Authors: Hye-Seon Oh (Korea), Won Gu Kim (Korea), Won Bae Kim (Korea), Jin-Sook Ryu (Korea), Min Ji Jeon (Korea), Tae Yong Kim (Korea)
Categories: Original Article, Thyroid hormone withdrawal, Radioactive iodine treatment, Patient education, Treatment Cancellation
Source: Endocrinology and Metabolism
Authors: Hye-Seon Oh, Won Gu Kim, Won Bae Kim, Jin-Sook Ryu, Min Ji Jeon, Tae Yong Kim
Radioactive iodine treatment (RAIT) is an essential therapy for differentiated thyroid cancer. However, unforeseen complications arising during thyroid hormone withdrawal (THW) can lead to Cancellation of the scheduled treatment. This study aimed to identify cases in which THW-RAIT was discontinued due to THW-related complications and to explore potentially preventable causes to improve patient management.
Among 4,174 patients who underwent THW-RAIT between 2012 and 2024, 39 did not complete the planned treatment. After excluding Cancellations unrelated to THW, 11 (0.26%) patients with unexpected THW-related medical issues were analyzed.
The median age of the included patients was 61 years (range, 23 to 70), and 10 were male. The reasons for THW-RAIT Cancellation were hyponatremia (n=1), abnormal liver function (n=1), renal dysfunction (n=3), and combined liver and renal dysfunction (n=6). The patient with hyponatremia was taking a thiazide diuretic. Most cases of liver dysfunction were associated with prior use of herbal medications, whereas renal dysfunction was linked to diuretic or nonsteroidal anti-inflammatory drug use, pre-existing conditions such as single kidney or diabetic nephropathy, or inadequate oral intake during low-iodine preparation. Two cases of concurrent liver and renal dysfunction were attributed to rhabdomyolysis following intense exercise or heavy physical labor.
Enhanced patient education, comprehensive pre-treatment assessment, and careful avoidance of high-risk medications are essential to prevent THW-related complications and minimize disruptions in RAIT.
Radioactive iodine treatment (RAIT) is one of the essential treatment for differentiated thyroid cancer [1–3]. Adequate stimulation of thyroid tissue is mandatory before RAIT and can be achieved through thyroid hormone withdrawal (THW) and administration of recombinant human thyroid-stimulating hormone (rhTSH) [2,3]. Previous studies have demonstrated that rhTSH-assisted RAIT provides comparable ablation efficacy with improved patient quality of life, and is widely used in many countries [4–6]. However, traditional THW remains the preferred method for RAIT in certain settings, due to disease status, cost considerations, and limited accessibility to rhTSH [7,8].
Preparation for RAIT with THW typically requires discontinuation of levothyroxine for 4 to 5 weeks, during which patients may develop hypothyroidism. This can range from mild symptomatic changes such as fatigue, depression, sleep disturbance, or constipation to more severe cardiometabolic disturbances, including dyslipidemia, electrolyte imbalance, renal impairment, and hepatic dysfunction [7,9–12]. In some cases, serious THW-related complications may necessitate the postponement or discontinuation of the scheduled RAIT [10,12–14].
Successful RAIT also depends on appropriate pre-treatment preparation [7,15], including adherence to a low-iodine diet for several weeks and avoidance of iodine-containing medications, supplements, or contrast agents. Pregnancy and breastfeeding must also be excluded prior to treatment [15,16]. However, current guidelines provide limited practical recommendations on other aspects of pre-treatment management, such as the use of herbal medications, intensity of physical activity, or recent dental procedures [15,17].
In this retrospective study, we investigated cases in which scheduled RAIT was discontinued due to THW-related complications. We further aimed to identify potentially preventable factors to enhance patient safety and improve pre-treatment management strategies.
In this retrospective study, 4,174 patients who underwent THW-RAIT between 2012 and 2024 at Asan Medical Center, Seoul, Republic of Korea, were reviewed. Among them, 39 (0.93%) patients did not complete the planned treatment. After excluding cases in which treatment was canceled for reasons unrelated to THW, 11 (0.26%) patients were ultimately included in the analysis (Fig. 1). Clinical presentations, medical histories, and laboratory findings were reviewed. Tumor staging was determined according to the eighth edition of the American Joint Committee on Cancer/Union for International Cancer Control tumor–node–metastasis classification system [18]. Categorical variables are presented as frequencies and percentages, and patient age is reported as medians with ranges. This study was approved by the Institutional Review Board of Asan Medical Center (N0. 2025–0123), and the requirement for written informed consent was waived due to the retrospective nature of the study.
All patients scheduled for RAIT underwent laboratory testing on the day of hospital admission, and the decision to proceed with treatment was based on these results. Patients’ blood test results before THW and after re-administration are listed in Supplemental Table S1. Laboratory values are reported using the International System of Units. The reference ranges were as creatinine (Cr) 61.89–123.79 μmol/L; aspartate transaminase (AST) ≤40 IU/L; alanine aminotransferase (ALT) ≤40 IU/L; sodium (Na) 135–145 mmol/L; potassium (K) 3.5–5.1 mmol/L; chloride (Cl) 98–110 mmol/L; creatine kinase (CK) 50–250 IU/L; and myoglobin ≤110 ng/mL. The estimated glomerular filtration rate (eGFR) was calculated using the Modification of Diet in Renal Disease equation, with values >60 mL/min/1.73 m^2^ considered within the normal range.
Treatment preparation and administration of I-131 therapeutic doses were decided according to the protocol of Asan Medical Center [19]. In general, treatment was contraindicated in patients with severe renal impairment (eGFR <30 mL/min/1.73 m^2^) or those on dialysis, unless the potential benefits outweighed the risks. RAIT was also relatively contraindicated in patients with Grade ≥2 hepatic dysfunction, voiding dysfunction, indwelling catheters (Foley or feeding tubes), colostomy, cognitive or psychiatric disorders, or significantly reduced mobility. Patients scheduled for THW-RAIT received structured education before treatment, including the following
(1) Discontinue levothyroxine 4 weeks before RAIT and initiate liothyronine three times daily.
(2) Discontinue liothyronine 2 weeks before treatment. During this period, patients may experience hypothyroidism-related symptoms such as fatigue, edema, weight gain, dyspepsia, or constipation. The use of digestive or laxative medications is permitted if required.
(3) Begin a low-iodine diet 2 weeks before treatment.
(4) Verify all daily medications for iodine content. Only iodine-free medications may be continued.
(5) Continue necessary medications for diabetes, hypertension, or calcium supplementation.
(6) Discontinue health supplements or multivitamins 2 months prior to treatment.
(7) Avoid any radiological examination within 2 months prior to treatment.
(8) Women of childbearing potential should use contraception before treatment. A urine pregnancy test is performed on the treatment day to confirm non-pregnant status.
Clinical characteristics of the 11 patients are summarized in Table 1. The median patient age was 61 years (range, 23 to 70), and 10 patients were male. The primary reasons for unexpected THW-RAIT Cancellation were hyponatremia (n=1), hepatic dysfunction (n=1), renal dysfunction (n=3), concurrent hepatic and renal dysfunction (n=4), and rhabdomyolysis (n=2) (Fig. 1).
A 63-year-old woman (patient 1) was admitted for a scheduled 5.5 GBq THW-RAIT. Her medical history included diabetes and hypertension, managed with sitagliptin, atorvastatin, ticlopidine, losartan, thiazide, and aspirin. The treatment was canceled due to severe hyponatremia (Na 120 mmol/L). Her electrolyte levels normalized within 3 days after resuming thyroid hormone replacement.
A 55-year-old man (patient 2) was admitted for planned 2.96 GBq THW-RAIT. The treatment was canceled due to markedly elevated liver enzymes (AST 286 IU/L, ALT 513 IU/L). His medications included metformin, valsartan, amlodipine, and atorvastatin for underlying diabetes and hypertension. Detailed history revealed that he had been consuming meat soup containing Kalopanax and Astragalus for 2 months to enhance stamina before treatment. Liver enzyme levels normalized after discontinuation of the herbal medication.
Three patients (patients 3–5) were unable to undergo THW-RAIT due to renal dysfunction identified on the day of admission. A 23-year-old man (patient 3) was scheduled for 5.55 GBq THW-RAIT but the treatment was canceled because of impaired renal function (Cr 180.34 μmol/L, eGFR 41 mL/min/1.73 m^2^). He had undergone left nephrectomy 1 year earlier for germ cell tumor invasion and was taking nonsteroidal anti-inflammatory drugs (NSAIDs) for pain control. Renal function normalized after resuming thyroid hormone replacement.
A 38-year-old man (patient 4) was admitted for 2.96 GBq THW-RAIT, but treatment was canceled due to renal dysfunction (Cr 258.13 μmol/L, eGFR 31 mL/min/1.73 m^2^). He had been dehydrated after several days of poor oral intake caused by laryngitis during the THW period and was taking thiazide diuretics for hypertension. His renal function improved after hydration therapy.
A 69-year-old man (patient 5) was admitted for 7.4 GBq THW-RAIT for lung metastasis from papillary thyroid carcinoma. Laboratory results revealed renal impairment (Cr 169.73 μmol/L, eGFR 35 mL/min/1.73 m^2^). He had been diagnosed with Birt–Hogg–Dubé syndrome involving the lungs 10 years earlier, and his renal function had been normal before THW (Cr 92.84 μmol/L). Despite thyroid hormone replacement, renal dysfunction persisted.
Four patients (patients 6–9) were unable to undergo THW-RAIT due to the development of concurrent hepatic and renal dysfunction. A 54-year-old man (patient 6) presented with elevated liver enzyme levels (AST 357 IU/L, ALT 392 IU/L) and impaired renal function (Cr 124.64 μmol/L, eGFR 52 mL/min/1.73 m^2^) upon admission for 5.55 GBq THW-RAIT. His medications included amlodipine, bisoprolol, thiazide, alfuzosin, tadalafil, and rosuvastatin. A detailed history revealed that he had been consuming dandelion root with every meal. His hepatic and renal functions normalized after discontinuing the herbal intake and resuming thyroid hormone replacement. He elected not to undergo further RAIT.
A 65-year-old man (patient 7) was scheduled for 5.55 GBq THW-RAIT, which was canceled due to hepatic (AST 195 IU/L, ALT 328 IU/L) and renal (Cr 152.93 μmol/L, eGFR 40 mL/min/1.73 m^2^) dysfunction. He had diabetes, hypertension, and a history of renal stones, and was taking metformin, vildagliptin, losartan, thiazide, sarpogrelate, and simvastatin. Retrospective review of prior computed tomography scans revealed bilateral renal atrophy. Both hepatic and renal functions improved after restarting thyroid hormone replacement therapy.
A 61-year-old man (patient 8) scheduled for 5.55 GBq THW-RAIT had his treatment canceled due to elevated AST (444 IU/L), ALT (540 IU/L), and Cr (126.41 μmol/L; eGFR 50 mL/min/1.73 m^2^) levels. His medications included amlodipine, olmesartan, thiazide, glipizide, metformin, empagliflozin, insulin glargine, and atorvastatin. He denied taking any herbal supplements, and atorvastatin was suspected as the likely cause. Liver function normalized after discontinuing atorvastatin.
A 67-year-old man (patient 9) with papillary thyroid carcinoma and lung metastases was admitted for 7.4 GBq THW-RAIT. On admission, his heart rate was 150/min, and electrocardiography revealed new-onset atrial flutter. Laboratory tests showed impaired renal function (Cr 184.76 μmol/L, eGFR 32 mL/min/1.73 m^2^) and mildly elevated liver enzyme levels (AST 58 IU/L, ALT 75 IU/L). He had hypertension and was taking amlodipine. Poor oral intake and general weakness during the THW period were presumed to have contributed to the arrhythmia and renal dysfunction. Despite resuming thyroid hormone replacement therapy, azotemia persisted (Cr 123.76 μmol/L, eGFR 45 mL/min/1.73 m^2^). Due to his condition, he declined further RAIT.
Two male patients were unable to undergo THW-RAIT due to rhabdomyolysis. A 70-year-old man (patient 10) (Fig. 2A, B) was admitted for 7.4 GBq RAIT for metastatic follicular thyroid carcinoma. Laboratory tests revealed concurrent renal (Cr 260.78 μmol/L, eGFR 21 mL/min/1.73 m^2^) and hepatic dysfunction (AST 289 IU/L, ALT 84 IU/L), accompanied by hyperkalemia (6.6 mmol/L). RAIT was canceled, and thyroid hormone replacement with intravenous fluid therapy was initiated. His renal function and hyperkalemia improved; however, liver enzyme levels worsened (AST 534 IU/L, ALT 173 IU/L), showing AST-predominant elevation. Detailed history taking revealed that he had engaged in strenuous exercise prior to admission and was taking a statin. Serum myoglobin (8,697 ng/mL) and CK (16,940 IU/L) were markedly elevated, confirming rhabdomyolysis. Both hepatic and renal functions improved following appropriate management.
A 50-year-old man (patient 11) (Fig. 2C, D) was scheduled for 5.55 GBq THW-RAIT but the procedure was canceled due to rhabdomyolysis. Laboratory results showed decreased renal function (Cr 147.63 μmol/L, eGFR 46 mL/min/1.73 m^2^) and AST-dominant liver enzyme elevation (AST 1,557 IU/L, ALT 423 IU/L). Myoglobin (21,419 ng/mL) and CK (120,480 IU/L) levels were elevated. Although he did not engage in excessive exercise, he reported heavy physical labor and was taking a statin. After receiving treatment for rhabdomyolysis, both renal and hepatic functions improved.
To our knowledge, this is the first case series to investigate the causes of treatment discontinuation during THW-RAIT and to identify potentially preventable factors. Among the 11 patients, one developed hyponatremia, one hepatic dysfunction alone, three renal dysfunction alone, four combined hepatic and renal dysfunction, and two rhabdomyolysis. All patients except for two, who decided not to proceed further RAIT (patient 7 and 9), completed rhTSH-assisted RAIT after recovery. Several of these cases could have been prevented through enhanced patient education, comprehensive pre-treatment evaluation, and careful avoidance of high-risk medications.
Hyponatremia is a recognized complication in hypothyroid patients following THW for RAIT preparation [14,20]. Usually it is mild, but rare severe and life-threatening cases have been reported [14,20]. Advanced age (≥60 years) and the use of thiazide diuretics are well-established risk factors for hyponatremia during the THW period, both of which may have contributed to the severe hyponatremia observed in our case [14]. Therefore, substituting thiazide diuretics with alternative antihypertensive agents in elderly patients should be considered to reduce this risk during THW-RAIT preparation.
Hypothyroidism during THW may also induce mild hepatic dysfunction [10,21,22]. In our series, five patients exhibited elevated liver enzyme levels during THW, with four showing grade ≥2 elevation that necessitated the Cancellation of RAIT [23]. The concurrent use of herbal medications exacerbated hepatic injury in several patients, while statins were implicated in one case. Providing clearer pre-treatment instructions, particularly regarding the avoidance of herbal remedies and hepatotoxic drugs, could help prevent unnecessary treatment interruptions.
A transient decline in renal function is also well documented during hypothyroidism and typically normalizes with thyroid hormone replacement [11,22]. This reduction in glomerular filtration rate is thought to result from both direct and indirect hemodynamic effects of hypothyroidism [24]. Renal dysfunction was observed in seven patients in our cohort, five of whom required treatment Cancellation. Most affected patients had predisposing risk factors such as advancing age, a single kidney, use of NSAIDs, or renal atrophy evident on previous imaging. Three patients were taking diuretics for hypertension, and two had inadequate oral intake during low-iodine preparation. Preventing dehydration through adequate hydration and adjusting medications that may exacerbate renal impairment in high-risk individuals (e.g., elderly patients, those with a solitary kidney, or diabetic nephropathy) may help mitigate renal deterioration prior to RAIT.
Interestingly, two patients canceled RAIT due to rhabdomyolysis, and both were receiving statin therapy for dyslipidemia. Statin-induced rhabdomyolysis is a rare but serious complication, with reported incidences ranging from 0.3 to 13.5 cases per 1,000,000 prescriptions [25]. Several case reports have also described an association between hypothyroidism and rhabdomyolysis [26–28]. Although it remains unclear whether statin use, hypothyroidism, or their combination was the primary trigger in our patients, these findings underscore the importance of advising patients preparing for RAIT to avoid strenuous physical activity during the hypothyroid state to reduce the risk of rhabdomyolysis.
Patients decided to perform THW-RAIT rather than rhTSH-assisted RAIT due to presence of metastatic disease, patients’ preference due to geographical accessibility for consecutive rhTSH injection or insurance coverage issues. The reasons for the limited use of rhTSH in certain patients is rooted in domestric insurance regulations. Following a series of clinical cases and a formal inquiry to the Health Insurance Review and Assessment Service, it has been established that rhTSH may be utilized for doses exceeding 3.7 GBq provided the patient assumes 100% of the cost (self-pay).
During the same period, 2,935 patients underwent rhTSH stimulated RAIT; however, 24 (0.8%) of them were unable to proceed with the scheduled treatment due to personal reasons (e.g., anxiety, coronavirus disease 2019 [COVID-19] infection, failure of low-iodine preparation). And only 0.26% of THW-RAIT patients in our cohort failed to complete the planned reatment due to THW-related complications. Due to this very low incidence, our study was conducted as a case series. Although this is a rare event, it highlights the need for preventative strategies, given the considerable burden placed on patients by prolonged iodine restriction, hypothyroid symptoms, and logistical constraints related to radioisotope disposal. The strength of our study lies in being, to our knowledge, the first to systematically analyze the causes of treatment discontinuation during THW-RAIT and to identify potentially preventable factors.
Based on our findings, patient education should emphasize maintaining adequate hydration and avoiding excessive physical exertion during RAIT preparation. Discontinuation of medications known to impair renal or hepatic function, such as NSAIDs and herbal supplements, should also be considered before treatment. However, given the low incidence of complications and potential benefits of these agents, the decision to discontinue diuretics or statins requires careful, individualized assessment of risks and benefits.
Enhanced patient education, comprehensive pre-treatment evaluation, and avoidance of high-risk medications may prevent some unexpected interruptions in RAIT. Larger and more systematic studies are warranted to develop evidence-based educational and clinical management guidelines for patients undergoing THW-RAIT preparation.