Radioactive iodine (RAI) therapy is a well-established treatment for differentiated thyroid cancer after thyroidectomy. Before RAI therapy or scanning, thyrotropin stimulation and a 2-week low-iodine diet (LID) are required. There are case reports of potentially life-threatening hyponatremia occurring in patients undergoing thyroid hormone withdrawal (THW) and a longer duration of LID.[2–4] Restriction of noniodized salt during LID in patients undergoing THW may be associated with hyponatremia.
Hyponatremia is the most common electrolyte abnormality in clinical practice. It can also be associated with longer hospital stays and higher mortality in patients with cancer. Hyponatremia has been reported in patients with noncancer conditions and with various cancer,[6,8] but few studies have assessed the frequency and clinical impact in patients with thyroid cancer.[9,10] The aim of this study was to evaluate whether the preparation for RAI therapy by THW or LID can be risk factors for development of hyponatremia in patients with differentiated thyroid cancer after thyroidectomy.
We retrospectively studied patients with papillary thyroid carcinoma treated with high dose (>1.11 GBq) I-131 at our institution between 2012 and 2014. Patients who underwent total thyroidectomy with or without dissection of lymph nodes and who had received initial RAI therapy were included. Patients without available medical records or laboratory examinations were excluded. Finally, 326 patients were enrolled in this study. The study was approved by the Institutional Review Board of our hospital.
1.2 Study design
The standard protocol for RAI therapy at our institution is presented in Fig. 1. Initial laboratory examinations for Na, K, Cl, and creatinine were performed the day before the operation. After the operation, the endocrine surgeon referred the patient to the department of nuclear medicine. Diagnostic I-123 whole body scanning was performed to identify appropriate patients for RAI therapy and determine the optimal dose of I-131 after preparation with LID and thyroid stimulating hormone (TSH) elevation. LID is recommended for a 1 to 2 weeks duration, according to major guidelines on this subject.[1,11,12] TSH elevation is accomplished by 2 methods: THW, discontinuing levothyroxine (LT4) and changing to liothyronine (LT3) for 2 to 4 weeks followed by withdrawal of LT3 for 2 weeks, or recombinant human TSH (rhTSH, Thyrogen) injection. Patients who meet the criteria for RAI therapy should have an extended period of LID and THW or injection of additional rhTSH. A second laboratory examination for Na, K, Cl, creatinine, free T4 (FT4), T3, thyroglobulin (Tg), antithyroglobulin antibody (anti-Tg), and TSH is performed on the morning of the admission day.
1.3 Clinical data collection
Demographic and clinical variables included the following: age, sex, hypertension (HTN), diabetes mellitus (DM), method of thyrotropin stimulation, duration of LID (days), and laboratory results before operation and before RAI therapy. Reference ranges were: serum Na, 135 to 147 mEq/L; K, 3.5 to 5.1 mEq/L; Cl, 98 to 112 mEq/L; creatinine, 0.5 to 1.3 mg/dL; FT4, 0.7 to 2 ng/dL; T3, 80 to 220 ng/dL; Tg, 2 to 60 ng/mL; anti-Tg, 0 to 55 U/mL; and TSH, 0.4 to 4.5 μIU/mL. The estimated glomerular filtration rate (eGFR) was calculated according to the simplified Modification of Diet in Renal Disease (MDRD) formula. Hyponatremia was defined as serum sodium (Na) level <135 mEq/L. Serum Na levels were used to classify patients as normonatremic (135–147 mEq/L), mildly hyponatremic (130–134 mEq/L), moderately hyponatremic (120–129 mEq/L), and severely hyponatremic (<120 mEq/L).
1.4 Statistical analysis
Continuous variables were expressed as the mean ± standard deviation (SD), and categorical variables were expressed as frequencies and percentages. Univariate analysis was performed using Student t test for continuous variables and the Chi-square test or Fisher exact test for categorical variables. Correlations between continuous variables for laboratory data were determined based on Pearson correlation coefficient. Logistic regression analyses were performed to evaluate the risk factors for hyponatremia in the preparation for RAI therapy. P-value less than 0.05 was considered statistically significant, and statistical analysis was performed using the software SPSS (version 21.0; IBM Corp., Armonk, NY).
2.1 Frequency and severity of hyponatremia
There were only 3 hyponatremic patients (0.9%) before operation, but there were 15 hyponatremic patients (4.6%) before RAI therapy (Fig. 2). After the preparation for RAI therapy, 13 (4.0%) of 323 patients with normonatremic had converted to hyponatremia. None of the patients had hypernatremia.
Before operation, there were 2 patients with mild hyponatremia (133 and 134 mEq/L) and 1 with moderate hyponatremia (127 mEq/L), whereas before RAI therapy, there were 14 with mild hyponatremia (134.1 ± 1.1 mEq/L) and 1 with moderate hyponatremia (125 mEq/L). Most patients with hyponatremia had only a mild degree after preparation for RAI therapy. None had severe hyponatremia.
2.2 Comparison of hyponatremic and normonatremic groups
Before operation, the mean serum levels of Na and Cl were lower in the hyponatremia group than in the normonatremia group; however, there were no differences in age, sex, HTN, DM, serum K, blood urea nitrogen (BUN), creatinine or eGFR between the 2 groups (Table 1). However, before RAI therapy, the percentage of DM patients was higher in the hyponatremia group (27%) than in the normonatremia group (6%). The mean level of preoperative Na was lower in the hyponatremia group. There were no differences in age, sex, HTN, duration of LID, method of thyrotropin stimulation, preoperative K, Cl, creatinine and eGFR, or pre-RAI therapy FT4, T3, Tg, anti-Tg, or TSH.
2.3 Factors associated with serum Na before RAI therapy
As shown in Table 2, for the continuous variables, pre-RAI therapy serum Na level was correlated with patient age (r = 0.129, P = 0.019), duration of LID (r = −0.131, P = 0.018) and preoperative Na level (r = 0.391, P < 0.001). However, pre-RAI therapy serum Na level was not correlated with preoperative K, Cl, creatinine, and eGFR, or pre-RAI therapy FT4, T3, Tg, anti-Tg, or TSH.
For the categorical variables, the method of thyrotropin stimulation and DM were associated with the change in serum Na level. Serum Na level was decreased significantly more in the THW group than in the rhTSH group (Fig. 3A, P = 0.014), and serum Na level decreased significantly more in the DM group than in the non-DM group (Fig. 3B, P = 0.059). However, sex (Fig. 3C) and HTN (Fig. 3D) were not associated with a change in serum Na level.
Logistic regression analyses were performed to evaluate factors associated with hyponatremia before RAI therapy (Table 3). Preoperative serum Na was the only significant factor associated with pre-RAI therapy hyponatremia (continuous variable; P = 0.001, odds ratio [OR]: 0.674; 95% confidence interval [CI], 0.538–0.846, hyponatremia; P = 0.001, OR: 61.096; 95% CI, 4.971–750.945). Age (continuous variable; P = 0.064, old age over 60 years; P = 0.068), DM (P = 0.057), and duration of LID (continuous variable; P = 0.063) showed borderline P values. However, the preparation for RAI therapy of THW and 2-week LID commonly recommended duration according to most guidelines did not affect the development of hyponatremia.
In the present study, we demonstrated that preparation for RAI therapy using THW and LID did not cause frequent or severe hyponatremia. Hyponatremia was only present in 3 cases (<1%) before operation, and in 15 cases (4.6%) before RAI therapy. After preparation for RAI therapy, there was only a 3.7% increase in hyponatremic patients. The hyponatremia rate in this study was lower than that obtained in previous reports. Doshi et al reported that the hyponatremia rate in patients with cancer admitted for the first time to the hospital was 47%. Such differences in the hyponatremia rate are attributable to the patients’ characteristics. Our study only included cases with thyroid papillary carcinoma, which is a less aggressive malignancy and younger patients (mean, 50 ± 12 years) than those studied by Doshi et al (mean, 56 ± 17 years) might be associated with the lower rate of hyponatremia. Another major finding was that none of the subjects showed severe hyponatremia after preparation for RAI therapy. Our study had only 1 patient with moderate hyponatremia with a serum Na level of 125 mEq/L. She had no symptoms suggesting hyponatremia and her hyponatremia became normalized after administration of an oral sodium chloride tablet. Our results correspond well to previous studies of patients undergoing preparation for RAI therapy. Baajafer et al showed that of 120 patients who were prepared for RAI therapy using both THW and LID, none had serum sodium values below 130 mEq/L. There were several case reports of moderate to severe hyponatremia after preparation for RAI therapy in patients with other contributing factors such as old age, thiazide use, etc.[3,4] Hyponatremia is frequent in patients with or without cancer admitted to the hospital, but is rare in patients with thyroid cancer admitted to the hospital. Severe hyponatremia can induce fatal complications, but there were no cases with severe hyponatremia during the preparation for RAI therapy and hyponatremic patients were successfully treated by sodium chloride tablets. Therefore, preparation for RAI therapy using THW or LID appears to be a safe procedure, and does not need intensive monitoring in patients with thyroid cancer.
Our results also showed that preparation for RAI therapy with THW or LID was not a risk factor for the development of hyponatremia in patients with thyroid cancer. Hypothyroidism induced by THW has been considered a major contributing factor for the development of hyponatremia.[10,14] Hypothyroid patients have a diminished ability to excrete free water, fail to achieve maximum urine dilution, and show delayed excretion of a water load leading to hyponatremia. Our study showed that patients with hypothyroidism induced by THW had a lower serum Na level before RAI therapy than euthyroid patients who received rhTSH injection, even with similar serum Na levels before operation. Low sodium intake along with LID might be additional contributing factors for the development of hyponatremia in patients with thyroid cancer.[3,14] Severe restriction of sodium intake often occurs during the LID period despite the availability of iodine-free salt. The deficit of sodium induces hyponatremia. Our study also showed that there was an inverse correlation between the duration of LID and serum Na level before RAI therapy; the longer the duration of LID, the lower the serum Na level. Our results demonstrated that a hypothyroid state and prolonged LID duration were significantly correlated with serum Na level before RAI therapy. However, THW and 2-week LID, which is the most commonly recommended duration from authoritative guidelines, were not risk factors for the development of hyponatremia in the logistic regression analysis. Other patients who reported the development of hyponatremia during preparation for RAI therapy also had contributing cofactors such as old age, thiazide use, and other comorbidities making them more prone to hyponatremia. This suggests that THW and LID could induce a somewhat low serum Na level, and excessive longer LID duration might increase the possibility of hyponatremia. However, THW or LID per se could not be a strong risk factor for the development of significant hyponatremia, because following the current recommendations for LID duration was not associated with a higher risk of hyponatremia. Thus, nuclear medicine physicians should consider causes other than THW or LID when patients have pre-RAI therapy hyponatremia.
Another major finding was that preoperative serum Na level was the only risk factor for the development of hyponatremia before RAI therapy. Among the hyponatremic patients before operation, 2 of 3 remained hyponatremic after preparation for RAI therapy. Moreover, increased fluid intake of over 2 L daily is recommended during hospitalization to promote excretion of residual RAI in the isolation room. Excessive oral hydration may potentiate an electrolyte imbalance and thus contribute to the development of hyponatremia in high risk patients. Therefore, patients who have lower preoperative serum Na levels should be monitored during the preparation for RAI therapy.
This study has several limitations. First, it is limited by its retrospective design and by the relatively small number of patients enrolled; thus its prediction power is relatively low. Further prospective studies including more patients with hyponatremia are therefore necessary. Second, serum and urine osmolarity tests or hormone assays were not evaluated to further investigate the causes of hyponatremia in this study. However, none of the patients had severe or symptomatic hyponatremia, and further examination was not essential before RAI therapy.
Preparation for RAI therapy using THW or LID is not a risk factor for the development of hyponatremia in patients with thyroid cancer. Hyponatremia was neither frequent nor severe during preparation for RAI therapy when developed. Physicians need not be greatly concerned about rare, life-threatening hyponatremia during preparation for RAI therapy, and should not overestimate the possibility of the development of severe hyponatremia.
. Haugen BR, Alexander EK, Bible KC, et al. 2015 American Thyroid
Association Management Guidelines for Adult Patients with Thyroid
Nodules and Differentiated Thyroid Cancer
: the American Thyroid
Association Guidelines Task Force on Thyroid
Nodules and Differentiated Thyroid Cancer
. Kim SK, Yun GY, Kim KH, et al. Severe hyponatremia
following radioactive iodine therapy
in patients with differentiated thyroid cancer
. Krishnamurthy VR, McDougall IR. Severe hyponatremia
: a danger of low-iodine diet
. Shakir MK, Krook LS, Schraml FV, et al. Symptomatic hyponatremia
in association with a low-iodine diet
and levothyroxine withdrawal prior to I131 in patients with metastatic thyroid
. Al Nozha OM, Vautour L, How J. Life-threatening hyponatremia
following a low-iodine diet
: a case report and review of all reported cases. Endocr Pract 2011;17:e113–7.
. Doshi SM, Shah P, Lei X, et al. Hyponatremia
in hospitalized cancer
patients and its impact on clinical outcomes. Am J Kidney Dis 2012;59:222–8.
. Upadhyay A, Jaber BL, Madias NE. Epidemiology of hyponatremia
. Semin Nephrol 2009;29:227–38.
. Upadhyay A, Jaber BL, Madias NE. Incidence and prevalence of hyponatremia
. Am J Med 2006;119(7 suppl 1):S30–5.
. Hammami MM, Almogbel F, Hammami S, et al. Acute severe hypothyroidism is not associated with hyponatremia
even with increased water intake: a prospective study in thyroid cancer
patients. BMC Endocr Disord 2013;13: DOI: 10.1186/1472-6823-13-27.
. Lee JE, Kim SK, Han KH, et al. Risk factors for developing hyponatremia
in thyroid cancer
patients undergoing radioactive iodine therapy
. PLoS ONE 2014;9:e106840.
. Luster M, Clarke SE, Dietlein M, et al. Guidelines for radioiodine therapy of differentiated thyroid cancer
. Eur J Nucl Med Mol Imaging 2008;35:1941–59.
. Yi KH, Park YJ, Koong SS, et al. Revised Korean Thyroid
Association Management Guidelines for Patients with Thyroid
Nodules and Thyroid Cancer
. Int J Thyroidol 2010;3:65–96.
. Baajafer FS, Hammami MM, Mohamed GE. Prevalence and severity of hyponatremia
and hypercreatininemia in short-term uncomplicated hypothyroidism. J Endocrinol Invest 1999;22:35–9.
. Nozu T, Yoshida Y, Ohira M, et al. Severe hyponatremia
in association with I(131) therapy in a patient with metastatic thyroid cancer
. Intern Med 2011;50:2169–74.
. Hanna FW, Scanlon MF. Hyponatraemia, hypothyroidism, and role of arginine-vasopressin. Lancet 1997;350:755–6.
. Sisson JC, Freitas J, et al. American Thyroid
Association Taskforce on Radioiodine Safety. Radiation safety in the treatment of patients with thyroid
diseases by radioiodine 131I: practice recommendations of the American Thyroid