Keywords
Thyrotropin
Immunoassay
Gel Filtration Chromatography
Thyroxine
Immunoglobulins
How to Cite
Abstract
Background: Immunoassays used to evaluate thyroid function can be affected by interferences such as macrothyrotropin (macro-TSH), a form of Thyrotropin (TSH) bound to anti-TSH antibodies. Although biologically inactive, it can lead to overdiagnosis of subclinical hypothyroidism and complicate levothyroxine management.
Case presentation: A 32-year-old woman with postoperative hypothyroidism after total thyroidectomy for Graves’ disease. While on levothyroxine 150 mcg/day, she presented with persistently elevated TSH (>100 mIU/L) without symptoms and with normal free T4. Malabsorption was ruled out using a pseudomalabsorption test. Given the biochemical discrepancy, polyethylene glycol (PEG) precipitation showed a recovery of 2.45%, suggesting macro-TSH. The absence of gel filtration chromatography (GFC) prevented confirmation. Treatment was maintained without adjustment, with follow-up of free T4 and PEG-diluted TSH.
Discussion and conclusion: Macro-TSH is an uncommon cause of elevated TSH (prevalence 0.6-1.6%). It can mimic subclinical hypothyroidism, leading to therapeutic errors. It should be suspected in cases of elevated TSH with normal thyroid hormone levels and absence of symptoms. The polyethylene glycol precipitation test is useful for screening but, whenever possible, should be confirmed with gel filtration chromatography.
It can be concluded that considering macro-TSH in unexplained TSH elevations helps prevent overtreatment and optimizes clinical management.
References
Gessl A, Blueml S, Bieglmayer C, Marculescu R. Anti-ruthenium antibodies mimic macro-TSH in electrochemiluminescent immunoassay. Clin Chem Lab Med. 2014;52(11):1589-94. https://doi.org/10.1515/cclm-2014-0067
Larsen CB, Brix Petersen ER, Overgaard M, Bonnema SJ. Macro-TSH: a diagnostic challenge. Eur Thyroid J. 2021;10(1):93-7. https://doi.org/10.1159/000509184
Favresse J, Burlacu MC, Maiter D, Gruson D. Interferences with thyroid function immunoassays: clinical implications and detection algorithm. Endocr Rev. 2018;39(5):830-50. https://doi.org/10.1210/er.2018-00119
Giusti M, Conte L, Repetto AM, Gay S, Marroni P, Mittica M, et al. Detection of polyethylene glycol thyrotropin (TSH) precipitable percentage (Macro-TSH) in patients with a history of thyroid cancer. Endocrinol Metab. 2017;32(4):460-5. https://doi.org/10.3803/enm.2017.32.4.460
Esfandiari NH, Papaleontiou M. Biochemical testing in thyroid disorders. Endocrinol Metab Clin North Am. 2017;46(3):631-48. https://doi.org/10.1016/j.ecl.2017.04.002
Nkuna X, Dire Z, Khoza S. A macro-TSH: a clinical diagnostic dilemma. EJIFCC. 2022;33(4):317-24.
Raverot V, Bordeau É, Periot C, Perrin P, Chardon L, Plotton I, et al. Letter to the editor: A case of laboratory-generated "thyroid dysfunction". Ann Endocrinol. 2019;80(2):140-1. https://doi.org/10.1016/j.ando.2018.10.001
Kirac CO, Abusoglu S, Paydas Hataysal E, Kebapcilar A, Ipekci SH, Ünlü A, et al. A rare cause of subclinical hypothyroidism: macro-thyroid-stimulating hormone. Diagnosis. 2020;7(1):75-7. https://doi.org/10.1515/dx-2019-0026
Hattori N, Ishihara T, Shimatsu A. Variability in the detection of macro TSH in different immunoassay systems. Eur J Endocrinol. 2016;174(1):9-15. https://doi.org/10.1530/eje-15-0883
Paczkowska K, Otlewska A, Loska O, Kola?kov K, Bolanowski M, Daroszewski J. Laboratory interference in the thyroid function test. Endokrynol Pol. 2020;71(6):551-60. https://doi.org/10.5603/ep.a2020.0079
Yamada A, Hattori N, Matsuda T, Nishiyama N, Shimatsu A. Clearance of macro-TSH from the circulation is slower than TSH. Clin Chem Lab Med. 2022;60(6):e132-5. https://doi.org/10.1515/cclm-2022-0131
Angelousi A, Alexandraki KI, Mytareli C, Grossman AB, Kaltsas G. New developments and concepts in the diagnosis and management of diabetes insipidus (AVP-deficiency and resistance). J Neuroendocrinol. 2023;35(1):e13233. https://doi.org/10.1111/jne.13233
Hattori N, Ishihara T, Yamagami K, Shimatsu A. Macro TSH in patients with subclinical hypothyroidism. Clin Endocrinol. 2015;83(6):923-30. https://doi.org/10.1111/cen.12643
Mills F, Jeffery J, Mackenzie P, Cranfield A, Ayling RM. An immunoglobulin G complexed form of thyroid-stimulating hormone (macro thyroid-stimulating hormone) is a cause of elevated serum thyroid-stimulating hormone concentration. Ann Clin Biochem. 2013;50(Pt 5):416-20. https://doi.org/10.1177/0004563213476271
Kadoya M, Koyama S, Morimoto A, Miyoshi A, Kakutani M, Hamamoto K, et al. Serum macro TSH level is associated with sleep quality in patients with cardiovascular risks-HSCAA Study. Sci Rep. 2017;7:44387. https://doi.org/10.1038/srep44387
Ohba K, Maekawa M, Iwahara K, Suzuki Y, Matsushita A, Sasaki S, et al. Abnormal thyroid hormone response to TRH in a case of macro-TSH and the cut-off value for screening cases of inappropriate TSH elevation. Endocr J. 2020;67(2):125-30. https://doi.org/10.1507/endocrj.ej19-0320
Chiardi I, Rotondi M, Cantù M, Keller F, Trimboli P. Macro-TSH: an uncommon explanation for persistent TSH elevation that thyroidologists have to keep in mind. J Pers Med. 2023;13(10):1471. https://doi.org/10.3390/jpm13101471
Piticchio T, Chiardi I, Tumminia A, Frasca F, Rotondi M, Trimboli P. PEG precipitation to detect Macro-TSH in clinical practice: a systematic review. Clin Endocrinol. 2025;102(3):235-44. https://doi.org/10.1111/cen.15179
D'Arcy R, Hunter S, Spence K, McDonnell M. A Case of macro-TSH masquerading as subclinical hypothyroidism. BMJ Case Rep. 2021;14(7):e243436. https://doi.org/10.1136/bcr-2021-243436
Nishiyama N, Hattori N, Tani Y, Matsuda T, Yamada A, Saito T. A rare case of both macro-TSH and macro-LH: laboratory analysis of the pathogenesis. Clin Chem Lab Med. 2022;61(6):e81-e4. https://doi.org/10.1515/cclm-2022-1149
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