{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,16]],"date-time":"2026-02-16T18:06:14Z","timestamp":1771265174808,"version":"3.50.1"},"reference-count":29,"publisher":"Public Library of Science (PLoS)","issue":"6","license":[{"start":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T00:00:00Z","timestamp":1749427200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000026","name":"National Institute of Drug Abuse","doi-asserted-by":"crossref","award":["R25DA050723"],"award-info":[{"award-number":["R25DA050723"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000026","name":"National Institute of Drug Abuse","doi-asserted-by":"crossref","award":["R25DA057713"],"award-info":[{"award-number":["R25DA057713"]}],"id":[{"id":"10.13039\/100000026","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100006545","name":"NIMHD","doi-asserted-by":"crossref","award":["S21 MD000103"],"award-info":[{"award-number":["S21 MD000103"]}],"id":[{"id":"10.13039\/100006545","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec010\">\n<jats:title>Background<\/jats:title>\n<jats:p>Reverse T<jats:sub>3<\/jats:sub> (rT<jats:sub>3<\/jats:sub>) is a biologically inactive form of T<jats:sub>3<\/jats:sub> (triiodothyronine), a thyroid hormone, that is created by peripheral 5 deiodination of T<jats:sub>4<\/jats:sub> (thyroxine) by type 1 and type 3 deiodinase enzymes (D1 and D3 respectively) and may block T<jats:sub>3<\/jats:sub> binding to the thyroid hormone receptor. Approximately 15% of patients on L-T<jats:sub>4<\/jats:sub> replacement therapy with a normalized thyroid-stimulating hormone (TSH) report experience continued fatigue and other hypothyroid symptoms; therefore, efforts are needed to understand why this occurs and how it can be corrected. Decades ago, endocrinologists realized that in patients with severe illnesses, rT<jats:sub>3<\/jats:sub> is typically high and T<jats:sub>3<\/jats:sub> is typically low; this was termed \u201ceuthyroid sick syndrome\u201d. More recently, functional medicine and other doctors, have argued that high rT<jats:sub>3<\/jats:sub> is detrimental and can block T<jats:sub>3<\/jats:sub> from binding to the thyroid hormone receptor. Due to the lack of peer-reviewed publications on this topic, functional medicine doctors continue to rely heavily on rT<jats:sub>3<\/jats:sub> levels to treat patients that may have no other laboratory findings of hypothyroidism and often prescribe L-T<jats:sub>3<\/jats:sub>-only preparations to patients in an effort to lower rT<jats:sub>3<\/jats:sub>.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec011\">\n<jats:title>Methods<\/jats:title>\n<jats:p>The initial rT<jats:sub>3<\/jats:sub> measurements done by liquid chromatography\/tandem mass spectrometry (LC\/MS-MS) were retrospectively analyzed from the initial blood tests in 976 consecutive patients, with symptoms of fatigue and treated for hypothyroidism, in a private Endocrinology practice. TSH, free T<jats:sub>3<\/jats:sub> and free T<jats:sub>4<\/jats:sub> were measured by electrochemiluminescence immunoassay (ECLIA). The upper limit of normal rT<jats:sub>3<\/jats:sub> (24.1\u2009ng\/dL) was used as a cut-off for results above the normal range.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec012\">\n<jats:title>Results<\/jats:title>\n<jats:p>The number of patients with rT<jats:sub>3<\/jats:sub> levels above normal range varied significantly with the type of thyroid hormone replacement prescribed. The highest rate of an elevated rT<jats:sub>3<\/jats:sub> was 20.9% (29\/139) in patients taking T<jats:sub>4<\/jats:sub> alone. Nine% (31\/345) of patients not taking thyroid hormone replacement had elevated rT<jats:sub>3<\/jats:sub>. Patients on all types of L-T<jats:sub>4<\/jats:sub> treatment had higher rT<jats:sub>3<\/jats:sub> levels than those not on L-T<jats:sub>4<\/jats:sub> treatment (p\u2009&lt;\u20090.00001) and they also had a higher percentage of rT<jats:sub>3<\/jats:sub> levels above the cutoff of 24.1\u2009ng\/dL (p\u2009&lt;\u20090.00001). Linear regression analysis showed rT<jats:sub>3<\/jats:sub> levels correlated with free T<jats:sub>4<\/jats:sub> and free T<jats:sub>3<\/jats:sub> levels and inversely with log TSH levels.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec013\">\n<jats:title>Conclusions<\/jats:title>\n<jats:p>This study found elevated rT<jats:sub>3<\/jats:sub> levels in patients with symptoms of fatigue on various thyroid hormone replacements with the highest levels of rT<jats:sub>3<\/jats:sub> in those taking L-T<jats:sub>4<\/jats:sub> replacement alone and the lowest levels of rT<jats:sub>3<\/jats:sub> in those on preparations that contained L-T<jats:sub>3<\/jats:sub> alone.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pone.0325046","type":"journal-article","created":{"date-parts":[[2025,6,9]],"date-time":"2025-06-09T20:01:23Z","timestamp":1749499283000},"page":"e0325046","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Reverse T3 in patients with hypothyroidism on different thyroid hormone replacement"],"prefix":"10.1371","volume":"20","author":[{"given":"Julian B.","family":"Wilson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thanh D.","family":"Hoang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Martin L.","family":"Lee","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6936-2232","authenticated-orcid":true,"given":"Ma\u2019ayan","family":"Epstein","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9555-7626","authenticated-orcid":true,"given":"Theodore C.","family":"Friedman","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2025,6,9]]},"reference":[{"key":"pone.0325046.ref001","article-title":"The thyroid gland.","volume-title":"Andreoli and Carpenter\u2019s Cecil Essentials of Medicine","author":"TC. 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