Efficacy of Low-dose and High-dose Radioactive Iodine Ablation With rhTSH in Korean Patients With Differentiated Thyroid Carcinoma: The First Report in Nonwestern Countries.

OBJECTIVE: The aim of this study was to confirm the equivalent efficacy of recombinant human TSH (rhTSH) and thyroid hormone withdrawal (THW) as used in the preparation for low-dose and high-dose radioactive iodine (RAI) ablation in Korean patients with differentiated thyroid carcinoma. SUBJECTS AND METHODS: This retrospective study was designed to compare the efficacy of rhTSH and THW when used before ablation with low-dose (30 mCi) and high-dose (100 mCi) RAI, respectively. The study group included 570 patients with DTC with tumors staged T1 to T3, N0 to N1, and M0. Before RAI ablation, 190 patients used rhTSH and 380 patients matched by age, sex, T-stage, and N-stage used THW. The success of ablation was evaluated in each group based on 4 criteria: (1) stimulated thyroglobulin (sTg) <2 ng/mL, (2) sTg<2 ng/mL and negative diagnostic whole-body scan (DxWBS), (3) sTg<1 ng/mL, and (4) sTg<1 ng/mL and negative DxWBS. RESULTS: When both sTg<2 ng/mL and negative DxWBS were selected as criteria for success in patients treated with low-dose RAI, the success rates were 80.5% and 77.0% with rhTSH and THW, respectively (95% confidence interval, 5.9-12.8). Using both sTg<1 ng/mL and negative DxWBS as criteria, success rates were 78.2% and 71.8% with rhTSH and THW, respectively (95% confidence interval, 3.6-16.2). Using any criteria for success, low-dose RAI ablation with rhTSH was as effective as THW. Similar results were found for high-dose RAI ablation in patients using either rhTSH or THW. CONCLUSIONS: Low-dose and high-dose RAI ablation were equally effective using either rhTSH or THW before ablation in Korean patients with DTC, respectively.

Iodine status in healthy pregnant women in Korea: a first report.

PURPOSE: Proper iodine intake is important during pregnancy for both fetal neurodevelopment and maternal thyroid function. Korea is known as a high iodine intake area. However, there are no data regarding iodine status in pregnant Korean women. Therefore, we evaluated the iodine status of pregnant women in Korea by measuring urine iodine concentration. METHODS: This study had an observational, prospective design. We enrolled 344 healthy pregnant women who visited Samsung Medical Center in Korea for a routine antenatal checkup between April 2012 and September 2013. We measured iodine and creatinine concentration (Cr) in spot urine samples and TSH level in serum at the time of enrollment. RESULTS: The median urinary iodine concentration (UIC) and UIC adjusted by Cr were 427.3 µg/L and 447.9 µg/gCr, respectively. There was no difference in median UIC according to trimester of pregnancy (P value = 0.953). Serum TSH level was not different according to UIC level when subjects were grouped according to WHO iodine recommendations (P value = 0.401). CONCLUSIONS: The median UIC of healthy pregnant women in Korea was 427.3 µg/L and 447.9 µg/gCr, which are more than adequate according to WHO criteria. Considering the wide range of UIC, we recommend active education about adequate iodine intake during pregnancy in areas where iodine intake is more than adequate according to WHO criteria.

A Modest Protective Effect of Thyrotropin against Bone Loss Is Associated with Plasma Triiodothyronine Levels.

BACKGROUND: The independent skeletal effect of thyrotropin (thyroid stimulating hormone, TSH) has been suggested in animal studies. However, clinical data on the association between bone loss and variations in TSH levels is inconsistent. This study aimed to investigate the relationship between TSH levels and bone mineral density (BMD). METHODS: We conducted a cross-sectional study with 37,431 subjects (33,052 cases with euthyroidism and 4,379 cases with subclinical thyroid dysfunction) aged over 35 years. We performed thyroid function tests and measured BMD at the lumbar spine, femur neck, and total hip. RESULTS: Levels of TSH and T3 were positively correlated in women (r = 0.076, P = 0.001) and uncorrelated in men. In both men and women, TSH levels correlated positively and T3 levels correlated negatively with BMD at all skeletal sites in age and body mass index adjusted analyses. BMD increased steadily with TSH levels from the subclinical hyperthyroid to subclinical hypothyroid range in subjects with T3 levels in the highest tertile (119.5-200.0 ng/dL), but was no longer significant in subjects with lower plasma T3 levels. CONCLUSIONS: The variations in TSH levels within the euthyroid and subclinical range were positively correlated with BMD in healthy men and women. The negative effect of T3 on BMD appears to be compensated for by increased TSH in subjects with plasma T3 levels in the upper normal range.

Characteristics of Korean Patients with Antithyroid Drug-Induced Agranulocytosis: A Multicenter Study in Korea.

BACKGROUND: Antithyroid drugs (ATDs) can lead to the development of agranulocytosis, which is the most serious adverse effect. Characteristics of ATD-induced agranulocytosis (AIA) have seldom been reported due to the rarity. In this study, we characterized the clinical features for AIA in Korean patients. METHODS: We retrospectively reviewed data from patients with AIA diagnosed between 1997 and 2014 at four tertiary hospitals. Agranulocytosis was defined as an absolute neutrophil count (ANC) below 500/mm³. RESULTS: The mean age of the patients (11 males, 43 females) was 38.2±14.9 years. Forty-eight patients (88.9%) with AIA had fever and sore throat on initial presentation, 20.4% of patients developed AIA during the second course of treatment, and 75.9% of patients suffered AIA within 3 months after initiation of ATD. The patients taking methimazole (n=39) showed lower levels of ANC and more frequent use of granulocyte-macrophage colony-stimulating factor than propylthiouracil (n=15) users. The median duration of agranulocytosis was 5.5 days (range, 1 to 20). No differences were observed between the long (≥6 days) and short recovery time (≤5 days) groups in terms of age, gender, ATDs, duration of ATDs, or initial ANC levels. Four patients (7.4%) who were taking ATDs for less than 2 months died of sepsis on the first or second day of hospitalization. CONCLUSION: The majority of AIA incidents occur in the early treatment period. Considering the high fatality rate of AIA, an early aggressive therapeutic approach is critical and patients should be well informed regarding the warning symptoms of the disease.

Weight Changes in Patients with Differentiated Thyroid Carcinoma during Postoperative Long-Term Follow-up under Thyroid Stimulating Hormone Suppression.

BACKGROUND: There are limited data about whether patients who receive initial treatment for differentiated thyroid cancer (DTC) gain or lose weight during long-term follow-up under thyroid stimulating hormone (TSH) suppression. This study was aimed to evaluate whether DTC patients under TSH suppression experience long-term weight gain after initial treatment. We also examined the impact of the radioactive iodine ablation therapy (RAIT) preparation method on changes of weight, comparing thyroid hormone withdrawal (THW) and recombinant human TSH (rhTSH). METHODS: We retrospectively reviewed 700 DTC patients who underwent a total thyroidectomy followed by either RAIT and levothyroxine (T4) replacement or T4 replacement alone. The control group included 350 age-matched patients with benign thyroid nodules followed during same period. Anthropometric data were measured at baseline, 1 to 2 years, and 3 to 4 years after thyroidectomy. Comparisons were made between weight and body mass index (BMI) at baseline and follow-up. RESULTS: Significant gains in weight and BMI were observed 3 to 4 years after initial treatment for female DTC but not in male patients. These gains among female DTC patients were also significant compared to age-matched control. Women in the THW group gained a significant amount of weight and BMI compared to baseline, while there was no increase in weight or BMI in the rhTSH group. There were no changes in weight and BMI in men according to RAIT preparation methods. CONCLUSION: Female DTC patients showed significant gains in weight and BMI during long-term follow-up after initial treatment. These changes were seen only in patients who underwent THW for RAIT.

Excessive iodine intake does not increase the recurrence rate of graves' disease after withdrawal of the antithyroid drug in an iodine-replete area.

BACKGROUND AND OBJECTIVES: The relationship between iodine intake and effects of antithyroid drugs (ATD) for Graves' disease, especially in iodine-deficient areas, has been demonstrated in many studies. However, it was not clear how chronic high iodine intake influenced the effectiveness of ATD in an iodine-replete area. This study aimed to clarify the effect of iodine intake on clinical outcomes of Graves' disease after discontinuation of ATD in Korea, an iodine-replete area. METHODS: A total of 142 patients with Graves' disease who visited the outpatient clinic regularly and stopped their ATD between October 2011 and April 2013 were enrolled in our study. Urinary iodine concentration (UIC) was measured just before and after the discontinuation of ATD. RESULTS: Median UIC was not significantly different between the remission and relapse groups, as well as among the four treatment groups (group 1, remission after initial treatment; group 2, remission after repeated treatment; group 3, early relapse within a year; group 4, late relapse after a year). Remission rates did not show a significant difference between the excessive iodine intake (UIC ≥300 µg/l) and average iodine intake groups (UIC <300 µg/l). CONCLUSIONS: The present study suggests that excessive iodine intake does not have an effect on the clinical outcomes of Graves' disease in an iodine-replete area, and therefore diet control with iodine restriction might not be necessary in the management of Graves' disease.

Trends in Thyroid Cancer Incidence in Korean Children (1999-2012) Based on Palpation and Nonpalpation Detection Methods.

BACKGROUND: The incidence of childhood thyroid cancer is increasing in several populations; however, contributing factors have not been adequately discussed. OBJECTIVES: Our aim was to identify trends of childhood thyroid cancer based on the Korea Central Cancer Registry (KCCR) database and to elucidate changes in detection methods of cancers using a single-center database. METHODS: Data from the KCCR and Statistics Korea between 1999 and 2012 were used to calculate the crude incidence of thyroid cancer in children. To analyze detection methods for cancers, pediatric patients (aged 0-19 years, n = 126) who underwent thyroid surgery for thyroid cancers at our institution were identified. Subjects were divided into two groups by detection method: (1) palpation group and (2) screening group. RESULTS: The crude incidence of childhood thyroid cancer increased from 0.5 per 100,000 in 1999 to 1.7 in 2012. The proportion of thyroid cancer among total cancers also increased from 4.4% in 1999 to 10.6% in 2012. Among 126 children from our institution, 91 cases (72%) were identified as palpable neck masses, and the remainder were discovered during imaging studies. The numbers in both groups gradually increased during the study period. CONCLUSIONS: The incidence of childhood thyroid cancer has steadily increased in Korea. Regarding the detection methods of cancers, most tumors are detected by palpation rather than screening, although the rate of masses identified during screening has increased.

Clinical characteristics, management, and outcome of 22 cases of primary hypophysitis.

BACKGROUND: Primary hypophysitis causes varying degrees of endocrine dysfunction and mass effect. The natural course and best treatment have not been well established. METHODS: Medical records of 22 patients who had been diagnosed with primary hypophysitis between January 2001 and March 2013 were retrospectively reviewed. Based on the anatomical location, we classified the cases as adenohypophysitis (AH), infundibuloneurohypophysitis (INH), and panhypophysitis (PH). Clinical presentation, endocrine function, pathologic findings, magnetic resonance imaging findings, and treatment courses were reviewed. RESULTS: Among 22 patients with primary hypophysitis, 81.8% (18/22) had involvement of the posterior pituitary lobe. Two patients of the AH (2/3, 66.6%) and three patients of the PH (3/10, 30%) groups initially underwent surgical mass reduction. Five patients, including three of the PH (3/10, 33.3%) group and one from each of the AH (1/3, 33.3%) and INH (1/9, 11.1%) groups, initially received high-dose glucocorticoid treatment. Nearly all of the patients treated with surgery or high-dose steroid treatment (9/11, 82%) required continuous hormone replacement during the follow-up period. Twelve patients received no treatment for mass reduction due to the absence of acute symptoms and signs related to a compressive mass effect. Most of them (11/12, 92%) did not show disease progression, and three patients recovered partially from hormone deficiency. CONCLUSION: Deficits of the posterior pituitary were the most common features in our cases of primary hypophysitis. Pituitary endocrine defects responded less favorably to glucocorticoid treatment and surgery. In the absence of symptoms related to mass effect and with the mild defect of endocrine function, it may not require treatment to reduce mass except hormone replacement.

High Dietary Sodium Intake Assessed by 24-hour Urine Specimen Increase Urinary Calcium Excretion and Bone Resorption Marker.

BACKGROUND: The average dietary sodium intake of Koreans is 2.6 times higher than the World Health Organization's recommended amount. The effect of a diet high in sodium on the skeletal system, especially osteoporosis, has not previously been examined in Korean postmenopausal women with low bone mass. We assessed the daily sodium intake, and determined the impact of sodium intake on urinary calcium excretion and bone resorption marker. METHODS: A retrospective review of medical records was performed for 86 postmenopausal subjects who were initially diagnosed with osteopenia or osteoporosis at the health promotion center. They were subsequently referred to the Division of Endocrinology and Metabolism between 2010 and 2013. All subjects completed a modified food frequency questionnaire. Twenty-four hour urine collection for sodium, calcium and creatinine excretion, and serum C-terminal telopeptides of type I collagen (CTX-I) were also obtained. RESULTS: The average amount of daily sodium and calcium intake were 3,466 mg and 813 mg, respectively. Average dietary sodium intake and 24-hour urinary sodium excretion showed significant positive linear correlation (r=0.29, P=0.006). There was also a significant positive linear correlation between 24-hour urine sodium and calcium excretion (r=0.42, P<0.001); CTX-I and 24-hour urinary calcium excretion (r=0.29, P=0.007). CONCLUSIONS: Excessive sodium intake assessed by 24-hour urine specimen is associated with high calcium excretion in urine. High calcium excretion is also related to increasing bone resorption marker.

Effect of iodine restriction on thyroid function in subclinical hypothyroid patients in an iodine-replete area: a long period observation in a large-scale cohort.

BACKGROUND: Excessive iodine intake is related to a higher prevalence of hypothyroidism, including subclinical hypothyroidism (SCH), in iodine-replete areas. This study aimed to evaluate the effect of iodine restriction on thyroid function in SCH patients in an iodine-replete area and analyze the relationship between serum thyrotropin (TSH) levels and iodine intake. METHODS: The study consisted of 146 consecutive patients who were diagnosed with SCH at the Samsung Medical Center between 2010 and 2012. Urinary iodine concentration (UIC) was measured in 82 patients. Of these, 20 patients with UIC < 300 µg/L were excluded, and 62 patients with UIC ≥ 300 µg/L were educated about the restriction of iodine-rich foods. Following the first follow-up visit, these patients were divided into two groups based on the UIC level: group A (well-controlled iodine intake, UIC < 300 µg/L, n = 40), and group B (poorly controlled iodine intake, UIC ≥ 300 µg/L, n = 22). The remaining 64 patients did not restrict iodine rich foods (group C). The 82 patients with measured UICs were reevaluated every 3-6 months, and the median follow-up was 13 months (range 3-32 months). Thyroid function and UIC were measured at each visit. The correlation between serum TSH level and UIC was determined for the 82 patients in whom UIC was measured. RESULTS: Following 3-6 months of iodine restriction, the serum TSH levels significantly decreased in group A (from 9.0 mU/L to 4.7 mU/L; p < 0.01). In addition, the serum free thyroxine (T4) levels in group A significantly increased (from 1.11 ± 0.23 ng/dL to 1.18 ± 0.17 ng/dL; p < 0.05). However, there were no significant changes in serum TSH or free T4 levels in groups B and C. Serum TSH levels significantly correlated with UIC (r = 0.33, p < 0.01). CONCLUSION: Iodine restriction may normalize or, at the very least, decrease serum TSH levels in SCH patients, and serum TSH levels are strongly correlated with UIC. Therefore, restriction of iodine intake could be a primary treatment option in SCH patients in an iodine-replete area.

Role of autophagy in the resistance to tumour necrosis factor-related apoptosis-inducing ligand-induced apoptosis in papillary and anaplastic thyroid cancer cells.

Current alternative therapies for refractory thyroid cancer such as kinase inhibitors have limitations including incomplete response and toxicity. Although tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce cancer cell-specific apoptosis, various degrees of TRAIL resistance have been reported for different types of thyroid cancer cells. Here, we investigated if modulation of autophagy could improve sensitivity to TRAIL in papillary and anaplastic thyroid cancer cells. Human papillary thyroid cancer cells (TPC-1 cells) and human anaplastic thyroid cancer cells (FRO cells) were treated with TRAIL after transfection with ATG7 siRNA or control siRNA. Levels of autophagy and apoptosis were confirmed by Western blot of ATG7, LC3, caspase-3 and poly (ADP-ribose) polymerase. Viability index was determined by dimethyl-thiazole-diphenyltetrazolium bromide assay. Fraction of apoptotic cells was determined by flow cytometry. In TPC-1 cells, treatment with TRAIL increased the levels of autophagy. A low concentration (20 ng/ml) of TRAIL resulted in significantly decreased viability index and increased apoptosis. However, inhibition of autophagy with ATG7 siRNA desensitised the cells to TRAIL-induced apoptosis. In FRO cells, TRAIL did not increase the levels of autophagy. In contrast to TPC-1 cells, inhibition of autophagy with ATG7 siRNA sensitised FRO cells to TRAIL-induced apoptosis. Autophagy might contribute to the known sensitivity of papillary thyroid cancer cells to TRAIL-induced apoptosis. Inhibition of autophagy in anaplastic thyroid cancer cells could sensitise these cells to TRAIL-induced apoptosis.

The impact of iodinated contrast agent administered during preoperative computed tomography scan on body iodine pool in patients with differentiated thyroid cancer preparing for radioactive iodine treatment.

BACKGROUND: Iodine in iodinated contrast agents (ICAs) interferes with radioactive iodine treatment (RAIT) and diagnostic scans in patients with differentiated thyroid carcinoma (DTC) because it can compete with ¹³¹I. Published guidelines recommend delaying RAIT for three to four months in patients who have been exposed to ICA. Spot urinary iodine concentration is a useful marker to reflect the body iodine pool. We investigated the impact of ICAs administered at preoperative computed tomography (CT) scan on the body iodine pool to determine the proper time interval between preoperative CT and RAIT in DTC patients. METHODS: We performed a retrospective review of 1023 patients with DTC who underwent a preoperative CT scan with ICA, total thyroidectomy, and one week of low-iodine diet in preparation for RAIT. Urine iodine excretion (UIE) was measured in spot urine by inductively coupled plasma mass spectrometry and reported both in simple concentration (µg/L) and divided by gram creatinine (µg/gCr). Patients were divided into five groups by time interval in days between preoperative CT scan and spot urine iodine measurement (A, 31-60 [n=29]; B, 61-90 [n=155]; C, 91-120 [n=546]; D, 121-150 [n=226]; E, 151-180 [n=67]). RESULTS: The median (interquartile range) of UIE (µg/gCr) in each group was 44.4 (27.7-73.2) in group A, 33.3 (22.8-64.7) in group B, 32.7 (20.8-63.0) in group C, 32.0 (20.6-67.0) in group D, and 30.4 (19.6-70.8) in group E. There was no significant difference between group A and the remaining groups (p>0.05) Also, the proportion of patients who achieved the appropriate UIE for RAIT according to our hospital's cutoff (≤66.2 µg/gCr) was not different between groups (A, 72.4%; B, 76.1%; C, 77.5%; D, 74.8%; E, 74.6%) (p=0.78). CONCLUSION: This study shows that a UIE of one month after preoperative CT scan with ICA was not higher than that of six months after CT scan in patients who underwent total thyroidectomy for DTC. Thus, current guidelines that recommend delay of RAIT for three to four months after CT scan with ICA should be revisited and future studies to clarify the appropriate time interval between CT scan with ICA and RAIT are warranted.

Postinfectious Guillain-Barre syndrome in a patient with methimazole-induced agranulocytosis.

Both Graves disease and Guillain-Barre syndrome (GBS) are autoimmune disorders caused by impaired self-tolerance mechanisms and triggered by interactions between genetic and environmental factors. GBS in patients who suffer from other autoimmune diseases is rarely reported, and the development of postinfectious GBS in a patient with Graves disease has not been previously reported in the literature. Herein, we report a patient with Graves disease who developed postinfectious GBS during a course of methimazole-induced agranulocytosis.

Clinical characteristics and follow-up of Korean patients with adrenal incidentalomas.

BACKGROUND/AIMS: We investigated the clinical characteristics and follow-up findings of subjects with adrenal incidentalomas in a single, tertiary-care hospital in South Korea. METHODS: The study consisted of a retrospective analysis of 282 adrenal incidentaloma patients who underwent radiographic and endocrinological evaluations at Samsung Medical Center in Seoul, South Korea, between January 2004 and July 2011. RESULTS: Most (86.2%) of the subjects were found to have nonfunctioning tumors. Functioning tumors were seen in 39 patients (13.8%). Among them, 28 (9.9%) had subclinical Cushing syndrome (SCS), six (2.1%) had pheochromocytoma, and five (1.8%) had primary hyperaldosteronism. Malignant adrenal tumors were discovered in three cases: two (0.7%) were primary adrenal cancers, and one (0.4%) was a secondary metastasis from a lung cancer. Significant risk factors for functional tumors were female gender (odds ratio [OR], 3.386; 95% confidence interval [CI], 1.611 to 7.117; p = 0.0013) and a noncontrast attenuation value of > 10 Hounsfield units (OR, 2.806; 95% CI, 1.231 to 6.397; p = 0.0141). During follow-up (mean, 22.5 months) of 72 of the patients, three (4.2%) developed hormonal changes due to functional tumors. One was confirmed as pheochromocytoma by histopathology, and the others were diagnosed with SCS and followed routinely without surgical intervention. No malignant transformation was found in these patients. CONCLUSIONS: Based on these findings, initial hormonal and radiographic evaluations for adrenal incidentalomas appear to be more important than follow-up tests because functional or malignant changes are rare.

A case of acute pulmonary embolism associated with dysplasminogenemia.

The incidence of pulmonary embolism (PE) rises markedly with age, and only a few cases have been reported in younger adults. Thrombophilia has been reported as one of the predisposing factors for PE in younger adults. Here we report an extraordinary case of PE complicated with dysplasminogenemia, a rare genetic disorder resulting in hypercoagulability, in a young male. An 18-yr-old male visited an emergency room in the United States complaining chest discomfort. He was diagnosed as PE with deep vein thrombosis without apparent risk factors. Anticoagulation therapy with warfarin had been initiated and discontinued after 6 months of treatment. After returning to Korea he was tested for thrombophilia which revealed decreased activity of plasminogen and subsequent analysis of PLG gene showed heterozygous Ala620Thr mutation. He was diagnosed with PE complicated with dysplasminogenemia. Life-long anticoagulation therapy was initiated. He is currently under follow-up without clinical events for 2 yr.

Colchicine-induced myoneuropathy in a cyclosporine-treated renal transplant recipient.

Colchicine is a relatively safe medication that is widely used for both prevention and treatment of gout attack. However, serious adverse events, including myoneuropathy and multiorgan failure, have been reported. We report a case of colchicine-induced myoneuropathy in a female kidney transplant recipient who had been taking cyclosporine. She developed gastrointestinal discomfort and paresthesia 5 days after the initiation of colchicine. She showed signs of myoneuropathy, and hepatic and renal injury. Colchicine toxicity was suspected, and colchicine was discontinued. Her symptoms and laboratory findings improved gradually. Literature was reviewed for previous reports of colchicine-induced myoneuropathy in solid organ transplant recipients.

Steroid responsive xanthomatous hypophysitis associated with autoimmune thyroiditis: a case report.

We report the case of a 36-year-old woman who presented with headache, fever, and amenorrhea. Laboratory analysis revealed hypopituitarism and autoimmune thyroiditis, while a cerebrospinal fluid study suggested concurrent aseptic meningitis. A magnetic resonance image (MRI) scan revealed a 1.0×0.9 cm cystic mass enlarging the sella turcica. Surgical resection via an endoscopic transsphenoidal route was performed. The histological finding of the excised tissue revealed foamy histiocytes with vacuolated cytoplasm, supporting the diagnosis of xanthomatous hypophysitis. Although a residual soft lesion was observed on the MRI image postoperatively, the patient's headache and fever improved. Ten months after surgery, the patient complained of visual impairment and headache, and the residual mass had enlarged into the suprasellar area. High dose (500 mg intravenous) methylprednisolone was administered for 3 days. During the methylprednisolone pulse therapy, the patient's visual acuity and headache improved. A follow-up MRI taken after methylprednisolone therapy showed a marked mass reduction. Our case supports an autoimmune pathophysiology for xanthomatous hypophysitis and suggests that high dose glucocorticoid therapy as a treatment option.