Vitamin D and Exercise Are Major Determinants of Natural Killer Cell Activity, Which Is Age- and Gender-Specific.

Background: The coronavirus-19 disease (COVID-19) pandemic reminds us of the importance of immune function, even in immunologically normal individuals. Multiple lifestyle factors are known to influence the immune function. Objective: The aim was to investigate the association between NK cell activity (NKA) and multiple factors including vitamin D, physical exercise, age, and gender. Methods: This was a cross-sectional association study using health check-up and NKA data of 2,095 subjects collected from 2016 to 2018 in a health check-up center in the Republic of Korea. NKA was measured using the interferon-γ (IFN-γ) stimulation method. The association of NKA with 25-(OH)-vitamin D (25(OH)D) and other factors was investigated by multiple logistic regression analysis. Results: The average age of subjects was 48.8 ± 11.6 years (52.9% of subjects were female). Among 2,095 subjects, 1,427 had normal NKA (NKA ≥ 500 pg IFN-γ/mL), while 506 had low NKA (100 ≤ NKA < 500 pg/mL), and 162 subjects had very low NKA (NKA < 100 pg/mL). Compared to men with low 25(OH)D serum level (< 20 ng/mL), vitamin D replete men (30-39.9 ng/mL) had significantly lower risk of very low NKA (OR: 0.358; 95% CI: 0.138, 0.929; P = 0.035). In women, both low exercise (OR: 0.529; 95% CI: 0.299, 0.939; P = 0.030) and medium to high exercise (OR: 0.522; 95% CI: 0.277, 0.981; P = 0.043) decreased the risk compared to lack of physical exercise. Interestingly, in men and women older than 60 years, physical exercise significantly decreased the risk. Older-age was associated with increased risk of very low NKA in men, but not in women. Conclusion: Physical exercise and vitamin D were associated with NKA in a gender- and age-dependent manner. Age was a major risk factor of very low NKA in men but not in women.

Differential expression of miRNA199b-5p as a novel biomarker for sporadic and hereditary parathyroid tumors.

MicroRNAs (miRNAs) are dysregulated in many tumors; however, miRNA regulation in parathyroid tumors remains poorly understood. To identify differentially expressed miRNAs between sporadic and hereditary parathyroid tumors and to analyze their correlation with clinicopathological features, a microarray containing 887 miRNAs was performed; then, the differentially expressed miRNAs were validated by qRT-PCR using 25 sporadic and 12 hereditary parathyroid tumors and 24 normal parathyroid tissue samples. A receiver operating characteristic curve (ROC) analysis was applied to evaluate the utility of the miRNAs for distinguishing parathyroid tumor types. Compared to the miRNAs in the normal parathyroid tissues, 10 miRNAs were differentially expressed between the sporadic and hereditary parathyroid tumors. Seven of these miRNAs (let-7i, miR-365, miR-125a-3p, miR-125a-5p, miR-142-3p, miR-193b, and miR-199b-5p) were validated in the parathyroid tumor samples. Among these miRNAs, only miR-199b-5p was differentially expressed (P < 0.001); miR-199b-5p was significantly downregulated and negatively associated with PTH levels (γ = -0.579, P = 0.002) in the sporadic tumors but was upregulated in the hereditary tumors. This miRNA showed 67% sensitivity and 100% specificity for distinguishing sporadic and hereditary parathyroid tumors. These results reveal altered expression of a miRNA between sporadic and hereditary parathyroid tumors and the potential role of miR-199b-5p as a novel biomarker for distinguishing these two types of parathyroid tumors.

Lipidomic differentiation of Graves' ophthalmopathy in plasma and urine from Graves' disease patients.

Approximately 50% of patients with Graves' disease (GD) develop retracted eyelids with bulging eyes, known as Graves' ophthalmopathy (GO). However, no simple diagnostic blood marker for distinguishing GO from GD has been developed yet. The objective of this study was to conduct comprehensive profiling of lipids using plasma and urine samples from patients with GD and GO undergoing antithyroid therapy using nanoflow ultrahigh performance liquid chromatography electrospray ionization tandem mass spectrometry. Plasma (n = 86) and urine (n = 75) samples were collected from 23 patients with GD without GO, 31 patients with GO, and 32 healthy controls. Among 389 plasma and 273 urinary lipids that were structurally identified, 281 plasma and 191 urinary lipids were quantified in selected reaction monitoring mode. High-abundance lipids were significantly altered, indicating that the development of GD is evidently related to altered lipid metabolism in both plasma and urine. Several urinary lysophosphatidylcholine species were found to be increased (3- to 10-fold) in both GD and GO. While the overall lipid profiles between GD and GO were similar, significant changes (area under receiver operating curve > 0.8) in GO vs. GD were observed in a few lipid profiles: 58:7-TG and (16:1,18:0)-DG from plasma, 16:1-PC and 50:1-TG from urine, and d18:1-S1P from both plasma and urine samples. An altered metabolism of lipids associated with the additional development of ophthalmopathy was confirmed with the discovery of several candidate markers. These can be suggested as candidate markers for differentiating the state of GO and GD patients based on plasma or urinary lipidomic analysis. Graphical abstract.

Biguanides Metformin and Phenformin Generate Therapeutic Effects via AMP-Activated Protein Kinase/Extracellular-Regulated Kinase Pathways in an In Vitro Model of Graves' Orbitopathy.

BACKGROUND: It was hypothesized that the biguanides metformin and phenformin, which are anti-hyperglycemic drugs used for diabetes mellitus, would have therapeutic effects in an in vitro model of Graves' orbitopathy (GO). Because adipogenesis, hyaluronan production, and inflammation are considered important in the pathogenesis of GO, this study aimed to determine the therapeutic effects and underlying mechanisms of biguanides on these parameters. METHODS: In vitro experiments were performed using primary cultured orbital fibroblasts from patients with GO. Orbital preadipocyte fibroblasts were allowed to differentiate into adipocytes and were treated with various concentrations of metformin or phenformin. Oil Red O staining was performed to evaluate lipid accumulation within the cells. Western blot analysis was used to measure the expression of adipogenic transcription factors and the phosphorylation of AMP-activated protein kinase and mitogen-activated protein kinase signaling proteins. Hyaluronan production was measured using enzyme-linked immunosorbent assay, and mRNA levels of proinflammatory molecules were determined using real-time polymerase chain reaction after interleukin (IL)-1ß stimulation with or without biguanide treatment. RESULTS: Lipid accumulation during adipogenesis in GO orbital fibroblasts was dose-dependently suppressed by both metformin and phenformin. Adipocyte differentiation was attenuated, and the adipogenic transcription factors peroxisome proliferator-activated receptor γ and CCAAT-enhancer-binding proteins-α/ß were downregulated. Furthermore, metformin and phenformin increased the phosphorylation of AMP-activated protein kinase and suppressed extracellular-regulated kinase activation. The IL-1ß-induced hyaluronan production and mRNA expression of IL-6, cyclooxygenase-2, and intercellular adhesion molecule-1 were also significantly suppressed after metformin or phenformin co-treatment. CONCLUSIONS: The present study indicates that the biguanides metformin and phenformin exert an anti-adipogenic and inhibitory effect on hyaluronan production and expression of pro-inflammatory molecules in GO orbital fibroblasts, suggesting that they could potentially be used for the treatment of GO.

The Association between Dehydroepiandrosterone Sulfate (DHEA-S) and Bone Mineral Density in Korean Men and Women.

BACKGROUND: The relationship between dehydroepiandrosterone sulfate (DHEA-S) and bone mineral density (BMD) is controversial. And findings of most studies that have investigated this relationship are restricted to postmenopausal women. In this study, we investigated the relationship between serum DHEA-S and BMD in both men and women. METHODS: This cross-sectional study evaluated a total of 294 healthy Korean participants through a medical examination program. And a subgroup of 154 participants was subjected to a longitudinal analysis. We measured BMD by dual energy X-ray absorptiometry and assayed DHEA-S by a chemiluminescent immunoassay. RESULTS: We evaluated the association between serum DHEA-S concentration and BMD at the femur trochanter after adjusting for cofounders such as age, body mass index, lifestyle factors, serum cortisol level, serum insulin-like growth factor 1 (IGF-1) level, and sex. Through our longitudinal study, we found that the changes in BMD at the total spine, at the femur neck, and at the femur trochanter were all smaller in the ΔDHEA-S <0 group than in the ΔDHEA-S >0 group. CONCLUSIONS: We found that there was a positive correlation between serum DHEA-S and femur BMD, which suggests that controlling serum DHEA-S levels may retard age-related BMD reduction in Koreans.

Association between Metformin Use and Risk of Lactic Acidosis or Elevated Lactate Concentration in Type 2 Diabetes.

PURPOSE: Metformin can reduce diabetes-related complications and mortality. However, its use is limited because of potential lactic acidosis-associated adverse effects, particularly in renal impairment patients. We aimed to investigate the association of metformin use with lactic acidosis and hyperlactatemia in patients with type 2 diabetes. MATERIALS AND METHODS: This was a cross-sectional study from a tertiary university-affiliated medical center. A total of 1954 type 2 diabetes patients were recruited in 2007-2011, and stratified according to the estimated glomerular filtration rate of 60 mL/min/1.73 m². Lactic acidosis was defined as plasma lactate levels >5 mmol/L and arterial pH <7.35. RESULTS: Metformin was used in 61.4% of the patients with type 2 diabetes mellitus. Plasma lactate levels were not different in the patients with and without metformin use. There was no difference in prevalence of hyperlactatemia and lactic acidosis between the patients with and without metformin use (18.9% vs. 18.7%, p=0.905 for hyperlactatemia and 2.8% vs. 3.3%, p=0.544 for lactic acidosis). Similar results were observed in the patients with estimated glomerular filtration rate <60 mL/min/1.73 m². Most patients with lactic acidosis had at least one condition related to hypoxia or poor tissue perfusion. Multiple regression analysis indicated no association between metformin use and lactic acidosis, whereas tissue hypoxia was an independent risk factor for lactic acidosis [odds ratio 4.603 (95% confidence interval, 1.327-15.965)]. CONCLUSION: Metformin use was not associated with hyperlactatemia or lactic acidosis in patients with type 2 diabetes.

Thyroid Isthmus Length and Iodine Turnover as Predictors of Successful Radioactive Iodine Therapy in Patients with Graves' Disease.

Radioactive iodine (RAI) therapy is an effective treatment option for Graves' disease. However, predicting treatment failures after RAI therapy remains controversial. The objective of this study was to investigate the factors associated with the success rate of RAI therapy for treatment of Graves' hyperthyroidism. Thyroid functional outcome, pre-RAI ultrasonographic features, and clinical parameters were evaluated retrospectively in 98 patients followed up for at least 12 months after RAI (mean RAI dose was 11.7 ± 1.8 mCi). Hypothyroidism was achieved in 59 patients (60.2%), and euthyroidism in 16 patients (16.3%), while 23 patients (23.5%) remained hyperthyroid. Age, sex, body mass index, pre-RAI thyroid function, or thyroid-stimulating immunoglobulin levels were not associated with treatment outcome. Length of thyroid isthmus (p = 0.028) and 2- to 24-hour iodine uptake ratios (p = 0.002) were significantly associated with treatment failure, which was defined as a persistent hyperthyroid status after RAI therapy. Patients with a longer isthmus had a higher risk of remaining hyperthyroid, with a threshold for isthmus length of 5.2 mm, with a sensitivity of 69.6% and specificity of 70.3% for treatment success. Measuring the length of the thyroid isthmus can be a simple and useful way to predict RAI treatment outcome.

Therapeutic Effect of Protocatechuic Aldehyde in an In Vitro Model of Graves' Orbitopathy.

PURPOSE: Protocatechuic aldehyde (3,4-dihydroxybenzaldehyde; PCA) is extracted from Salvia miltiorrhiza, and has been reported to possess antiproliferative, antioxidant, and antiadipogenesis properties in various in vivo and in vitro experiments. This study aimed to outline the antioxidant and suppressive effects of PCA on adipogenesis and hyaluronan production in orbital fibroblasts to help with designing therapeutic approaches for Graves' orbitopathy (GO). METHODS: We assessed the in vitro effects of PCA on orbital fibroblasts, which were cultured from orbital fat tissue obtained from patients undergoing orbital decompression for severe GO. Control tissue was obtained from patients undergoing orbital surgery with no history of GO or Graves' hyperthyroidism. RESULTS: The 2,2-diphenyl-1-picrylhydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) diammonium salt assay results confirmed the free radical scavenging effect of PCA after treatment. Protocatechuic aldehyde exhibited a suppressive effect on intracellular reactive oxygen species generation and upregulated heme oxygenase-1 expression in Western blot analysis. Protocatechuic aldehyde attenuated TNF-α and IL-1ß-induced hyaluronan production. Oil Red-O staining results revealed a decrease in lipid droplets and suppressed expression of the adipogenesis-related proteins peroxisome proliferator-activated receptor (PPAR)-γ, CCAAT/enhancer binding protein (c/EBP)-α, and c/EBP-ß upon treatment with PCA during adipose differentiation. CONCLUSIONS: In this study, PCA exerted significant antioxidant and antiadipogenic effects and inhibited the production of hyaluronan in GO orbital fibroblasts. Accordingly, PCA potentially could be used as a novel treatment option for GO.

Distinct Features of Nonthyroidal Illness in Critically Ill Patients With Infectious Diseases.

Nonthyroidal illness (NTI), often observed in critically ill patients, arises through diverse alterations in the hypothalamus-pituitary-thyroid (HPT) axis. However, the causal relationship between underlying disease and NTI diversity in critically ill patients is poorly understood.The aim of this study was to examine NTI severity and adverse outcomes in critically ill patients with respect to their underlying disease(s).The medical records of 616 patients admitted to the intensive care unit (ICU) between January 2009 and October 2014 were retrospectively reviewed. Patients with known diseases or taking medications that affect thyroid function were excluded. All-cause mortality (ACM) and length of stay (LOS) in the ICU were assessed as adverse outcomes.The enrolled patients (n = 213) were divided into the following 4 groups according to the severity of NTI at the nadir of their thyroid function test (TFT): normal (n = 11, 5.2%), mild NTI (n = 113, 53.1%), moderate NTI (n = 78, 36.6%), and severe NTI (n = 11, 5.2%). There was no significant difference between the groups in terms of age and gender. NTI severity showed a significantly strong association with ACM (P < 0.0001) and a significant positive association with LOS in the ICU (P = 0.031). After adjusting for age, gender, and current medications affecting TFT, increasing NTI severity led to increased ACM (odds ratio = 3.101; 95% confidence interval = 1.711-5.618; P < 0.0001). Notably, the prevalence of moderate-to-severe NTI was markedly higher in patients with infectious disease than in those with noninfectious disease (P = 0.012). Consistent with this, serum C-reactive protein levels were higher in patients with moderate-to-severe NTI (P = 0.016).NTI severity is associated with increased ACM, LOS, and underlying infectious disease. Future studies will focus on the biological and clinical implications of infectious disease on the HPT axis.

Inhibitory Effects of α-Lipoic Acid on Oxidative Stress-Induced Adipogenesis in Orbital Fibroblasts From Patients With Graves Ophthalmopathy.

A choice of the optimal treatment for Graves ophthalmopathy (GO) is a challenge due to the complexity of the pathogenesis. Alpha-lipoic acid (ALA) is well known as a multifunctional antioxidant, helping to protect cells against oxidative stress and inflammatory damage.The aim of this study was to investigate the effects of ALA on intracellular production of reactive oxygen species (ROS), inflammation, and adipogenesis using primary cultured orbital fibroblasts from patients with GO.Intracellular ROS levels and mRNA expressions of proinflammatory cytokines and chemokines including intercellular adhesion molecule-1 (ICAM-1), interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1, and regulated upon activation normal T cell expressed and presumably secreted (RANTES) were measured. After adipogenesis, the expressions of peroxisome proliferator-activated receptor (PPAR)γ, CCAAT-enhancer-binding proteins (C/EBP)α and ß, and heme oxygenase-1 (HO-1) were investigated.H2O2 dose-dependently stimulated ROS production and HO-1 expression. Addition of ALA strongly attenuated ROS production and further increased HO-1 expression. However, by pretreatment of zinc protoporphyrin (ZnPP), HO-1 inhibitor, ALA inhibition of ROS generation by H2O2 was abolished. Tumor necrosis factor (TNF)α-induced mRNA expressions of ICAM-1, IL-6, MCP-1, and RANTES were inhibited by ALA treatment. In this context, TNFα-induced phosphorylation of P65 was also inhibited. In addition, ALA dose-dependently inhibited H2O2-induced intracellular accumulation of lipid droplets. The expression of adipogenic transcription factors, including PPARγ, C/EBPα, and ß, was also inhibited.ALA is a potential therapeutic agent for GO because of the inhibitory effects on ROS production and gene expression of proinflammatory cytokines and chemokines, resulting in prevention of adipose-tissue expansion.

Untreated Congenital Adrenal Hyperplasia with 17-α Hydroxylase/17,20-Lyase Deficiency Presenting as Massive Adrenocortical Tumor.

Congenital adrenal hyperplasia (CAH) with 17α-hydroxylase/17,20-lyase deficiency is usually characterized by hypertension and primary amenorrhea, sexual infantilism in women, and pseudohermaphroditism in men. hypertension, and sexual infantilism in women and pseudohermaphroditism in men. In rare cases, a huge adrenal gland tumor can present as a clinical manifestation in untreated CAH. Adrenal cortical adenoma is an even more rare phenotype in CAH with 17α-hydroxylase/17,20-lyase deficiency. A 36-year-old female presented with hypertension and abdominal pain caused by a huge adrenal mass. Due to mass size and symptoms, left adrenalectomy was performed. After adrenalectomy, blood pressure remained high. Based on hormonal and genetic evaluation, the patient was diagnosed as CAH with 17α-hydroxylase/17,20-lyase deficiency. The possibility of a tumorous change in the adrenal gland due to untreated CAH should be considered. It is important that untreated CAH not be misdiagnosed as primary adrenal tumor as these conditions require different treatments. Adequate suppression of adrenocorticotropic hormone (ACTH) in CAH is also important to treat and to prevent the tumorous changes in the adrenal gland. Herein, we report a case of untreated CAH with 17α-hydroxylase/17,20-lyase deficiency presenting with large adrenal cortical adenoma and discuss the progression of adrenal gland hyperplasia due to inappropriate suppression of ACTH secretion.

Focal Lymphocytic Thyroiditis Nodules Share the Features of Papillary Thyroid Cancer on Ultrasound.

PURPOSE: It is often difficult to discriminate focal lymphocytic thyroiditis (FLT) or adenomatous hyperplasia (AH) from thyroid cancer if they both have suspicious ultrasound (US) findings. We aimed to make a predictive model of FLT from papillary thyroid cancer (PTC) in suspicious nodules with benign cytologic results. MATERIALS AND METHODS: We evaluated 214 patients who had undergone fine-needle aspiration biopsy (FNAB) and had shown thyroid nodules with suspicious US features. PTC was confirmed by surgical pathology. FLT and AH were confirmed through more than two separate FNABs. Clinical and biochemical findings, as well as US features, were evaluated. RESULTS: Of 214 patients, 100 patients were diagnosed with PTC, 55 patients with FLT, and 59 patients with AH. The proportion of elevated thyrotropin (TSH) levels (p=0.014) and thyroglobulin antibody (Tg-Ab) or thyroid peroxidase antibody (TPO-Ab) positivity (p<0.001) in the FLT group was significantly higher than that in the PTC group. Regarding US features, absence of calcification (p=0.006) and "diffuse thyroid disease" (DTD) pattern on US (p<0.001) were frequently seen in the FLT group. On multivariate analysis, Tg-Ab positivity, presence of a DTD pattern on US, and absence of calcification in nodules were associated with FLT with the best specificity of 99% and positive predictive value of 96%. In contrast, a taller than wide shape of nodules was the only variable significant for differentiating AH from PTC. CONCLUSION: Suspicious thyroid nodules with cytologic benign results could be followed up with US rather than repeat FNAB, if patients exhibit Tg-Ab positivity, no calcifications in nodules, and a DTD pattern on US.

Follicular variant of papillary thyroid carcinoma with B-type Raf(V600E) showing higher frequency of suspicious sonographic features and multifocality.

BACKGROUND: The purpose of this study was to investigate the correlation between B-type Raf (BRAF) kinase mutation and clinicopathological features of follicular variant of papillary thyroid carcinoma (PTC). METHODS: Eighty-four patients with pathologically confirmed follicular variant of PTC, who underwent a preoperative BRAF(V600E) study, were analyzed. Clinicopathological parameters and ultrasonographic features were compared between the BRAF(V600E) -positive and negative groups. RESULTS: A total of 41.7% of the patients showed BRAF(V600E) . The BRAF(V600E) -positive group showed the smaller tumor size (7.3 ± 3.6 mm vs 10.7 ± 8.9 mm; p = .018) and the more frequent multifocality (25.7% vs 8.2%; p = .028). Follicular variant of PTC with BRAF(V600E) showed suspicious ultrasonographic features (88.6% vs 57.1%; p = .002) more frequently. BRAF(V600E) positivity is associated with multifocality after adjusting for age, sex, the presence of suspicious ultrasonographic features, pathological tumor size, and thyrotropin level. CONCLUSION: BRAF(V600E) was correlated with smaller tumor size and suspicious ultrasonographic features in follicular variant of PTC. BRAF(V600E) was a significant parameter for predicting multifocality of follicular variant of PTC.

High cut-off value of a chimeric TSH receptor (Mc4)-based bioassay may improve prediction of relapse in Graves' disease for 12 months.

There are scarce reports regarding a functional prognostic value of thyroid-stimulating autoantibody (TSAb) levels using a thyroid-stimulating hormone receptor chimera (Mc4) in Graves' disease (GD) in iodine sufficient area. The aim of this study was to investigate whether Mc4-TSAb can predict GD remission/relapse after antithyroid drug (ATD) treatment and to compare Mc4-TSAb with a binding assay using M22 monoclonal antibody (M22-TRAb) in GD patients. We retrospectively reviewed the results of M22-TRAb and Mc4-TSAb in GD patients treated with ATD for 12 months. GD patients who underwent ATD treatment for at least 12 months were included. We compared the predictive values of M22-TRAb and Mc4-TSAb for GD remission and relapse. Of the 92 patients, 60 (65.2%) achieved remission and 32 (34.8%) relapsed within 12 months. In receiver operating characteristic analysis, there were no significant differences in the area under the curves (AUCs) between Mc4-TSAb [AUC=0.79 (95% CI 0.69-0.89)] and M22-TRAb [AUC=0.69 (95% CI 0.58-0.81)]. The optimal predictive cut-off values of M22-TRAb and Mc4-TSAb were 2.23 IU/L and 230%, respectively. At a high Mc4-TSAb cut-off, the better specificity of 85.0% and positive predictive value (PPV) of 69.0% were shown compared with those at the best cut-off for M22-TRAb. In conclusion, a high cut-off for an Mc4 assay may improve the predictive value of relapse with superior specificity and PPV compared with M22-TRAb in treated GD.

Postprandial C-peptide to glucose ratio as a predictor of ß-cell function and its usefulness for staged management of type 2 diabetes.

AIMS/INTRODUCTION: Type 2 diabetes is characterized by progressive deterioration of ß-cell function. Recently, it was suggested that the C-peptide-to-glucose ratio after oral glucose ingestion is a better predictor of ß-cell mass than that during fasting. We investigated whether postprandial C-peptide-to-glucose ratio (PCGR) reflects ß-cell function, and its clinical application for management of type 2 diabetes. MATERIALS AND METHODS: We carried out a two-step retrospective study of 919 Korean participants with type 2 diabetes. In the first step, we evaluated the correlation of PCGR level with various markers for ß-cell function in newly diagnosed and drug-naïve patients after a mixed meal test. In the second step, participants with well-controlled diabetes (glycated hemoglobin <7%) were divided into four groups according to treatment modality (group I: insulin, group II: sulfonylurea and/or dipeptityl peptidase IV inhibitor, group III: metformin and/or thiazolidinedione and group IV: diet and exercise group). RESULTS: In the first step, PCGR was significantly correlated with various insulin secretory indices. Furthermore, PCGR showed better correlation with glycemic indices than homeostatic model assessment of ß-cell function (HOMA-ß). In the second step, the PCGR value significantly increased according to the following order: group I, II, III, and IV after adjusting for age, sex, body mass index and duration of diabetes. The cut-off values of PCGR for separating each group were 1.457, 2.870 and 3.790, respectively (P < 0.001). CONCLUSIONS: We suggest that PCGR might be a useful marker for ß-cell function and an ancillary parameter in the choice of antidiabetic medication in type 2 diabetes.

Genetic and epigenetic analysis in korean patients with multiple endocrine neoplasia type 1.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is a familial syndrome characterized by the parathyroid, pancreas and pituitary tumors. Parathyroid tumors are the most common clinical manifestations, occurring in more than 90% of MEN1 patients. Heterozygous germline mutations of the MENIN gene underlie the tumorigenesis in MEN1 and epigenetic alterations along with germline mutations may contribute to tumorigenesis. Here, we investigated the associations between genotype and phenotype in Korean MEN1 patients. METHODS: We analyzed medical records from 14 unrelated MEN1 patients who had newly confirmed MENIN germline mutations, together with 14 previous reports in Korea. Aberrant DNA methylations were also examined in MEN1-related parathyroid tumors using the Infinium HumanMethylation 450 BeadChip. RESULTS: Total 28 germline mutations of MENIN were relatively highly concentrated in exons 7 and 8 compared to previous reports from Western countries. Six mutations (c.111dupT/p.S38Ffs(*)79, c.225_226insT/p.T76Yfs(*)41, c.383_398del16/p.S128Tfs(*)52, c.746dupT/p.H250Afs(*)20, c.1150G>T/p.E384(*), and c.1508G>A/p.G503N) were newly found in the present study. Of interest, four patients (15%) showed unusual initial presentations and three patients were diagnosed incidentally at the general medical checkup. We also found three distinct sites in exon 2 of MENIN were significantly hypomethylated in the MEN1 parathyroid tumors, comparing correspondent blood samples. CONCLUSION: We also have found a lack of genotype/phenotype correlation in Korean MEN1 patients. There were not a few unusual initial manifestations in MEN1 patients, thus, genetic testing for the MENIN germline mutations can provide important information for the better prognosis. Further studies are warranted to investigate altered DNA methylations in the MENIN gene involved in tumorigenesis.

Thyroid cancers with benign-looking sonographic features have different lymph node metastatic risk and histologic subtypes according to nodule size.

A decision to perform fine needle aspiration (FNA) on thyroid nodules mainly depends on sonographic features. We investigated if lymph node metastasis (LNM) risk differed by tumor size of thyroid cancers without suspicious sonographic features. Three hundred sixty patients with thyroid cancers with benign looking sonographic features were grouped by nodule size on ultrasonography (US) (≤ or >1 cm). The clinicopathologic parameters were compared between the groups. A multivariate analysis was performed to discover the independent factors predicting the presence of LNM. The nodules greater than 10 mm on US (n = 157) demonstrated a larger tumor size on histology (17.9 ± 14.5 vs. 5.6 ± 2.4 mm, P < 0.001), a lower frequency of classical papillary thyroid carcinoma (PTC) (58.6 vs. 87.2 %, P < 0.001), and a higher frequency of follicular variant PTC and follicular thyroid carcinoma (19.7 and 17.8 % vs. 9.4 and 1.5 %, respectively, P < 0.01). In subgroup analysis of 269 patients with classical PTC, the larger nodule size on US was associated with a higher prevalence of LNM (28.3 vs. 14.7 %, P = 0.007). A multivariate analysis revealed that classical PTC, extrathyroidal extension, and the US nodule size >10 mm were independent predictive factors of LNM after adjusting for age, sex, TSH level, and multifocality. Thyroid cancers larger than 10 mm with benign US features are more likely to be nonclassical PTC than those with smaller diameters. The larger ones also have an increased risk of LNM in classical PTC. These cases require a more aggressive approach to FNA.

Body Mass Index Is Associated with Hypercholesterolemia following Thyroid Hormone Withdrawal in Thyroidectomized Patients.

Thyroid hormone withdrawal (THW) for postoperative radioiodine adjuvant therapy or diagnostic radioiodine whole body scan in patients with differentiated thyroid cancers results in acute thyroid hormone deficiency and abnormal lipid profiles. To better clarify the clinical pattern of dyslipidemia occurring after THW, we retrospectively analyzed the association between serum total cholesterol level after THW and various clinical factors in a total of 61 patients who underwent total thyroidectomy due to papillary thyroid cancers from January 2010 to March 2012, in Severance Hospital, Seoul, Korea. Preoperative baseline total cholesterol was significantly correlated with post-THW total cholesterol level; however, age, gender, or elevated TSH level after THW itself was not correlated with post-THW total cholesterol level. A significant correlation between preoperative measured BMI and post-THW total cholesterol level was found (r = 0.263, P = 0.041). In multiple logistic analysis, BMI was an independent determining factor of post-THW total cholesterol level (P = 0.012).

Germline mutation of Glu70Lys is highly frequent in Korean patients with von Hippel-Lindau (VHL) disease.

Von Hippel-Lindau (VHL) disease is an inherited tumor syndrome caused by germline mutations in the VHL tumor suppressor gene. It is characterized by hemangioblastoma in the central nervous system and retina, renal cell carcinoma, pancreatic tumor and cysts, and pheochromocytoma. In this study, we detected 26 germline mutations in the VHL gene of Korean patients, of which 1 was a novel mutation, c.417_418insT. We also integrated our data from this study with the published literature to identify 55 VHL germline mutations in Koreans, and identified a unique hotspot at codon 70. Nine unrelated patients (9/55, 16.4%) had the same amino-acid substitution at codon 70 (Glu70Lys) and showed VHL type 1 phenotypes. Although this mutation was shown to have a mild effect on VHL function, four of the nine patients (44.4%) subsequently developed multiple central nervous system hemangioblastomas or retinal hemangioblastoma. However, this hotspot has not been identified in Chinese or Japanese patients. This study provides information on the spectrum of VHL mutations in Korean VHL disease and contributes to a better understanding of VHL disease in terms of improvements in the clinical management of VHL families.

The biochemical prognostic factors of subclinical hypothyroidism.

BACKGROUND: Patients with subclinical hypothyroidism (SHT) are common in clinical practice. However, the clinical significance of SHT, including prognosis, has not been established. Further clarifying SHT will be critical in devising a management plan and treatment guidelines for SHT patients. Thus, the aim of this study was to investigate the prognostic factors of SHT. METHODS: We reviewed the medical records of Korean patients who visited the endocrinology outpatient clinic of Severance Hospital from January 2008 to September 2012. Newly-diagnosed patients with SHT were selected and reviewed retrospectively. We compared two groups: the SHT maintenance group and the spontaneous improvement group. RESULTS: The SHT maintenance group and the spontaneous improvement group had initial thyroid-stimulating hormone (TSH) levels that were significantly different (P=0.035). In subanalysis for subjects with TSH levels between 5 to 10 µIU/mL, the spontaneous improvement group showed significantly lower antithyroid peroxidase antibody (anti-TPO-Ab) titer than the SHT maintenance group (P=0.039). Regarding lipid profiles, only triglyceride level, unlike total cholesterol and low density lipoprotein cholesterol, was related to TSH level, which is correlated with the severity of SHT. Diffuse thyroiditis on ultrasonography only contributed to the severity of SHT, not to the prognosis. High sensitivity C-reactive protein and urine iodine excretion, generally regarded as possible prognostic factors, did not show any significant relation with the prognosis and severity of SHT. CONCLUSION: Only initial TSH level was a definite prognostic factor of SHT. TPO-Ab titer was also a helpful prognostic factor for SHT in cases with mildly elevated TSH. Other than TSH and TPO-Ab, we were unable to validate biochemical prognostic factors in this retrospective study for Korean SHT patients.