Correlation between the reduction of IL-6 and TNF-α with muscle mass restoration in hyperthyroid patients post-radioactive iodine therapy

Abstract

Objective To investigate whether dynamic resolution of IL-6 and TNF-α after radioactive iodine (RAI) therapy is a key determinant of muscle recovery in Graves’ disease and to evaluate their potential as longitudinal biomarkers. Methods A prospective cohort of 157 patients with Graves’ disease was enrolled. Skeletal muscle index (SMI) was assessed by dual-energy X-ray absorptiometry (DXA), and serum IL-6 and TNF-α were measured by enzyme-linked immunosorbent assay (ELISA). Patients were re-evaluated 6 months after 131 I therapy. Gaussian graphical modeling (GGM) assessed interaction network centrality, linear mixed models (LMM) evaluated longitudinal effects, and random forest modeling quantified the predictive importance of Δ values for ΔSMI. Results At baseline, IL-6 and TNF-α levels were higher in participants with adverse muscle-status phenotypes than in those with normal muscle mass (P < 0.05). Both markers were negatively correlated with SMI (IL-6: r=−0.19; TNF-α: r=−0.23; both P < 0.05) and showed high strength centrality in the exploratory network analysis. Among the 29 participants with low muscle mass at baseline, 7 (24.1%) no longer met the low-muscle-mass criterion at 6 months. However, neither within-participant nor between-participant levels of IL-6 or TNF-α were significantly associated with SMI in the mixed-effects models. Changes in IL-6 and TNF-α were also not associated with ΔSMI in correlation or adjusted regression analyses, and natural spline models provided no evidence of nonlinear or threshold relationships. The exploratory random forest ranked ΔFT3 and ΔFT4 highest in permutation importance, but its cross-validated performance was poor (mean R²=−0.204), indicating no reliable out-of-sample predictive ability. Conclusion IL-6 and TNF-α were associated with poorer skeletal muscle status at baseline in patients with Graves’ hyperthyroidism, but their longitudinal changes did not independently predict SMI recovery after RAI therapy. Although skeletal muscle mass improved in some patients, neither inflammatory nor thyroid-function changes demonstrated clinically useful predictive performance in this cohort. Larger studies with repeated assessments and external validation are needed to clarify the temporal and mechanistic relationships among thyroid recovery, inflammation, and skeletal muscle restoration.