Endocrinology and Metabolism

Original Article

Sodium-Glucose Cotransporter-2 Inhibitor Enhances Hepatic Gluconeogenesis and Reduces Lipid Accumulation via AMPK-SIRT1 Activation and Autophagy Induction: Si Woo Lee, Hyunki Park, Minyoung Lee, Hyangkyu Lee, Eun Seok Kang; Received October 25, 2024 Accepted February 12, 2025 Published online May 12, 2025; DOI: https://doi.org/10.3803/EnM.2024.2223 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Sodium-glucose cotransporter type 2 (SGLT2) inhibitors, such as dapagliflozin, are primarily used to lower glucose in type 2 diabetes. Recent studies suggest broader metabolic effects, particularly in the liver. This study explores the molecular mechanisms by which dapagliflozin influences hepatic glucose and lipid metabolism, hypothesizing that it activates the 5’-adenosine monophosphate-activated protein kinase (AMPK)-sirtuin 1 (Sirt1) pathway to promote gluconeogenesis and reduce lipid accumulation via autophagy.
Methods
HepG2 hepatocellular carcinoma cells were treated with dapagliflozin, and Western blotting, quantitative reverse transcription polymerase chain reaction, and fluorescence microscopy were used to assess gluconeogenic enzyme expression and autophagy. In vivo, mice with liver-specific autophagy related 7 (Atg7) deletion and those on a high-fat diet were used to evaluate glucose regulation, lipid metabolism, and autophagy.
Results
Dapagliflozin significantly increased expression of gluconeogenic enzymes like phosphoenolpyruvate carboxykinase (PEPCK) in HepG2 cells and enhanced autophagic flux, evidenced by increased light chain 3B (LC3B)-II levels and autophagosome formation. AMPK-Sirt1 activation was confirmed as the underlying mechanism. Additionally, dapagliflozin reduced fatty acid synthesis by suppressing enzymes such as acetyl-CoA carboxylase and fatty acid synthase, while promoting fatty acid degradation via carnitine palmitoyltransferase 1α (CPT1α) upregulation. In high-fat diet mice, dapagliflozin increased hepatic gluconeogenesis and reduced lipid accumulation, though serum cholesterol and triglyceride levels were unaffected.
Conclusion
Dapagliflozin enhances hepatic gluconeogenesis and reduces steatosis by activating the AMPK-Sirt1 pathway and promoting autophagy. These findings suggest that SGLT2 inhibitors could offer therapeutic benefits for managing hepatic lipid disorders, beyond glycemic control.

Review Articles

Hypothalamus and pituitary gland
Medical Treatment of Cushing’s Syndrome: Laurence Guignat, Jerome Bertherat; Endocrinol Metab. 2025;40(1):26-38. Published online January 13, 2025; DOI: https://doi.org/10.3803/EnM.2024.501

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Abstract PDF PubReader ePub: Endogenous Cushing’s syndrome (CS) refers to the manifestations of chronic cortisol excess. This rare disease is associated with multiple comorbidities, impaired quality of life, and increased mortality. The management of CS remains challenging. Regardless of the underlying cause, surgical resection of the tumor is typically the first-line and preferred treatment. However, when surgery is not feasible or has been unsuccessful, medical therapies may be employed to control CS. The therapeutic strategy should be individualized based on the recommendations of a multidisciplinary team of experts and the patient’s preferences, informed by detailed information on the available options. All medications require careful monitoring, along with adequate instructions for patients and caregivers. The aim of this mini-review is to provide an overview of the main medical therapies currently used to treat CS, including their efficacy, safety, and management. Despite the availability of new drugs in recent years, the need remains for more effective specific targeted pharmacological therapies.

Diabetes, obesity and metabolism
Brown Fat and Metabolic Health: The Diverse Functions of Dietary Components: Zachary Brown, Takeshi Yoneshiro; Endocrinol Metab. 2024;39(6):839-846. Published online November 20, 2024; DOI: https://doi.org/10.3803/EnM.2024.2121

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Abstract PDF PubReader ePub: Brown and beige adipocytes utilize a variety of substrates for cold-induced thermogenesis, contributing to the clearance of metabolites in circulation and, consequently, metabolic health. Food-derived compounds that exhibit agonistic activity at temperature-sensitive transient receptor potential channels may serve as cold mimics to elicit thermogenesis and substrate utilization in brown adipose tissue (BAT). In addition to fatty acids and glucose, branched-chain amino acids (BCAAs), which are essential amino acids obtained from foods, are actively catabolized in BAT through mitochondrial BCAA carrier (MBC). The relative contribution of BCAAs to fueling the tricarboxylic acid cycle as a substrate (i.e., anaplerosis) is estimated to be relatively small, yet BCAA catabolism in BAT exerts a critical role in systemic insulin sensitivity. The nature of this apparent tension remained unclear until the recent discovery that active BCAA catabolism in BAT through MBC is critical for the synthesis of metabolites such as glutathione, which is delivered to the liver to improve hepatic insulin sensitivity through redox homeostasis. Novel mechanistic insights into the control of BAT function and systemic metabolism reveal the therapeutic potential of food-derived compounds for improving metabolic flexibility and insulin sensitivity.

Original Articles

Thyroid
In Vitro Investigation of HIF-1α as a Therapeutic Target for Thyroid-Associated Ophthalmopathy: Jeongmin Lee, Jinsoo Lee, Hansang Baek, Dong-Jun Lim, Seong-Beom Lee, Jung-Min Lee, Sang-Ah Jang, Moo Il Kang, Suk-Woo Yang, Min-Hee Kim; Endocrinol Metab. 2024;39(5):767-776. Published online October 16, 2024; DOI: https://doi.org/10.3803/EnM.2024.1952

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Abstract PDF Supplementary Material PubReader ePub: Background
Thyroid-associated ophthalmopathy (TAO) involves tissue expansion and inflammation, potentially causing a hypoxic microenvironment. Hypoxia-inducible factor (HIF)-1α is crucial in fibrosis and adipogenesis, which are observed in TAO progression. We investigated the effects of hypoxia on orbital fibroblasts (OFs) in TAO, focusing on the role of HIF-1α in TAO progression.
Methods
OFs were isolated from TAO and non-TAO patients (as controls). In addition to HIF-1α, adipogenic differentiation markers including peroxisome proliferator-activated receptor γ (PPARγ) and CCAAT/enhancer binding protein (CEBP) were measured by Western blot, and phenotype changes were evaluated by Oil Red O staining under both normoxia and hypoxia. To elucidate the effect of HIF-1α inhibition, protein expression changes after HIF-1α inhibitor treatment were evaluated under normoxia and hypoxia.
Results
TAO OFs exhibited significantly higher HIF-1α expression than non-TAO OFs, and the difference was more distinct under hypoxia than under normoxia. Oil Red O staining showed that adipogenic differentiation of TAO OFs was prominent under hypoxia. Hypoxic conditions increased the expression of adipogenic markers, namely PPARγ and CEBP, as well as HIF-1α in TAO OFs. Interleukin 6 levels also increased in response to hypoxia. The effect of hypoxia on adipogenesis was reduced at the protein level after HIF-1α inhibitor treatment, and this inhibitory effect was sustained even with IGF-1 stimulation in addition to hypoxia.
Conclusion
Hypoxia induces tissue remodeling in TAO by stimulating adipogenesis through HIF-1α activation. These data could provide insights into new treatment strategies and the mechanisms of adipose tissue remodeling in TAO.

Thyroid
TSHR Gene (rs179247) Polymorphism and Susceptibility to Autoimmune Thyroid Disease: A Systematic Review and Meta-Analysis: Hendra Zufry, Timotius Ivan Hariyanto; Endocrinol Metab. 2024;39(4):603-614. Published online August 1, 2024; DOI: https://doi.org/10.3803/EnM.2024.1987

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Abstract PDF Supplementary Material PubReader ePub: Background
Both Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) are classified as autoimmune thyroid diseases (AITDs). It has been hypothesized that changes in the thyroid-stimulating hormone receptor (TSHR) gene may contribute to the development of these conditions. This study aimed to analyze the correlation between the TSHR rs179247 gene polymorphism and susceptibility to AITD.
Methods
We conducted a thorough search of the Google Scholar, Scopus, Medline, and Cochrane Library databases up until March 2, 2024, utilizing a combination of relevant keywords. This review examines data on the association between TSHR rs179247 and susceptibility to AITD. Random-effect models were employed to assess the odds ratio (OR), and the findings are presented along with their respective 95% confidence intervals (CIs).
Results
The meta-analysis included 12 studies. All genetic models of the TSHR rs179247 gene polymorphism were associated with an increased risk of developing GD. Specifically, the associations were observed in the dominant model (OR, 1.65; P<0.00001), recessive model (OR, 1.65; P<0.00001), as well as for the AA genotype (OR, 2.09; P<0.00001), AG genotype (OR, 1.39; P<0.00001), and A allele (OR, 1.44; P<0.00001). Further regression analysis revealed that these associations were consistent regardless of the country of origin, sample size, age, and sex distribution. However, no association was found between TSHR rs179247 and the risk of HT across all genetic models.
Conclusion
This study suggests that the TSHR rs179247 gene polymorphism is associated with an increased risk of GD, but not with HT, and may therefore serve as a potential biomarker.

Diabetes, obesity and metabolism
Inhibition of Sodium-Glucose Cotransporter-2 during Serum Deprivation Increases Hepatic Gluconeogenesis via the AMPK/AKT/FOXO Signaling Pathway: Jinmi Lee, Seok-Woo Hong, Min-Jeong Kim, Yu-Mi Lim, Sun Joon Moon, Hyemi Kwon, Se Eun Park, Eun-Jung Rhee, Won-Young Lee; Endocrinol Metab. 2024;39(1):98-108. Published online January 3, 2024; DOI: https://doi.org/10.3803/EnM.2023.1786

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Background
Sodium-dependent glucose cotransporter 2 (SGLT2) mediates glucose reabsorption in the renal proximal tubules, and SGLT2 inhibitors are used as therapeutic agents for treating type 2 diabetes mellitus. This study aimed to elucidate the effects and mechanisms of SGLT2 inhibition on hepatic glucose metabolism in both serum deprivation and serum supplementation states.
Methods
Huh7 cells were treated with the SGLT2 inhibitors empagliflozin and dapagliflozin to examine the effect of SGLT2 on hepatic glucose uptake. To examine the modulation of glucose metabolism by SGLT2 inhibition under serum deprivation and serum supplementation conditions, HepG2 cells were transfected with SGLT2 small interfering RNA (siRNA), cultured in serum-free Dulbecco’s modified Eagle’s medium for 16 hours, and then cultured in media supplemented with or without 10% fetal bovine serum for 8 hours.
Results
SGLT2 inhibitors dose-dependently decreased hepatic glucose uptake. Serum deprivation increased the expression levels of the gluconeogenesis genes peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), glucose 6-phosphatase (G6pase), and phosphoenolpyruvate carboxykinase (PEPCK), and their expression levels during serum deprivation were further increased in cells transfected with SGLT2 siRNA. SGLT2 inhibition by siRNA during serum deprivation induces nuclear localization of the transcription factor forkhead box class O 1 (FOXO1), decreases nuclear phosphorylated-AKT (p-AKT), and p-FOXO1 protein expression, and increases phosphorylated-adenosine monophosphate-activated protein kinase (p-AMPK) protein expression. However, treatment with the AMPK inhibitor, compound C, reversed the reduction in the protein expression levels of nuclear p- AKT and p-FOXO1 and decreased the protein expression levels of p-AMPK and PEPCK in cells transfected with SGLT2 siRNA during serum deprivation.
Conclusion
These data show that SGLT2 mediates glucose uptake in hepatocytes and that SGLT2 inhibition during serum deprivation increases gluconeogenesis via the AMPK/AKT/FOXO1 signaling pathway.

Citations

Citations to this article as recorded by

Effects of Sodium–Glucose Cotransporter 2 Inhibitors on Transcription Regulation of AgRP and POMC Genes
Dong Hee Kim, Min Jin Lee, Dasol Kang, Ah Reum Khang, Ji Hyun Bae, Joo Yeon Kim, Su Hyun Kim, Yang Ho Kang, Dongwon Yi
Current Issues in Molecular Biology.2024; 46(7): 7505. CrossRef
Sodium-glucose cotransporter 2 inhibitors ameliorate ER stress-induced pro-inflammatory cytokine expression by inhibiting CD36 in NAFLD progression in vitro
Jinmi Lee, Seok-Woo Hong, Min-Jeong Kim, Yu-Mi Lim, Sun Joon Moon, Hyemi Kwon, Se Eun Park, Eun-Jung Rhee, Won-Young Lee
Biochemical and Biophysical Research Communications.2024; 735: 150620. CrossRef

Mineral, Bone & Muscle
MicroRNA-181a-5p Curbs Osteogenic Differentiation and Bone Formation Partially Through Impairing Runx1-Dependent Inhibition of AIF-1 Transcription: Jingwei Liu, Xueying Chang, Daming Dong; Endocrinol Metab. 2023;38(1):156-173. Published online January 6, 2023; DOI: https://doi.org/10.3803/EnM.2022.1516

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Background
Evidence has revealed the involvement of microRNAs (miRNAs) in modulating osteogenic differentiation, implying the promise of miRNA-based therapies for treating osteoporosis. This study investigated whether miR-181a-5p influences osteogenic differentiation and bone formation and aimed to establish the mechanisms in depth.
Methods
Clinical serum samples were obtained from osteoporosis patients, and MC3T3-E1 cells were treated with osteogenic induction medium (OIM) to induce osteogenic differentiation. miR-181a-5p-, Runt-related transcription factor 1 (Runx1)-, and/or allograft inflammatory factor-1 (AIF-1)-associated oligonucleotides or vectors were transfected into MC3T3-E1 cells to explore their function in relation to the number of calcified nodules, alkaline phosphatase (ALP) staining and activity, expression levels of osteogenesis-related proteins, and apoptosis. Luciferase activity, RNA immunoprecipitation, and chromatin immunoprecipitation assays were employed to validate the binding relationship between miR-181a-5p and Runx1, and the transcriptional regulatory relationship between Runx1 and AIF-1. Ovariectomy (OVX)-induced mice were injected with a miR-181a-5p antagonist for in vivo verification.
Results
miR-181a-5p was highly expressed in the serum of osteoporosis patients. OIM treatment decreased miR-181a-5p and AIF-1 expression, but promoted Runx1 expression in MC3T-E1 cells. Meanwhile, upregulated miR-181a-5p suppressed OIM-induced increases in calcified nodules, ALP content, and osteogenesis-related protein expression. Mechanically, miR-181a-5p targeted Runx1, which acted as a transcription factor to negatively modulate AIF-1 expression. Downregulated Runx1 suppressed the miR-181a-5p inhibitor-mediated promotion of osteogenic differentiation, and downregulated AIF-1 reversed the miR-181a-5p mimic-induced inhibition of osteogenic differentiation. Tail vein injection of a miR-181a-5p antagonist induced bone formation in OVX-induced osteoporotic mice.
Conclusion
In conclusion, miR-181a-5p affects osteogenic differentiation and bone formation partially via the modulation of the Runx1/AIF-1 axis.

Citations

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Review Article

Thyroid
The Role of Thyroid Hormone in the Regulation of Cerebellar Development: Sumiyasu Ishii, Izuki Amano, Noriyuki Koibuchi; Endocrinol Metab. 2021;36(4):703-716. Published online August 9, 2021; DOI: https://doi.org/10.3803/EnM.2021.1150

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The proper organized expression of specific genes in time and space is responsible for the organogenesis of the central nervous system including the cerebellum. The epigenetic regulation of gene expression is tightly regulated by an intrinsic intracellular genetic program, local stimuli such as synaptic inputs and trophic factors, and peripheral stimuli from outside of the brain including hormones. Some hormone receptors are expressed in the cerebellum. Thyroid hormones (THs), among numerous circulating hormones, are well-known major regulators of cerebellar development. In both rodents and human, hypothyroidism during the postnatal developmental period results in abnormal morphogenesis or altered function. THs bind to the thyroid hormone receptors (TRs) in the nuclei and with the help of transcriptional cofactors regulate the transcription of target genes. Gene regulation by TR induces cell proliferation, migration, and differentiation, which are necessary for brain development and plasticity. Thus, the lack of TH action mediators may directly cause aberrant cerebellar development. Various kinds of animal models have been established in a bid to study the mechanism of TH action in the cerebellum. Interestingly, the phenotypes differ greatly depending on the models. Herein we summarize the actions of TH and TR particularly in the developing cerebellum.

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Thyroid hormone suppresses medulloblastoma progression through promoting terminal differentiation of tumor cells
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Targeting Thyroid Hormone/Thyroid Hormone Receptor Axis: An Attractive Therapy Strategy in Liver Diseases
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Histone Deacetylase 3 Inhibitor Alleviates Cerebellar Defects in Perinatal Hypothyroid Mice by Stimulating Histone Acetylation and Transcription at Thyroid Hormone-Responsive Gene Loci
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Original Articles

Clinical Study
Molecular Correlates and Nuclear Features of Encapsulated Follicular-Patterned Thyroid Neoplasms: Chan Kwon Jung, Andrey Bychkov, Dong Eun Song, Jang-Hee Kim, Yun Zhu, Zhiyan Liu, Somboon Keelawat, Chiung-Ru Lai, Mitsuyoshi Hirokawa, Kaori Kameyama, Kennichi Kakudo; Endocrinol Metab. 2021;36(1):123-133. Published online February 24, 2021; DOI: https://doi.org/10.3803/EnM.2020.860

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Background
Assessing nuclear features is diagnostically challenging in the aspect of thyroid pathology. The aim of this study was to determine whether pathologists could distinguish BRAF-like and RAS-like nuclear features morphologically and identify morphological features to differentiate thyroid tumors with RAS-like mutations from encapsulated papillary thyroid carcinoma (PTC) with predominant follicular growth and BRAFV^600E mutation.
Methods
Representative whole slide images of 16 encapsulated thyroid tumors with predominant follicular growth were reviewed by 12 thyroid pathologists using a web browser-based image viewer. Total nuclear score was calculated from semi-quantitatively scored eight nuclear features. The molecular profile of RAS and BRAF genes was determined by Sanger sequencing.
Results
Total nuclear score ranging 0 to 24 could differentiate BRAF-like tumors from RAS-like tumors with a cut-off value of score 14. The interobserver agreement was the highest for the assessment of nuclear pseudoinclusions (NPIs) but the lowest for nuclear elongation and sickle-shaped nuclei. NPIs were found in tumors with BRAFV^600E mutation, but not in tumors with RAS-like mutations. Total nuclear scores were significantly higher for tumors with BRAFV^600E than for those with RAS-like mutations (P<0.001).
Conclusion
Our results suggest that NPIs and high nuclear scores have diagnostic utility as rule-in markers for differentiating PTC with BRAFV^600E mutation from benign or borderline follicular tumors with RAS-like mutations. Relaxation of rigid criteria for nuclear features resulted in an overdiagnosis of PTC. Immunostaining or molecular testing for BRAFV^600E mutation is a useful adjunct for cases with high nuclear scores to identify true PTC.

Citations

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Prognosis of invasive encapsulated follicular variant and classical papillary thyroid carcinoma: a propensity score-matched study using the SEER database
Shuai Jin, Lang Xie, Gongyou Zhang, Lei Liu, Kaide Xia, Hongzhou Liu, Haiwang Zhang, Peng Li
Scientific Reports.2025;[Epub] CrossRef
Nuclear pseudoinclusion is associated with BRAFV600E mutation: Analysis of nuclear features in papillary thyroid carcinoma
Agnes Stephanie Harahap, Dina Khoirunnisa, Salinah, Maria Francisca Ham
Annals of Diagnostic Pathology.2025; 75: 152434. CrossRef
“Letter to the Editor: Nuclear pseudo inclusion is associated with BRAFV600E mutation: Analysis of nuclear features in papillary thyroid carcinoma”
Noor Ul Huda, Hafsa Ahsun, Muhammad Fahad Mukhtar
Annals of Diagnostic Pathology.2025; 79: 152516. CrossRef
DICER1 mutations in Bethesda category II, III, and IV thyroid nodules: A mutually exclusive relationship with BRAFV600E mutation
Yulian Wang, Guangqi Li, Weimao Kong, Jianxia Hu, Longnv Bao, Xingzhu Pan, Xueqing Li, Jigang Wang
Cancer Cytopathology.2025;[Epub] CrossRef
Differentiating BRAF V600E- and RAS-like alterations in encapsulated follicular patterned tumors through histologic features: a validation study
Chankyung Kim, Shipra Agarwal, Andrey Bychkov, Jen-Fan Hang, Agnes Stephanie Harahap, Mitsuyoshi Hirokawa, Kennichi Kakudo, Somboon Keelawat, Chih-Yi Liu, Zhiyan Liu, Truong Phan-Xuan Nguyen, Chanchal Rana, Huy Gia Vuong, Yun Zhu, Chan Kwon Jung
Virchows Archiv.2024; 484(4): 645. CrossRef
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Kun-Ping Shih, Yu-Cheng Lee, Jia-Jiun Tsai, Shu-Hui Lin, Chih-Yi Liu, Wan-Shan Li, Chien-Feng Li, Jen-Fan Hang
Endocrine Pathology.2024; 35(2): 134. CrossRef
Small Multi-Gene DNA Panel Can Aid in Reducing the Surgical Resection Rate and Predicting the Malignancy Risk of Thyroid Nodules
Moon Young Oh, Hye-Mi Choi, Jinsun Jang, Heejun Son, Seung Shin Park, Minchul Song, Yoo Hyung Kim, Sun Wook Cho, Young Jun Chai, Woosung Chung, Young Joo Park
Endocrinology and Metabolism.2024; 39(5): 777. CrossRef
Diagnostic challenges in the assessment of thyroid neoplasms using nuclear features and vascular and capsular invasion: a multi-center interobserver agreement study
Agnes Stephanie Harahap, Mutiah Mutmainnah, Maria Francisca Ham, Dina Khoirunnisa, Abdillah Hasbi Assadyk, Husni Cangara, Aswiyanti Asri, Diah Prabawati Retnani, Fairuz Quzwain, Hasrayati Agustina, Hermawan Istiadi, Indri Windarti, Krisna Murti, Muhammad
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The Presence of Typical “BRAFV600E-Like” Atypia in Papillary Thyroid Carcinoma is Highly Specific for the Presence of the BRAFV600E Mutation
John Turchini, Loretta Sioson, Adele Clarkson, Amy Sheen, Leigh Delbridge, Anthony Glover, Mark Sywak, Stan Sidhu, Anthony J. Gill
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Agnes Stephanie Harahap, Imam Subekti, Sonar Soni Panigoro, Asmarinah, Lisnawati, Retno Asti Werdhani, Hasrayati Agustina, Dina Khoirunnisa, Mutiah Mutmainnah, Fajar Lamhot Gultom, Abdillah Hasbi Assadyk, Maria Francisca Ham
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The Asian Thyroid Working Group, from 2017 to 2023
Kennichi Kakudo, Chan Kwon Jung, Zhiyan Liu, Mitsuyoshi Hirokawa, Andrey Bychkov, Huy Gia Vuong, Somboon Keelawat, Radhika Srinivasan, Jen-Fan Hang, Chiung-Ru Lai
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Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP): Tumour Entity with a Short History. A Review on Challenges in Our Microscopes, Molecular and Ultrasonographic Profile
Ivana Kholová, Elina Haaga, Jaroslav Ludvik, David Kalfert, Marie Ludvikova
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Update from the 2022 World Health Organization Classification of Thyroid Tumors: A Standardized Diagnostic Approach
Chan Kwon Jung, Andrey Bychkov, Kennichi Kakudo
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Different Threshold of Malignancy for RAS-like Thyroid Tumors Causes Significant Differences in Thyroid Nodule Practice
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The Incidence of Noninvasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features: A Meta-Analysis Assessing Worldwide Impact of the Reclassification
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Thyroid.2021;[Epub] CrossRef

Endocrine Research
Danshen Extracts Prevents Obesity and Activates Mitochondrial Function in Brown Adipose Tissue: Yoon Hee Cho, Cheol Ryong Ku, Young-Suk Choi, Hyeon Jeong Lee, Eun Jig Lee; Endocrinol Metab. 2021;36(1):185-195. Published online February 24, 2021; DOI: https://doi.org/10.3803/EnM.2020.835

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Background
Danshen has been widely used in oriental medicine to improve body function. The purpose of this study is to investigate the effect of water-soluble Danshen extract (DE) on weight loss and on activation proteins involved in mitochondrial biogenesis in brown adipose tissue (BAT) in obese mice.
Methods
BAT was isolated from 7-week-old male Sprague-Dawley rats, and expression of proteins related to mitochondrial biogenesis was confirmed in both brown preadipocytes and mature brown adipocytes treated with DE. For the in vivo study, low-density lipoprotein receptor knock out mice were divided into three groups and treated for 17 weeks with: standard diet; high fat diet (HFD); HFD+DE. Body weight was measured every week, and oral glucose tolerance test was performed after DE treatment in streptozotocin-induced diabetic mice. To observe the changes in markers related to thermogenesis and adipogenesis in the BAT, white adipose tissue (WAT) and liver of experimental animals, tissues were removed and immediately frozen in liquid nitrogen.
Results
DE increased the expression of uncoupling protein 1 and peroxisome proliferator-activated receptor gamma coactivator 1-alpha in brown preadipocytes, and also promoted the brown adipocyte differentiation and mitochondrial function in the mature brown adipocytes. Reactive oxygen species production in brown preadipocytes was increased depending on the concentration of DE. DE activates thermogenesis in BAT and normalizes increased body weight and adipogenesis in the liver due to HFD. Browning of WAT was increased in WAT of DE treatment group.
Conclusion
DE protects against obesity and activates mitochondrial function in BAT.

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Pharmacological Benefits and Underlying Mechanisms of Salvia miltiorrhiza against Molecular Pathology of Various Liver Diseases: A Review
Cho Hyun Hwang, Eungyeong Jang, Jang-Hoon Lee
The American Journal of Chinese Medicine.2023; 51(07): 1675. CrossRef

Clinical Study
Identification of Novel Genetic Variants Related to Trabecular Bone Score in Community-Dwelling Older Adults: Sung Hye Kong, Ji Won Yoon, Jung Hee Kim, JooYong Park, Jiyeob Choi, Ji Hyun Lee, A Ram Hong, Nam H. Cho, Chan Soo Shin; Endocrinol Metab. 2020;35(4):801-810. Published online November 24, 2020; DOI: https://doi.org/10.3803/EnM.2020.735

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Background
As the genetic variants of trabecular bone microarchitecture are not well-understood, we performed a genome-wide association study to identify genetic determinants of bone microarchitecture analyzed by trabecular bone score (TBS).
Methods
TBS-associated genes were discovered in the Ansung cohort (discovery cohort), a community-based rural cohort in Korea, and then validated in the Gene-Environment Interaction and Phenotype (GENIE) cohort (validation cohort), consisting of subjects who underwent health check-up programs. In the discovery cohort, 2,451 participants were investigated for 1.42 million genotyped and imputed markers.
Results
In the validation cohort, identified as significant variants were evaluated in 2,733 participants. An intronic variant in iroquois homeobox 3 (IRX3), rs1815994, was significantly associated with TBS in men (P=3.74E-05 in the discovery cohort, P=0.027 in the validation cohort). Another intronic variant in mitogen-activated protein kinase kinase 5 (MAP2K5), rs11630730, was significantly associated with TBS in women (P=3.05E-09 in the discovery cohort, P=0.041 in the validation cohort). Men with the rs1815994 variant and women with the rs11630730 variant had lower TBS and lumbar spine bone mineral density. The detrimental effects of the rs1815994 variant in men and rs11630730 variant in women were also identified in association analysis (β=–0.0281, β=–0.0465, respectively).
Conclusion
In this study, the rs1815994 near IRX3 in men and rs11630730 near MAP2K5 in women were associated with deterioration of the bone microarchitecture. It is the first study to determine the association of genetic variants with TBS. Further studies are needed to confirm our findings and identify additional variants contributing to the trabecular bone microarchitecture.

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A novel genetic mouse model of osteoporosis with double heterozygosity of Irx3 and Irx5 characterizes sex-dependent phenotypes in bone homeostasis
Xinyu Chen, Zhengchao Dou, Joe Eun Son, Meng Duan, Fei Yang, Shankuan Zhu, Chi-Chung Hui
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Yunfeng Zhao, Jin Gao, Hong Feng, Li Jiang
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The 14-year cumulative genetic high blood pressure and risk of type 2 diabetes in Korean: observational and Mendelian randomization evidence
Jooeun Jeon, Keum Ji Jung, Heejin Kimm, Ji-young Lee, Chung-Mo Nam, Sun Ha Jee
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Neural EGFL like 1 as a novel gene for Trabecular Bone Score in older adults: The Bushehr Elderly Health (BEH) program
Mohammad Bidkhori, Mahdi Akbarzadeh, Noushin Fahimfar, Mina Jahangiri, Sahar Seddiq, Bagher Larijani, Iraj Nabipour, Mahsa Mohammad Amoli, Nekoo Panahi, Abbas Dehghan, Kourosh Holakouie-Naieni, Afshin Ostovar, Dengshun Miao
PLOS ONE.2024; 19(9): e0309401. CrossRef

Endocrine Research
Serotonin Regulates De Novo Lipogenesis in Adipose Tissues through Serotonin Receptor 2A: Ko Eun Shong, Chang-Myung Oh, Jun Namkung, Sangkyu Park, Hail Kim; Endocrinol Metab. 2020;35(2):470-479. Published online June 24, 2020; DOI: https://doi.org/10.3803/EnM.2020.35.2.470; Correction in: Endocrinol Metab 2020;35(3):672

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Background
Obesity is defined as excessive fat mass and is a major cause of many chronic diseases such as diabetes, cardiovascular disease, and cancer. Increasing energy expenditure and regulating adipose tissue metabolism are important targets for the treatment of obesity. Serotonin (5-hydroxytryptophan [5-HT]) is a monoamine metabolite of the essential amino acid tryptophan. Here, we demonstrated that 5-HT in mature adipocytes regulated energy expenditure and lipid metabolism.
Methods
Tryptophan hydroxylase 1 (TPH1) is the rate-limiting enzyme during 5-HT synthesis in non-neural peripheral tissues. We generated adipose tissue-specific Tph1 knockout (Tph1 FKO) mice and adipose tissue-specific serotonin receptor 2A KO (Htr2a FKO) mice and analyzed their phenotypes during high-fat diet (HFD) induced obesity.
Results
Tph1 FKO mice fed HFD exhibited reduced lipid accumulation, increased thermogenesis, and resistance to obesity. In addition, Htr2a FKO mice fed HFD showed reduced lipid accumulation in white adipose tissue and resistance to obesity.
Conclusion
These data suggest that the inhibition of serotonin signaling might be an effective strategy in obesity.

Citations

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Serotonin signaling to regulate energy metabolism: a gut microbiota perspective
Guoli Li, Sijing Dong, Chunhao Liu, Jing Yang, Patrick C N Rensen, Yanan Wang
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Gut Bacteria-Derived Tryptamine Ameliorates Diet-Induced Obesity and Insulin Resistance in Mice
Jongjun Lee, Hye-Rim Jang, Dongjin Lee, Yeonmi Lee, Hui-Young Lee
International Journal of Molecular Sciences.2025; 26(3): 1327. CrossRef
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Lili Jiang, Dandan Han, Youling Hao, Zhuan Song, Zhiyuan Sun, Zhaolai Dai
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Qin Zhang, Gaopeng Guan, Jie Liu, Wenmu Hu, Ping Jin, Yung-Fu Chang
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Sena L. Field, Everardo Anta Galvan, Laura L. Hernandez, Jimena Laporta, Sina Safayi
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Carmen Arto, Elena Cristina Rusu, Helena Clavero‐Mestres, Andrea Barrientos‐Riosalido, Laia Bertran, Razieh Mahmoudian, Carmen Aguilar, David Riesco, Javier Ugarte Chicote, David Parada, Salomé Martínez, Fàtima Sabench, Cristóbal Richart, Teresa Auguet
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Peripheral Serotonin Controls Dietary Fat Absorption and Chylomicron Secretion via 5-HT4 Receptor in Males
Fitore Raka, Simon Hoffman, Asal Nady, Henry Guan, Rianna Zhang, Huaqing Wang, Waliul I Khan, Khosrow Adeli
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The 5-HT-related gut-brain axis in obesity
Chaoyong Jiang, Qiong Zhan, Chang Zeng
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The Chain-Mediating Effect of Obesity, Depressive Symptoms on the Association between Dietary Quality and Cardiovascular Disease Risk
Shuai Zhang, Limei E, Zhonghai Lu, Yingying Yu, Xuebin Yang, Yao Chen, Xiubo Jiang
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Metabolic and Molecular Response to High-Fat Diet Differs between Rats with Constitutionally High and Low Serotonin Tone
Petra Baković, Maja Kesić, Darko Kolarić, Jasminka Štefulj, Lipa Čičin-Šain
International Journal of Molecular Sciences.2023; 24(3): 2169. CrossRef
Serotonin transporter-deficient mice display enhanced adipose tissue inflammation after chronic high-fat diet feeding
Johannes Hoch, Niklas Burkhard, Shanshan Zhang, Marina Rieder, Timoteo Marchini, Vincent Geest, Krystin Krauel, Timm Zahn, Nicolas Schommer, Muataz Ali Hamad, Carolina Bauer, Nadine Gauchel, Daniela Stallmann, Claus Normann, Dennis Wolf, Rüdiger Eberhard
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The role of serotonin in prenatal ontogenesis
Inna I. Evsyukova
Journal of obstetrics and women's diseases.2023; 72(4): 81. CrossRef
Genome-wide survey and functional analysis reveal TCF21 promotes chicken preadipocyte differentiation by directly upregulating HTR2A
Xinyang Zhang, Bohan Cheng, Yanyan Ma, Yumeng Liu, Ning Wang, Hui Zhang, Yumao Li, Yuxiang Wang, Peng Luan, Zhiping Cao, Hui Li
Biochemical and Biophysical Research Communications.2022; 587: 131. CrossRef
Maternal Metabolic State and Fetal Sex and Genotype Modulate Methylation of the Serotonin Receptor Type 2A Gene (HTR2A) in the Human Placenta
Marina Horvatiček, Maja Perić, Ivona Bečeheli, Marija Klasić, Maja Žutić, Maja Kesić, Gernot Desoye, Sandra Nakić Radoš, Marina Ivanišević, Dubravka Hranilovic, Jasminka Štefulj
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Synthesis and biological evaluation of tyrosine derivatives as peripheral 5HT2A receptor antagonists for nonalcoholic fatty liver disease
Minhee Kim, Wonil Choi, Jihyeon Yoon, Byung-kwan Jeong, Suvarna H. Pagire, Haushabhau S. Pagire, Jungsun Park, Jung Eun Nam, Chang Joo Oh, Jae-Han Jeon, Seong Soon Kim, Byung Hoi Lee, Jin Sook Song, Myung Ae Bae, In-Kyu Lee, Hail Kim, Jin Hee Ahn
European Journal of Medicinal Chemistry.2022; 239: 114517. CrossRef
Serotonin in the regulation of systemic energy metabolism
Joon Ho Moon, Chang‐Myung Oh, Hail Kim
Journal of Diabetes Investigation.2022; 13(10): 1639. CrossRef
Traumatic brain injury alters the gut-derived serotonergic system and associated peripheral organs
Natosha M. Mercado, Guanglin Zhang, Zhe Ying, Fernando Gómez-Pinilla
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Modulation of adipose tissue metabolism by microbial-derived metabolites
Wenyun Liu, Ge Yang, Pinyi Liu, Xin Jiang, Ying Xin
Frontiers in Microbiology.2022;[Epub] CrossRef
Risperidone Exacerbates Glucose Intolerance, Nonalcoholic Fatty Liver Disease, and Renal Impairment in Obese Mice
Hsiao-Pei Tsai, Po-Hsun Hou, Frank-Chiahung Mao, Chia-Chia Chang, Wei-Cheng Yang, Ching-Feng Wu, Huei-Jyuan Liao, Tzu-Chun Lin, Lan-Szu Chou, Li-Wei Hsiao, Geng-Ruei Chang
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Pancreatic Sirtuin 3 Deficiency Promotes Hepatic Steatosis by Enhancing 5-Hydroxytryptamine Synthesis in Mice With Diet-Induced Obesity
Xing Ming, Arthur C.K. Chung, Dandan Mao, Huanyi Cao, Baoqi Fan, Willy K.K. Wong, Chin Chung Ho, Heung Man Lee, Kristina Schoonjans, Johan Auwerx, Guy A. Rutter, Juliana C.N. Chan, Xiao Yu Tian, Alice P.S. Kong
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Eun Jung Bae, Won Gun Choi, Haushabhau S. Pagire, Suvarna H. Pagire, Saravanan Parameswaran, Jun-Ho Choi, Jihyeon Yoon, Won-il Choi, Ji Hun Lee, Jin Sook Song, Myung Ae Bae, Mijin Kim, Jae-Han Jeon, In-Kyu Lee, Hail Kim, Jin Hee Ahn
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A Systems Biology Approach to Investigating the Interaction between Serotonin Synthesis by Tryptophan Hydroxylase and the Metabolic Homeostasis
Suhyeon Park, Yumin Kim, Jibeom Lee, Jeong Yun Lee, Hail Kim, Sunjae Lee, Chang-Myung Oh
International Journal of Molecular Sciences.2021; 22(5): 2452. CrossRef
Metabolic Disturbances in Rat Sublines with Constitutionally Altered Serotonin Homeostasis
Maja Kesić, Petra Baković, Ranko Stojković, Jasminka Štefulj, Lipa Čičin-Šain
International Journal of Molecular Sciences.2021; 22(10): 5400. CrossRef
The Mechanism of Secretion and Metabolism of Gut-Derived 5-Hydroxytryptamine
Ning Liu, Shiqiang Sun, Pengjie Wang, Yanan Sun, Qingjuan Hu, Xiaoyu Wang
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Inhibiting serotonin signaling through HTR2B in visceral adipose tissue improves obesity-related insulin resistance
Won Gun Choi, Wonsuk Choi, Tae Jung Oh, Hye-Na Cha, Inseon Hwang, Yun Kyung Lee, Seung Yeon Lee, Hyemi Shin, Ajin Lim, Dongryeol Ryu, Jae Myoung Suh, So-Young Park, Sung Hee Choi, Hail Kim
Journal of Clinical Investigation.2021;[Epub] CrossRef
Serotonergic Regulation of Hepatic Energy Metabolism
Jiwon Park, Wooju Jeong, Chahyeon Yun, Hail Kim, Chang-Myung Oh
Endocrinology and Metabolism.2021; 36(6): 1151. CrossRef

Endocrine Research
Transformation of Mature Osteoblasts into Bone Lining Cells and RNA Sequencing-Based Transcriptome Profiling of Mouse Bone during Mechanical Unloading: A Ram Hong, Kwangsoo Kim, Ji Yeon Lee, Jae-Yeon Yang, Jung Hee Kim, Chan Soo Shin, Sang Wan Kim; Endocrinol Metab. 2020;35(2):456-469. Published online June 24, 2020; DOI: https://doi.org/10.3803/EnM.2020.35.2.456; Correction in: Endocrinol Metab 2021;36(6):1314

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Background
We investigated RNA sequencing-based transcriptome profiling and the transformation of mature osteoblasts into bone lining cells (BLCs) through a lineage tracing study to better understand the effect of mechanical unloading on bone loss.
Methods
Dmp1-CreERt2(+):Rosa26R mice were injected with 1 mg of 4-hydroxy-tamoxifen three times a week starting at postnatal week 7, and subjected to a combination of botulinum toxin injection with left hindlimb tenotomy starting at postnatal week 8 to 10. The animals were euthanized at postnatal weeks 8, 9, 10, and 12. We quantified the number and thickness of X-gal(+) cells on the periosteum of the right and left femoral bones at each time point.
Results
Two weeks after unloading, a significant decrease in the number and a subtle change in the thickness of X-gal(+) cells were observed in the left hindlimbs compared with the right hindlimbs. At 4 weeks after unloading, the decrease in the thickness was accelerated in the left hindlimbs, although the number of labeled cells was comparable. RNA sequencing analysis showed downregulation of 315 genes in the left hindlimbs at 2 and 4 weeks after unloading. Of these, Xirp2, AMPD1, Mettl11b, NEXN, CYP2E1, Bche, Ppp1r3c, Tceal7, and Gadl1 were upregulated during osteoblastogenic/osteocytic and myogenic differentiation in vitro.
Conclusion
These findings demonstrate that mechanical unloading can accelerate the transformation of mature osteoblasts into BLCs in the early stages of bone loss in vivo. Furthermore, some of the genes involved in this process may have a pleiotropic effect on both bone and muscle.

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Review Article

Miscellaneous
Rare PTH Gene Mutations Causing Parathyroid Disorders: A Review: Joon-Hyop Lee, Munkhtugs Davaatseren, Sihoon Lee; Endocrinol Metab. 2020;35(1):64-70. Published online March 19, 2020; DOI: https://doi.org/10.3803/EnM.2020.35.1.64

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Since parathyroid hormone (PTH) was first isolated and its gene (PTH) was sequenced, only eight PTH mutations have been discovered. The C18R mutation in PTH, discovered in 1990, was the first to be reported. This autosomal dominant mutation induces endoplasmic reticulum stress and subsequent apoptosis in parathyroid cells. The next mutation, which was reported in 1992, is associated with exon skipping. The substitution of G with C in the first nucleotide of the second intron results in the exclusion of the second exon; since this exon includes the initiation codon, translation initiation is prevented. An S23P mutation and an S23X mutation at the same residue were reported in 1999 and 2012, respectively. Both mutations resulted in hypoparathyroidism. In 2008, a somatic R83X mutation was detected in a parathyroid adenoma tissue sample collected from a patient with hyperparathyroidism. In 2013, a heterozygous p.Met1_Asp6del mutation was incidentally discovered in a case-control study. Two years later, the R56C mutation was reported; this is the only reported hypoparathyroidism-causing mutation in the mature bioactive part of PTH. In 2017, another heterozygous mutation, M14K, was detected. The discovery of these eight mutations in the PTH gene has provided insights into its function and broadened our understanding of the molecular mechanisms underlying mutation progression. Further attempts to detect other such mutations will help elucidate the functions of PTH in a more sophisticated manner.

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Valerie Walker
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Case report: Familial hypoparathyroidism with elevated parathyroid hormone due to an inactivating PTH mutation
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Primary Hyperparathyroidism With Undetectable Intact Parathyroid Hormone
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Homozygous Ser-1 to Pro-1 mutation in parathyroid hormone identified in hypocalcemic patients results in secretion of a biologically inactive pro-hormone
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Stine Linding Andersen, Anja Lisbeth Frederiksen, Astrid Bruun Rasmussen, Mette Madsen, Ann-Margrethe Rønholt Christensen
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Case Report

A Case of Thyroid Hemiagenesis with Papillary Adenocarcinoma.: Je Ho Han, Bong Yun Cha, Ho Young Son, Yoo Bae Ahn, Kwang Woo Lee, Sung Koo Kang, Se Jeong Oh, Jong Soon Na, Sang Ah Jang, Moo Il Kang; J Korean Endocr Soc. 1994;9(4):385-389. Published online November 6, 2019

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Abstract PDF: Variation in the gross anatomy of the thyroid is relatively common. Although thyroid hemiagenesis is considered to be a rare congenital anomaly, its incidence is probably underestimated because the diagnosis is usually incidental.We present the case of a 26-year-old woman with right thyroid hemiagenesis associated with papillary adenocarcinoma. The diagnosis of hemiagenesis was established by isotope imaging, which showed hot nodule, thyroid ultrasonography and surgical exploration for proper management of a nodule in the left lobe of thyroid gland. As she was diagnosed to have papillary adenocarcinoma, total thyroidectomy was performed and at present she remains disease-free.

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