Interpreting Thyroid Function Tests in Difficult Clinical Contexts: A Practical Approach to Avoiding Diagnostic Pitfalls and Accurately Diagnosing Thyroid Dysfunction
Abstract
Background: Thyroid function tests (TFTs) are essential for diagnosing thyroid disease, but their interpretation is problematic during pregnancy, critical illness, and biotin interference due to physiological changes and analytic interference. Aim: To provide a practical manual for clinicians to circumvent diagnostic pitfalls and correctly interpret TFTs in these scenarios. Methods: A narrative review (PubMed, Scopus, Web of Science; 2000–2025) of English peer-reviewed studies on TFT interpretation in pregnancy, non-thyroidal illness syndrome (NTIS), and biotin interference. Data were summarized to highlight physiological processes, diagnostic challenges, and management strategies. Results: Pregnancy requires trimester-specific TFT ranges because of hormonal change, NTIS needs distinction between adaptive responses and true hypothyroidism, and biotin interference needs assay awareness and supplement withdrawal. Trimester-specific ranges, conservative NTIS management, and non-biotin-based assays improve diagnostic accuracy. Conclusion: Understanding of physiological and analytical aspects, use of good-quality assays, and adherence to guidelines are crucial for the accurate interpretation of TFT, which results in improved patient outcomes in difficult clinical circumstances.
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References
Alexander, E. K., Pearce, E. N., Brent, G. A., Brown, R. S., Chen, H., Dosiou, C., ... & Sullivan, S. (2017). 2017 Guidelines of the American Thyroid Association for the diagnosis and management of thyroid disease during pregnancy and the postpartum. Thyroid, 27(3), 315-389. https://doi.org/10.1089/thy.2016.0457
Aljehani, M. R., & Alhayek , A. A. (2024). Renal Function Assessment: Core Responsibilities of Clinical Pathologists and Laboratory Technicians in Diagnostic Evaluation. Saudi Journal of Medicine and Public Health, *1*(1), 65–74. https://doi.org/10.64483/jmph-39
Avery, G. (2019). Biotin interference in immunoassay: a review for the laboratory scientist. Annals of clinical biochemistry, 56(4), 424-430. https://doi.org/10.1177/0004563219842231
Barbesino, G. (2016). Misdiagnosis of Graves' disease with apparent severe hyperthyroidism in a patient taking biotin megadoses. Thyroid, 26(6), 860-863. https://doi.org/10.1089/thy.2015.0664
Batista, M. C., Ferreira, C. E., Faulhaber, A. C., Hidal, J. T., Lottenberg, S. A., & Mangueira, C. L. (2017). Biotin interference in immunoassays mimicking subclinical Graves’ disease and hyperestrogenism: a case series. Clinical Chemistry and Laboratory Medicine (CCLM), 55(6), e99-e103. https://doi.org/10.1515/cclm-2016-0628
Boelen, A., Kwakkel, J., & Fliers, E. (2011). Beyond low plasma T3: local thyroid hormone metabolism during inflammation and infection. Endocrine reviews, 32(5), 670-693.
Brent, G. A., & Hershman, J. M. (1986). Thyroxine therapy in patients with severe nonthyroidal illnesses and low serum thyroxine concentration. The Journal of Clinical Endocrinology & Metabolism, 63(1), 1-8. https://doi.org/10.1210/jcem-63-1-1
Casey, B. M., & Leveno, K. J. (2006). Thyroid disease in pregnancy. Obstetrics & Gynecology, 108(5), 1283-1292. DOI: 10.1097/01.AOG.0000244103.91597.c5
De Groot, L., Abalovich, M., Alexander, E. K., Amino, N., Barbour, L., Cobin, R. H., ... & Sullivan, S. (2012). Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society clinical practice guideline. The Journal of Clinical Endocrinology & Metabolism, 97(8), 2543-2565. https://doi.org/10.1210/jc.2011-2803
Elston, M. S., Sehgal, S., Du Toit, S., Yarndley, T., & Conaglen, J. V. (2016). Factitious Graves’ disease due to biotin immunoassay interference—a case and review of the literature. The Journal of Clinical Endocrinology & Metabolism, 101(9), 3251-3255. https://doi.org/10.1210/jc.2016-1971
Fathi-Karkan, S., Sargazi, S., Shojaei, S., Far, B. F., Mirinejad, S., Cordani, M., ... & Ghavami, S. (2024). Biotin-functionalized nanoparticles: an overview of recent trends in cancer detection. Nanoscale, 16(27), 12750-12792. https://doi.org/10.1039/D4NR00634H
Feldt-Rasmussen, U., & Rasmussen, Å. K. (2010). Autoimmunity in differentiated thyroid cancer: significance and related clinical problems. Hormones, 9(2), 109-117. https://doi.org/10.14310/horm.2002.1261
Fliers, E., Bianco, A. C., Langouche, L., & Boelen, A. (2015). Thyroid function in critically ill patients. The lancet Diabetes & endocrinology, 3(10), 816-825. https://doi.org/10.1016/S2213-8587(15)00225-9
Garber, J. R., Cobin, R. H., Gharib, H., Hennessey, J. V., Klein, I., Mechanick, J. I., ... & Woeber, K. A. (2012). Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American Association of Clinical Endocrinologists and the American Thyroid Association. Endocrine practice, 18(6), 988-1028. https://doi.org/10.4158/EP12280.GL
Glinoer, D. (1997). The regulation of thyroid function in pregnancy: pathways of endocrine adaptation from physiology to pathology. Endocrine reviews, 18(3), 404-433.
Haddow, J. E., Palomaki, G. E., Allan, W. C., Williams, J. R., Knight, G. J., Gagnon, J., ... & Klein, R. Z. (1999). Maternal thyroid deficiency during pregnancy and subsequent neuropsychological development of the child. New England Journal of Medicine, 341(8), 549-555. DOI: 10.1056/NEJM199908193410801
Hazazi, Y. O. (2025). Strengthening Postpartum Depression Screening and Treatment within Primary Healthcare Centers in Riyadh 1st Cluster. Saudi Journal of Medicine and Public Health, *2*(2), 105–113. https://doi.org/10.64483/jmph-56
Holmes, E. W., Samarasinghe, S., Emanuele, M. A., & Meah, F. (2017). Biotin interference in clinical immunoassays: a cause for concern. Archives of pathology & laboratory medicine, 141(11), 1459-1460. https://doi.org/10.5858/arpa.2017-0107-LE
Jonklaas, J., Bianco, A. C., Bauer, A. J., Burman, K. D., Cappola, A. R., Celi, F. S., ... & Sawka, A. M. (2014). Guidelines for the treatment of hypothyroidism: prepared by the american thyroid association task force on thyroid hormone replacement. thyroid, 24(12), 1670-1751. https://doi.org/10.1089/thy.2014.0028
Krassas, G. E., Poppe, K., & Glinoer, D. (2010). Thyroid function and human reproductive health. Endocrine reviews, 31(5), 702-755. https://doi.org/10.1210/er.2009-0041
Kwakkel, J., Fliers, E., & Boelen, A. (2011). Illness-induced changes in thyroid hormone metabolism: focus on the tissue level. Neth J Med, 69(5), 224-8.
Laurberg, P., Andersen, S. L., Hindersson, P., Nohr, E. A., & Olsen, J. (2016). Dynamics and predictors of serum TSH and fT4 reference limits in early pregnancy: a study within the Danish National Birth Cohort. The Journal of Clinical Endocrinology & Metabolism, 101(6), 2484-2492. https://doi.org/10.1210/jc.2016-1387
Li, D., Radulescu, A., Shrestha, R. T., Root, M., Karger, A. B., Killeen, A. A., ... & Burmeister, L. A. (2017). Association of biotin ingestion with performance of hormone and nonhormone assays in healthy adults. Jama, 318(12), 1150-1160. doi:10.1001/jama.2017.13705
Maraka, S., Ospina, N. M. S., O'Keeffe, D. T., Espinosa De Ycaza, A. E., Gionfriddo, M. R., Erwin, P. J., ... & Montori, V. M. (2016). Subclinical hypothyroidism in pregnancy: a systematic review and meta-analysis. Thyroid, 26(4), 580-590. https://doi.org/10.1089/thy.2015.0418
Madkhali, A. M., Bouri, H. A., Alotaibi, F. O. E., ALMUTAIRI, A. M. M., Albalawi, T. suliman, Alotaibi, G. S., … Alotaibi, A. S. (2024). Potential Health Implications of Fifth Generation (5G) Wireless Communication Technology: A Review of Emerging Biological and Epidemiological Concerns. Saudi Journal of Medicine and Public Health, *1*(1), 94–105. https://doi.org/10.64483/jmph-53
Sahib, N. A. H. F., & Mohammed, K. G. (2024). Evaluation of Anti-Thyroglobulin, Anti-Thyroid Peroxidase Autoantibodies and Thyroid Stimulating Hormone in Autoimmune Thyroiditis Patients. Medical Science Journal for Advance Research, 5(4). https://doi.org/10.46966/msjar.v5i4.205
Saud Faleh Alanazi. (2024). Comparative Evaluation of the Pharmacological Mechanisms, Clinical Indications, and Risk Management Strategies of Epidural Anesthesia in Surgical and Obstetric Interventions. Saudi Journal of Medicine and Public Health, *1*(1), 47–57. https://doi.org/10.64483/jmph-36
Soh, S. B., & Aw, T. C. (2019). Laboratory testing in thyroid conditions-pitfalls and clinical utility. Annals of laboratory medicine, 39(1). https://doi.org/10.3343/alm.2019.39.1.3
Soldin, O. P., Tractenberg, R. E., Hollowell, J. G., Jonklaas, J., Janicic, N., & Soldin, S. J. (2004). Trimester-specific changes in maternal thyroid hormone, thyrotropin, and thyroglobulin concentrations during gestation: trends and associations across trimesters in iodine sufficiency. Thyroid, 14(12), 1084-1090. https://doi.org/10.1089/thy.2004.14.1084
Surks, M. I., Ortiz, E., Daniels, G. H., Sawin, C. T., Col, N. F., Cobin, R. H., ... & Weissman, N. J. (2004). Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. Jama, 291(2), 228-238. doi:10.1001/jama.291.2.228
Thienpont, L. M., Van Uytfanghe, K., Beastall, G., Faix, J. D., Ieiri, T., Miller, W. G., ... & IFCC Working Group on Standardization of Thyroid Function Tests. (2010). Report of the IFCC Working Group for Standardization of Thyroid Function Tests; part 2: free thyroxine and free triiodothyronine. Clinical Chemistry, 56(6), 912-920. https://doi.org/10.1373/clinchem.2009.140194
Trambas, C. M., Sikaris, K. A., & Lu, Z. X. (2016). More on biotin treatment mimicking Graves' disease. The New England journal of medicine, 375(17), 1698. https://doi.org/10.1056/nejmc1611875
Van den Berghe, G. (2014). Non-thyroidal illness in the ICU: a syndrome with different faces. Thyroid, 24(10), 1456-1465. https://doi.org/10.1089/thy.2014.0201
Vassiliadi, D. A., Ilias, I., Pratikaki, M., Jahaj, E., Vassiliou, A. G., Detsika, M., ... & Dimopoulou, I. (2021). Thyroid hormone alterations in critically and non-critically ill patients with SARS-CoV-2 infection. Endocrine connections, 10(6), 646-655. https://doi.org/10.1530/EC-21-0029
Warner, M. H., & Beckett, G. J. (2009). Mechanisms behind the non-thyroidal illness syndrome: an update. The Journal of endocrinology, 205(1), 1-13. https://doi.org/10.1677/joe-09-0412
Authors
Copyright (c) 2024 Faheed Mothib Almutairi, Faisal Naji Alsahabi, Fahdah Ateeq Alboanen, Tahani Othman Baharthi, Nawal Nasser Albishi, Moteb Attalh Almotery, Yahya Ibrahim Hassan Khurmi, Bader Abdulqader Joumah, Ashwaq Ibrahim Altehini, Wadha Abdulaziz Alsumayt

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