{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T06:45:02Z","timestamp":1782629102411,"version":"3.54.5"},"reference-count":20,"publisher":"SAGE Publications","license":[{"start":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:00:00Z","timestamp":1776729600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T00:00:00Z","timestamp":1776729600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.sagepub.com\/page\/policies\/text-and-data-mining-license"}],"content-domain":{"domain":["journals.sagepub.com"],"crossmark-restriction":true},"short-container-title":["Thyroid\u00ae"],"abstract":"<jats:sec>\n                    <jats:title>Background:<\/jats:title>\n                    <jats:p>The relationship between thyrotropin (TSH) and free thyroxine (FT4) is commonly assumed to be log-linear. However, this assumption may oversimplify hypothalamic\u2013pituitary\u2013thyroid axis regulation. Characterizing the empirical structure of this relationship could inform the interpretation of thyroid function tests and the validity of current TSH reference intervals. Segmented regression was used to examine the TSH\u2013FT4 relationship to determine whether statistically derived TSH breakpoints corresponded to the current reference limits.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods:<\/jats:title>\n                    <jats:p>This study retrospectively analyzed 782 paired TSH\u2013FT4 measurements obtained from untreated outpatients (median age, 43 years; interquartile range, 33\u201354 years) between July 2021 and March 2024. Patients positive for TSH receptor antibodies were excluded. Measurements obtained during treatment with levothyroxine, liothyronine, or antithyroid drugs, as well as those obtained during pregnancy, were also excluded. Segmented regression was used to model FT4 as a function of log-transformed TSH and identify the optimal breakpoints.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results:<\/jats:title>\n                    <jats:p>Model comparison using the Akaike Information Criterion indicated that the two-breakpoint model provided the best fit. Breakpoints occurred at TSH values of 0.22 and 4.25 mIU\/L, partitioning the relationship into three segments with distinct slopes. The lower breakpoint closely matched the assay-specific lower reference limit (0.27 mIU\/L) but lay below the harmonized lower reference limits in Japan and the United States, whereas the upper breakpoint was close to both the assay-specific upper limit (4.20 mIU\/L) and the corresponding harmonized upper limits (4.23 and 4.27 mIU\/L, respectively). FT4 changed little across TSH values of 0.22\u20134.25 mIU\/L, consistent with an approximate homeostatic plateau.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions:<\/jats:title>\n                    <jats:p>The TSH\u2013FT4 relationship over the entire functional TSH range is segmented rather than uniformly log-linear, and the interval over which FT4 changes little may represent physiological homeostasis. Population-based TSH reference intervals showed partial concordance with the empirically derived homeostatic range, particularly at the upper end, whereas the lower boundary was less closely aligned. Empirically derived breakpoints and population-based reference intervals may therefore offer complementary perspectives for interpreting borderline biochemical abnormalities.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1177\/10507256261445291","type":"journal-article","created":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T10:47:11Z","timestamp":1776768431000},"update-policy":"https:\/\/doi.org\/10.1177\/sage-journals-update-policy","source":"Crossref","is-referenced-by-count":0,"title":["Empirical Thyrotropin-Free Thyroxine Relationship Across the Thyrotropin Spectrum and Implications for Reference Intervals"],"prefix":"10.1177","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6408-507X","authenticated-orcid":false,"given":"Toshihiko","family":"Kasahara","sequence":"first","affiliation":[{"name":"Kasahara Clinic, Osaka, Japan."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"179","published-online":{"date-parts":[[2026,4,21]]},"reference":[{"key":"e_1_3_4_2_1","first-page":"267","volume-title":"Werner & Ingbar\u2019s The Thyroid: A Fundamental and Clinical Text","author":"Feldt-Rasmussen U","year":"2021","unstructured":"1.Feldt-Rasmussen U. Laboratory measurement of thyroid-related hormones, proteins, and autoantibodies in serum. In: Werner & Ingbar\u2019s The Thyroid: A Fundamental and Clinical Text, 11th edn (Braverman LE, , Cooper DS, , Kopp PA., eds.) Wolters Kluwer: Philadelphia, PA; 2021; pp. 267\u2013299.","edition":"11"},{"key":"e_1_3_4_3_1","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2022.0397"},{"key":"e_1_3_4_4_1","doi-asserted-by":"publisher","DOI":"10.1089\/105072503321086962"},{"key":"e_1_3_4_5_1","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-10-0106"},{"key":"e_1_3_4_6_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2012-4223"},{"key":"e_1_3_4_7_1","doi-asserted-by":"publisher","DOI":"10.1111\/cen.12527"},{"key":"e_1_3_4_8_1","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-4011"},{"key":"e_1_3_4_9_1","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2015.00177"},{"key":"e_1_3_4_10_1","doi-asserted-by":"publisher","DOI":"10.1111\/cen.13107"},{"key":"e_1_3_4_11_1","doi-asserted-by":"publisher","DOI":"10.15252\/msb.202210919"},{"key":"e_1_3_4_12_1","unstructured":"11.Japan Thyroid Association. List of harmonization-compatible TSH reagents and platforms [in Japanese]. Available from: https:\/\/www.japanthyroid.jp\/doctor\/img\/harmo_list.pdf [Last accessed: March16 2026]."},{"key":"e_1_3_4_13_1","volume-title":"R Foundation for Statistical Computing","author":"R Core Team","year":"2024","unstructured":"12.R Core Team. R: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing: Vienna, Austria; 2024."},{"issue":"1","key":"e_1_3_4_14_1","first-page":"20","article-title":"segmented: An R package to fit regression models with broken-line relationships","volume":"8","author":"Muggeo VM","year":"2008","unstructured":"13.Muggeo VM. segmented: An R package to fit regression models with broken-line relationships. R News 2008;8(1):20\u201325.","journal-title":"R News"},{"key":"e_1_3_4_15_1","doi-asserted-by":"publisher","DOI":"10.1109\/TAC.1974.1100705"},{"key":"e_1_3_4_16_1","doi-asserted-by":"publisher","DOI":"10.1177\/0049124104268644"},{"issue":"3","key":"e_1_3_4_17_1","first-page":"27","article-title":"Elecsys TSH, FT4, T4, T-uptake, FT3 and T3. Clinical results of a multicentre study","volume":"110","author":"Ebert C","year":"1998","unstructured":"16.Ebert C, , Bieglmayer C, , Igari J, et al. Elecsys TSH, FT4, T4, T-uptake, FT3 and T3. Clinical results of a multicentre study. Wien Klin Wochenschr 1998;110(Suppl 3):27\u201340.","journal-title":"Wien Klin Wochenschr"},{"key":"e_1_3_4_18_1","unstructured":"17.Hishinuma A. TSH reference interval study in Japan. Japan Endocrine Society; 2020. Available from: https:\/\/www.j-endo.jp\/uploads\/files\/news\/20200130_tsh_e.pdf [Last accessed: March16 2026]."},{"key":"e_1_3_4_19_1","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2016.269456"},{"key":"e_1_3_4_20_1","doi-asserted-by":"publisher","DOI":"10.1373\/clinchem.2016.256511"},{"issue":"2","key":"e_1_3_4_21_1","first-page":"99","article-title":"The case for common reference intervals","volume":"25","author":"Jones GR","year":"2004","unstructured":"20.Jones GR, , Barker A, , Tate J, et al. The case for common reference intervals. Clin Biochem Rev 2004;25(2):99\u2013104.","journal-title":"Clin Biochem Rev"}],"container-title":["Thyroid\u00ae"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/10507256261445291","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/full-xml\/10.1177\/10507256261445291","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.sagepub.com\/doi\/pdf\/10.1177\/10507256261445291","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,28]],"date-time":"2026-06-28T05:55:21Z","timestamp":1782626121000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.sagepub.com\/doi\/10.1177\/10507256261445291"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,21]]},"references-count":20,"alternative-id":["10.1177\/10507256261445291"],"URL":"https:\/\/doi.org\/10.1177\/10507256261445291","relation":{},"ISSN":["1050-7256","1557-9077"],"issn-type":[{"value":"1050-7256","type":"print"},{"value":"1557-9077","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,21]]},"article-number":"10507256261445291"}}