The importance of sequential evaluation of refractory hypothyroidism cases

Abstract

Objective: To identify causes of refractoriness to oral levothyroxine (LT4) and propose a sequential investigation protocol including gastrointestinal and psychiatric assessments and the LT4 absorption test. Methods: A prospective case series included adults (18–65 years) using ≥2.5 µg/kg/day or ≥250 µg/day of LT4. Ten patients completed full evaluation: medical interview, empirical antiparasitic therapy, upper endoscopy with biopsies, tests for malabsorption and lactose intolerance, psychiatric screening (M.I.N.I. Plus), and a standardized 4-hour LT4 absorption test applying four diagnostic criteria. Results: Most participants were women (80%), mean BMI 28.6 kg/m². At least one contributing factor was identified in 90%. Endoscopic abnormalities were common (80%); half were Helicobacter pylori positive, 40% lactose intolerant, 40% screened positive for depression, and 60% used interfering medications. Based on absorption criteria, three patients had true malabsorption, while most showed adequate LT4 absorption, suggesting pseudo malabsorption linked to nonadherence. Total T4-based criteria yielded the highest concordance, while free T4 and TSH changes were more variable. Conclusion: Refractory hypothyroidism is typically multifactorial. Drug interactions, gastrointestinal disorders, and psychiatric comorbidities frequently impair control. Most patients demonstrated adequate LT4 absorption, highlighting nonadherence as a major cause. A structured, multidisciplinary approach optimizes diagnostic accuracy.