Endocrinology and Metabolism

Original Article

Thyroid Big Data Articles (National Health Insurance Service Database)
Risk of Subsequent Primary Cancers in Thyroid Cancer Survivors according to the Dose of Levothyroxine: A Nationwide Cohort Study: Min-Su Kim, Jang Won Lee, Min Kyung Hyun, Young Shin Song; Endocrinol Metab. 2024;39(2):288-299. Published online March 4, 2024; DOI: https://doi.org/10.3803/EnM.2023.1815

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Abstract PDF Supplementary Material PubReader ePub: Background
Current research has not investigated the effect of thyroid-stimulating hormone suppression therapy with levothyroxine on the risk for developing subsequent primary cancers (SPCs). This study aimed to investigate the association between levothyroxine dosage and the risk for SPCs in thyroid cancer patients.
Methods
We conducted a nationwide population-based retrospective cohort study form Korean National Health Insurance database. This cohort included 342,920 thyroid cancer patients between 2004 and 2018. Patients were divided into the non-levothyroxine and the levothyroxine groups, the latter consisting of four dosage subgroups according to quartiles. Cox proportional hazard models were performed to evaluate the risk for SPCs by adjusting for variables including cumulative doses of radioactive iodine (RAI) therapy.
Results
A total of 17,410 SPC cases were observed over a median 7.3 years of follow-up. The high-dose levothyroxine subgroups (Q3 and Q4) had a higher risk for SPC (adjusted hazard ratio [HR], 1.14 and 1.27; 95% confidence interval [CI], 1.05–1.24 and 1.17– 1.37; respectively) compared to the non-levothyroxine group. In particular, the adjusted HR of stomach (1.31), colorectal (1.60), liver and biliary tract (1.95), and pancreatic (2.48) cancers were increased in the Q4 subgroup. We consistently observed a positive association between high levothyroxine dosage per body weight and risk of SPCs, even after adjusting for various confounding variables. Moreover, similar results were identified in the stratified analyses according to thyroidectomy type and RAI therapy, as well as in a subgroup analysis of patients with good adherence.
Conclusion
High-dose levothyroxine use was associated with increased risk of SPCs among thyroid cancer patients regardless of RAI therapy.

Review Article

Thyroid
Management of Subclinical Hypothyroidism: A Focus on Proven Health Effects in the 2023 Korean Thyroid Association Guidelines: Eu Jeong Ku, Won Sang Yoo, Hyun Kyung Chung; Endocrinol Metab. 2023;38(4):381-391. Published online August 8, 2023; DOI: https://doi.org/10.3803/EnM.2023.1778

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Subclinical hypothyroidism (SCH) is characterized by elevated thyroid-stimulating hormone (TSH) and normal free thyroxine levels. The Korean Thyroid Association recently issued a guideline for managing SCH, which emphasizes Korean-specific TSH diagnostic criteria and highlights the health benefits of levothyroxine (LT4) treatment. A serum TSH level of 6.8 mIU/L is presented as the reference value for diagnosing SCH. SCH can be classified as mild (TSH 6.8 to 10.0 mIU/L) or severe (TSH >10.0 mIU/L), and patients can be categorized as adults (age <70 years) or elderly (age ≥70 years), depending on the health effects of LT4 treatment. An initial increase in serum TSH levels should be reassessed with a subsequent measurement, including a thyroid peroxidase antibody test, preferably 2 to 3 months after the initial assessment. While LT4 treatment is not generally recommended for mild SCH in adults, it is necessary for severe SCH in patients with underlying coronary artery disease or heart failure and it may be considered for those with concurrent dyslipidemia. Conversely, LT4 treatment is generally not recommended for elderly patients, regardless of SCH severity. For those SCH patients who are prescribed LT4 treatment, the dosage should be personalized, and serum TSH levels should be regularly monitored to maintain the optimal LT4 regimen.

Citations

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Clinical Implications of Different Thyroid-Stimulating Hormone (TSH) Reference Intervals between TSH Kits for the Management of Subclinical Hypothyroidism
Won Sang Yoo
Endocrinology and Metabolism.2024; 39(1): 188. CrossRef

Original Articles

Thyroid
Identification of Mutations in the Thyroxine-Binding Globulin (TBG) Gene in Patients with TBG Deficiency in Korea: Jung Heo, Sang-Mi Kim, Hyun Jin Ryu, Hyunju Park, Tae Hyuk Kim, Jae Hoon Chung, Hyung-Doo Park, Sun Wook Kim; Endocrinol Metab. 2022;37(6):870-878. Published online December 7, 2022; DOI: https://doi.org/10.3803/EnM.2022.1591

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Background
Thyroxine-binding globulin (TBG) is a major transporter protein for thyroid hormones. The serpin family A member 7 (SERPINA7) gene codes for TBG, and mutations of the SERPINA7 gene result in TBG deficiency. Although more than 40 mutations have been reported in several countries, only a few studies of TBG deficiency and SERPINA7 gene mutation have been performed in Korea. The aim of this study is to review the clinical presentations and laboratory findings of patients with TBG deficiency and to investigate the types of SERPINA7 gene mutation.
Methods
Five unrelated Korean adults with TBG deficiency attending endocrinology clinic underwent SERPINA7 gene sequencing. Four patients harbored a SERPINA7 gene mutation. Serum thyroid hormones, anti-microsomal antibodies, and TBG were measured. Genomic DNA was extracted from whole blood. All exons and intron-exon boundaries of the TBG gene were amplified and sequencing was performed.
Results
Two patients were heterozygous females, and the other two were hemizygous males. One heterozygous female had coexisting hypothyroidism. The other heterozygous female was erroneously prescribed levothyroxine at a local clinic. One hemizygous male harbored a novel mutation, p.Phe269Cysfs*18, which caused TBG partial deficiency. Three patients had the p.Leu372Phefs*23 mutation, which is known as TBG-complete deficiency Japan (TBG-CDJ) and was also presented in previous mutation analyses in Korea.
Conclusion
This study presents four patients diagnosed with TBG deficiency and provides the results of SERPINA7 gene sequencing. One novel mutation, p.Phe269Cysfs*18, causing TBD-partial deficiency and three cases of TBG-CDJ were demonstrated. It is necessary to identify TBG deficiency to prevent improper treatment. Also, sequencing of the SERPINA7 gene would provide valuable information about the TBG variants in Korea.

Citations

Citations to this article as recorded by

Development and basic performance verification of a rapid homogeneous bioassay for agonistic antibodies against the thyroid-stimulating hormone receptor
Motoki Hoshina, Shiomi Ojima, Atsushi Kawasaki, Kosuke Doi, Satoshi Ohta, Asuka Inoue, Hiroshi Murayama
Journal of Immunological Methods.2024; 528: 113655. CrossRef

Thyroid
A Multicenter, Randomized, Controlled Trial for Assessing the Usefulness of Suppressing Thyroid Stimulating Hormone Target Levels after Thyroid Lobectomy in Low to Intermediate Risk Thyroid Cancer Patients (MASTER): A Study Protocol: Eun Kyung Lee, Yea Eun Kang, Young Joo Park, Bon Seok Koo, Ki-Wook Chung, Eu Jeong Ku, Ho-Ryun Won, Won Sang Yoo, Eonju Jeon, Se Hyun Paek, Yong Sang Lee, Dong Mee Lim, Yong Joon Suh, Ha Kyoung Park, Hyo-Jeong Kim, Bo Hyun Kim, Mijin Kim, Sun Wook Kim, Ka Hee Yi, Sue K. Park, Eun-Jae Jung, June Young Choi, Ja Seong Bae, Joon Hwa Hong, Kee-Hyun Nam, Young Ki Lee, Hyeong Won Yu, Sujeong Go, Young Mi Kang, MASTER study group; Endocrinol Metab. 2021;36(3):574-581. Published online May 26, 2021; DOI: https://doi.org/10.3803/EnM.2020.943

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Background
Postoperative thyroid stimulating hormone (TSH) suppression therapy is recommended for patients with intermediate- and high-risk differentiated thyroid cancer to prevent the recurrence of thyroid cancer. With the recent increase in small thyroid cancer cases, the extent of resection during surgery has generally decreased. Therefore, questions have been raised about the efficacy and long-term side effects of TSH suppression therapy in patients who have undergone a lobectomy.
Methods
This is a multicenter, prospective, randomized, controlled clinical trial in which 2,986 patients with papillary thyroid cancer are randomized into a high-TSH group (intervention) and a low-TSH group (control) after having undergone a lobectomy. The principle of treatment includes a TSH-lowering regimen aimed at TSH levels between 0.3 and 1.99 μIU/mL in the low-TSH group. The high-TSH group targets TSH levels between 2.0 and 7.99 μIU/mL. The dose of levothyroxine will be adjusted at each visit to maintain the target TSH level. The primary outcome is recurrence-free survival, as assessed by neck ultrasound every 6 to 12 months. Secondary endpoints include disease-free survival, overall survival, success rate in reaching the TSH target range, the proportion of patients with major cardiovascular diseases or bone metabolic disease, the quality of life, and medical costs. The follow-up period is 5 years.
Conclusion
The results of this trial will contribute to establishing the optimal indication for TSH suppression therapy in low-risk papillary thyroid cancer patients by evaluating the benefit and harm of lowering TSH levels in terms of recurrence, metabolic complications, costs, and quality of life.

Citations

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Effect of thyroid-stimulating hormone suppression on quality of life in thyroid lobectomy patients: interim analysis of a multicenter, randomized controlled trial in low- to intermediate-risk thyroid cancer patients (MASTER study)
Ja Kyung Lee, Eu Jeong Ku, Su-jin Kim, Woochul Kim, Jae Won Cho, Kyong Yeun Jung, Hyeong Won Yu, Yea Eun Kang, Mijin Kim, Hee Kyung Kim, Junsun Ryu, June Young Choi
Annals of Surgical Treatment and Research.2024; 106(1): 19. CrossRef
Clinical impact of coexistent chronic lymphocytic thyroiditis on central lymph node metastasis in low- to intermediate-risk papillary thyroid carcinoma: The MASTER study
Da Beom Heo, Ho-Ryun Won, Kyung Tae, Yea Eun Kang, Eonju Jeon, Yong Bae Ji, Jae Won Chang, June Young Choi, Hyeong Won Yu, Eu Jeong Ku, Eun Kyung Lee, Mijin Kim, Jun-Ho Choe, Bon Seok Koo
Surgery.2024; 175(4): 1049. CrossRef
Dynamic Changes in Treatment Response af-ter ¹³¹I in Differentiated Thyroid Cancer and Their Relationship with Recurrence Risk Stratification and TNM Staging
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ASO Author Reflections: Active Surveillance may be Possible in Patients with T1b Papillary Thyroid Carcinoma Over 55 Years of Age Without High-Risk Features on Preoperative Examinations
Ho-Ryun Won, Eonju Jeon, Da Beom Heo, Jae Won Chang, Minho Shong, Je Ryong Kim, Hyemi Ko, Yea Eun Kang, Hyon-Seung Yi, Ju Hee Lee, Kyong Hye Joung, Ji Min Kim, Younju Lee, Sung-Woo Kim, Young Ju Jeong, Yong Bae Ji, Kyung Tae, Bon Seok Koo
Annals of Surgical Oncology.2023; 30(4): 2254. CrossRef
Outcomes and Trends of Treatments in High‐Risk Differentiated Thyroid Cancer
Arash Abiri, Khodayar Goshtasbi, Sina J. Torabi, Edward C. Kuan, William B. Armstrong, Tjoson Tjoa, Yarah M. Haidar
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Current Controversies in Low-Risk Differentiated Thyroid Cancer: Reducing Overtreatment in an Era of Overdiagnosis
Timothy M Ullmann, Maria Papaleontiou, Julie Ann Sosa
The Journal of Clinical Endocrinology & Metabolism.2023; 108(2): 271. CrossRef
Age-Dependent Clinicopathological Characteristics of Patients with T1b Papillary Thyroid Carcinoma: Implications for the Possibility of Active Surveillance
Ho-Ryun Won, Eonju Jeon, Da Beom Heo, Jae Won Chang, Minho Shong, Je Ryong Kim, Hyemi Ko, Yea Eun Kang, Hyon-Seung Yi, Ju Hee Lee, Kyong Hye Joung, Ji Min Kim, Younju Lee, Sung-Woo Kim, Young Ju Jeong, Yong Bae Ji, Kyung Tae, Bon Seok Koo
Annals of Surgical Oncology.2023; 30(4): 2246. CrossRef
Potential impact of obesity on the aggressiveness of low- to intermediate-risk papillary thyroid carcinoma: results from a MASTER cohort study
Mijin Kim, Yae Eun Kang, Young Joo Park, Bon Seok Koo, Eu Jeong Ku, June Young Choi, Eun Kyung Lee, Bo Hyun Kim
Endocrine.2023; 82(1): 134. CrossRef
Differentiated thyroid cancer: a focus on post-operative thyroid hormone replacement and thyrotropin suppression therapy
Benjamin J. Gigliotti, Sina Jasim
Endocrine.2023; 83(2): 251. CrossRef
Thyroid stimulating hormone suppression and recurrence after thyroid lobectomy for papillary thyroid carcinoma
Mi Rye Bae, Sung Hoon Nam, Jong-Lyel Roh, Seung-Ho Choi, Soon Yuhl Nam, Sang Yoon Kim
Endocrine.2022; 75(2): 487. CrossRef
The Concept of Economic Evaluation and Its Application in Thyroid Cancer Research
Kyungsik Kim, Mijin Kim, Woojin Lim, Bo Hyun Kim, Sue K. Park
Endocrinology and Metabolism.2021; 36(4): 725. CrossRef

Review Article

Thyroid
Update on Thyroid Hormone Levels and Thyroid Dysfunction in the Korean Population Based on Data from the Korea National Health and Nutrition Examination Survey VI (2013 to 2015): Jae Hoon Chung; Endocrinol Metab. 2020;35(1):7-13. Published online March 19, 2020; DOI: https://doi.org/10.3803/EnM.2020.35.1.7

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In 2017, the first Korean nationwide data on serum thyroid stimulating hormone (TSH) levels, serum free thyroxine (fT₄) levels, and urinary iodine concentration (UIC) were published based on a population of 7,061 Koreans who participated in the Korea National Health and Nutrition Examination Survey VI. The mean TSH level was 2.16 mIU/L, with a reference interval of 0.59 to 7.03 mIU/L (men 2.09 mIU/L, women 2.24 mIU/L, P<0.001). A U-shaped association was found between serum TSH levels and age. The mean fT₄ level was 1.25 ng/dL, and its reference interval was 0.92 to 1.60 ng/dL (men 1.29 ng/dL, women 1.20 ng/dL, P<0.0001). Serum fT₄ levels decreased with age (P for trend <0.0001). Serum thyroid peroxidase antibody (TPOAb) was detected in 7.30% of participants (men 4.33%, women 10.62%). TPOAb titers tended to increase with age, and were higher in women than in men. The median UIC was 294 µg/L, and UIC showed a U-shaped relationship with age. According to the World Health Organization recommendations, only 23% of participants were in the adequate range of iodine intake, while 65% were in the above requirements or excessive, and 12% in insufficient. The prevalence of overt hyperthyroidism and hypothyroidism in Koreans was 0.34% to 0.54% and 0.73% to 1.43%, respectively.

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Eunji Mun, Hye Ah Lee, Jung Eun Choi, Rosie Lee, Kyung Hee Kim, Hyesook Park, Hae Soon Kim
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Xiaoying Meng, Fei Li, Wenpei Wu, Juncang Wu
International Journal of General Medicine.2024; Volume 17: 1263. CrossRef
Hyperthyroidism
Sun Y. Lee, Elizabeth N. Pearce
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Exploring the Association between Thyroid Function and Frailty: Insights from Representative Korean Data
Youn-Ju Lee, Min-Hee Kim, Dong-Jun Lim, Jung-Min Lee, Sang Ah Chang, Jeongmin Lee
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Original Articles

Clinical Study
Association between Serum Free Thyroxine and Anemia in Euthyroid Adults: A Nationwide Study: Mijin Kim, Bo Hyun Kim, Hyungi Lee, Min Hee Jang, Jeong Mi Kim, Eun Heui Kim, Yun Kyung Jeon, Sang Soo Kim, In Joo Kim; Endocrinol Metab. 2020;35(1):106-114. Published online March 19, 2020; DOI: https://doi.org/10.3803/EnM.2020.35.1.106

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Background

Studies on the relationship between thyroid function and anemia in the euthyroid range are scarce. We aimed to evaluate the association between anemia and serum free thyroxine (fT4) and thyrotropin (TSH) in euthyroid adults.

Methods

Data on 5,352 participants aged ≥19 years were obtained from the Korea National Health and Nutrition Examination Survey VI (2013 to 2015). Anemia was defined as hemoglobin (Hb) <13 and <12 g/dL for men and women, respectively.

Results

Overall, 6.1% of participants had anemia, and more women (9.9%) had anemia than men (2.8%, P<0.001). In multivariate analysis, serum fT4 levels, but not TSH, were positively associated with serum Hb levels in both sexes (P<0.001, each). Serum Hb levels linearly reduced across decreasing serum fT4 quartile groups in both sexes (P<0.001, each). After adjusting for potential confounding factors, participants with low-normal fT4 had 4.4 (P=0.003) and 2.8 times (P<0.001) higher risk for anemia than those with high-normal fT4 among men and women, respectively. When participants were divided into two groups at 50 years of age, in younger participants, men and women with the first quartile were at higher risk of anemia than men with the second quartile (odds ratio [OR], 3.3; P=0.029) and women with the forth quartile (OR, 3.2; P<0.001), respectively. This association was not observed in older participants.

Conclusion

These results suggest that a low-normal level of serum fT4 was associated with a lower serum Hb level and a higher risk of anemia in euthyroid adults, especially in younger participants.

Citations

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Thyroid Function and Risk of Anemia: A Multivariable-Adjusted and Mendelian Randomization Analysis in the UK Biobank
Nicolien A van Vliet, Annelies E P Kamphuis, Wendy P J den Elzen, Gerard J Blauw, Jacobijn Gussekloo, Raymond Noordam, Diana van Heemst
The Journal of Clinical Endocrinology & Metabolism.2022; 107(2): e643. CrossRef
Thyroid function, pernicious anemia and erythropoiesis: a two-sample Mendelian randomization study
Alisa D Kjaergaard, Alexander Teumer, Eirini Marouli, Panos Deloukas, Aleksander Kuś, Rosalie Sterenborg, Bjørn O Åsvold, Marco Medici, Christina Ellervik
Human Molecular Genetics.2022; 31(15): 2548. CrossRef
Changes of hematological indices in patients with diffuse toxic goiter
F. H. Saidova, L. M. Ahmedova, Zh. B. Aslanova, N. A. Najafov
Klinicheskaia khirurgiia.2021; 88(3-4): 76. CrossRef
Association between Serum Free Thyroxine and Anemia in Euthyroid Adults: A Nationwide Study (Endocrinol Metab 2020;35:106-14, Mijin Kim et al.)
Zheng Feei Ma
Endocrinology and Metabolism.2020; 35(2): 484. CrossRef
Association between Serum Free Thyroxine and Anemia in Euthyroid Adults: A Nationwide Study (Endocrinol Metab 2020;35:106-14, Mijin Kim et al.)
Mijin Kim, Bo Hyun Kim
Endocrinology and Metabolism.2020; 35(3): 669. CrossRef

Changes in Serum Lipids and Apolipoproteins Levels According to the Thyroxine Treatment in The Patients with Subclinical Hypothyroidism.: Hye Young Park, Bo Youn Cho, Won Bae Kim, Hong Gyu Lee, Chang Soon Koh, Geon Sang Park, Hyung Kyu Park, Sook Kyung Kim, Chan Soo Shin, Seong Yeon Kim; J Korean Endocr Soc. 1996;11(1):41-51. Published online November 7, 2019

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Abstract PDF: Background
Subclinical hypothyroidism(SCH) is a common biochemical abnormality which can be found in routine screening tests of thyroid function. We are increasingly faced with the question of whether its an indication for thyroxine replacement therapy. The effect of thyroxine replacement on lipid profile in SCH has aroused a great interest because of an association of overt hypothyroidism(OVH) with hyperlipidemia and increased risk of coronary artery disease. Method: We prospectively evaluated the changes in lipids and apoproteins before and after thyroxine replacement therapy in 23 patients with SCH and in 37 patients with OVH. We measured serum total cholesterol and triglyceride using autoanalyzer, high density lipoprotein(HDL) chole-sterol by dextran sulfate method, Apo A1 and Apo B by immunonephelometric assay. Results: Thyroxine replacement therapy significantly decreased total cholesterol, low density lipoprotein(LDL) cholesterol and apo B levels, but did not affect the level of triglyceride, HDL cholesterol or apo AI in patients with OVH. In SCH, thyroxine replacement therapy with the doses to normalize serum TSH concentrations also decreased significantly the level of cholesterol and LDL cholesterol albeit apo B levels did not change. Moreover, in most of patients with OVH (11 of 12) and in all of patients with SCH(5 of 5) who had had hyperchlesterolemia before treatment, thyroxine replament normalized their cholesterol and LDL cholesterol levels. Conclusion: In regard to the beneficial changes in blood lipid levels, patients with SCH should be treated, especially in cases who have other risk factors for the development of atherosclerosis. If thyroxine replacement only will reduce the incidence of coronary artery disease in SCH remains to be elucidated by long-term prospective studies.

Changes of Thyroid Function According to the Stages of Normal Pregnancy.: W B Kim, B H Yoon, J H Chung, S I Lee, M S Kim, T G Oh, B Y Cho, H K Lee, C S Koh; J Korean Endocr Soc. 1994;9(3):183-189. Published online November 6, 2019

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Abstract PDF: It is well known that normal pregnancy is accompanied by a rise in serum concentrations of thyroxine-binding globulin(TBG) and human chorionic gonadotropin (hCG). Alterations of biochemical parameters of thyroid function are recognized during gestation and sensitive tests to evaluate the alterations easily are required. Therefore, a cross-sectional study was undertaken in 140 healthy pregnant women to evaluate the efficacy of free T_4 measured by 2-step RIA compared to other thyroid function tests and to confirm the changes of thyroid function according to the stages of normal pregnancy.The sensitivities of free T_4 index, free T_4(by 2-step RIA), T_3 and TSH were realtively high(99.3%, 93.6%, 92.9%, 83.6%, respectively) compared to those of T_4 and T_3 bead upgake(49.3%, 21.4%) during all stages of pregnancy. There were positive correlations between free T_4 index and free T_4 or total T_4(r=0.68, r=0.72; p<0.001). The values of free T_4 index sharply decreased from 3.22+-0.10(meam +-SEM) during 6th-12th week to an plateau after 16th-20th week of gestation(p<0.01). The serum concentrations free T_4 and T_3 bead uptake also significantly decreased from 1.65+-0.05 ng/dl, 24.7+- 0.7% during 6th-12th week to an plateau after 16th-20th week of gestation, respectively(p<0.001), No differences were found in the changes of serum concentrations of T_3, T_4 and TSH according to the stages of pregnancy.In conclusion, it is adequate to measure some tests including free T_4 index and free T_4 to evaluate thyroid function during pregnancy. The thyroid physiology and changes of thyroid function according to the stages of pregnancy should be considered in the interpretation of thyroid function status during pregnancy.

Evaluation of the Usefulness of Free T4 Measured by 2 - Step Iimmunoextraction in the Patients with Thyroid and Non - Thyroid Diseases.: Bo Youn Cho, Hong Kyu Lee, Jae Hoon Chung, Seok In Lee, Won Bae Kim, Chang Soon Koh; J Korean Endocr Soc. 1994;10(2):98-104. Published online November 6, 2019

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Abstract PDF: Many methods and commercial kits have become available for directly measuring free thyroxine(free T_4). However, most of them are inadequate for routine laboratory use because of their complexity and inaccuracy. Recently, 2-step RIA methods by immunoextraction(2-step immunoextraction) for free T_4 have been developed to improve its accuracy and convenience. We evaluated the usefulness of free T_4 measured by 2-step immunoextraction compared to free T_4 index(FT_4I), free T_4 measured by 1-step RIA, and TSH in 204 patients with thyroid and non-thyroid disease. There were no differences in sensitivities and specificities of free T_4(1-step, 2-step), FT_4I and TSH in the patients with hyperthyroidism and euthyroid nodule. However, the sensitivity of TSH in hypothyroidism was remarkablely higher than the others(100.0% vs. 61.5-81.5%). The sensitivity of free T_4(2-step) was also higher than those of free T_4(1-step), FT_4I and TSH in the patients with non-thyroid disease(94.3% vs. 74.3-83.8%). The values of free T_4 measured by 1-step RIA were significantly lower than those by 2-step immunoextraction, especially in the patients with non-thyroid disease(1.10+-0.04 vs. 1.55+-0.03ng/dL, p<0.05).In conclusion, no significant differences were found in sensitivity and specificity of free T_4(1-step, 2-step), FT_4I, and TSH in the patients with thyroid diseases except in hypothyroidism. However, the sensitivity of free T_4 measured by 2-step immunoextraction was significantly higher than the other tests, especially in the patients with non-thyroid disease. Therefore, free T_4 assay using 2-step immunoextraction is useful to differentiate the non-thyroid disease from thyroid diseases.

Clinical Study
Detection of Polyethylene Glycol Thyrotropin (TSH) Precipitable Percentage (Macro-TSH) in Patients with a History of Thyroid Cancer: Massimo Giusti, Lucia Conte, Anna Maria Repetto, Stefano Gay, Paola Marroni, Miranda Mittica, Michele Mussap; Endocrinol Metab. 2017;32(4):460-465. Published online December 14, 2017; DOI: https://doi.org/10.3803/EnM.2017.32.4.460

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Background

Owing to its large molecular size, polyethylene glycol (PEG)-precipitable thyrotropin (TSH) can accumulate in the circulation, elevating TSH levels. PEG-precipitable TSH can be used to detect macro-TSH (mTSH) in serum. Our aim was to evaluate the prevalence of mTSH in patients who had undergone thyroidectomy for thyroid cancer.

Methods

Seventy-three thyroid cancer patients and 24 control subjects on levothyroxine (LT4) TSH-suppressive or replacement therapy were evaluated. Screening for mTSH was performed by adding PEG to serum in order to precipitate γ-globulin. A percentage of PEG-precipitable TSH ≥80% was considered suggestive of mTSH.

Results

No correlation between free-T4 (fT4) and TSH levels was found. PEG-precipitable TSH was 39.3%±1.9% in thyroid cancer patients and 44.1%±3.9% in controls. Macro-TSH was deemed to be present in one thyroid cancer patient and in two control subjects. Only in the thyroid cancer group was PEG-precipitable TSH found to be negatively correlated with fT4 concentration. No correlation was found between PEG-precipitable TSH and other clinical conditions in any patients.

Conclusion

The presence of mTSH seems to be a rare phenomenon in thyroid cancer. In some patients with low PEG-precipitable TSH, a reduction in LT4 dosage could be suggested. LT4 dosage adjusted to body weight is the main factor in maintaining TSH in a semi-suppressed or normal range. Evaluation of mTSH could be necessary in patients in whom a balance is required between adequate TSH suppression and the avoidance of unnecessary exogenous hyperthyroxinemia.

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Free Thyroxine, Anti-Thyroid Stimulating Hormone Receptor Antibody Titers, and Absence of Goiter Were Associated with Responsiveness to Methimazole in Patients with New Onset Graves' Disease: Hoon Sung Choi, Won Sang Yoo; Endocrinol Metab. 2017;32(2):281-287. Published online June 23, 2017; DOI: https://doi.org/10.3803/EnM.2017.32.2.281

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Background

Anti-thyroid drug therapy is considered a treatment of choice for Graves' disease; however, treatment response varies among individuals. Although several studies have reported risk factors for relapse after initial treatment, few have assessed responsiveness during the early treatment period. Our study aimed to identify the clinical characteristics for responsiveness to methimazole.

Methods

We included 99 patients diagnosed with Graves' disease for the first time. Drug responsiveness was defined as the correlation coefficients between decreasing rates of free thyroxine level per month and methimazole exposure dose. According to their responsiveness to treatment, the patients were classified into rapid or slow responder groups, and age, sex, free thyroxine level, and thyrotropin binding inhibiting immunoglobulin (TBII) titers were compared between groups.

Results

The mean patient age was 44.0±13.5 years and 40 patients were male (40%). The mean TBII titer was 36.6±74.4 IU/L, and the mean free thyroxine concentration was 48.9±21.9 pmol/L. The rapid responder group showed higher TBII titer and free thyroxine level at diagnosis, while age, sex, smoking, and presence of goiter did not differ between the two groups. Logistic regression analyses revealed that high level of serum thyroxine, high titer of TBII, and absence of goiter were significantly associated with a rapid response, while age, sex, and smoking were not significant factors for the prediction of responsiveness.

Conclusion

In patients with new onset Graves' disease, high level of free thyroxine, high titer of TBII, and absence of goiter were associated with rapid responsiveness to methimazole treatment.

Citations

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Review Article

Thyroid
Clinical Update in Aspects of the Management of Autoimmune Thyroid Diseases: Duncan J. Topliss; Endocrinol Metab. 2016;31(4):493-499. Published online December 20, 2016; DOI: https://doi.org/10.3803/EnM.2016.31.4.493

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Abstract PDF PubReader

Aspects of autoimmune thyroid disease updated in this review include: immunoglobulin G4 (IgG4)-related thyroid disease (Riedel's thyroiditis, fibrosing variant of Hashimoto's thyroiditis, IgG4-related Hashimoto's thyroiditis, and Graves' disease with elevated IgG4 levels); recent epidemiological studies from China and Denmark indicating that excess iodine increases the incidence of Hashimoto's thyroiditis and hypothyroidism; immunomodulatory agents (ipilimumab, pembrolizumab, nivolumab) activate immune response by inhibiting T-cell surface receptors which down-regulate immune response, i.e., cytotoxic T-lymphocyte antigen 4 and programmed cell death protein 1 pathways; alemtuzumab is a humanised monoclonal antibody to CD52 which causes immune depletion and thyroid autoimmune disease especially Graves' hyperthyroidism; small molecule ligand (SML) agonists which activate receptors, SML neutral antagonists, which inhibit receptor activation by agonists, and SML inverse agonists which inhibit receptor activation by agonists and inhibit constitutive agonist independent signaling have been identified. SML antagonism of thyroid-stimulating hormone-receptor stimulatory antibody could treat Graves' hyperthyroidism and Graves' ophthalmopathy; and thyroxine treatment of subclinical hypothyroidism can produce iatrogenic subclinical hyperthyroidism with the risk of atrial fibrillation and osteoporosis. The increased risk of harm from subclinical hyperthyroidism may be stronger than the potential benefit from treatment of subclinical hypothyroidism.

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Case Report

A Case of Sheehan's Syndrome with Pancytopenia.: Hyun Suk Lee, Byung Woon Kwon, Jin Hyung Han, Hee Jin Kim; Endocrinol Metab. 2012;27(1):54-58. Published online March 1, 2012; DOI: https://doi.org/10.3803/EnM.2012.27.1.54

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Abstract PDF: Sheehan's syndrome is characterized by varying degrees of anterior pituitary dysfunction due to postpartum ischemic necrosis of the pituitary gland after massive bleeding. The spectrum of clinical presentation of Sheehan's syndrome is broad, with changes from nonspecific complaints, such as weakness, fatigue, and anemia, to severe pituitary insufficiency resulting in coma and death. Normochromic anemia is commonly associated with Sheehan's syndrome, but pancytopenia is rarely observed in patients with Sheehan's syndrome. We describe a 57-year-old woman with Sheehan's syndrome who presented with pancytopenia that was treated by hormone replacement with levothyroxine and glucocorticoid.

Original Articles

Factors Influencing Peripheral Conversion of Thyroxine to Tri-Iodothyronine in Athyreotic Individuals during Levothyroxine Replacement.: Eui Young Kim, Won Gu Kim, Tae Yong Kim, Jong Ho Yoon, Suck Joon Hong, Young Kee Shong, Won Bae Kim; Endocrinol Metab. 2010;25(2):119-124. Published online June 1, 2010; DOI: https://doi.org/10.3803/EnM.2010.25.2.119

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Abstract PDF: BACKGROUND
Tri-iodothyronine (T3) is the main active hormone, and 20% of this is derived from the thyroid gland and 80% is from the peripheral tissue according to 5'-monodeiodination of thyroxine (T4). In the previous studies, normal T3 levels were achieved with traditional levothyroxine (LT4) therapy alone in athyreotic patients, but there has been no data about the factors influencing peripheral conversion of LT4. The aim of this study was to determine the factor(s) influencing peripheral conversion of LT4 to T3 in athyreotic patients during LT4 replacement. METHODS: The patients who underwent total-thyroidectomy for any cause, and mostly for thyroid cancers, at Asan Medical Center between 2000 and 2008 were enrolled. The free T4, T3 and thyroid stimulating hormone (TSH) levels and age, gender, weight, height, body mass index (BMI) and the T4 dose were measured. Only patients with normal ranges of free T4 and TSH were included in the analysis. RESULTS: A total of 143 patients were enrolled. The mean T3, free T4 and TSH levels were 143.7 ng/dL, 1.4 ng/dL and 1.6 microU/mL, respectively. The mean weight and BMI were 62.9 kg and 24.6 kg/m2, respectively. We divided them into two groups according to the serum T3 level and we compared the characteristics of the groups. There were no differences in age, the gender distribution, the T4 dose/weight and the BMI between the low T3 group (T3 < or = 122 ng/dL, n = 14) and the normal T3 group (T3 > 122 ng/dL, n = 129). In the low T3 group, the mean body weight was significantly lower than that of the normal T3 group (59.0 +/- 6.0 vs. 63.4 +/- 9.9, respectively, P = 0.025). CONCLUSION: Lean body mass seems to be an important factor for determining the peripheral conversion of T4 to T3 in human. This suggest that a combination of T3/T4 is better than T4 only when we treat the patients with hypothyroidism and who have a negligible amount of functioning thyroid tissue, if they have a low lean body mass.

The Efficacy of Thyroxine Suppression Therapy in Benign Thyroid Nodules.: Seog Ki Yun, Chul Hee Kim, Young Sun Kim, Dong Won Byun, Kyo Il Suh, Myung Hi Yoo; J Korean Endocr Soc. 2000;15(4-5):532-541. Published online January 1, 2001

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Abstract PDF: BACKGROUND
Benign pathologic findings are shown in 800% of thyroid nodules by fine needle aspiration cytology (FNAC) or needle biopsy. About half of these benign nodules are follicular lesions which are presented only as thyroid follicles or thyroid cell clumps. Differential diagnosis of follicular adenoma, follicular carcinoma and adenomatous goiter is impossible by FNAC or needle biopsy. Thyroxine suppression therapy has been performed traditionally in order to discriminate malignant nodules, but few studies are available which confirmed the efficacy of thyroxine suppression therapy in thyroid nodules of those the initial pathologic findings were follicular lesions. So we tried to evaluate the efficacy of thyroxine suppression therapy in benign thyroid nodules and also the incidence of thyroid cancer of the thyroid nosules which were not decreased on thyroxine suppression therapy after surgical resection. METHODS: Total 1027 patients with thyroid nodules were evaluated by FNAC or needle biopsy at Soonchunhyang university hospital from 1990 to 1996. Among 1027 patients, 507 patients showed follicular lesions in FNAC or needle biopsy and they received thyroxine suppression therapy. Thyroid nodule volume was measured before and after thyroxine suppression therapy using ultrasonography. We studied 184 patients who were followed up for more than 1 year. Serial changes of thyroid function tests, thyroid nodule volume, serum thyroglubulin (Tg) level before and after therapy were analyzed. RESULTS: l. In 80 (43.5%) of the 184 patients, nodule volumes decreased more than 50 percent after thyroxine suppression therapy. 2. There was no significant difference in serum T3, T4, TSH levels before and after thyroxine suppression therapy between group I (nodule volume decreased less than 50%) and group II (nodule volume decreased more than 50%). 3. In group II patients, thyroid nodule volumes were decreased continuously at 12 month, 18 month and 30 month after thyroxine suppression (p<0.05). 4. There was no significant difference between the group I and group II in the frequency of multiple thyroid nodules on ultrasonography. 5. Among 37 patients who underwent thyroidectomy, 19 cases (51.4%) were revealed as malignant thyroid nodules (papillary cancer 4 cases, follicular cancer 15 cases). Eighteen cases (48.6%) were revealed as benign thyroid nodules (follicular adenoma 10 cases, adenomatous goiter 8 cases). 6. There was no significant difference in the frequency of multiple nodules on ultrasonography between benign and malignant nodules. CONCLUSION: Our data suggested thyroxine suppression therapy was effective in discriminating malignant thyroid nodules from benign nodules, especially in selecting follicular carcinoma from follicular lesion by FNAC or biopsy.

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