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BACKGROUND Hyponatremia is a common clinical electrolyte disorder. However, the association between hyponatremia and acute hypothyroidism is unclear. Acute hypothyroidism is usually seen in patients who undergo preparation for radioactive iodine therapy. AIM To analyze the incidence and influencing factors of hyponatremia in a condition of iatrogenic acute hypothyroidism in patients with differentiated thyroid cancer (DTC) before 131I treatment. METHODS The study group consisted of 903 DTC patients who received 131I treatment. The clinical data before and after surgery, as well as on the day of 131I treatment were analyzed. According to the blood sodium level before 131I treatment, patients were divided into the non-hyponatremia group and hyponatremia group. Correlations between serum sodium levels before 131I treatment and baseline data were analyzed. Univariate analysis and binary logistic regression were performed to identify the influencing factors of hyponatremia. RESULTS A total of 903 patients with DTC, including 283 (31.3%) males and 620 (68.7%) females, with an average age of 43.8 ± 12.7 years, were included in this study. The serum sodium levels before surgery and 131I treatment were 141.3 ± 2.3 and 140.5 ± 2.1 mmol/L, respectively (P = 0.001). However, the serum sodium levels in males and females before 131I treatment were lower than those before surgery. Patients aged more than 60 years and less than 60 years also showed decreased serum sodium levels before 131I treatment. In addition, the estimated glomerular filtration rate (eGFR) in males and females decreased before 131I treatment compared with those before surgery (P = 0.001). Moreover, eGFR in patients over 60 years and under 60 years decreased before 131I treatment, when compared with that before surgery. There were no significant differences in serum potassium, calcium, albumin, hemoglobin, and blood glucose in patients before surgery and 131I treatment (P > 0.05). Among the 903 patients, 23 (2.5%) were diagnosed with hyponatremia before 131I treatment, including 21 cases (91.3%) of mild hyponatremia and 2 cases (8.7%) of moderate hyponatremia. Clinical data showed that patients with mild hyponatremia had no specific clinical manifestations, while moderate hyponatremia cases were mainly characterized by fatigue and dizziness, which were similar to neurological symptoms caused by hypothyroidism and were difficult to distinguish. Correlation analysis showed a correlation between serum sodium before 131I treatment and the preoperative level (r = 0.395, P = 0.001). There was no significant correlation between blood sodium and thyroid-stimulating hormone (TSH) levels and urine iodine before 131I treatment (r = 0.045, P = 0.174; r = 0.013, P = 0.697). Univariate analysis showed that there were significant differences in age, sex, history of diuretic use, distant metastasis, preoperative blood sodium, blood urea nitrogen (BUN), eGFR, TSH and urinary iodine between the two groups (all P < 0.05). Logistic regression analysis showed that factors such as history of diuretic use, distant metastases, preoperative sodium and BUN were all influencing factors of hyponatremia. The Hosmer and Lemeshow test (c2 = 2.841, P = 0.944) suggested a high fit of the model. Omnibus tests of model coefficients indicated the overall significance of the model in this fitted model (P < 0.05). Preoperative serum sodium was a significant factor associated with pre-131I therapy hyponatremia (OR = 0.763; 95%CI: 0.627-0.928; P = 0.007). CONCLUSION The incidence of hyponatremia induced by 131I treatment preparation was not high. Preparation for radioactive iodine therapy was not a risk factor for the development of hyponatremia in thyroid cancer patients.