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Here, we review the pharmaceutical, pathophysiological and behavioural factors influencing the absorption, distribution, metabolism and excretion of LT4. Any factor that alters the state of the epithelium in the stomach or small intestine will reduce and\/or slow absorption of LT4; these include ulcerative colitis, coeliac disease, bariatric surgery, <jats:italic>Helicobacter pylori<\/jats:italic> infection, food intolerance, gastritis, mineral supplements, dietary fibre, resins, and various drugs. Once in the circulation, LT4 is almost fully bound to plasma proteins. Although free T4 (FT4) and liothyronine concentrations are extensively buffered, it is possible that drug- or disorder-induced changes in plasma proteins levels can modify free hormone levels. The data on the clinical significance of genetic variants in deiodinase genes are contradictory, and wide-scale genotyping of hypothyroid patients is not currently justified. We developed a decision tree for the physician faced with an abnormally high thyroid-stimulating hormone (TSH) level in a patient reporting adequate compliance with the recommended LT4 dose. The physician should review medications, the medical history and the serum FT4 level and check for acute adrenal insufficiency, heterophilic anti-TSH antibodies, antibodies against gastric and intestinal components (gastric parietal cells, endomysium, and tissue transglutaminase 2), and <jats:italic>Helicobacter pylori<\/jats:italic> infection. The next step is an LT4 pharmacodynamic absorption test; poor LT4 absorption should prompt a consultation with a gastroenterologist and (depending on the findings) an increase in the LT4 dose level. An in-depth etiological investigation can reveal visceral disorders and, especially, digestive tract disorders.<\/jats:p>","DOI":"10.1007\/s11154-021-09691-9","type":"journal-article","created":{"date-parts":[[2021,10,20]],"date-time":"2021-10-20T22:41:15Z","timestamp":1634769675000},"page":"463-483","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["Factors influencing the levothyroxine dose in the hormone replacement therapy of primary hypothyroidism in adults"],"prefix":"10.1007","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5391-7582","authenticated-orcid":false,"given":"Philippe","family":"Caron","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Solange","family":"Grunenwald","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luca","family":"Persani","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fran\u00e7oise","family":"Borson-Chazot","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Remy","family":"Leroy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonidas","family":"Duntas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,20]]},"reference":[{"issue":"1","key":"9691_CR1","doi-asserted-by":"publisher","first-page":"6","DOI":"10.1007\/s12020-016-1199-8","volume":"55","author":"JV Hennessey","year":"2017","unstructured":"Hennessey JV. 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