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.

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.

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.

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.

Low serum vitamin D is associated with anti-thyroid peroxidase antibody in autoimmune thyroiditis.

PURPOSE: The association between autoimmune thyroid diseases (AITDs) and vitamin D deficiency is controversial. We aimed to evaluate the relationship between serum 25-hydroxy-vitamin D3 [25(OH)D3] and anti-thyroid antibody levels. MATERIALS AND METHODS: 25(OH)D3, anti-thyroid antibodies, and thyroid function measured in 304 patients who visited the endocrinology clinic were analyzed. The patients were subgrouped into the AITDs or non-AITDs category according to the presence or absence of anti-thyroid antibodies. The relationship between anti-thyroid peroxidase antibody (TPOAb) and 25(OH)D3 was evaluated. RESULTS: The patients with elevated anti-thyroid antibodies had lower levels of serum 25(OH)D3 than those who did not (12.6±5.5 ng/mL vs. 14.5±7.3 ng/mL, respectively, p<0.001). Importantly, after adjusting for age, sex, and body mass index, a negative correlation (r=-0.252, p<0.001) was recognized between 25(OH)D3 and TPOAb levels in the AITDs group, but this correlation did not exist in the non-AITDs group (r=0.117, p=0.127). 25(OH)D3 level was confirmed as an independent factor after adjusting for co-factors that may affect the presence of TPOAb in the AITDs group. CONCLUSION: 25(OH)D3 level is an independent factor affecting the presence of TPOAb in AITDs. The causal effect of 25(OH)D3 deficiency to AITDs is to be elucidated.

A case of esophageal intramural pseudodiverticulosis.

Esophageal intramural pseudodiverticulosis (EIP) is a rare benign disease that is characterized by multiple tiny flask-shaped outpouching lesions of the esophageal wall. The etiology is unknown, but the pathologic findings include dilatation of excretory ducts of submucosal glands. The predominant symptom is dysphagia, and esophageal stricture occurs frequently. Diseases such as diabetes mellitus, esophageal candidiasis, gastroesophageal reflux disease, and chronic alcoholism are often combined. Since most EIP cases are benign, the mainstream treatment is symptom relief by endoscopic dilatation or medical treatment of accompanied diseases. This report describes the case of a 68-year-old male patient who suffered from chest tightness for 2 months and was diagnosed with EIP. This symptom disappeared after 2 months of medical treatment, and the patient is now being regularly followed up.

Effect of zoledronic acid on acro-osteolysis and osteoporosis in a patient with Hajdu-Cheney syndrome.

Hajdu-Cheney syndrome is a rare, autosomal dominant skeletal dysplasia marked by acro-osteolysis of the distal phalanges and severe osteoporosis. Although there are more than 60 reports published to date, proper treatment and subsequent outcome have been scarce. Herein, we report a progress of anti-resorptive therapy with zoledronic acid, in a woman with Hajdu-Cheney syndrome. Results suggest that anti-resorptive therapy may be important in delaying the progress of osteoporosis and preventing fractures, but not necessarily acro-osteolysis itself.

[Deficiencies in proteins C and S in a patient with idiopathic portal hypertension accompanied by portal vein thrombosis].

Portal vein thrombosis (PVT) is an uncommon cause of presinusoidal portal hypertension. Among various hepatoportal disorders, noncirrhotic portal hypertension conditions such as idiopathic portal hypertension (IPH) are considered to have a close relation with PVT. PVT is known to have several predisposing conditions, including infection, malignancies, and coagulation disorders. There is growing interest and recognition that deficiencies in proteins C and S are associated with a hypercoagulable state. These deficiencies are regarded as key factors of systemic hypercoagulability and recurrent venous thromboembolism. We report the case of a 19-year-old male diagnosed as IPH with PVT and combined deficiencies in proteins C and S.