Endocrinology and Metabolism

Volume 36(3); June 2021

Review Articles

Diabetes, Obesity and Metabolism
Recent Advances in Understanding Peripheral Taste Decoding I: 2010 to 2020: Jea Hwa Jang, Obin Kwon, Seok Jun Moon, Yong Taek Jeong; Endocrinol Metab. 2021;36(3):469-477. Published online June 18, 2021; DOI: https://doi.org/10.3803/EnM.2021.302

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Taste sensation is the gatekeeper for direct decisions on feeding behavior and evaluating the quality of food. Nutritious and beneficial substances such as sugars and amino acids are represented by sweet and umami tastes, respectively, whereas noxious substances and toxins by bitter or sour tastes. Essential electrolytes including Na⁺ and other ions are recognized by the salty taste. Gustatory information is initially generated by taste buds in the oral cavity, projected into the central nervous system, and finally processed to provide input signals for food recognition, regulation of metabolism and physiology, and higher-order brain functions such as learning and memory, emotion, and reward. Therefore, understanding the peripheral taste system is fundamental for the development of technologies to regulate the endocrine system and improve whole-body metabolism. In this review article, we introduce previous widely-accepted views on the physiology and genetics of peripheral taste cells and primary gustatory neurons, and discuss key findings from the past decade that have raised novel questions or solved previously raised questions.

Citations

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Multidimensional exploration of the bitterness amelioration effect of roasting on Wuyi Rock tea
Weiying Su, Li Ni, Yizhe Chen, Daoliang Wang, Chih-Cheng Lin, Yuan Liu, Zhibin Liu
Food Chemistry.2024; 437: 137954. CrossRef
Reassessing the genetic lineage tracing of lingual Lgr5 + and Lgr6 + cells in vivo
Hyun Ji Kim, Dong Woo Seo, Jaewon Shim, Jun-Seok Lee, Sang-Hyun Choi, Dong-Hoon Kim, Seok Jun Moon, Han-Sung Jung, Yong Taek Jeong
Animal Cells and Systems.2024; 28(1): 353. CrossRef
Dietary Habit and Oral Condition
Norio Aoyama, Sayuri Kida, Tomomi Yata, Masahiro Takase, Toshiya Fujii, Shuntaro Sugihara, Takahisa Hirata, Kentaro Taniguchi, Motohiro Komaki
Current Oral Health Reports.2024; 11(4): 283. CrossRef
Phosphorylated Tau in the Taste Buds of Alzheimer’s Disease Mouse Models
Hyun Ji Kim, Bo Hye Kim, Dong Kyu Kim, Hanbin Kim, Sang-Hyun Choi, Dong-Hoon Kim, Myunghwan Choi, Inhee Mook-Jung, Yong Taek Jeong, Obin Kwon
Experimental Neurobiology.2024; 33(4): 202. CrossRef
Longitudinal Analysis of Sweet Taste Preference Through Genetic and Phenotypic Data Integration
Ji Hyun Bae, Hyunju Kang
Foods.2024; 13(21): 3370. CrossRef
Recent advances in biomimetic taste-based biosensors and their applications
Jialu Kang, Jiejing Liu, Yufei Geng, Yuxuan Yuan, Shuge Liu, Yushuo Tan, Liping Du, Chunsheng Wu
Sensors & Diagnostics.2024;[Epub] CrossRef
Glia-like taste cells mediate an intercellular mode of peripheral sweet adaptation
Gha Yeon Park, Geehyun Lee, Jongmin Yoon, Jisoo Han, Pyonggang Choi, Minjae Kim, Sungho Lee, Chaeri Park, Zhaofa Wu, Yulong Li, Myunghwan Choi
Cell.2024;[Epub] CrossRef
Physiology of the tongue with emphasis on taste transduction
Máire E. Doyle, Hasitha U. Premathilake, Qin Yao, Caio H. Mazucanti, Josephine M. Egan
Physiological Reviews.2023; 103(2): 1193. CrossRef
Polycystic kidney disease 2-like 1 channel contributes to the bitter aftertaste perception of quinine
Takahiro Shimizu, Takuto Fujii, Keisuke Hanita, Ryo Shinozaki, Yusaku Takamura, Yoshiro Suzuki, Teppei Kageyama, Mizuki Kato, Hisao Nishijo, Makoto Tominaga, Hideki Sakai
Scientific Reports.2023;[Epub] CrossRef
Sweet Taste Preference: Relationships with Other Tastes, Liking for Sugary Foods and Exploratory Genome-Wide Association Analysis in Subjects with Metabolic Syndrome
Rebeca Fernández-Carrión, Jose V. Sorlí, Oscar Coltell, Eva C. Pascual, Carolina Ortega-Azorín, Rocío Barragán, Ignacio M. Giménez-Alba, Andrea Alvarez-Sala, Montserrat Fitó, Jose M. Ordovas, Dolores Corella
Biomedicines.2021; 10(1): 79. CrossRef

Diabetes, Obesity and Metabolism
Receptor-Mediated Muscle Homeostasis as a Target for Sarcopenia Therapeutics: Jong Hyeon Yoon, Ki-Sun Kwon; Endocrinol Metab. 2021;36(3):478-490. Published online June 28, 2021; DOI: https://doi.org/10.3803/EnM.2021.1081

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Sarcopenia is a disease characterized by age-related decline of skeletal muscle mass and function. The molecular mechanisms of the pathophysiology of sarcopenia form a complex network due to the involvement of multiple interconnected signaling pathways. Therefore, signaling receptors are major targets in pharmacological strategies in general. To provide a rationale for pharmacological interventions for sarcopenia, we herein describe several druggable signaling receptors based on their role in skeletal muscle homeostasis and changes in their activity with aging. A brief overview is presented of the efficacy of corresponding drug candidates under clinical trials. Strategies targeting the androgen receptor, vitamin D receptor, Insulin-like growth factor-1 receptor, and ghrelin receptor primarily focus on promoting anabolic action using natural ligands or mimetics. Strategies involving activin receptors and angiotensin receptors focus on inhibiting catabolic action. This review may help to select specific targets or combinations of targets in the future.

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The Current Landscape of Pharmacotherapies for Sarcopenia
Gulistan Bahat, Serdar Ozkok
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Associations of micronutrient dietary patterns with sarcopenia among US adults: a population-based study
Yining Liu, Xiangliang Liu, Linnan Duan, Yixin Zhao, Yuwei He, Wei Li, Jiuwei Cui
Frontiers in Nutrition.2024;[Epub] CrossRef
Impact of Vitamin D Level on Sarcopenia in Elderly People: A Critical Review
Saniya Khan, Sunil Kumar, Sourya Acharya, Anil Wanjari
Journal of Health and Allied Sciences NU.2023; 13(04): 453. CrossRef
Novel Potential Targets for Function-Promoting Therapies: Orphan Nuclear Receptors, Anti-inflammatory Drugs, Troponin Activators, Mas Receptor Agonists, and Urolithin A
Waly Dioh, Vihang Narkar, Anurag Singh, Fady Malik, Luigi Ferrucci, Cendrine Tourette, Jean Mariani, Rob van Maanen, Roger A Fielding, Lewis A Lipsitz
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Alverine citrate promotes myogenic differentiation and ameliorates muscle atrophy
Jong Hyeon Yoon, Seung-Min Lee, Younglang Lee, Min Ju Kim, Jae Won Yang, Jeong Yi Choi, Ju Yeon Kwak, Kwang-Pyo Lee, Yong Ryoul Yang, Ki-Sun Kwon
Biochemical and Biophysical Research Communications.2022; 586: 157. CrossRef
Adeno-associated virus-mediated expression of an inactive CaMKIIβ mutant enhances muscle mass and strength in mice
Takahiro Eguchi, Yuji Yamanashi
Biochemical and Biophysical Research Communications.2022; 589: 192. CrossRef
Gastric Mobility and Gastrointestinal Hormones in Older Patients with Sarcopenia
Hsien-Hao Huang, Tse-Yao Wang, Shan-Fan Yao, Pei-Ying Lin, Julia Chia-Yu Chang, Li-Ning Peng, Liang-Kung Chen, David Hung-Tsang Yen
Nutrients.2022; 14(9): 1897. CrossRef
Molecular Mechanisms Underlying Intensive Care Unit-Acquired Weakness and Sarcopenia
Marcela Kanova, Pavel Kohout
International Journal of Molecular Sciences.2022; 23(15): 8396. CrossRef

Thyroid
Antithyroid Drug Treatment in Graves’ Disease: Jae Hoon Chung; Endocrinol Metab. 2021;36(3):491-499. Published online June 16, 2021; DOI: https://doi.org/10.3803/EnM.2021.1070

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Graves’ disease is associated with thyrotropin (TSH) receptor stimulating antibody, for which there is no therapeutic agent. This disease is currently treated through inhibition of thyroid hormone synthesis or destruction of the thyroid gland. Recurrence after antithyroid drug (ATD) treatment is common. Recent studies have shown that the longer is the duration of use of ATD, the higher is the remission rate. Considering the relationship between clinical outcomes and iodine intake, recurrence of Graves’ disease is more common in iodine-deficient areas than in iodine-sufficient areas. Iodine restriction in an iodine-excessive area does not improve the effectiveness of ATD or increase remission rates. Recently, Danish and Korean nationwide studies noted significantly higher prevalence of birth defects in newborns exposed to ATD during the first trimester compared to that of those who did not have such exposure. The prevalence of birth defects was lowest when propylthiouracil (PTU) was used and decreased by only 0.15% when methimazole was changed to PTU in the first trimester. Therefore, it is best not to use ATD in the first trimester or to change to PTU before pregnancy.

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Dynamic Risk Model for the Medical Treatment of Graves’ Hyperthyroidism according to Treatment Duration
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Выраженность окислительного стресса и энзиматическая активность нейтрофилов крови у пациентов с болезнью Грейвса в зависимости от компенсации гипертиреоза
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Jooyoung Lee, Jinmo Kang, Hwa Young Ahn, Jeong Kyu Lee
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Methimazole, an Effective Neutralizing Agent of the Sulfur Mustard Derivative 2-Chloroethyl Ethyl Sulfide
Albert Armoo, Tanner Diemer, Abigail Donkor, Jerrod Fedorchik, Severine Van slambrouck, Rachel Willand-Charnley, Brian A. Logue
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The influence of thionamides on intra-thyroidal uptake of 131I during radioiodine-131 treatment of Graves’ disease
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Usefulness of Real-Time Quantitative Microvascular Ultrasonography for Differentiation of Graves’ Disease from Destructive Thyroiditis in Thyrotoxic Patients
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Risk of Diabetes in Patients with Long-Standing Graves’ Disease: A Longitudinal Study
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Thyroid
Subclinical Hypothyroidism: Prevalence, Health Impact, and Treatment Landscape: Won Sang Yoo, Hyun Kyung Chung; Endocrinol Metab. 2021;36(3):500-513. Published online June 18, 2021; DOI: https://doi.org/10.3803/EnM.2021.1066

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Subclinical hypothyroidism (sHypo) is defined as normal serum free thyroid hormone levels coexisting with elevated serum thyroid-stimulating hormone (TSH) levels. sHypo is a common condition observed in clinical practice with several unique features. Its diagnosis should be based on an understanding of geographic and demographic differences in biochemical criteria versus a global reference range for TSH that is based on the 95% confidence interval of a healthy population. During the differential diagnosis, it is important to remember that a considerable proportion of sHypo cases are transient and reversible in nature; the focus is better placed on persistent or progressive forms, which mainly result from chronic autoimmune thyroiditis. Despite significant evidence documenting the health impacts of sHypo, the effects of levothyroxine treatment (LT4-Tx) in patients with sHypo remains controversial, especially in patients with grade 1 sHypo and older adults. Existing evidence suggests that it is reasonable to refrain from immediate LT4-Tx in most patients if they are closely monitored, except in women who are pregnant or in progressive cases. Future research is needed to further characterize the risks and benefits of LT4-Tx in different patient cohorts.

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THYROID FUNCTION ABNORMALITIES IN PATIENTS WITH CHOLELITHIASIS: A HOSPITAL-BASED CROSS-SECTIONAL STUDY
AVANISH KUMAR SAXENA, ANAM FATIMA, KUNDRAPU VEERA VENKATA SIVA, ANUSHKA PARIYA, VAYALAPALLI SYAMA CHINMAYI
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The Relationship between Subclinical Hypothyroidism and Carotid Intima-Media Thickness as a Potential Marker of Cardiovascular Risk: A Systematic Review and a Meta-Analysis
Oana-Maria Isailă, Victor Eduard Stoian, Iuliu Fulga, Alin-Ionut Piraianu, Sorin Hostiuc
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O.V. Bilookyi, V.L. Vasiuk, O.A. Shupik
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Retrospective cohort analysis comparing changes in blood glucose level and body composition according to changes in thyroid‐stimulating hormone level
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Thyroid
Current Guidelines for Management of Medullary Thyroid Carcinoma: Mijin Kim, Bo Hyun Kim; Endocrinol Metab. 2021;36(3):514-524. Published online June 22, 2021; DOI: https://doi.org/10.3803/EnM.2021.1082

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Medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor originating from the parafollicular cells. The diagnostic and therapeutic strategies for the condition are different from those used for well-differentiated thyroid cancer. Since the 2015 American Thyroid Association guidelines for the diagnosis and treatment of MTC, the latest, including the National Comprehensive Cancer Network and European Association for Medical Oncology guidelines have been updated to reflect several recent advances in the management of MTC. Advances in molecular diagnosis and postoperative risk stratification systems have led to individualized treatment and follow-up strategies. Multi-kinase inhibitors, such as vandetanib and cabozantinib, can prolong disease progression-free survival with favorable adverse effects. In addition, potent selective rearranged during transfection (RET) inhibitors (selpercatinib and pralsetinib) have shown a promising efficacy in recent clinical trials. This review summarizes the management of MTC in recent guidelines focused on sporadic MTC.

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Bone Metabolism
Normocalcemic Primary Hyperparathyroidism: Need for a Standardized Clinical Approach: Guido Zavatta, Bart L. Clarke; Endocrinol Metab. 2021;36(3):525-535. Published online June 1, 2021; DOI: https://doi.org/10.3803/EnM.2021.1061

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Since normocalcemic primary hyperparathyroidism (NHPT) was first defined at the Third International Workshop on the Management of Asymptomatic Primary Hyperparathyroidism in 2008, many papers have been published describing its prevalence and possible complications. Guidelines for the management of this condition are still lacking, and making the diagnosis requires fulfillment of strict criteria. Recent studies have shown that intermittent oscillations of serum calcium just below and slightly above the normal limits are very frequent, therefore challenging the assumption that serum calcium must be consistently normal to make the diagnosis. There is debate if these variations in serum calcium outside the normal range should be included under the rubric of NHPT or, rather, a milder form of classical primary hyperparathyroidism. Innovative approaches to define NHPT have been proposed that still need to be validated in prospective studies. Non-classical complications, especially cardiovascular complications, have been associated with NHPT, indicating that hyperparathyroidism may be a cardiovascular risk factor. New associations between parathyroid hormone (PTH) and several other comorbidities have also been reported from observational studies, suggesting that excessive PTH secretion might cause tissue dysfunction independent of serum calcium. Heterogeneous studies using different definitions of NHPT, however, make it difficult to draw definitive conclusions regarding the role of PTH excess when complications other than osteoporosis or kidney stones are described. This review will focus on clinical aspects and suggest an approach to NHPT.

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Bone Metabolism
Update on Glucocorticoid Induced Osteoporosis: Soo-Kyung Cho, Yoon-Kyoung Sung; Endocrinol Metab. 2021;36(3):536-543. Published online June 1, 2021; DOI: https://doi.org/10.3803/EnM.2021.1021

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Glucocorticoids are used to treat many autoimmune and inflammatory diseases. However, an adverse systemic effect is a deleterious effect on bone, which may lead to glucocorticoid-induced osteoporosis, characterized by a rapid and transient increase in bone resorption and fracture risk, which may increase rapidly within 3 months of commencing oral glucocorticoids. Therefore, early risk assessment and intervention are crucial for preventing fractures in patients receiving glucocorticoids. Recent practice guidelines recommend an assessment for fracture risk in patients beginning or receiving glucocorticoids for more than 3 months, and they have suggested fracture risk assessment tool values for identifying patients who need preventive treatment. Bisphosphonates are currently the recommended first-line therapy for the prevention and treatment of glucocorticoid-induced osteoporosis. These have been shown to increase the bone mineral density in the spine and hip and to decrease the incidence of vertebral fractures. Recently, a more potent antiresorptive agent, denosumab, has been shown to increase the bone density in patients receiving glucocorticoids. Teriparatide has been shown to have a preventive effect on vertebral fractures, but not on nonvertebral fractures. In this article we aimed to provide an update on glucocorticoid-induced osteoporosis by focusing on the assessment of its risk and treatment options.

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Bone Metabolism
Long-Term Treatment of Postmenopausal Osteoporosis: Jacques P. Brown; Endocrinol Metab. 2021;36(3):544-552. Published online June 22, 2021; DOI: https://doi.org/10.3803/EnM.2021.301

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Osteoporosis is an incurable chronic condition, like heart disease, diabetes, or hypertension. A large gap currently exists in the primary prevention of fractures, and studies show that an estimated 80% to 90% of adults do not receive appropriate osteoporosis management even in the secondary prevention setting. Case finding strategies have been developed and effective pharmacological interventions are available. This publication addresses how best to use the pharmacological options available for postmenopausal osteoporosis to provide lifelong fracture protection in patients at high and very high risk of fracture. The benefit of osteoporosis therapies far outweighs the rare risks.

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Adrenal Gland
Asian Conference on Tumor Ablation Guidelines for Adrenal Tumor Ablation: Byung Kwan Park, Masashi Fujimori, Shu-Huei Shen, Uei Pua; Endocrinol Metab. 2021;36(3):553-563. Published online June 1, 2021; DOI: https://doi.org/10.3803/EnM.2021.1008

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Thermal ablation is a good alternative treatment in patients who are unable to undergo adrenalectomy. Even though the Asian Conference on Tumor Ablation (ACTA) has been held for many years, adrenal ablation guidelines have not been established. No guidelines for adrenal ablation are established in American and European countries, either. The aim of this review was to introduce the first version of ACTA guidelines for adrenal tumor ablation.

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Miscellanenous
Cushing Syndrome Associated Myopathy: It Is Time for a Change: Martin Reincke; Endocrinol Metab. 2021;36(3):564-571. Published online June 18, 2021; DOI: https://doi.org/10.3803/EnM.2021.1069

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Cushing syndrome is the result of excessive levels of glucocorticoids. Endogenous Cushing syndrome is rare with an incidence of two to three cases per million per year. Clinically, the presentation consists of a characteristic phenotype including skin symptoms and metabolic manifestations. A frequent co-morbidity with high impact on quality of life is Cushing syndrome associated myopathy. It characteristically affects the proximal myopathy, impairing stair climbing and straightening up. The pathophysiology is complex and involves protein degradation via the forkhead box O3 (FOXO3) pathway, intramuscular fat accumulation, and inactivity-associated muscle atrophy. Surgical remission of Cushing syndrome is the most important step for recovery of muscle function. Restoration depends on age, co-morbidities and postoperative insulin-like growth factor concentrations. At average, functionality remains impaired during the long-term compared to age and sex matched control persons. Growth hormone therapy in individuals with impaired growth hormone secretion could be an option but has not been proved in a randomized trial.

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Editorial

Diabetes, Obesity and Metabolism
Identification of Protein Z as a Potential Novel Biomarker for the Diagnosis of Prediabetes: Seung-Hoi Koo; Endocrinol Metab. 2021;36(3):572-573. Published online June 28, 2021; DOI: https://doi.org/10.3803/EnM.2021.303

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Original Articles

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.

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Thyroid
Insights from a Prospective Follow-up of Thyroid Function and Autoimmunity among COVID-19 Survivors: David Tak Wai Lui, Chi Ho Lee, Wing Sun Chow, Alan Chun Hong Lee, Anthony Raymond Tam, Carol Ho Yi Fong, Chun Yiu Law, Eunice Ka Hong Leung, Kelvin Kai Wang To, Kathryn Choon Beng Tan, Yu Cho Woo, Ching Wan Lam, Ivan Fan Ngai Hung, Karen Siu Ling Lam; Endocrinol Metab. 2021;36(3):582-589. Published online June 8, 2021; DOI: https://doi.org/10.3803/EnM.2021.983

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Background
The occurrence of Graves’ disease and Hashimoto thyroiditis after coronavirus disease 2019 (COVID-19) raised concerns that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may trigger thyroid autoimmunity. We aimed to address the current uncertainties regarding incident thyroid dysfunction and autoimmunity among COVID-19 survivors.
Methods
We included consecutive adult COVID-19 patients without known thyroid disorders, who were admitted to Queen Mary Hospital from July 21 to September 21, 2020 and had serum levels of thyroid-stimulating hormone, free thyroxine, free triiodothyronine (fT3), and anti-thyroid antibodies measured both on admission and at 3 months.
Results
In total, 122 patients were included. Among 20 patients with abnormal thyroid function tests (TFTs) on admission (mostly low fT3), 15 recovered. Among 102 patients with initial normal TFTs, two had new-onset abnormalities that could represent different phases of thyroiditis. Among 104 patients whose anti-thyroid antibody titers were reassessed, we observed increases in anti-thyroid peroxidase (TPO) (P<0.001) and anti-thyroglobulin (P<0.001), but not anti-thyroid stimulating hormone receptor titers (P=0.486). Of 82 patients with negative anti-TPO findings at baseline, 16 had a significant interval increase in anti-TPO titer by >12 U, and four became anti-TPO-positive. Worse baseline clinical severity (P=0.018), elevated C-reactive protein during hospitalization (P=0.033), and higher baseline anti-TPO titer (P=0.005) were associated with a significant increase in anti-TPO titer.
Conclusion
Most patients with thyroid dysfunction on admission recovered during convalescence. Abnormal TFTs suggestive of thyroiditis occurred during convalescence, but infrequently. Importantly, our novel observation of an increase in anti-thyroid antibody titers post-COVID-19 warrants further follow-up for incident thyroid dysfunction among COVID-19 survivors.

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The Influence of SARS-CoV-2 Infection on the Thyroid Gland
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Thyroid
Effect of Cigarette Smoking on Thyroid Cancer: Meta-Analysis: Joon-Hyop Lee, Young Jun Chai, Ka Hee Yi; Endocrinol Metab. 2021;36(3):590-598. Published online May 26, 2021; DOI: https://doi.org/10.3803/EnM.2021.954

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Background
Although smoking is generally carcinogenic, its effect on thyroid cancers is still subject to controversy. The purpose of this study was to summarize the role of smoking in relation to thyroid cancer occurrence.
Methods
We performed a meta-analysis of 24 eligible studies: 21 case-control studies and three prospective cohort studies. The summary odds ratio (OR) and 95% confidence interval (CI) of all studies were acquired based on random effect model. Further subgroup analyses were conducted according to gender, histological type of thyroid cancer, and smoking status of patients for the case-control studies.
Results
The summary effect size indicated a negative association of smoking for thyroid cancer (OR, 0.798; 95% CI, 0.681 to 0.935). From the subgroup analyses for the case-control studies, reduced risk of thyroid cancer was observed in both men (OR, 0.734; 95% CI, 0.553 to 0.974) and women (OR, 0.792; 95% CI, 0.700 to 0.897). The protective effect of smoking was observed in studies in which thyroid cancer was limited to differentiated thyroid cancers (DTCs) (OR, 0.798; 95% CI, 0.706 to 0.902).
Conclusion
Our results suggests that smoking may have a protective effect on thyroid cancer, especially on DTCs. Further studies with larger sample sizes should be conducted in elucidating the dose and time dependent effect of smoking on thyroid cancer with specific focus on the types of thyroid cancers.

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Thyroid
Programmed Cell Death-Ligand 1 (PD-L1) gene Single Nucleotide Polymorphism in Graves’ Disease and Hashimoto’s Thyroiditis in Korean Patients: Jee Hee Yoon, Min-ho Shin, Hee Nam Kim, Wonsuk Choi, Ji Yong Park, A Ram Hong, Hee Kyung Kim, Ho-Cheol Kang; Endocrinol Metab. 2021;36(3):599-606. Published online June 2, 2021; DOI: https://doi.org/10.3803/EnM.2021.965

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Background
Programmed cell death-ligand 1 (PD-L1) has an important role in regulating immune reactions by binding to programmed death 1 (PD-1) on immune cells, which could prevent the exacerbation of autoimmune thyroid disease (AITD). The aim of this study was to evaluate the association of PD-L1 polymorphism with AITD, including Graves’ disease (GD) and Hashimoto’s thyroiditis (HT).
Methods
A total of 189 GD patients, 234 HT patients, and 846 healthy age- and sex-matched controls were enrolled in this study. We analyzed PD-L1 single nucleotide polymorphism (SNP) (rs822339) and investigated the associations with clinical disease course and outcome.
Results
Genotype frequency at the PD-L1 marker RS822339 in GD (P=0.219) and HT (P=0.764) patients did not differ from that among healthy controls. In patients with GD, the A/G or G/G genotype group demonstrated higher TBII titer (20.6±20.5 vs. 28.0± 25.8, P=0.044) and longer treatment duration (39.0±40.4 months vs. 62.4±65.0 months, P=0.003) compared to the A/A genotype group. Among patients in whom anti-thyroid peroxidase (TPO) antibody was measured after treatment of GD, post-treatment antiTPO positivity was higher in the A/G or G/G genotype group compared to the A/A genotype group (48.1% vs. 69.9%, P=0.045). Among patients with HT, there was no significant difference of anti-TPO antibody positivity (79.4% vs. 68.6%, P=0.121), anti-thyroglobulin antibody positivity (80.9% vs. 84.7%, P=0.661), or development to overt hypothyroidism (68.0% vs. 71.1%, P=0.632) between the A/A genotype group and the A/G or G/G genotype group.
Conclusion
The genotype frequency of PD-L1 (rs822339) is not different in patients with AITD compared with healthy controls. The intact PD-1/PD-L1 pathway in GD and HT might be important to maintain chronicity of AITD by protecting immune tolerance. However, the PD-L1 SNP could be associated with difficulty in achieving remission in patients with GD, which may be helpful to predict the possibility of longer treatment. Further studies are required to investigate the complex immune tolerance system in patients with AITD.

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