The interplay between glomerular hyperfiltration (GHF) and downstream renal dysfunction and hepatic fibrosis in metabolic dysfunction–associated steatotic (or fatty) liver disease (MASLD or MAFLD) remains insufficiently understood. We investigated these associations in a large cohort of generally healthy adults with a low prevalence of obesity. In a longitudinal health-screening cohort, 47,741 adults aged 18–70 years were followed from 2002 to 2019, with baseline liver ultrasonography and annual renal assessments. Hepatic steatosis was diagnosed by ultrasonography. GHF was defined as a residual estimated glomerular filtration rate (eGFR) above the age- and sex-specific 95th percentile. Chronic kidney disease (CKD) progression was defined by eGFR-based criteria only because urinary albumin-creatinine ratio was frequently missing. The primary endpoint was CKD progression; the secondary endpoint was progression to advanced liver fibrosis, assessed using noninvasive markers. In fully adjusted models for CKD progression, GHF was an independent risk factor irrespective of MASLD status (hazard ratio, 3.55; 95

Objective:Given the limitations of conventional approaches in managing indeterminate thyroid nodules, there remains an unmet need for non-invasive assistant tools to improve risk stratification. This study aimed to evaluate the clinical applicability of an artificial intelligence (AI) model for thyroid nodules with atypia of undetermined significance (AUS) cytology. Methods:We retrospectively reviewed patients who underwent fine-needle aspiration (FNA) for thyroid nodules between January 2019 and December 2020 across five medical institutions in Korea. Nodules initially diagnosed as AUS and later confirmed as benign or malignant were included. A previously developed deep learning-based AI model, AI-Thyroid, was employed to provide binary classifications (benign or malignant) and malignancy risk estimates. Results:A total of 165 thyroid nodules were analyzed. The median (interquartile range) longest diameter was 1.30 cm (0.80-2.10), and the malignancy rate of the cohort was 39%. In binary classification tasks, the model achieved a sensitivity of 0.91 and a negative predictive value of 0.87. The area under the curve (AUC) based on estimated malignancy risk was 0.75 (95% confidence interval (CI): 0.68-0.83), and the AUC derived from K-TIRADS categories 2-5 was 0.76 (95% CI: 0.69-0.83), indicating comparable diagnostic accuracy with the traditional scoring system. Subgroup analyses demonstrated that the model achieved a sensitivity of 98% in nodules smaller than 1.5 cm. Conclusion:AI-assisted ultrasound analysis offers supplementary diagnostic information for thyroid nodules with AUS cytology. Its high sensitivity and negative predictive value may assist clinicians in decision-making processes, particularly for small, low-risk thyroid nodules.

Background:Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors that can be fatal if not diagnosed early or adequately managed. This study investigated the risk of all-cause mortality and secondary malignancies in patients with PPGL compared to age- and sex-matched controls without PPGL. Methods:This nationwide population-based cohort study included 1,672 patients with PPGL and 16,790 controls with a median follow-up of approximately 7.1 years. A Cox proportional hazard model was used to estimate the adjusted hazard ratio (HR) and 95% confidence intervals (CI). Results:The mean age was 46.5 years and 50.5% were male. All-cause mortality was identified in 118 patients with PPGL (7.06%) and 749 controls (4.46%) during the follow-up period. The incidence of all-cause mortality in patients with PPGL was significantly higher than that in controls (9.92 per 1,000 person-years vs. 6.49 per 1,000 person-years, P=0.0003). The risk of all-cause mortality was significantly higher in patients with PPGL than in the controls (HR, 1.372; 95% CI, 1.124 to 1.675). The risk of secondary malignancies was significantly higher in patients with PPGL than in controls (HR, 1.612; 95% CI, 1.33 to 1.954) after adjusting. Among the various cancer subtypes, thyroid and prostate cancers were observed more frequently in PPGL patients, and these findings should be interpreted as descriptive trends. Conclusion:Patients with PPGL exhibited significantly increased risks of all-cause mortality and secondary malignancies compared with controls, highlighting the importance of appropriate assessment and follow-up.

BACKGROUND AND AIMS:With the growing prevalence of lean Type 2 diabetes mellitus (T2DM) and limited research on stratified underweight categories, this study investigated the association between underweight status and cardiovascular disease (CVD) risk in T2DM patients, focusing on the impact of underweight severity. METHODS:A nationwide cohort study analysed data from 2 064 406 adults with T2DM who underwent health examinations between 2015 and 2016, sourced from the Korean National Health Insurance Service database. Participants were classified by body mass index into underweight, normal weight, overweight, and obesity, with underweight further stratified into mild (17-18.4 kg/m2), moderate (16-16.9 kg/m2), and severe (<16 kg/m2). Primary outcomes were CVDs, including myocardial infarction and ischaemic stroke, assessed using Cox proportional hazards models adjusted for demographic, clinical, and lifestyle factors. RESULTS:During a mean follow-up of 5.7 years, 111 522 CVD events, including 55 622 MI and 62 099 ischaemic stroke events, were documented. Compared with the normal weight group, all underweight groups showed significantly higher CVD risks (adjusted hazard ratio [95% confidence interval]: 1.49 [1.28-1.73], 1.47 [1.33-1.63], and 1.19 [1.13-1.25] for severe, moderate, and mild underweight, respectively). These risks exceeded those for body mass index ≥ 35 kg/m2 (1.14 [1.08-1.22]), showing a reverse J-shaped association. Stratified analyses indicated stronger associations in younger individuals and non-smokers. CONCLUSIONS:Underweight status in T2DM patients is significantly associated with increased risk of CVDs, particularly in those severely underweight, exceeding the risks observed with obesity. These findings emphasize the need for dedicated guidelines for managing underweight T2DM patients to mitigate cardiovascular risks.

Hyperthyroidism is a condition marked by excessive thyroid hormone production, most commonly due to Graves' disease. Treatment options include antithyroid drugs (ATD), radioactive iodine (RAI) therapy, and thyroidectomy. To develop standardized clinical recommendations for RAI therapy with a focus on safety, efficacy, and monitoring, the Korean Thyroid Association formed a task force to create evidence-based guidelines. Six key clinical questions were identified through expert consensus, and a systematic literature review from 2013 to 2022 was conducted. Clinical indications for RAI therapy were categorized into three groups: strongly recommended, may be considered, and not recommended. A fixed dose of 10 to 15 mCi is recommended. Although a strict low-iodine diet is unnecessary, iodine-rich foods should be avoided for at least 1 week before treatment. ATD should be stopped 3 to 7 days before RAI and may be resumed in select cases. Prophylactic glucocorticoids are recommended for patients with mildly active thyroid eye disease and may be considered for others at risk. Thyroid function should be monitored at 4-6 weeks post-treatment, every 2-3 months until stabilized, and then every 6-12 months. These guidelines highlight recent advances and underscore the importance of individualized treatment based on clinical features, comorbidities, and patient preferences in Korea.

Background Polyunsaturated fatty acids (PUFAs) reportedly have protective effects on pancreatic β-cells; however, the underlying mechanisms are unknown. Methods To investigate the cellular mechanism of PUFA-induced cell protection, mouse insulinoma 6 (MIN6) cells were cultured with palmitic acid (PA) and/or docosahexaenoic acid (DHA), and alterations in cellular signaling and apoptosis were examined. Results DHA treatment remarkably repressed caspase-3 cleavage and terminal deoxynucleotidyl transferase-mediated UTP nick end labeling (TUNEL)-positive red dot signals in PA-treated MIN6 cells, with upregulation of autophagy, an increase in microtubule-associated protein 1-light chain 3 (LC3)-II, autophagy-related 5 (Atg5), and decreased p62. Upstream factors involved in autophagy regulation (Beclin-1, unc51 like autophagy activating kinase 1 [ULK1], phosphorylated mammalian target of rapamycin [mTOR], and protein kinase B) were also altered by DHA treatment. DHA specifically induced phosphorylation on S2448 in mTOR; however, phosphorylation on S2481 decreased. The role of G protein-coupled receptor 120 (GPR120) in the effect of DHA was demonstrated using a GPR120 agonist and antagonist. Additional treatment with AH7614, a GPR120 antagonist, significantly attenuated DHA-induced autophagy and protection. Taken together, DHA-induced autophagy activation with protection against PA-induced apoptosis mediated by the GPR120/mTOR axis. Conclusion These findings indicate that DHA has therapeutic effects on PA-induced pancreatic β-cells, and that the cellular mechanism of β-cell protection by DHA may be a new research target with potential pharmacotherapeutic implications in β-cell protection.

CONTEXT Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of metabolic syndrome. Obesity and metabolic syndrome are known risk factors for thyroid cancer. OBJECTIVE We investigated the association between NAFLD and thyroid cancer risk in young adults. METHODS This nationwide cohort study included 1 135 967 participants aged 20 to 39 years who underwent 4 consecutive health screenings in South Korea. NAFLD was categorized using the fatty liver index (FLI), as follows: ≥60, 30 to 60, and <30. The cumulative FLI points were defined as the number of times participants had a FLI of ≥30 (0-4). RESULTS During a median follow-up of 5.2 years, 4126 participants (0.36%) were newly diagnosed with thyroid cancer. Compared with the participants with an FLI of <30, those with an FLI of 30 to 60 (men: hazard ratio [HR] 1.36 [95% CI, 1.22-1.51] and women: HR 1.44 [1.21-1.70]) and those with an FLI of ≥60 (men: HR 1.71 [1.53-1.92] and women: HR 1.81 [1.46-2.25]) had a significantly higher risk of thyroid cancer. Participants with higher cumulative FLI points had a higher risk of thyroid cancer compared to those with a cumulative FLI point of 0 (P < .001). During the follow-up period, the participants with an increased FLI exhibited an increased risk of thyroid cancer. CONCLUSION NAFLD was associated with an increased risk of thyroid cancer in young adults. Repeatedly elevated FLI and progression of NAFLD were associated with an increased risk of thyroid cancer in this study.

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.

Background This is the first gene therapy trial in patients with Charcot-Marie-Tooth disease type 1A (CMT1A). Intramuscular injectionsof VM202, a plasmid DNA encoding human hepatocyte growth factor, was safe, tolerable and potentially effective in patients with CMT1A. Methods This study was a phase 1/2a, nonrandomized controlled trial. Thirteen patients with CMT1A were screened, and 12 consented and enrolled between September 2020 and November 2020. Patients received intramuscular injections of 14 mg of VM202 at baseline, and on days 14, 90, and 104 in both legs. Safety evaluations and clinical assessments using the CMT neuropathy score version 2 (CMTNSv2), CMT examination score (CMTES), Rasch-modified CMTNSv2 (CMTNSv2-R), Rasch-modified CMTES (CMTES-R), functional disability scale (FDS), overall neuropathy limitation score, and 10-meter walk test were performed throughout a 270-day follow-up period. A Wilcoxon signed-rank test was used for statistical comparisons of continuous variables. Results The primary objective of this study was to assess the safety and tolerability of intramuscular injections of VM202 in patients with CMT1A. All participants tolerated VM202 well, without any serious adverse events related to the study drug. The secondary objective was to evaluate potential therapeutic efficacy. CMTNSv2, CMTES, CMTNSv2-R, and CMTES-R significantly decreased between baseline and day 270 with mean decreases of 2.17, 2.50, 2.08, and 2.33 points, respectively (p < 0.01). Also FDS significantly decreased with a mean percent decrease of 0.58 (p < 0.05). ConclusionsIntramuscular injections of VM202 appear to be safe and well tolerated in CMT1A patients with potentially encouraging clinical results.

Sodium-dependent glucose cotransporter-2 (SGLT2) inhibitors, antidiabetic drugs that reduce blood sugar levels by inhibiting glucose reabsorption in the renal proximal tubules, also ameliorate nonalcoholic fatty liver disease (NAFLD). This study aimed to examine the effects of SGLT2 inhibition on hepatic steatosis and nonalcoholic steatohepatitis (NASH) using an in vitro model of NAFLD progression. HepG2 cells and a coculture of Hepa1c1c7 and Raw 264.7 cells were treated with 400 μM palmitic acid (PA), followed by treatment with or without 10 μM empagliflozin and dapagliflozin. In HepG2 cells, PA increased hepatic lipid accumulation, the expression of pro-inflammatory cytokines (TNF-α, IL-6, and IL-1β), exocytosis mediators (VAMP3 and SNAP23), and ER stress markers (GRP78, PERK, IRE1α, ATF6, ATF4, and CHOP), and the gene and protein expression of CD36. SGLT2 inhibitors reversed the effects of PA. SGLT2 inhibition via siRNA reduced proinflammatory-cytokine gene expression in thapsigargin-treated HepG2 cells. Transfection with CD36 siRNA reversed the elevated ATF4 and CHOP expression in PA-treated HepG2 cells. SGLT2 inhibition via an SGTL2 inhibitor and SGLT2 siRNA reduced CD36, Tnf-α, Il-6, Il-1β, Vamp2, Snap23, Atf4, and Chop expression in the PA-treated Hepa1c1c7-Raw 264.7 cell coculture and suppressed Tnf-α release in the Hepa1c1c7-Raw 264.7 cell coculture treated with lipopolysaccharide and PA. These findings indicate that SGLT2 inhibitors inhibited NAFLD progression by reducing hepatic lipid accumulation and inflammation.

OBJECTIVE:Pheochromocytomas (PHEOs) are chromaffin cell-derived adrenal tumors. 6-[ 18 F]-L-fluoro-L-3, 4-dihydroxyphenylalanine ( 18 F-FDOPA) is a radiotracer taken up in neuroendocrine chromaffin cells via the L-type amino-acid transporter. 18 F-FDOPA is useful in patients with PHEO. However, more information about the use of 18 F-FDOPA PET/CT scan is needed. Thus, the current study investigated various PET parameters on preoperative 18 F-FDOPA PET/CT scan. METHODS:The 18 F-FDOPA PET/CT scan findings of 29 patients who underwent adrenalectomy after PET/CT scans were evaluated according to their pathologic diagnosis. Thereafter, the patients were classified under different risk groups which were compared based on the Grading System for Adrenal Pheochromocytoma and Paraganglioma (GAPP). RESULTS:In terms of histopathologic results after surgery, 24 patients presented with PHEO. The remaining 5 patients were diagnosed with adrenal cortical adenomas or adrenal medullary hyperplasia. The maximum standardized uptake value, mean standardized uptake value, tumor-to-liver ratio, and tumor-to-contralateral adrenal gland ratio of PHEOs on preoperative 18 F-FDOPA PET/CT scan were higher than those of other tumors. The metabolic tumor volume (MTV) and total lesion uptake of PHEOs in the intermediate-risk group (n = 19) were higher than those in the low-risk group (n = 5). The MTV and total lesion uptake were significantly correlated with the GAPP score. CONCLUSION:Preoperative 18 F-FDOPA PET/CT is helpful to identifying PHEOs. In addition, imaging interpretation using the standardized uptake value of the suspected tumor or the tumor-to-liver/contralateral adrenal gland ratio can be effective. The metabolic parameters of PHEOs are positively correlated with the GAPP score.

Background Glucagon-like peptide-1 receptor agonist (GLP-1RA), which is a therapeutic agent for the treatment of type 2 diabetes mellitus, has a beneficial effect on the cardiovascular system. Methods To examine the protective effects of GLP-1RAs on proliferation and migration of vascular smooth muscle cells (VSMCs), A-10 cells exposed to angiotensin II (Ang II) were treated with either exendin-4, liraglutide, or dulaglutide. To examine the effects of GLP-1RAs on vascular calcification, cells exposed to high concentration of inorganic phosphate (Pi) were treated with exendin-4, liraglutide, or dulaglutide. Results Ang II increased proliferation and migration of VSMCs, gene expression levels of Ang II receptors AT1 and AT2, proliferation marker of proliferation Ki-67 (Mki-67), proliferating cell nuclear antigen (Pcna), and cyclin D1 (Ccnd1), and the protein expression levels of phospho-extracellular signal-regulated kinase (p-Erk), phospho-c-JUN N-terminal kinase (p-JNK), and phospho-phosphatidylinositol 3-kinase (p-Pi3k). Exendin-4, liraglutide, and dulaglutide significantly decreased the proliferation and migration of VSMCs, the gene expression levels of Pcna, and the protein expression levels of p-Erk and p-JNK in the Ang II-treated VSMCs. Erk inhibitor PD98059 and JNK inhibitor SP600125 decreased the protein expression levels of Pcna and Ccnd1 and proliferation of VSMCs. Inhibition of GLP-1R by siRNA reversed the reduction of the protein expression levels of p-Erk and p-JNK by exendin-4, liraglutide, and dulaglutide in the Ang II-treated VSMCs. Moreover, GLP-1 (9-36) amide also decreased the proliferation and migration of the Ang II-treated VSMCs. In addition, these GLP-1RAs decreased calcium deposition by inhibiting activating transcription factor 4 (Atf4) in Pi-treated VSMCs. Conclusion These data show that GLP-1RAs ameliorate aberrant proliferation and migration in VSMCs through both GLP-1R-dependent and independent pathways and inhibit Pi-induced vascular calcification.

The utility of the next-generation sequencing (NGS) panel could be increased in hereditary peripheral neuropathies, given that the duplication of PMP22 is a major abnormality. In the present study, the analytical performance of an algorithm for detecting PMP22 copy number variation (CNV) from the NGS panel data was evaluated. The NGS panel covers 141 genes, including PMP22 and five genes within 1.5-megabase duplicated region at 17p11.2. CNV calling was performed using a laboratory-developed algorithm. Among the 92 cases subjected to targeted NGS panel from March 2018 to January 2021, 26 were suggestive of PMP22 CNV. Multiplex ligation-dependent probe amplification analysis was performed in 58 cases, and the results were 100% concordant with the NGS data (23 duplications, 2 deletions, and 33 negatives). Analytical performance of the pipeline was further validated by another blind data set, including 14 positive and 20 negative samples. Reliable detection of PMP22 CNV was possible by analyzing not only PMP22 but also the adjacent genes within the 1.5-megabase region of 17p11.2. On the basis of the high accuracy of CNV calling for PMP22, the testing strategy for diagnosis of peripheral polyneuropathies could be simplified by reducing the need for multiplex ligation-dependent probe amplification.

In this national cohort study, the patients with acromegaly had significantly higher risks of clinical vertebral (HR 2.09 [1.58–2.78]) and hip (HR 2.52 [1.61–3.95]) fractures than the controls. The increased fracture risk in patients with acromegaly was time-dependent and was observed even during the early period of follow-up. Acromegaly is characterized by the overproduction of growth hormone (GH) and insulin-like growth factor-1 (IGF-1), both play important roles in regulating bone metabolism. We investigated the risk of vertebral and hip fractures in patients with acromegaly compared to age- and sex-matched controls. This nationwide population-based cohort study included 1,777 patients with acromegaly aged 40 years or older in 2006–2016 and 8,885 age- and sex-matched controls. A Cox proportional hazards model was used to estimate the adjusted hazard ratio (HR) [95% confidence interval]. The mean age was 54.3 years and 58.9% were female. For approximately 8.5 years of follow-up, the patients with acromegaly had significantly higher risks of clinical vertebral (HR 2.09 [1.58–2.78]) and hip (HR 2.52 [1.61–3.95]) fractures than the controls in the multivariate analyses. There were significant differences in the risks of clinical vertebral (P < 0.0001) and hip (P < 0.0001) fractures between the patients with acromegaly and the controls in the Kaplan–Meier survival analysis. The multivariable-adjusted HRs for clinical vertebral fractures comparing the patients with acromegaly with controls during and excluding the first 7 years of observation were 1.69 [1.15–2.49] and 2.70 [1.75–4.17], respectively. The HRs for hip fractures during and excluding the first 7 years of observation were 2.29 [1.25–4.18] and 3.36 [1.63–6.92], respectively. The patients with acromegaly had a higher risk of hip fractures as well as clinical vertebral fractures than the controls. The increased fracture risk in patients with acromegaly was time-dependent and was observed even during the early period of follow-up.

Aims: Physical inactivity is a modifiable risk factor for cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (T2DM); however, little is known about its association with mortality due to other causes. Herein, we investigated the association between physical activity (PA) and cause-specific mortality in patients with T2DM.Methods: We analyzed data from the Korean National Health Insurance Service and claims database of adults with T2DM aged >20 years at baseline (n = 2,651,214). Each participant's PA volume was measured as the metabolic equivalent of tasks (METs)-min per week, and hazard ratios of all-cause and cause-specific mortality relative to PA levels were estimated.Results: During the 7.8 years of follow-up, all-cause, CVD, respiratory, cancer, and other causes of mortality were lowest in patients engaged in vigorous PA. MET-min/week was inversely associated with mortality after adjusting for covariates. The reduction in total and cause-specific mortality was greater in patients aged & GE;65 years than in those aged <65 years.Conclusions: Increasing PA may facilitate a reduction in mortality from various causes, especially among older patients with T2DM. Clinicians should encourage such patients to increase their daily PA levels to reduce their risk of mortality.

Background Coronary artery calcium score (CACS) has become an important tool for evaluating cardiovascular disease (CVD). This study evaluated the significance of CACS for future CVD through more than 10 years of follow-up in asymptomatic Korean populations with type 2 diabetes mellitus (T2DM) known to have a relatively low CACS burden. Methods We enrolled 981 asymptomatic T2DM patients without CVD at baseline who underwent CACS evaluation using multidetector computed tomography between January 2008 and December 2014. They were grouped into five predefined CACS categories based on Agatston scores and followed up by August 2020. The primary endpoint was incident CVD events, including coronary, cerebrovascular, and peripheral arterial disease. Results The relative risk of CVD was significantly higher in patients with CACS ≥10, and the significance persisted after adjustment for known confounders. A higher CACS category indicated a higher incidence of future CVD: hazard ratio (95% confidence interval) 4.09 (1.79 to 9.36), 12.00 (5.61 to 25.69), and 38.79 (16.43 to 91.59) for 10≤ CACS <100, 100≤ CACS <400, and CACS ≥400, respectively. During the 12-year follow-up period, the difference in event-free survival more than doubled as the category increased. Patients with CACS below 10 had very low CVD incidence throughout the follow-up. The receiver operating characteristic analysis showed better area under curve when the CACS cutoff was 10 than 100. Conclusion CACS can be a sensitive marker of CVD risk. Specifically, CACS above 10 is an indicator of CVD high-risk requiring more intensive medical treatment in Koreans with T2DM.

AbstractWhole-genome sequencing is the most comprehensive form of next-generation sequencing method. We aimed to assess the additional diagnostic yield of whole-genome sequencing in patients with clinically diagnosed Charcot–Marie–Tooth disease when compared with whole-exome sequencing, which has not been reported in the literature. Whole-genome sequencing was performed on 72 families whose genetic cause of clinically diagnosed Charcot–Marie–Tooth disease was not revealed after the whole-exome sequencing and 17p12 duplication screening. Among the included families, 14 (19.4%) acquired genetic diagnoses that were compatible with their phenotypes. The most common factor that led to the additional diagnosis in the whole-genome sequencing was genotype-driven analysis (four families, 4/14), in which a wider range of genes, not limited to peripheral neuropathy-related genes, were analysed. Another four families acquired diagnosis due to the inherent advantage of whole-genome sequencing such as better coverage than the whole-exome sequencing (two families, 2/14), structural variants (one family, 1/14) and non-coding variants (one family, 1/14). In conclusion, an evident gain in diagnostic yield was obtained from whole-genome sequencing of the whole-exome sequencing-negative cases. A wide range of genes, not limited to inherited peripheral neuropathy-related genes, should be targeted during whole-genome sequencing.

Thyroid hormones increase tissue thermogenesis and the basal metabolic rate, and reduce serum cholesterol levels and systemic vascular resistance [1]. Hyperthyroidism occurs due to excessive synthesis and secretion of thyroid hormones by the thyroid [2]. Since hyperthyroidism is a potential risk factor for weight loss, cardiovascular disease, arrhythmia, osteoporosis, fragility fractures, and neuropsychiatric disease, it is of the utmost importance to understand the current status of this condition [3]. The prevalence and incidence of thyroid dysfunction vary across populations and can be influenced by several factors such as age, sex, ethnicity, and iodine status [4-7]. The prevalence of overt hyperthyroidism has been reported to be 0.5% to 0.8% in Europe and 0.5% in the United States [3,8]. Several studies have reported the prevalence and incidence of hyperthyroidism in Korea [9-11]. A recent study using the National Health Insurance (NHI) database after excluding subjects with thyroid cancer reported that the prevalence of hyperthyroidism in patients undergoing treatment was 2.76 per 1,000 population in Korea in 2015 with a noteworthy sex disparity shown by rates of 1.79 per 1,000 population among men and 3.74 per 1,000 population among women [11]. The prevalence of hyperthyroidism reported in previous Korean studies was similar to the rates in other countries [3,8]. In a study published in 2013 using the Health Insurance Review & Assessment Service (HIRA) database, the prevalence of hyperthyroidism was 3.40 per 1,000 population (2.09 among men and 4.70 among women) [10]. The study using Korea National Health and Nutrition Examination Survey VI reported that the prevalence of overt and subclinical hyperthyroidism was 0.54% and 2.98%, respectively, using the reference interval of serum thyroid-stimulating hormone in the Korean reference population [9]. A recent study using the NHI database found that the number of incident cases of hyperthyroidism steadily increased from 2006 to 2012, and then decreased through 2015 [11]. The incidence of hyperthyroidism in patients undergoing treatment was 0.55 per 1,000 population in Korea in 2015 [11]. In the study published in 2013 using HIRA database, the incidence of hyperthyroidism was 0.72 per 1,000 population (0.40 among men and 1.03 among women) [10]. Ahn et al. [12] reported the current status of hyperthyroidism in Korea from 2003 to 2018 using nationwide population-based data from the NHI. The authors evaluated the prevalence and the changes in annual age-standardized incidence during the study period. In Korea, hyperthyroidism occurred about 2.5 times more in women than in men. As of 2018, the prevalence of hyperthyroidism was 3.04 per 1,000 population, and the agestandardized prevalence was 2.48 per 1,000 population. The average age-standardized incidence of hyperthyroidism from 2003 to 2018 was 42.23 and 105.13 per 100,000 men and women, respectively. In addition, Ahn et al. [12] evaluated the treatment of choice for hyperthyroidism and its changes during the study period. In Korea, antithyroid drugs were preferred as the first-line treatment

Immune checkpoint inhibitors (ICIs) including an anti-cytotoxic T-lymphocyte-associated antigen 4 inhibitor, anti-programmed cell death protein 1 (PD-1) inhibitors, and anti-PD-ligand 1 inhibitors are representative therapeutics for various malignancies. In oncol-ogy, the application of ICIs is currently expanding to a wider range of malignancies due to their remarkable clinical outcomes. ICIs target immune checkpoints which suppress the activity of T-cells that are specific for tumor antigens, thereby allowing tumor cells to escape the immune response. However, immune checkpoints also play a crucial role in preventing autoimmune reactions. Therefore, ICIs targeting immune checkpoints can trigger various immune-related adverse events (irAEs), especially in endocrine organs. Con-sidering the endocrine organs that are frequently involved, irAEs associated endocrinopathies are frequently life-threatening and have unfavorable clinical implications for patients. However, there are very limited data from large clinical trials that would inform the development of clinical guidelines for patients with irAEs associated endocrinopathies. Considering the current clinical situation, in which the scope and scale of the application of ICIs are increasing, position statements from clinical specialists play an essential role in providing the appropriate recommendations based on both medical evidence and clinical experience. As endocrinologists, we would like to present precautions and recommendations for the management of immune-related endocrine disorders, especially those involving the adrenal, thyroid, and pituitary glands caused by ICIs.

Background Dulaglutide, a long-acting glucagon-like peptide-1 receptor agonist (GLP-1RA), has been shown to reduce body weight and liver fat content in patients with type 2 diabetes. Family with sequence similarity 3 member A (FAM3A) plays a vital role in regulating glucose and lipid metabolism. The aim of this study was to determine the mechanisms by which dulaglutide protects against hepatic steatosis in HepG2 cells treated with palmitic acid (PA). Methods HepG2 cells were pretreated with 400 μM PA for 24 hours, followed by treatment with or without 100 nM dulaglutide for 24 hours. Hepatic lipid accumulation was determined using Oil red O staining and triglyceride (TG) assay, and the expression of lipid metabolism-associated factor was analyzed using quantitative real time polymerase chain reaction and Western blotting. Results Dulaglutide significantly decreased hepatic lipid accumulation and reduced the expression of genes associated with lipid droplet binding proteins, de novo lipogenesis, and TG synthesis in PA-treated HepG2 cells. Dulaglutide also increased the expression of proteins associated with lipolysis and fatty acid oxidation and FAM3A in PA-treated cells. However, exendin-(9–39), a GLP-1R antagonist, reversed the expression of FAM3A, and fatty acid oxidation-associated factors increased due to dulaglutide. In addition, inhibition of FAM3A by siRNA attenuated the reducing effect of dulaglutide on TG content and its increasing effect on regulation of fatty acid oxidation. Conclusion These results suggest that dulaglutide could be used therapeutically for improving nonalcoholic fatty liver disease, and its effect could be mediated in part via upregulation of FAM3A expression through a GLP-1R-dependent pathway.