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While few hypothyroid patients require more than the expected weight-related dose of levothyroxine, the underlying causes of larger-than-expected dosing requirements have not been studied in a single cohort. Our aim was to determine and quantify the multiple factors contributing to high-dose levothyroxine requirements in a cohort of patients with hypothyroidism.The Grampian Automated Follow-Up Register (GAFUR) monitors around 17,500 hypothyroid patients. In 2008, 190 (1%) patients took225 μg of levothyroxine daily. A questionnaire was sent to 174 patients (16 were untraceable) to assess causes and to offer blood tests for endomysial, parietal cell (PCA), and thyroid peroxidase (TPO) autoantibodies. Primary care practices were contacted for medication details. All patients with positive endomysial autoantibodies were referred to a gastroenterologist. Thyroid function tests and levothyroxine doses were re-evaluated in 2011.A total of 125 questionnaires (72%) were returned. Mean levothyroxine dose was 248 μg daily. Twenty-six patients (20.8%) took medication known to interfere with levothyroxine absorption, and 21 patients (16.8%) admitted to compliance issues. Seven patients had positive anti-endomysial antibodies on initial screening, with four being new diagnoses of celiac disease, and PCA were positive in 27 (21.6%) patients. At follow-up in 2011, the mean levothyroxine dose had decreased in patients on interfering medications and in the four new cases of celiac disease.Causes of patients needing high-dose levothyroxine replacement include poor compliance, medication interference, PCA (as a marker of atrophic/autoimmune gastritis), and celiac disease. Doses can be decreased following advice regarding medication or after management of underlying conditions.