Challenges in diagnosing central hypothyroidism

Abstract

Purpose: A decline in serum free thyroxine (fT4), accompanied by an inadequate thyroid-stimulating-hormone (TSH) increase, indicates central hypothyroidism (CH) or non-thyroidal illness syndrome (NTIS). Distinguishing between two clinical circumstances is crucial due to variations in treatment approaches. In this study, we aimed to obtain clinical clues to distinguish between two conditions. Materials and methods: This retrospective study was conducted on 650 children and adolescents referred to the pediatric endocrine outpatient clinic due to low fT4 levels and TSH levels below 10 mIU/L. fT3, fT4, and TSH were measured at least 2 weeks apart for 3-times, and the patients with no fT4 increase in the third measurement were diagnosed with CH. Levothyroxine was started for patients with CH. After levothyroxine withdrawal, normal fT4 indicated transient CH; low fT4 indicated permanent CH. Factors affecting the development of permanent CH were investigated. Results: Fifty-three patients (25 females, 28 males) had low fT4 and a TSH level below 10 mIU/L by 6 weeks. The patients with permanent CH were found to have substantially lower fT4 and TSH levels, whereas fT3 was lower in the patients with transient CH (p<0.001, p=0.03, p=0.01, respectively). Lower fT4 was the only significant predictor that was independently associated with increased likelihood of permanent CH (OR:-0.52, 95% CI:0.3-0.9, p=0.014). Furthermore, the cut-off value for fT4 in the diagnosis of permanent CH was determined to be below 8.5 ng/L (Sensitivity: 75%, specificity: 71%). Conclusion: Likelihood of permanent CH is reduced in the patients with fT4 levels exceeding 8.5 ng/L. Prolonged follow-up would be a cost-effective measure in such patients, avoiding unnecessary laboratory investigations and therapeutic interventions.

Keywords

• Non-thyroidal illness syndrome
• central hypothyroidism
• low fT4

Project Number

Haseki Training and Research Hospital, 103-2024

Ethical Statement

The study was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the Ethics in Research Committee of the Haseki Training and Resarch Hospital, İstanbul. Informed consent was not obtained, because of the nature of the study was retrospective. All data were obtained from routine clinical practice (İstanbul Haseki Training and Research Hospital, 103-2024).

Santral hipotiroidi tanısında karşılaşılan zorluklar

Abstract

Amaç: Serum serbest tiroksin (fT4) seviyesindeki düşüş, yetersiz tiroid uyarıcı hormon (TSH) artışıyla birlikte, santral hipotiroidizm (SH) veya tiroid dışı hastalık sendromu (NTIS) belirtisidir. Tedavi yaklaşımlarındaki farklılıklar nedeniyle iki klinik durum arasında ayrım yapmak çok önemlidir. Bu çalışmada, iki klinik durumu ayırt edebilmek için ipuçları elde etmeyi amaçladık. Gereç ve yöntem: Bu retrospektif çalışmaya, düşük fT4 ve TSH düzeyinin 10 mIU/L'nin altında olması nedeniyle pediatrik endokrinoloji polikliniğine yönlendirilen 650 çocuk ve adölesan alındı. fT3, fT4 ve TSH en az 2 hafta arayla 3 kez ölçüldü ve üçüncü ölçümde serum fT4 düzeyinde artış olmayan hastalara SH tanısı konuldu. SH'li hastalara levotiroksin başlandı. Levotiroksin kesildikten sonra, fT4 normal saptanırsa geçici SH; düşük saptanırsa kalıcı SH tanısı konuldu. Kalıcı SH gelişimini etkileyen faktörler araştırıldı. Bulgular: Elli üç hastanın (25 kadın, 28 erkek) 6 hafta boyunca serum fT4 düzeyi düşük ve TSH düzeyi 10 mIU/L'nin altında idi. Kalıcı SH'li hastaların fT4 ve TSH seviyelerinin önemli ölçüde düşük olduğu, geçici SH'li hastalarda ise fT3'ün daha düşük olduğu bulundu (p<0,001, p=0,03, p=0,01, sırasıyla). Düşük fT4, kalıcı SH olasılığının artmasıyla bağımsız olarak ilişkili olan tek önemli öngörücüydü (OR:-0,52, %95 CI:0,3-0,9, p=0,014). Ayrıca, fT4 kesme değerinin 8,5 ng/L'nin altında olması kalıcı SH için tanısal idi (Duyarlılık: %75, özgüllük: %71). Sonuç: fT4 seviyelerinin 8,5 ng/L'nin üzerinde olması kalıcı SH olasılığı düşürmektedir. Bu hastalarda uzun süreli takip, gereksiz laboratuvar incelemeleri ve tedavi edici girişimlerin önüne geçerek maliyet açısından etkili bir önlem olacaktır.

Keywords

• Tiroid dışı hastalık sendromu
• santral hipotiroidizm
• düşük fT4

Project Number

Haseki Training and Research Hospital, 103-2024

References

1. 1. Mullur R, Liu YY, Brent GA. Thyroid hormone regulation of metabolism. Physiol Rev. 2014;94(2):355-382. doi:10.1152/physrev.00030.2013
2. 2. Lee S, Farwell AP. Euthyroid Sick Syndrome. Compr Physiol. 2016;6(2):1071-1080. Published 2016 Mar 15. doi:10.1002/cphy.c150017
3. 3. Boelen A, Wiersinga WM, Fliers E. Fasting-induced changes in the hypothalamus-pituitary-thyroid axis. Thyroid. 2008;18(2):123-129. doi:10.1089/thy.2007.0253
4. 4. Guo J, Hong Y, Wang Z, Li Y. Analysis of the Incidence of Euthyroid Sick Syndrome in Comprehensive Intensive Care Units and Related Risk Factors. Front Endocrinol (Lausanne). 2021;12:656641. Published 2021 Jun 9. doi:10.3389/fendo.2021.656641
5. 5. El Ella SSA, El Mekkawy MS, El Dihemey MA. Prevalencia y valor pronóstico del síndrome del enfermo eutiroideo en niños críticos [Prevalence and prognostic value of non-thyroidal illness syndrome among critically ill children]. An Pediatr (Engl Ed). 2019;90(4):237-243. doi:10.1016/j.anpedi.2018.01.021
6. 6. Boelen A, Kwakkel J, Fliers E. Beyond low plasma T3: local thyroid hormone metabolism during inflammation and infection. Endocr Rev. 2011;32(5):670-693. doi:10.1210/er.2011-0007
7. 7. Lechan RM, Fekete C. Infundibular tanycytes as modulators of neuroendocrine function: hypothetical role in the regulation of the thyroid and gonadal axis. Acta Biomed. 2007;78 Suppl 1:84-98.
8. 8. Jonklaas J, Bianco AC, Bauer AJ, et al. Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. Thyroid. 2014;24(12):1670-1751. doi:10.1089/thy.2014.0028

9. 9. Neyzi O, Günöz H, Furman A, et al. Türk çocuklarında vücut ağırlığı, boy uzunluğu, baş çevresi ve vücut kitle indeksi referans değerleri. Çocuk Sağlığı ve Hastalıkları Dergisi. 2008;51(1):1-14.
10. 10. Ghigo E, Bellone J, Aimaretti G, et al. Reliability of provocative tests to assess growth hormone secretory status. Study in 472 normally growing children. J Clin Endocrinol Metab. 1996;81(9):3323-3327. doi:10.1210/jcem.81.9.8784091
11. 11. Mushtaq T, Shakur F, Wales JK, Wright NP. Reliability of the low dose synacthen test in children undergoing pituitary function testing. J Pediatr Endocrinol Metab. 2008;21(12):1129-1132. doi:10.1515/jpem.2008.21.12.1129
12. 12. Gill H, Barrowman N, Webster R, Ahmet A. Evaluating the Low-Dose ACTH Stimulation Test in Children: Ideal Times for Cortisol Measurement. J Clin Endocrinol Metab. 2019;104(10):4587-4593. doi:10.1210/jc.2019-00295
13. 13. Van den Berghe G. Non-thyroidal illness in the ICU: a syndrome with different faces. Thyroid. 2014;24(10):1456-1465. doi:10.1089/thy.2014.0201
14. 14. Fliers E, Boelen A. An update on non-thyroidal illness syndrome. J Endocrinol Invest. 2021;44(8):1597-1607. doi:10.1007/s40618-020-01482-4
15. 15. DeGroot LJ: The Non-Thyroidal Illness Syndrome. In: Endotext. edn. Edited by Feingold KR, Ahmed SF, Anawalt B, Blackman MR, Boyce A, Chrousos G, Corpas E, de Herder WW, Dhatariya K, Dungan K et al. South Dartmouth (MA): MDText.com, Inc. Copyright © 2000-2025, MDText.com, Inc.; 2000.
16. 16. Burch HB. Drug Effects on the Thyroid. N Engl J Med. 2019;381(8):749-761. doi:10.1056/NEJMra1901214
17. 17. du Souich P, Pison C, Pedneault L, et al. Effect of aminoglycosides on the disposition of thyroid hormones and thyroglobulin. Clin Pharmacol Ther. 1985;38(6):686-691. doi:10.1038/clpt.1985.246
18. 18. Geng M, Gao H, Wang B, et al. Urinary tetracycline antibiotics exposure during pregnancy and maternal thyroid hormone parameters: A repeated measures study. Sci Total Environ. 2022;838(Pt 2):156146. doi:10.1016/j.scitotenv.2022.156146
19. 19. Tal E, Mohari K, Koranyi L, Kovacs Z, Endroczi E. The effect of indomethacin, ibuprofen and paracetamol on the TRH induced TSH secretion in the rat. Gen Pharmacol. 1988;19(4):579-581. doi:10.1016/0306-3623(88)90167-x
20. 20. Samuels MH, Pillote K, Asher D, Nelson JC. Variable effects of nonsteroidal antiinflammatory agents on thyroid test results. J Clin Endocrinol Metab. 2003;88(12):5710-5716. doi:10.1210/jc.2002-021869
21. 21. Kummer S, Hermsen D, Distelmaier F. Biotin Treatment Mimicking Graves' Disease. N Engl J Med. 2016;375(7):704-706. doi:10.1056/NEJMc1602096
22. 22. Stockigt J. Assessment of thyroid function: towards an integrated laboratory--clinical approach. Clin Biochem Rev. 2003;24(4):109-122.
23. 23. El Nawawy A, Elwafa RAHA, Khalil Abouahmed A, Rasheed RA, Omar OM. Evaluation of non-thyroidal illness syndrome in shock patients admitted to pediatric intensive care unit in a developing country. Eur J Pediatr. 2024;183(2):769-778. doi:10.1007/s00431-023-05338-w
24. 24. Feelders RA, Swaak AJ, Romijn JA, et al. Characteristics of recovery from the euthyroid sick syndrome induced by tumor necrosis factor alpha in cancer patients. Metabolism. 1999;48(3):324-329. doi:10.1016/s0026-0495(99)90080-x
25. 25. Zargar AH, Ganie MA, Masoodi SR, et al. Prevalence and pattern of sick euthyroid syndrome in acute and chronic non-thyroidal illness--its relationship with severity and outcome of the disorder. J Assoc Physicians India. 2004;52:27-31.
26. 26. Abucham J, Martins M. Subclinical central hypothyroidism in patients with hypothalamic-pituitary disease: does it exist?. Rev Endocr Metab Disord. 2024;25(3):609-618. doi:10.1007/s11154-024-09876-y
27. 27. Yamakita N, Komaki T, Takao T, Murai T, Hashimoto K, Yasuda K. Usefulness of thyrotropin (TSH)-releasing hormone test and nocturnal surge of TSH for diagnosis of isolated deficit of TSH secretion. J Clin Endocrinol Metab. 2001;86(3):1054-1060. doi:10.1210/jcem.86.3.7267
28. 28. Tajima T, Nakamura A, Oguma M, Yamazaki M. Recent advances in research on isolated congenital central hypothyroidism. Clin Pediatr Endocrinol. 2019;28(3):69-79. doi:10.1297/cpe.28.69
29. 29. van Tijn DA, de Vijlder JJ, Verbeeten B Jr, Verkerk PH, Vulsma T. Neonatal detection of congenital hypothyroidism of central origin. J Clin Endocrinol Metab. 2005;90(6):3350-3359. doi:10.1210/jc.2004-2444
30. 30. Samuels MH, Ridgway EC. Central hypothyroidism. Endocrinol Metab Clin North Am. 1992;21(4):903-919.
31. 31. Giavoli C, Porretti S, Ferrante E, et al. Recombinant hGH replacement therapy and the hypothalamus-pituitary-thyroid axis in children with GH deficiency: when should we be concerned about the occurrence of central hypothyroidism?. Clin Endocrinol (Oxf). 2003;59(6):806-810. doi:10.1046/j.1365-2265.2003.01892.x
32. 32. Boonen E, Van den Berghe G. Cortisol metabolism in critical illness: implications for clinical care. Curr Opin Endocrinol Diabetes Obes. 2014;21(3):185-192. doi:10.1097/MED.0000000000000066