atrial conduction time, left atrial volume index and Fas ligand were independent predictors of POAF. Conclusion: This study confirms reduced FT3 concentrations in patients with POAF and is the first to report on elevated 3,5-T2 concentrations in cardiac NTIS. The pathogenesis of NTIS therefore seems to involve more differentiated allostatic mechanisms.
© 2015 European Thyroid Association Published by S. Karger AG, Basel
- van den Berghe G: Non-thyroidal illness in the ICU: a syndrome with different faces. Thyroid 2014;24:1456-1465.
- Boelen A, Kwakkel J, Fliers E: Beyond low plasma T3: local thyroid hormone metabolism during inflammation and infection. Endocr Rev 2011;32:670-693.
- Dietrich JW, Landgrafe G, Fotiadou EH: TSH and thyrotropic agonists: key actors in thyroid homeostasis. J Thyroid Res 2012;2012:351864.
- Iervasi G, Pingitore A, Landi P, Raciti M, Ripoli A, Scarlattini M, L'Abbate A, Donato L: Low-T3 syndrome: a strong prognostic predictor of death in patients with heart disease. Circulation 2003;107:708-713.
- Klemperer JD, Klein IL, Ojamaa K, Helm RE, Gomez M, Isom OW, Krieger KH: Triiodothyronine therapy lowers the incidence of atrial fibrillation after cardiac operations. Ann Thorac Surg 1996;61:1323-1329.
- Ranasinghe AM, Quinn DW, Pagano D, Edwards N, Faroqui M, Graham TR, Keogh BE, Mascaro J, Riddington DW, Rooney SJ, Townend JN, Wilson IC, Bonser RS: Glucose-insulin-potassium and tri-iodothyronine individually improve hemodynamic performance and are associated with reduced troponin I release after on-pump coronary artery bypass grafting. Circulation 2006;114:I245-I250.
- Ronald A, Dunning J: Does perioperative thyroxine have a role during adult cardiac surgery? Interact Cardiovasc Thorac Surg 2006;5:166-178.
- Utiger RD: Altered thyroid function in nonthyroidal illness and surgery. To treat or not to treat? N Engl J Med 1995;333:1562-1563.
- De Groot LJ: Dangerous dogmas in medicine: the nonthyroidal illness syndrome. J Clin Endocrinol Metab 1999;84:151-164.
- Caplan RH: Comment on dangerous dogmas in medicine: the nonthyroidal illness syndrome. J Clin Endocrinol Metab 1999;84:2261-2262, author reply 2262-2263.
- Midgley JE, Sheehan CP, Christofides ND, Fry JE, Browning D, Mardell R: Concentrations of free thyroxin and albumin in serum in severe nonthyroidal illness: assay artefacts and physiological influences. Clin Chem 1990;36:765-771.
- Tognini S, Marchini F, Dardano A, Polini A, Ferdeghini M, Castiglioni M, Monzani F: Non-thyroidal illness syndrome and short-term survival in a hospitalised older population. Age Ageing 2010;39:46-50.
- Klein I, Danzi S: Thyroid disease and the heart. Circulation 2007;116:1725-1735.
- Biondi B: Mechanisms in endocrinology: heart failure and thyroid dysfunction. Eur J Endocrinol 2012;167:609-618.
- Kahaly GJ, Dillmann WH: Thyroid hormone action in the heart. Endocr Rev 2005;26:704-728.
- Dietrich JW: Thyroid storm. Med Klin Intensivmed Notfmed 2012;107:448-453.
- Vadiveloo T, Donnan PT, Cochrane L, Leese GP: The Thyroid Epidemiology, Audit, and Research Study (TEARS): morbidity in patients with endogenous subclinical hyperthyroidism. J Clin Endocrinol Metab 2011;96:1344-1351.
- Nacar AB, Acar G, Yorgun H, Akcay A, Ozkaya M, Canpolat U, Akkoyun M, Tuncer C: The effect of antithyroid treatment on atrial conduction times in patients with subclinical hyperthyroidism. Echocardiography 2012;29:950-955.
- Müller P, Deneke T, Schiedat F, Bösche L, Strauch J, Dietrich JW, Vogt M, Tannapfel A, Stiegler H, Mügge A, Ewers A: Increased preoperative serum apoptosis marker Fas ligand correlates with histopathology and new-onset of atrial fibrillation in patients after cardiac surgery. J Cardiovasc Electrophysiol 2013;24:1110-1115.
- Auer J, Weber T, Berent R, Ng CK, Lamm G, Eber B: Postoperative atrial fibrillation independently predicts prolongation of hospital stay after cardiac surgery. J Cardiovasc Surg (Torino) 2005;46:583-588.
- El-Chami MF, Kilgo P, Thourani V, Lattouf OM, Delurgio DB, Guyton RA, Leon AR, Puskas JD: New-onset atrial fibrillation predicts long-term mortality after coronary artery bypass graft. J Am Coll Cardiol 2010;55:1370-1376.
- Saxena A, Dinh DT, Smith JA, Shardey GC, Reid CM, Newcomb AE: Usefulness of postoperative atrial fibrillation as an independent predictor for worse early and late outcomes after isolated coronary artery bypass grafting (multicenter Australian study of 19,497 patients). Am J Cardiol 2012;109:219-225.
- Maesen B, Nijs J, Maessen J, Allessie M, Schotten U: Post-operative atrial fibrillation: a maze of mechanisms. Europace 2012;14:159-174.
- Müller P, Hars C, Schiedat F, Bösche LI, Gotzmann M, Strauch J, Dietrich JW, Vogt M, Tannapfel A, Deneke T, Mügge A, Ewers A: Correlation between total atrial conduction time estimated via tissue Doppler imaging (PA-TDI interval), structural atrial remodeling and new-onset of atrial fibrillation after cardiac surgery. J Cardiovasc Electrophysiol 2013;24:626-631.
- Cerillo AG, Bevilacqua S, Storti S, Mariani M, Kallushi E, Ripoli A, Clerico A, Glauber M: Free triiodothyronine: a novel predictor of postoperative atrial fibrillation. Eur J Cardiothorac Surg 2003;24:487-492.
- Park YJ, Yoon JW, Kim KI, Lee YJ, Kim KW, Choi SH, Lim S, Choi DJ, Park KH, Choh JH, Jang HC, Kim SY, Cho BY, Lim C: Subclinical hypothyroidism might increase the risk of transient atrial fibrillation after coronary artery bypass grafting. Ann Thorac Surg 2009;87:1846-1852.
- Kaptein EM, Sanchez A, Beale E, Chan LS: Clinical review: thyroid hormone therapy for postoperative nonthyroidal illnesses: a systematic review and synthesis. J Clin Endocrinol Metab 2010;95:4526-4534.
Dietrich JW, Fischer MR, Jauch J, Pantke E, Gärtner R, Pickardt CR: SPINA-THYR: a novel systems theoretic approach to determine the secretion capacity of the thyroid gland. Eur J Intern Med 1999;10(suppl 1):S34.
- 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.
- Peeters RP, van der Geyten S, Wouters PJ, Darras VM, van Toor H, Kaptein E, Visser TJ, van den Berghe G: Tissue thyroid hormone levels in critical illness. J Clin Endocrinol Metab 2005;90:6498-6507.
- Peeters RP, Wouters PJ, van Toor H, Kaptein E, Visser TJ, Van den Berghe G: Serum 3,3′,5′-triiodothyronine (rT3) and 3,5,3′-triiodothyronine/rT3 are prognostic markers in critically ill patients and are associated with postmortem tissue deiodinase activities. J Clin Endocrinol Metab 2005;90:4559-4565.
- Roef G, Taes Y, Toye K, Goemaere S, Fiers T, Verstraete A, Kaufman JM: Heredity and lifestyle in the determination of between-subject variation in thyroid hormone levels in euthyroid men. Eur J Endocrinol 2013;169:835-844.
- Lehmphul I, Brabant G, Wallaschofski H, Ruchala M, Strasburger CJ, Köhrle J, Wu Z: Detection of 3,5-diiodothyronine in sera of patients with altered thyroid status using a new monoclonal antibody-based chemiluminescence immunoassay. Thyroid 2014;24:1350-1360.
- Hoefig CS, Köhrle J, Brabant G, Dixit K, Yap B, Strasburger CJ, Wu Z: Evidence for extrathyroidal formation of 3-iodothyronamine in humans as provided by a novel monoclonal antibody-based chemiluminescent serum immunoassay. J Clin Endocrinol Metab 2011;96:1864-1872.
- Perret G, Yin YL, Nicolas P, Pussard E, Vassy R, Uzzan B, Berdeaux A: Amiodarone decreases cardiac beta-adrenoceptors through an antagonistic effect on 3,5,3′ triiodothyronine. J Cardiovasc Pharmacol 1992;19:473-478.
- Bahouth SW: Thyroid hormones transcriptionally regulate the β1-adrenergic receptor gene in cultured ventricular myocytes. J Biol Chem 1991;266:15863-15869.
- Fazio S, Palmieri EA, Lombardi G, Biondi B: Effects of thyroid hormone on the cardiovascular system. Recent Prog Horm Res 2004;59:31-50.
- Craelius W, Green WL, Harris DR: Acute effects of thyroid hormone on sodium currents in neonatal myocytes. Biosci Rep 1990;10:309-315.
- Bielecka-Dabrowa A, Mikhailidis DP, Rysz J, Banach M: The mechanisms of atrial fibrillation in hyperthyroidism. Thyroid Res 2009;2:4.
- Pinna G, Meinhold H, Hiedra L, Thoma R, Hoell T, Graf KJ, Stoltenburg-Didinger G, Eravci M, Prengel H, Brodel O, Finke R, Baumgartner A: Elevated 3,5-diiodothyronine concentrations in the sera of patients with nonthyroidal illnesses and brain tumors. J Clin Endocrinol Metab 1997;82:1535-1542.
- Ittermann T, Dörr M, Völzke H, Tost F, Lehmphul I, Köhrle J, Jürgens C: High serum thyrotropin levels are associated with retinal arteriolar narrowing in the general population. Thyroid 2014;24:1473-1478.
- Pietzner M, Lehmphul I, Friedrich N, Schurmann C, Ittermann T, Dörr M, Nauck M, Laqua R, Volker U, Brabant G, Völzke H, Köhrle J, Homuth G, Wallaschofski H: Translating pharmacological findings from hypothyroid rodents to euthyroid humans: is there a functional role of endogenous 3,5-T2? Thyroid 2015;25:188-197.
- Köhrle J: Thyroid hormone transporters in health and disease: advances in thyroid hormone deiodination. Best Pract Res Clin Endocrinol Metab 2007;21:173-191.
- Horst C, Rokos H, Seitz HJ: Rapid stimulation of hepatic oxygen consumption by 3,5-di-iodo-L-thyronine. Biochem J 1989;261:945-950.
- Kvetny J: 3,5-T2 stimulates oxygen consumption, but not glucose uptake in human mononuclear blood cells. Horm Metab Res 1992;24:322-325.
- Cimmino M, Mion F, Goglia F, Minaire Y, Geloen A: Demonstration of in vivo metabolic effects of 3,5-di-iodothyronine. J Endocrinol 1996;149:319-325.
- Lanni A, Moreno M, Lombardi A, Goglia F: Rapid stimulation in vitro of rat liver cytochrome oxidase activity by 3,5-diiodo-L-thyronine and by 3,3′-diiodo-L-thyronine. Mol Cell Endocrinol 1994;99:89-94.
- Mebis L, Paletta D, Debaveye Y, Ellger B, Langouche L, D'Hoore A, Darras VM, Visser TJ, van den Berghe G: Expression of thyroid hormone transporters during critical illness. Eur J Endocrinol 2009;161:243-250.
- 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 2013;47:153-159.
- Moura Neto A, Parisi MC, Tambascia MA, Alegre SM, Pavin EJ, Zantut-Wittmann DE: The influence of body mass index and low-grade systemic inflammation on thyroid hormone abnormalities in patients with type 2 diabetes. Endocr J 2013;60:877-884.
Cavusoglu C, Bilgili S, Erkizan Ö, Arican H, Karaca B: Thyroid hormone reference intervals and the prevalence of thyroid antibodies. Turk J Med Sci 2010;40:665-672.
- Fillee C, Cumps J, Ketelslegers JM: Comparison of three free T4 (FT4) and free T3 (FT3) immunoassays in healthy subjects and patients with thyroid diseases and severe non-thyroidal illnesses. Clin Lab 2012;58:725-736.
- Müller P, Schiedat F, Bialek A, Bösche L, Ewers A, Kara K, Dietrich JW, Mügge A, Deneke T: Total atrial conduction time assessed by tissue Doppler imaging (PA-TDI interval) to predict early recurrence of persistent atrial fibrillation after successful electrical cardioversion. J Cardiovasc Electrophysiol 2014;25:161-167.
Article / Publication Details
Copyright / Drug Dosage / DisclaimerCopyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.