Endocrinology and Metabolism

Volume 36(4); August 2021

Review Articles

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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Neuropeptides and Their Roles in the Cerebellum
Zi-Hao Li, Bin Li, Xiao-Yang Zhang, Jing-Ning Zhu
International Journal of Molecular Sciences.2024; 25(4): 2332. CrossRef
Mapping Thyroid Hormone Action in the Human Brain
Federico Salas-Lucia
Thyroid®.2024; 34(7): 815. CrossRef
Thyroid hormone suppresses medulloblastoma progression through promoting terminal differentiation of tumor cells
Yijun Yang, Silvia Anahi Valdés-Rives, Qing Liu, Tong Gao, Chakkapong Burudpakdee, Yuzhe Li, Jun Tan, Yinfei Tan, Christian A. Koch, Yuan Rong, Steven R. Houser, Shuanzeng Wei, Kathy Q. Cai, Jinhua Wu, Sheue-yann Cheng, Robert Wechsler-Reya, Zeng-jie Yang
Cancer Cell.2024; 42(8): 1434. CrossRef
The Effects of Thyroid Hormones on Brain Development
Izuki Amano
The Kitakanto Medical Journal.2024; 74(3): 213. CrossRef
Exploring the underlying molecular mechanism of tri(1,3-dichloropropyl) phosphate-induced neurodevelopmental toxicity via thyroid hormone disruption in zebrafish by multi-omics analysis
Ying Xu, Lei Yang, Yanguo Teng, Jian Li, Na Li
Aquatic Toxicology.2023; 258: 106510. CrossRef
Association of Maternal TSH, FT4 With Children's BMI Trajectories, and Obesity: A Birth Cohort Study
Mengting Yang, Shanshan Zhang, Yuzhu Teng, Xue Ru, Linlin Zhu, Yan Han, Xingyong Tao, Hui Cao, Shuangqin Yan, Fangbiao Tao, Kun Huang
The Journal of Clinical Endocrinology & Metabolism.2023; 109(1): e190. CrossRef
Thyroid hormone receptor beta: Relevance in human health and diseases
Ghausiya Rehman, Neha Kumari, Farhad Bano, Rakesh K. Tyagi
Endocrine and Metabolic Science.2023; 13: 100144. CrossRef
Targeting Thyroid Hormone/Thyroid Hormone Receptor Axis: An Attractive Therapy Strategy in Liver Diseases
Qianyu Tang, Min Zeng, Linxi Chen, Nian Fu
Frontiers in Pharmacology.2022;[Epub] CrossRef
Histone Deacetylase 3 Inhibitor Alleviates Cerebellar Defects in Perinatal Hypothyroid Mice by Stimulating Histone Acetylation and Transcription at Thyroid Hormone-Responsive Gene Loci
Alvin Susetyo, Sumiyasu Ishii, Yuki Fujiwara, Izuki Amano, Noriyuki Koibuchi
International Journal of Molecular Sciences.2022; 23(14): 7869. CrossRef
Selection-driven adaptation to the extreme Antarctic environment in the Emperor penguin
Federica Pirri, Lino Ometto, Silvia Fuselli, Flávia A. N. Fernandes, Lorena Ancona, Nunzio Perta, Daniele Di Marino, Céline Le Bohec, Lorenzo Zane, Emiliano Trucchi
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Long-term depression–inductive stimulation causes long-term potentiation in mouse Purkinje cells with a mutant thyroid hormone receptor
Ayane Ninomiya, Izuki Amano, Michifumi Kokubo, Yusuke Takatsuru, Sumiyasu Ishii, Hirokazu Hirai, Nobutake Hosoi, Noriyuki Koibuchi
Proceedings of the National Academy of Sciences.2022;[Epub] CrossRef

Thyroid
Active Surveillance as an Effective Management Option for Low-Risk Papillary Thyroid Microcarcinoma: Min Ji Jeon, Won Gu Kim, Tae Yong Kim, Young Kee Shong, Won Bae Kim; Endocrinol Metab. 2021;36(4):717-724. Published online August 11, 2021; DOI: https://doi.org/10.3803/EnM.2021.1042; Correction in: Endocrinol Metab 2022;37(1):180

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Active surveillance (AS) for low-risk papillary thyroid microcarcinoma (PTMC) has been accepted worldwide as safe and effective. Despite the growing acceptance of AS in the management of low-risk PTMCs, there are barriers to AS in real clinical settings, and it is important to understand and establish appropriate AS protocol from initial evaluation to follow-up. PTMC management strategies should be decided upon after careful consideration of patient and tumor characteristics by a multidisciplinary team of thyroid cancer specialists. Patients should understand the risks and benefits of AS, participate in decision-making and follow structured monitoring strategies. In this review, we discuss clinical outcomes of AS from previous studies, optimal indications and follow-up strategies for AS, and unresolved questions about AS.

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Diagnostic Accuracy of Preoperative Radiologic Findings in Papillary Thyroid Microcarcinoma: Discrepancies with the Postoperative Pathologic Diagnosis and Implications for Clinical Outcomes
Ying Li, Seul Ki Kwon, Hoonsung Choi, Yoo Hyung Kim, Sunyoung Kang, Kyeong Cheon Jung, Jae-Kyung Won, Do Joon Park, Young Joo Park, Sun Wook Cho
Endocrinology and Metabolism.2024; 39(3): 450. CrossRef
Serum thyroglobulin testing after thyroid lobectomy in patients with 1–4 cm papillary thyroid carcinoma
Ahreum Jang, Meihua Jin, Chae A Kim, Min Ji Jeon, Yu-Mi Lee, Tae-Yon Sung, Tae Yong Kim, Won Bae Kim, Young Kee Shong, Won Gu Kim
Endocrine.2023; 81(2): 290. CrossRef
Papillary Thyroid Microcarcinoma: Active Surveillance Against Surgery. Considerations of an Italian Working Group From a Systematic Review
Giuseppina Orlando, Gregorio Scerrino, Alessandro Corigliano, Irene Vitale, Roberta Tutino, Stefano Radellini, Francesco Cupido, Giuseppa Graceffa, Gianfranco Cocorullo, Giuseppe Salamone, Giuseppina Melfa
Frontiers in Oncology.2022;[Epub] CrossRef
Prognosis of Patients with 1–4 cm Papillary Thyroid Cancer Who Underwent Lobectomy: Focus on Gross Extrathyroidal Extension Invading Only the Strap Muscles
Ahreum Jang, Meihua Jin, Won Woong Kim, Min Ji Jeon, Tae-Yon Sung, Dong Eun Song, Tae Yong Kim, Ki-Wook Chung, Won Bae Kim, Young Kee Shong, Yu-Mi Lee, Won Gu Kim
Annals of Surgical Oncology.2022; 29(12): 7835. CrossRef

Thyroid
The Concept of Economic Evaluation and Its Application in Thyroid Cancer Research: Kyungsik Kim, Mijin Kim, Woojin Lim, Bo Hyun Kim, Sue K. Park; Endocrinol Metab. 2021;36(4):725-736. Published online August 27, 2021; DOI: https://doi.org/10.3803/EnM.2021.1164

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Economic evaluation is a type of comparative analysis between interventions in terms of both their resource use and health outcomes. Due to the good prognosis of thyroid cancer (TC), the socioeconomic burden of TC patients post-diagnosis is increasing. Therefore, economic evaluation studies focusing on TC are recommended. This study aimed to describe the concept and methods of economic evaluation and reviewed previous TC studies. Several previous studies compared the costs of interventions or evaluated recurrence, complications, or quality of life as measures of their effectiveness. Regarding costs, most studies focused on direct costs and applied hypothetical models. Cost-minimization analysis should be distinguished from simple cost analysis. Furthermore, due to the universality of the term “cost-effectiveness analysis” (CEA), several studies have not distinguished CEA from cost-utility analysis; this point needs to be considered in future research. Cost-benefit analyses have not been conducted in previous TC research. Since TC has a high survival rate and good prognosis, the need for economic evaluations has recently been pointed out. Therefore, correct concepts and methods are needed to obtain clear economic evaluation results. On this basis, it will be possible to provide appropriate guidelines for TC treatment and management in the future.

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Cost-Utility Analysis of Early Detection with Ultrasonography of Differentiated Thyroid Cancer: A Retrospective Study on a Korean Population
Han-Sang Baek, Jeonghoon Ha, Kwangsoon Kim, Ja Seong Bae, Jeong Soo Kim, Sungju Kim, Dong-Jun Lim, Chul-Min Kim
Endocrinology and Metabolism.2024; 39(2): 310. CrossRef
Role of Prehabilitation and Rehabilitation on Functional Recovery and Quality of Life in Thyroid Cancer Patients: A Comprehensive Review
Lorenzo Lippi, Alessio Turco, Stefano Moalli, Marco Gallo, Claudio Curci, Antonio Maconi, Alessandro de Sire, Marco Invernizzi
Cancers.2023; 15(18): 4502. CrossRef
Sex-specific Associations between Body Mass Index and Thyroid Cancer Incidence among Korean Adults
Kyoung-Nam Kim, Kyungsik Kim, Sangjun Lee, Sue K. Park
Cancer Epidemiology, Biomarkers & Prevention.2023; 32(9): 1227. CrossRef
Active Surveillance Versus Immediate Surgery for Low-Risk Papillary Thyroid Microcarcinoma Patients in South Korea: A Cost-Minimization Analysis from the MAeSTro Study
Kyungsik Kim, June Young Choi, Su-jin Kim, Eun Kyung Lee, Young Ki Lee, Jun Sun Ryu, Kyu Eun Lee, Jae Hoon Moon, Young Joo Park, Sun Wook Cho, Sue K. Park
Thyroid.2022; 32(6): 648. CrossRef
A Systematic Review of Economic Evaluation of Thyroid Cancer
Mijin Kim, Woojin Lim, Kyungsik Kim, Ja Seong Bae, Byung Joo Lee, Bon Seok Koo, Eun Kyung Lee, Eu Jeong Ku, June Young Choi, Bo Hyun Kim, Sue K. Park
International Journal of Thyroidology.2022; 15(2): 74. CrossRef

Diabetes, Obesity and Metabolism
Exercise/Resistance Training and Muscle Stem Cells: So-ichiro Fukada, Ayasa Nakamura; Endocrinol Metab. 2021;36(4):737-744. Published online August 10, 2021; DOI: https://doi.org/10.3803/EnM.2021.401

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Skeletal muscle has attracted attention as endocrine organ, because exercise-dependent cytokines called myokines/exerkines are released from skeletal muscle and are involved in systemic functions. While, local mechanical loading to skeletal muscle by exercise or resistance training alters myofiber type and size and myonuclear number. Skeletal muscle-resident stem cells, known as muscle satellite cells (MuSCs), are responsible for the increased number of myonuclei. Under steady conditions, MuSCs are maintained in a mitotically quiescent state but exit from that state and start to proliferate in response to high physical activity. Alterations in MuSC behavior occur when myofibers are damaged, but the lethal damage to myofibers does not seem to evoke mechanical loading-dependent MuSC activation and proliferation. Given that MuSCs proliferate without damage, it is unclear how the different behaviors of MuSCs are controlled by different physical activities. Recent studies demonstrated that myonuclear number reflects the size of myofibers; hence, it is crucial to know the properties of MuSCs and the mechanism of myonuclear accretion by MuSCs. In addition, the elucidation of mechanical load-dependent changes in muscle resident cells, including MuSCs, will be necessary for the discovery of new myokines/exerkines and understating skeletal muscle diseases.

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Diabetes, Obesity and Metabolism
Effects of Intermittent Fasting on the Circulating Levels and Circadian Rhythms of Hormones: Bo Hye Kim, Yena Joo, Min-Seon Kim, Han Kyoung Choe, Qingchun Tong, Obin Kwon; Endocrinol Metab. 2021;36(4):745-756. Published online August 27, 2021; DOI: https://doi.org/10.3803/EnM.2021.405

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Intermittent fasting has become an increasingly popular strategy in losing weight and associated reduction in obesity-related medical complications. Overwhelming studies support metabolic improvements from intermittent fasting in blood glucose levels, cardiac and brain function, and other health benefits, in addition to weight loss. However, concerns have also been raised on side effects including muscle loss, ketosis, and electrolyte imbalance. Of particular concern, the effect of intermittent fasting on hormonal circadian rhythms has received little attention. Given the known importance of circadian hormonal changes to normal physiology, potential detrimental effects by dysregulation of hormonal changes deserve careful discussions. In this review, we describe the changes in circadian rhythms of hormones caused by intermittent fasting. We covered major hormones commonly pathophysiologically involved in clinical endocrinology, including insulin, thyroid hormones, and glucocorticoids. Given that intermittent fasting could alter both the level and frequency of hormone secretion, decisions on practicing intermittent fasting should take more considerations on potential detrimental consequences versus beneficial effects pertaining to individual health conditions.

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Special Article

Miscellaneous
COVID-19 Vaccination for Endocrine Patients: A Position Statement from the Korean Endocrine Society: Cheol Ryong Ku, Kyong Yeun Jung, Chang Ho Ahn, Jun Sung Moon, Ju Hee Lee, Eun Heui Kim, Hyemi Kwon, Hee Kyung Kim, Sunghwan Suh, Sangmo Hong, Jeonghoon Ha, Eun Roh, Jin Hwa Kim, Mi-kyung Kim, the Committee of Clinical Practice Guideline of the Korean Endocrine Society; Endocrinol Metab. 2021;36(4):757-765. Published online August 17, 2021; DOI: https://doi.org/10.3803/EnM.2021.404

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Since the first outbreak of coronavirus disease 2019 (COVID-19), ongoing efforts have been made to discover an efficacious vaccine against COVID-19 to combat the pandemic. In most countries, both mRNA and DNA vaccines have been administered, and their side effects have also been reported. The clinical course of COVID-19 and the effects of vaccination against COVID-19 are both influenced by patients’ health status and involve a systemic physiological response. In view of the systemic function of endocrine hormones, endocrine disorders themselves and the therapeutics used to treat them can influence the outcomes of vaccination for COVID-19. However, there are very limited data to support the development of clinical guidelines for patients with specific medical backgrounds based on large clinical trials. In the current severe circumstances of the COVID-19 pandemic, position statements made by clinical specialists are essential to provide appropriate recommendations based on both medical evidence and clinical experiences. As endocrinologists, we would like to present the medical background of COVID-19 vaccination, as well as precautions to prevent the side effects of COVID-19 vaccination in patients with specific endocrine disorders, including adrenal insufficiency, diabetes mellitus, osteoporosis, autoimmune thyroid disease, hypogonadism, and pituitary disorders.

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Editorial

Diabetes, Obesity and Metabolism
Higher Weight Variability Could Bring You a Fatty Liver: Yeoree Yang, Jae-Hyoung Cho; Endocrinol Metab. 2021;36(4):766-768. Published online August 27, 2021; DOI: https://doi.org/10.3803/EnM.2021.403

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Original Articles

Thyroid
Thyroid Hormone Profile and Its Prognostic Impact on the Coronavirus Disease 2019 in Korean Patients: Jiyeon Ahn, Min Kyung Lee, Jae Hyuk Lee, Seo Young Sohn; Endocrinol Metab. 2021;36(4):769-777. Published online August 27, 2021; DOI: https://doi.org/10.3803/EnM.2021.1109

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Background
Data on the association between coronavirus disease 2019 (COVID-19) and thyroid have been reported, including overt thyrotoxicosis and suppression of thyroid function. We aimed to evaluate the thyroid hormone profile and its association with the prognosis of COVID-19 in Korean patients.
Methods
The clinical data of 119 patients with COVID-19, admitted in the Myongji Hospital, Goyang, South Korea, were retrospectively evaluated. The thyroid hormone profiles were analyzed and compared based on disease severity (non-severe disease vs. severe to critical disease). Clinical outcomes were analyzed according to the tertiles of thyroid hormones.
Results
Of the 119 patients, 76 (63.9%) were euthyroid, and none presented with overt thyroid dysfunction. Non-thyroidal illness syndrome was the most common manifestation (18.5%), followed by subclinical thyrotoxicosis (14.3%) among patients with thyroid dysfunction. Thyroid stimulating hormone (TSH) and triiodothyronine (T3) levels were significantly lower in patients with severe to critical disease than in those with non-severe disease (P<0.05). Patients in the lowest T3 tertile (<0.77 ng/mL) had higher rates of mechanical ventilation, intensive care unit admission, and death than those in the middle and highest (>1.00 ng/mL) T3 tertiles (P<0.05). COVID-19 patients in the lowest T3 tertile were independently associated with mortality (hazard ratio, 5.27; 95% confidence interval, 1.09 to 25.32; P=0.038) compared with those in the highest T3 tertile.
Conclusion
Thyroid dysfunction is common in COVID-19 patients. Changes in serum TSH and T3 levels may be important markers of disease severity in COVID-19. Decreased T3 levels may have a prognostic significance in COVID-19 related outcome.

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Anamarija Zrilic Vrkljan, Ana Majic Tengg, Tanja Palaversa, Srecko Marusic, Lana Ruzic, Ines Bilic-Curcic, Maja Cigrovski Berkovic
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Thyroid
The Positive Association between Subclinical Hypothyroidism and Newly-Diagnosed Hypertension Is More Explicit in Female Individuals Younger than 65: Xichang Wang, Haoyu Wang, Li Yan, Lihui Yang, Yuanming Xue, Jing Yang, Yongli Yao, Xulei Tang, Nanwei Tong, Guixia Wang, Jinan Zhang, Youmin Wang, Jianming Ba, Bing Chen, Jianling Du, Lanjie He, Xiaoyang Lai, Yanbo Li, Zhaoli Yan, Eryuan Liao, Chao Liu, Libin Liu, Guijun Qin, Yingfen Qin, Huibiao Quan, Bingyin Shi, Hui Sun, Zhen Ye, Qiao Zhang, Lihui Zhang, Jun Zhu, Mei Zhu, Yongze Li, Weiping Teng, Zhongyan Shan; Endocrinol Metab. 2021;36(4):778-789. Published online August 10, 2021; DOI: https://doi.org/10.3803/EnM.2021.1101

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Background
Subclinical hypothyroidism (SCH) is the most common thyroid dysfunction, and its relationship with blood pressure (BP) has been controversial. The aim of the study was to analyze the association between SCH and newly-diagnosed hypertension.
Methods
Based on data from the Thyroid disease, Iodine nutrition and Diabetes Epidemiology (TIDE) study, 49,433 euthyroid individuals and 7,719 SCH patients aged ≥18 years were enrolled. Patients with a history of hypertension or thyroid disease were excluded. SCH was determined by manufacturer reference range. Overall hypertension and stage 1 and 2 hypertension were diagnosed according to the guidelines issued by the American College of Cardiology/American Heart Association in 2017.
Results
The prevalence of overall hypertension (48.7%), including stage 1 (28.9%) and 2 (19.8%) hypertension, increased significantly in SCH patients compared with euthyroid subjects. With elevated serum thyroid stimulating hormone (TSH) level, the hypertension prevalence also increased significantly from the euthyroid to different SCH subgroups, which was more profound in females or subjects aged <65 years. The age- and sex-specific regression analysis further demonstrated the same trends in the general population and in the 1:1 propensity matched population. Similarly, several BP components (i.e., systolic, diastolic, and mean arterial BP) were positively associated with TSH elevation, and regression analysis also confirmed that all BP components were closely related with SCH in female subjects aged <65 years.
Conclusion
The prevalence of hypertension increases for patients with SCH. SCH tends to be associated with hypertension and BP components in females younger than 65 years.

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Thyroid
Association between Iodine Intake, Thyroid Function, and Papillary Thyroid Cancer: A Case-Control Study: Kyungsik Kim, Sun Wook Cho, Young Joo Park, Kyu Eun Lee, Dong-Wook Lee, Sue K. Park; Endocrinol Metab. 2021;36(4):790-799. Published online August 11, 2021; DOI: https://doi.org/10.3803/EnM.2021.1034

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Background
This study aimed to assess the effects of iodine intake, thyroid function, and their combined effect on the risk of papillary thyroid cancer (PTC) and papillary thyroid microcarcinoma (PTMC).
Methods
A case-control study was conducted including 500 community-based controls who had undergone a health check-up, and 446 overall PTC cases (209 PTC and 237 PTMC) from the Thyroid Cancer Longitudinal Study. Urinary iodine concentration (UIC), was used as an indicator of iodine intake, and serum for thyroid function. The risk of PTC and PTMC was estimated using unconditional logistic regression.
Results
Excessive iodine intake (UIC ≥220 μg/gCr) was associated with both PTC (odds ratio [OR], 18.13 95% confidence interval [CI], 8.87 to 37.04) and PTMC (OR, 8.02; 95% CI, 4.64 to 13.87), compared to adequate iodine intake (UIC, 85 to 219 μg/gCr). Free thyroxine (T4) levels ≥1.25 ng/dL were associated with PTC (OR, 1.97; 95% CI, 1.36 to 2.87) and PTMC (OR, 2.98; 95% CI, 2.01 to 4.41), compared to free T4 levels of 0.7 to 1.24 ng/dL. Individuals with excessive iodine intake and high free T4 levels had a greatly increased OR of PTC (OR, 43.48; 95% CI, 12.63 to 149.62), and PTMC (OR, 26.96; 95% CI, 10.26 to 70.89), compared to individuals with adequate iodine intake and low free T4 levels.
Conclusion
Excessive iodine intake using creatinine-adjusted UIC and high free T4 levels may have a synergistic effect on PTC and PTMC. Considering both iodine intake and thyroid function is important to assess PTC and PTMC risk.

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Kyoung-Nam Kim, Kyungsik Kim, Sangjun Lee, Sue K. Park
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Vladimir Zaichick
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Vladimir Zaichick
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Diabetes, Obesity and Metabolism
High Fibrosis-4 Index Is Related with Worse Clinical Outcome in Patients with Coronavirus Disease 2019 and Diabetes Mellitus: A Multicenter Observational Study: Sung-Woo Kim, Jae-Han Jeon, Jun Sung Moon, Mi Kyung Kim; Endocrinol Metab. 2021;36(4):800-809. Published online August 20, 2021; DOI: https://doi.org/10.3803/EnM.2021.1040

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Background
Based on recent evidence on the importance of the presence of diabetes mellitus (DM) and fibrosis-4 (FIB-4) index in coronavirus disease 2019 (COVID-19) mortality, we analyzed whether these factors could additively predict such mortality.
Methods
This multicenter observational study included 1,019 adult inpatients admitted to university hospitals in Daegu. The demographic and laboratory findings, mortality, prevalence of severe disease, and duration of quarantine were compared between patients with and without DM and/or a high FIB-4 index. The mortality risk and corresponding hazard ratio (HR) were analyzed using the Kaplan-Meier method and Cox proportional hazard models.
Results
The patients with DM (n=217) exhibited significantly higher FIB-4 index and mortality compared to those without DM. Although DM (HR, 2.66; 95% confidence interval [CI], 1.63 to 4.33) and a high FIB-4 index (HR, 4.20; 95% CI, 2.21 to 7.99) were separately identified as risk factors for COVID-19 mortality, the patients with both DM and high FIB-4 index had a significantly higher mortality (HR, 9.54; 95% CI, 4.11 to 22.15). Higher FIB-4 indices were associated with higher mortality regardless of DM. A high FIB-4 index with DM was more significantly associated with a severe clinical course with mortality (odds ratio, 11.24; 95% CI, 5.90 to 21.41) than a low FIB-4 index without DM, followed by a high FIB-4 index alone and DM alone. The duration of quarantine and hospital stay also tended to be longer in those with both DM and high FIB-4 index.
Conclusion
Both DM and high FIB-4 index are independent and additive risk factors for COVID-19 mortality.

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Diabetes, Obesity and Metabolism
Tetrahydrocurcumin Ameliorates Kidney Injury and High Systolic Blood Pressure in High-Fat Diet-Induced Type 2 Diabetic Mice: Weerapon Sangartit, Kyung Bong Ha, Eun Soo Lee, Hong Min Kim, Upa Kukongviriyapan, Eun Young Lee, Choon Hee Chung; Endocrinol Metab. 2021;36(4):810-822. Published online August 27, 2021; DOI: https://doi.org/10.3803/EnM.2021.988

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Background
Activation of the intrarenal renin-angiotensin system (RAS) is implicated in the pathogenesis of kidney injury and hypertension. We aimed to investigate the protective effect of tetrahydrocurcumin (THU) on intrarenal RAS expression, kidney injury, and systolic blood pressure (SBP) in high-fat diet (HFD)-induced type 2 diabetic mice.
Methods
Eight-week-old male mice were fed a regular diet (RD) or HFD for 12 weeks, and THU (50 or 100 mg/kg/day) was intragastrically administered with HFD. Physiological and metabolic changes were monitored and the expression of RAS components and markers of kidney injury were assessed.
Results
HFD-fed mice exhibited hyperglycemia, insulin resistance, and dyslipidemia compared to those in the RD group (P<0.05). Kidney injury in these mice was indicated by an increase in the ratio of albumin to creatinine, glomerular hypertrophy, and the effacement of podocyte foot processes. Expression of intrarenal angiotensin-converting enzyme, angiotensin II type I receptor, nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-4, and monocyte chemoattractant protein-1 was also markedly increased in HFD-fed mice. HFD-fed mice exhibited elevated SBP that was accompanied by an increase in the wall thickness and vascular cross-sectional area (P<0.05), 12 weeks post-HFD consumption. Treatment with THU (100 mg/kg/day) suppressed intrarenal RAS activation, improved insulin sensitivity, and reduced SBP, thus, attenuating kidney injury in these mice.
Conclusion
THU alleviated kidney injury in mice with HFD-induced type 2 diabetes, possibly by blunting the activation of the intrarenal RAS/nicotinamide adenine dinucleotide phosphate oxidase IV (NOX4)/monocyte chemoattractant protein 1 (MCP-1) axis and by lowering the high SBP.

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Diabetes, Obesity and Metabolism
Non-Laboratory-Based Simple Screening Model for Nonalcoholic Fatty Liver Disease in Patients with Type 2 Diabetes Developed Using Multi-Center Cohorts: Jiwon Kim, Minyoung Lee, Soo Yeon Kim, Ji-Hye Kim, Ji Sun Nam, Sung Wan Chun, Se Eun Park, Kwang Joon Kim, Yong-ho Lee, Joo Young Nam, Eun Seok Kang; Endocrinol Metab. 2021;36(4):823-834. Published online August 27, 2021; DOI: https://doi.org/10.3803/EnM.2021.1074

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Background
Nonalcoholic fatty liver disease (NAFLD) is the most prevalent cause of chronic liver disease worldwide. Type 2 diabetes mellitus (T2DM) is a risk factor that accelerates NAFLD progression, leading to fibrosis and cirrhosis. Thus, here we aimed to develop a simple model to predict the presence of NAFLD based on clinical parameters of patients with T2DM.
Methods
A total of 698 patients with T2DM who visited five medical centers were included. NAFLD was evaluated using transient elastography. Univariate logistic regression analyses were performed to identify potential contributors to NAFLD, followed by multivariable logistic regression analyses to create the final prediction model for NAFLD.
Results
Two NAFLD prediction models were developed, with and without serum biomarker use. The non-laboratory model comprised six variables: age, sex, waist circumference, body mass index (BMI), dyslipidemia, and smoking status. For a cutoff value of ≥60, the prediction accuracy was 0.780 (95% confidence interval [CI], 0.743 to 0.817). The second comprehensive model showed an improved discrimination ability of up to 0.815 (95% CI, 0.782 to 0.847) and comprised seven variables: age, sex, waist circumference, BMI, glycated hemoglobin, triglyceride, and alanine aminotransferase to aspartate aminotransferase ratio. Our non-laboratory model showed non-inferiority in the prediction of NAFLD versus previously established models, including serum parameters.
Conclusion
The new models are simple and user-friendly screening methods that can identify individuals with T2DM who are at high-risk for NAFLD. Additional studies are warranted to validate these new models as useful predictive tools for NAFLD in clinical practice.

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Diabetes, Obesity and Metabolism
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Background
Both intra-abdominal fat (IAF) and high-density lipoprotein cholesterol (HDL-C) are known to be associated with cardiometabolic health. We evaluated whether the accumulation of computed tomography (CT)-measured IAF over 5 years was related to baseline HDL-C concentration in a prospective cohort study.
Methods
All participants were Japanese-Americans between the ages of 34 and 74 years. Plasma HDL-C concentration and CT measurements of IAF, abdominal subcutaneous fat (SCF), and thigh SCF cross-sectional areas were assessed at baseline and at 5-year follow-up visits.
Results
A total of 397 subjects without diabetes were included. The mean±standard deviation HDL-C concentration was 51.6±13.0 mg/dL in men and 66.0±17.0 mg/dL in women, and the IAF was 91.9±48.4 cm² in men and 63.1±39.5 cm² in women. The baseline plasma concentration of HDL-C was inversely associated with the change in IAF over 5 years using multivariable regression analysis with adjustment for age, sex, family history of diabetes, weight change over 5 years, and baseline measurements of body mass index, IAF, abdominal SCF, abdominal circumference, thigh SCF, and homeostatic model assessment for insulin resistance.
Conclusion
These results demonstrate that HDL-C concentration significantly predicts future accumulation of IAF over 5 years independent of age, sex, insulin sensitivity, and body composition in Japanese-American men and women without diabetes.

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Diabetes, Obesity and Metabolism
Increased Risk of Nonalcoholic Fatty Liver Disease in Individuals with High Weight Variability: Inha Jung, Dae-Jeong Koo, Mi Yeon Lee, Sun Joon Moon, Hyemi Kwon, Se Eun Park, Eun-Jung Rhee, Won-Young Lee; Endocrinol Metab. 2021;36(4):845-854. Published online August 27, 2021; DOI: https://doi.org/10.3803/EnM.2021.1098

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146 Download
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Background
Weight loss through lifestyle modification is recommended for patients with nonalcoholic fatty liver disease (NAFLD). Recent studies have suggested that repeated loss and gain of weight is associated with worse health outcomes. This study aimed to examine the association between weight variability and the risk of NAFLD in patients without diabetes.
Methods
We examined the health-checkup data of 30,708 participants who had undergone serial examinations between 2010 and 2014. Weight variability was assessed using coefficient of variation and the average successive variability of weight (ASVW), which was defined as the sum of absolute weight changes between successive years over the 5-year period divided by 4. The participants were classified according to the baseline body mass index and weight difference over 4 years.
Results
On dividing the participants into four groups according to ASVW quartile groups, those in the highest quartile showed a significantly increased risk of NAFLD compared to those in the lowest quartile (odds ratio [OR], 1.89; 95% confidence interval [CI], 1.63 to 2.19). Among participants without obesity at baseline, individuals with high ASVW showed increased risk of NAFLD (OR, 1.80; 95% CI, 1.61 to 2.01). Participants with increased weight over 4 years and high ASVW demonstrated higher risk of NAFLD compared to those with stable weight and low ASVW (OR, 4.87; 95% CI, 4.29 to 5.53).
Conclusion
Regardless of participant baseline obesity status, high weight variability was associated with an increased risk of developing NAFLD. Our results suggest that further effort is required to minimize weight fluctuations after achieving a desirable body weight.

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Mohammed Eslam, Hashem B. El-Serag, Sven Francque, Shiv K. Sarin, Lai Wei, Elisabetta Bugianesi, Jacob George
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Ángel Arturo López-González, Bárbara Altisench Jané, Luis Masmiquel Comas, Sebastiana Arroyo Bote, Hilda María González San Miguel, José Ignacio Ramírez Manent
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Yeoree Yang, Jae-Hyoung Cho
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Autonomic Imbalance Increases the Risk for Non-alcoholic Fatty Liver Disease
Inha Jung, Da Young Lee, Mi Yeon Lee, Hyemi Kwon, Eun-Jung Rhee, Cheol-Young Park, Ki-Won Oh, Won-Young Lee, Sung-Woo Park, Se Eun Park
Frontiers in Endocrinology.2021;[Epub] CrossRef

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