{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T16:01:02Z","timestamp":1792080062413,"version":"4.4.0"},"reference-count":48,"publisher":"The Endocrine Society","issue":"5","license":[{"start":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T00:00:00Z","timestamp":1769126400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,22]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Refractory primary hypothyroidism is defined by persistently elevated thyroid-stimulating hormone despite supraphysiological oral levothyroxine dosing. The distinction between true malabsorption and pseudomalabsorption (nonadherence) is critical for management planning. In 2023, Quiroz-Aldave et al proposed a comprehensive framework for the evaluation and management of refractory primary hypothyroidism, while Liu et al provided an updated overview of both conventional and novel levothyroxine formulations. This mini-review synthesizes recent evidence published since 2023 and presents 2 illustrative cases managed within our clinical service. A PubMed search identified 41 relevant publications, including case reports, pharmacological studies, and clinical investigations. Case 1, a young woman with congenital hypothyroidism, demonstrated adequate intestinal absorption on a supervised levothyroxine absorption test, with subsequent findings supporting pseudomalabsorption. Recent studies have validated rapid absorption protocols (2-3 hours), offering feasible and cost-effective alternatives to conventional prolonged protocols. Case 2, a man with papillary thyroid carcinoma and end-stage renal failure, exhibited impaired gastrointestinal absorption confirmed by absorption testing. Management required escalation to parenteral therapy, with subcutaneous levothyroxine ultimately achieving biochemical stability. Importantly, no standardized absorption test exists for off-label intramuscular or subcutaneous administration; pharmacokinetic principles, particularly area under the curve calculations, may help estimate absorption readiness in these contexts. Emerging literature highlights gastrointestinal, surgical, and pharmacologic contributors to true malabsorption, as well as the superiority of liquid formulations in selected contexts. Subcutaneous administration is gaining interest as a tolerable, patient-friendly alternative to intramuscular dosing, although safety and pharmacokinetic validation of parenteral T4 remain necessary. Novel formulations under development may further optimize therapeutic options.<\/jats:p>","DOI":"10.1210\/clinem\/dgag024","type":"journal-article","created":{"date-parts":[[2026,1,23]],"date-time":"2026-01-23T05:54:03Z","timestamp":1769147643000},"page":"1203-1211","source":"Crossref","is-referenced-by-count":2,"title":["Beyond the Gut: thyroxine malabsorption, pharmacokinetics, and delivery"],"prefix":"10.1210","volume":"111","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0429-2632","authenticated-orcid":false,"given":"Lawrence Siu-Chun","family":"Law","sequence":"first","affiliation":[{"name":"Endocrinology Division, Department of Medicine, National University Hospital , Singapore 119074 ,","place":["Singapore"]},{"name":"Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore , Singapore 119228 ,","place":["Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9217-1455","authenticated-orcid":false,"given":"Nicholas Wei Xiang","family":"Kuu","sequence":"additional","affiliation":[{"name":"Duke-NUS Medical School , Singapore 169857 ,","place":["Singapore"]},{"name":"Department of Pharmacy, National University Hospital , Singapore 119074 ,","place":["Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-1897-5762","authenticated-orcid":false,"given":"Melissa Hui Ting","family":"Leong","sequence":"additional","affiliation":[{"name":"Endocrinology Division, Department of Medicine, National University Hospital , Singapore 119074 ,","place":["Singapore"]},{"name":"Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore , Singapore 119228 ,","place":["Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9241-9236","authenticated-orcid":false,"given":"Elaine Ah Gi","family":"Lo","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, National University Hospital , Singapore 119074 ,","place":["Singapore"]},{"name":"Department of Pharmacy and Pharmaceutical Sciences, Faculty of Science, National University of Singapore , Singapore 117559 ,","place":["Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0763-2639","authenticated-orcid":false,"given":"Siang Fei","family":"Yeoh","sequence":"additional","affiliation":[{"name":"Department of Pharmacy, National University Hospital , Singapore 119074 ,","place":["Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0838-6721","authenticated-orcid":false,"given":"Samantha Peiling","family":"Yang","sequence":"additional","affiliation":[{"name":"Endocrinology Division, Department of Medicine, National University Hospital , Singapore 119074 ,","place":["Singapore"]},{"name":"Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore , Singapore 119228 ,","place":["Singapore"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2026,1,23]]},"reference":[{"issue":"12","key":"2026042119583403900_dgag024-B1","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1007\/s40618-017-0706-y","article-title":"Diagnosis and management of treatment-refractory hypothyroidism: an expert consensus report","volume":"40","author":"Centanni","year":"2017","journal-title":"J Endocrinol Invest"},{"issue":"12","key":"2026042119583403900_dgag024-B2","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1016\/j.eprac.2023.09.003","article-title":"Refractory hypothyroidism: unraveling the complexities of diagnosis and management","volume":"29","author":"Quiroz-Aldave","year":"2023","journal-title":"Endocr Pract"},{"issue":"3","key":"2026042119583403900_dgag024-B3","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1210\/endrev\/bnac030","article-title":"Levothyroxine: conventional and novel drug delivery formulations","volume":"44","author":"Liu","year":"2023","journal-title":"Endocr Rev"},{"issue":"8","key":"2026042119583403900_dgag024-B4","doi-asserted-by":"crossref","first-page":"1875","DOI":"10.1210\/clinem\/dgad132","article-title":"The use of levothyroxine absorption tests in clinical practice","volume":"108","author":"Caron","year":"2023","journal-title":"J Clin Endocrinol Metab"},{"issue":"10","key":"2026042119583403900_dgag024-B5","doi-asserted-by":"crossref","first-page":"e240277","DOI":"10.1530\/EC-24-0277","article-title":"Rapid supervised levothyroxine absorption test in refractory hypothyroidism: suggestion for assessing absorption using two blood samples in low-resource settings","volume":"13","author":"Amiyangoda","year":"2024","journal-title":"Endocr Connect"},{"issue":"4","key":"2026042119583403900_dgag024-B6","first-page":"e37776","article-title":"Validity of the rapid thyroxine absorption test for the differentiation between levothyroxine non-compliance and malabsorption in thyroid-stimulating hormone refractory hypothyroidism","volume":"15","author":"Alhassan","year":"2023","journal-title":"Cureus"},{"issue":"6","key":"2026042119583403900_dgag024-B7","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/j.ando.2007.09.003","article-title":"Pseudomalabsorption of thyroid hormones: case report and review of the literature","volume":"68","author":"Livadariu","year":"2007","journal-title":"Ann Endocrinol (Paris)"},{"issue":"1","key":"2026042119583403900_dgag024-B8","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1507\/endocrj.47.45","article-title":"Pseudomalabsorption of levothyroxine: a case report","volume":"47","author":"Ogawa","year":"2000","journal-title":"Endocr J"},{"issue":"1","key":"2026042119583403900_dgag024-B9","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1159\/000452489","article-title":"Pseudomalabsorption of levothyroxine: a challenge for the endocrinologist in the treatment of hypothyroidism","volume":"6","author":"Van Wilder","year":"2017","journal-title":"Eur Thyroid J"},{"issue":"4","key":"2026042119583403900_dgag024-B10","doi-asserted-by":"crossref","first-page":"bvaf017","DOI":"10.1210\/jendso\/bvaf017","article-title":"Levothyroxine absorption test with the daily levothyroxine dose in patients with \u201cRefractory Hypothyroidism\u201d","volume":"9","author":"Caron","year":"2025","journal-title":"J Endocr Soc"},{"issue":"1","key":"2026042119583403900_dgag024-B11","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s13256-023-03760-0","article-title":"Levothyroxine absorption test followed by directly observed treatment on an outpatient basis to address long-term high thyrotropin levels in a hypothyroid patient: a case report","volume":"17","author":"Kiran","year":"2023","journal-title":"J Med Case Rep"},{"issue":"6","key":"2026042119583403900_dgag024-B12","doi-asserted-by":"crossref","first-page":"luaf085","DOI":"10.1210\/jcemcr\/luaf085","article-title":"Pseudo-malabsorption in high dose levothyroxine-resistant hypothyroidism","volume":"3","author":"Shimba","year":"2025","journal-title":"JCEM Case Rep"},{"issue":"1","key":"2026042119583403900_dgag024-B13","first-page":"109","article-title":"Refractory hypothyroidism","volume":"46","author":"Lai","year":"2024","journal-title":"Malays J Pathol"},{"issue":"6","key":"2026042119583403900_dgag024-B14","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1530\/EJE-12-1035","article-title":"A thyroxine absorption test followed by weekly thyroxine administration: a method to assess non-adherence to treatment","volume":"168","author":"Walker","year":"2013","journal-title":"Eur J Endocrinol"},{"issue":"1","key":"2026042119583403900_dgag024-B15","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1177\/10507256251409071","article-title":"Subcutaneous levothyroxine administration in treatment of refractory primary hypothyroidism: a case report","volume":"36","author":"Law","year":"2026","journal-title":"Thyroid"},{"issue":"1","key":"2026042119583403900_dgag024-B16","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/thy.2015.0020","article-title":"2015 American thyroid association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American thyroid association guidelines task force on thyroid nodules and differentiated thyroid cancer","volume":"26","author":"Haugen","year":"2016","journal-title":"Thyroid"},{"issue":"2","key":"2026042119583403900_dgag024-B17","doi-asserted-by":"crossref","first-page":"e757","DOI":"10.1210\/clinem\/dgaa872","article-title":"Severity of proteinuria is directly associated with risk of hypothyroidism in adults","volume":"106","author":"Kwong","year":"2021","journal-title":"J Clin Endocrinol Metab"},{"issue":"1","key":"2026042119583403900_dgag024-B18","doi-asserted-by":"crossref","first-page":"14999","DOI":"10.1038\/s41598-022-19226-0","article-title":"The association between hypothyroidism and proteinuria in patients with chronic kidney disease: a cross-sectional study","volume":"12","author":"Matsuoka-Uchiyama","year":"2022","journal-title":"Sci Rep"},{"issue":"1","key":"2026042119583403900_dgag024-B19","doi-asserted-by":"crossref","first-page":"97","DOI":"10.4158\/EP.14.1.97","article-title":"Exacerbation of underlying hypothyroidism caused by proteinuria and induction of urinary thyroxine loss: case report and subsequent investigation","volume":"14","author":"Chandurkar","year":"2008","journal-title":"Endocr Pract"},{"issue":"3","key":"2026042119583403900_dgag024-B20","first-page":"89","article-title":"A yet unrecognized cause of unusually high levothyroxine replacement dose: protein-losing enteropathy","volume":"9","author":"Yu","year":"2023","journal-title":"AACE Clin Case Rep"},{"issue":"6","key":"2026042119583403900_dgag024-B21","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.eprac.2024.03.005","article-title":"Liquid thyroxine improves outcomes in hypothyroid patients with small intestinal bacterial overgrowth and irritable bowel syndrome","volume":"30","author":"Henderson","year":"2024","journal-title":"Endocr Pract"},{"issue":"3","key":"2026042119583403900_dgag024-B22","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1007\/s12020-022-03289-0","article-title":"The performance of levothyroxine tablet is impaired by bariatric surgery","volume":"80","author":"Trimboli","year":"2023","journal-title":"Endocrine"},{"key":"2026042119583403900_dgag024-B23","doi-asserted-by":"crossref","first-page":"621616","DOI":"10.3389\/fendo.2020.621616","article-title":"Levothyroxine therapy in gastric malabsorptive disorders","volume":"11","author":"Virili","year":"2020","journal-title":"Front Endocrinol (Lausanne)"},{"issue":"1","key":"2026042119583403900_dgag024-B24","first-page":"e240115","article-title":"Levothyroxine malabsorption following sleeve gastrectomy","volume":"2025","author":"Gruneisen","year":"2025","journal-title":"Endocrinol Diabetes Metab Case Rep"},{"key":"2026042119583403900_dgag024-B25","doi-asserted-by":"crossref","first-page":"2050313X231209229","DOI":"10.1177\/2050313X231209229","article-title":"Levothyroxine liquid oral substitution as an alternative treatment for refractory hypothyroidism due to gastrointestinal malabsorption: a case report","volume":"11","author":"Cherchir","year":"2023","journal-title":"SAGE Open Med Case Rep"},{"issue":"10","key":"2026042119583403900_dgag024-B26","first-page":"e71551","article-title":"Phosphate binder impairs levothyroxine absorption in a hypothyroid patient with end-stage renal disease","volume":"16","author":"Ko","year":"2024","journal-title":"Cureus"},{"issue":"1","key":"2026042119583403900_dgag024-B27","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1007\/s12020-018-1574-8","article-title":"Liquid L-thyroxine versus tablet L-thyroxine in patients on L- thyroxine replacement or suppressive therapy: a meta-analysis","volume":"61","author":"Laurent","year":"2018","journal-title":"Endocrine"},{"issue":"4","key":"2026042119583403900_dgag024-B28","first-page":"e83123","article-title":"Managing levothyroxine malabsorption in refractory hypothyroidism: a case report","volume":"17","author":"Rashwan","year":"2025","journal-title":"Cureus"},{"key":"2026042119583403900_dgag024-B29","doi-asserted-by":"crossref","first-page":"e230095","DOI":"10.20945\/2359-4292-2023-0095","article-title":"Myxedema coma secondary to levothyroxine malabsorption in a patient previously submitted to bariatric surgery","volume":"68","author":"Buoso","year":"2024","journal-title":"Arch Endocrinol Metab"},{"issue":"2","key":"2026042119583403900_dgag024-B30","doi-asserted-by":"crossref","first-page":"793","DOI":"10.1007\/s12020-025-04375-9","article-title":"Comparison of tablet versus liquid ethanol-free levothyroxine in thyroidectomised patients","volume":"90","author":"Croce","year":"2025","journal-title":"Endocrine"},{"issue":"1","key":"2026042119583403900_dgag024-B31","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1186\/s13044-025-00236-9","article-title":"Are liquid levothyroxine formulations comparable? The LETI study","volume":"18","author":"Gatta","year":"2025","journal-title":"Thyroid Res"},{"issue":"2","key":"2026042119583403900_dgag024-B32","doi-asserted-by":"crossref","first-page":"e250012","DOI":"10.1530\/ETJ-25-0012","article-title":"Intramuscular and subcutaneous levothyroxine: success in treating refractory hypothyroidism","volume":"14","author":"Chaudhury","year":"2025","journal-title":"Eur Thyroid J"},{"issue":"4","key":"2026042119583403900_dgag024-B33","first-page":"622","article-title":"[Subcutaneous administration of levothyroxine in refractory hypothyroidism]","volume":"83","author":"Ramirez Stieben","year":"2023","journal-title":"Medicina (B Aires)"},{"issue":"5","key":"2026042119583403900_dgag024-B34","doi-asserted-by":"crossref","first-page":"e70244","DOI":"10.1111\/cts.70244","article-title":"Phase 1 study evaluating the pharmacokinetics, dose proportionality, bioavailability, and tolerability of subcutaneous levothyroxine sodium (XP-8121)","volume":"18","author":"Fitch","year":"2025","journal-title":"Clin Transl Sci"},{"issue":"2","key":"2026042119583403900_dgag024-B35","doi-asserted-by":"crossref","first-page":"181","DOI":"10.18433\/J3RG78","article-title":"Modifications of the method for calculating absolute drug bioavailability","volume":"19","author":"Jiang","year":"2016","journal-title":"J Pharm Pharm Sci"},{"issue":"6","key":"2026042119583403900_dgag024-B36","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1111\/j.1365-2885.2004.00604.x","article-title":"Bioavailability and its assessment","volume":"27","author":"Toutain","year":"2004","journal-title":"J Vet Pharmacol Ther"},{"issue":"11","key":"2026042119583403900_dgag024-B37","doi-asserted-by":"crossref","first-page":"1635","DOI":"10.1111\/jphp.13154","article-title":"Optimising time samples for determining area under the curve of pharmacokinetic data using non-compartmental analysis","volume":"71","author":"Hughes","year":"2019","journal-title":"J Pharm Pharmacol"},{"issue":"3","key":"2026042119583403900_dgag024-B38","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1111\/j.1365-2125.2005.02433.x","article-title":"Effects of grapefruit juice on the absorption of levothyroxine","volume":"60","author":"Lilja","year":"2005","journal-title":"Br J Clin Pharmacol"},{"key":"2026042119583403900_dgag024-B39","author":"United States Food and Drug Administration"},{"issue":"1-2","key":"2026042119583403900_dgag024-B40","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cca.2006.08.026","article-title":"Usefulness of monitoring free (unbound) concentrations of therapeutic drugs in patient management","volume":"377","author":"Dasgupta","year":"2007","journal-title":"Clin Chim Acta"},{"issue":"15","key":"2026042119583403900_dgag024-B41","doi-asserted-by":"crossref","first-page":"1753","DOI":"10.4155\/bio.11.187","article-title":"Monitoring free drug concentrations: challenges","volume":"3","author":"Musteata","year":"2011","journal-title":"Bioanalysis"},{"issue":"10","key":"2026042119583403900_dgag024-B42","doi-asserted-by":"crossref","first-page":"3331","DOI":"10.1016\/j.xphs.2021.05.018","article-title":"Impact of changes in free concentrations and drug-protein binding on drug dosing regimens in special populations and disease states","volume":"110","author":"Celestin","year":"2021","journal-title":"J Pharm Sci"},{"issue":"12","key":"2026042119583403900_dgag024-B43","doi-asserted-by":"crossref","first-page":"1200","DOI":"10.1089\/thy.2012.0205","article-title":"Clinical practice guidelines for hypothyroidism in adults: cosponsored by the American association of clinical endocrinologists and the American thyroid association","volume":"22","author":"Garber","year":"2012","journal-title":"Thyroid"},{"issue":"9","key":"2026042119583403900_dgag024-B44","doi-asserted-by":"crossref","first-page":"925","DOI":"10.4158\/EP13487.OR","article-title":"The clinical utility of free thyroxine in oral levothyroxine absorption testing","volume":"20","author":"Sun","year":"2014","journal-title":"Endocr Pract"},{"issue":"8","key":"2026042119583403900_dgag024-B45","doi-asserted-by":"crossref","first-page":"897","DOI":"10.1089\/thy.2021.0604","article-title":"A novel levothyroxine solution results in similar bioavailability whether taken 30 or just 15 minutes before a high-fat high-calorie meal","volume":"32","author":"Ducharme","year":"2022","journal-title":"Thyroid"},{"key":"2026042119583403900_dgag024-B46","author":"European Medicines Agency"},{"issue":"2","key":"2026042119583403900_dgag024-B47","doi-asserted-by":"crossref","first-page":"217","DOI":"10.18433\/J3FG63","article-title":"How critical is the duration of the sampling scheme for the determination of half-life, characterization of exposure and assessment of bioequivalence?","volume":"14","author":"Colucci","year":"2011","journal-title":"J Pharm Pharm Sci"},{"issue":"12","key":"2026042119583403900_dgag024-B48","doi-asserted-by":"crossref","first-page":"1734","DOI":"10.1089\/thy.2019.0256","article-title":"The levothyroxine absorption test: a four-year experience (2015-2018) at the mayo clinic","volume":"29","author":"Gonzales","year":"2019","journal-title":"Thyroid"}],"container-title":["The Journal of Clinical Endocrinology &amp; Metabolism"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jcem\/advance-article-pdf\/doi\/10.1210\/clinem\/dgag024\/66548997\/dgag024.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/111\/5\/1203\/66548997\/dgag024.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jcem\/article-pdf\/111\/5\/1203\/66548997\/dgag024.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,21]],"date-time":"2026-04-21T23:58:43Z","timestamp":1776815923000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jcem\/article\/111\/5\/1203\/8439091"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,23]]},"references-count":48,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,1,23]]},"published-print":{"date-parts":[[2026,4,22]]}},"URL":"https:\/\/doi.org\/10.1210\/clinem\/dgag024","relation":{},"ISSN":["0021-972X","1945-7197"],"issn-type":[{"value":"0021-972X","type":"print"},{"value":"1945-7197","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,5]]},"published":{"date-parts":[[2026,1,23]]}}}