Background: Graves’ Disease (GD) represents the most prevalent cause of hyperthyroidism, with approximately 15% of patients treated with Radioactive Iodine (RAI) demonstrating rapid I-131 turnover, which results in ineffective therapy outcomes. Lithium (Li) has emerged as a potential adjunctive treatment, capable of enhancing intrathyroidal iodine accumulation through its inhibition of I-131 discharge from the thyroid gland, without impacting thyroidal radioactive iodine uptake (RAIU) over a 24-hour period. However, existing studies on the effectiveness of I-131 have yielded inconclusive results, partly due to a lack of comprehensive evaluation of other thyroid function parameters. Therefore, this review aims to systematically investigate the adjunctive role of Li in RAI therapy for hyperthyroidism, focusing on GD. Materials and Methods: This study was conducted using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guideline. Articles were retrieved from MEDLINE, ScienceDirect, Clinical Key, Cochrane, and Wiley Online Library databases using pre-specified PICOTS-SD criteria. Inclusion criteria included all published and unpublished studies evaluating lithium as an add-on therapy for RAI treatment in hyperthyroidism. Meta-analysis was performed utilizing Review Manager 5.4 with Mantel–Haenszel and Inverse Variance Method, using Odds Ratio (OR) and Mean Difference (MD) as the most appropriate effect sizes. Results: The inclusion criteria were met by fourteen studies (8 RCTs, 2 non-randomized trials, and 4 cohort studies), from which twelve were incorporated into the quantitative synthesis. Pooled analysis revealed a significantly higher cure rate in RAI+Li groups compared to RAI alone (OR=1.89, 95% CI: 1.35–2.63, P = 0.0002, I2=33%). Although the overall results indicate that RAI+Li treatment resulted in lower thyroid hormone levels, statistically significant changes were observed only in FT4 levels (MD = -8.34, 95% CI: -11.84 to -4.83, P < 0.00001). Additionally, the RAI+Li group exhibited a minor reduction in thyroid gland size by the end of the treatment period (MD = -4.47, 95% CI: -11.83 to 2.89, P = 0.23).

Conclusion: Addition of lithium in RAI therapy holds potential advantages for patients with Grave’s Disease, with growing evidence of RAI+Li combination underscores its potential for informing effective treatment strategies.