Background: Preparation for radioactive iodine (RAI) therapy requires achieving elevated thyroid-stimulating hormone (TSH) levels to enhance I-131 uptake through sodium–iodide symporter upregulation. A TSH ≥30 µIU/mL is typically achieved via levothyroxine withdrawal. Severe hypothyroidism may reduce renal perfusion, impair free water clearance, and disrupt electrolyte homeostasis, potentially causing hyponatremia or potassium abnormalities. Evidence describing electrolyte imbalance during RAI preparation remains limited. This study aimed to evaluate whether hypothyroid preparation for RAI is associated with clinically significant electrolyte changes.

Methods: A retrospective observational study was conducted from 1 July to 15 November 2025. A total of 307 differentiated thyroid carcinoma (DTC) patients undergoing standard four-week levothyroxine withdrawal were included; those with incomplete laboratory data were excluded. Patients were categorized by TSH level: 0.4–4.5 µIU/mL, 4.5–10 µIU/mL, 10–30 µIU/mL, and >30 µIU/mL. Serum sodium and potassium values were summarized as mean ± SD. ANOVA and chi-square tests were applied.

Results: Mean serum sodium showed a slight decreasing trend across TSH categories, ranging from 140.63 ± 3.61 mEq/L (TSH 0.4–4.5 µIU/mL) to 139.34 ± 2.29 mEq/L (TSH >30 µIU/mL), although the differences were not statistically significant (p = 0.135) and were not clinically meaningful. Mean serum potassium increased modestly from 3.85 ± 0.48 to 4.01 ± 0.47 mEq/L, but this difference was also not significant (p = 0.277). No cases of clinically relevant hyponatremia or hyperkalemia were identified. Differences in baseline characteristics—specifically age (p = 0.005) and BMI (p = 0.007)—were observed between groups, suggesting potential residual confounding.

Conclusion: In this cohort of 307 DTC patients, hypothyroid preparation through four-week levothyroxine withdrawal did not result in clinically significant electrolyte imbalance. These findings suggest that routine electrolyte monitoring before RAI may not be necessary in otherwise stable patients unless symptoms or comorbidities indicate higher risk.