The Radioiodine–Gut–Thyroxine Axis: Radiation-Induced Enteric Dysfunction as a Novel Mechanism of Reduced Levothyroxine Bioavailability After Iodine-131 Therapy

Abstract

Background: Levothyroxine (LT4) is the standard treatment for thyroid hormone replacement after total thyroidectomy, but patients often need different oral LT4 doses after radioactive Iodine (I-131) therapy for differentiated thyroid carcinoma. This variation is usually explained by metabolic adaptation or adherence, but the possible role of radiation-related gastrointestinal dysfunction has received little attention. This study examines the proposed Radioiodine–Gut–Thyroxine Axis, suggesting that enteric radiation exposure may reduce intestinal LT4 absorption and lower systemic bioavailability. Methods: This retrospective cohort study included 148 adults who underwent total thyroidectomy for differentiated thyroid carcinoma between January 2018 and December 2025. Patients were divided into a radioactive iodine group (n=94) and a non-radioiodine group (n=54). Demographic, biochemical, and treatment data were reviewed over 12 months. The primary outcome was the change in weight-adjusted LT4 dose needed to maintain target thyroid-stimulating hormone suppression. Secondary outcomes were TSH variability, number of dose adjustments, time to biochemical stabilization, and predictors of increased LT4 requirements. Results: Patients treated with I-131 had a significant rise in mean LT4 requirements, increasing from 1.82 ± 0.24 to 2.14 ± 0.31 µg/kg/day, a 17.6% increase (p<0.001). No significant change was seen in the control group. TSH variability, number of dose adjustments, and time to biochemical stabilization were also significantly higher in the radioiodine-treated group (all p<0.001). Cumulative I-131 dose was positively correlated with LT4 dose escalation (r=0.46, p<0.001). Conclusion: Radioactive iodine therapy was associated with higher levothyroxine requirements and longer biochemical instability after thyroidectomy. These findings support the Radioiodine–Gut–Thyroxine Axis as a plausible mechanism linking radiation-related enteric dysfunction to reduced LT4 bioavailability, and they justify further prospective pharmacokinetic and mechanistic studies.