Jae Hyun Bae

Preoperative Predictive Factors for Parathyroid Carcinoma in Patients with Primary Hyperparathyroidism

This study was conducted to review the clinical characteristics of parathyroid carcinoma (PC) and to evaluate potential preoperative predictive factors for PC in patients with primary hyperparathyroidism (PHPT). We performed a retrospective review of electronic medical records of 194 patients with pathologically confirmed PHPT in affiliated teaching hospitals of Seoul National University from January 2000 to March 2011. Adenoma was diagnosed in 171 patients, hyperplasia in 12, and carcinoma in 11. Several biochemical measurements were higher in patients with PC than in patients with benign disease, including serum total calcium (P < 0.001), intact parathyroid hormone (P = 0.003), and alkaline phosphatase (ALP) (P < 0.001). Tumors were larger in PC than in benign disease (P < 0.001). Multivariate analysis revealed that serum ALP level (P < 0.001) and tumor size were associated with PC (P = 0.03). Tumor size and serum ALP level were evaluated as preoperative predictive factors for PC using ROC analyses: a tumor size of 3.0 cm (sensitivity 90.9%, specificity 92.1%) and serum ALP level of 285 IU/L (83.3%, 97.0%) had predictive value for the diagnosis of PC in patients with PHPT. In conclusion, elevated serum ALP and a large parathyroid mass at the time of diagnosis can be helpful to predict PC in patients with PHPT.

Clinical Characteristics of the Responders to Dipeptidyl Peptidase-4 Inhibitors in Korean Subjects with Type 2 Diabetes

We investigated characteristics associated with the efficacy of dipeptidyl peptidase-4 inhibitors (DPP4i) in Korean patients with type 2 diabetes. We reviewed medical records of 477 patients who had taken sitagliptin or vildagliptin longer than 40 weeks. Response to DPP4i was evaluated with HbA1c change after therapy (ΔHbA1c). The Students t-test between good responders (GR: ΔHbA1c > 1.0%) and poor responders (PR: ΔHbA1c < 0.5%), a correlation analysis among clinical parameters, and a linear multivariate regression analysis were performed. The mean age was 60 yr, duration of diabetes 11 yr and HbA1c was 8.1%. Baseline fasting plasma glucose (FPG), HbA1c, C-peptide, and creatinine were significantly higher in the GR compared to the PR. Duration of diabetes, FPG, HbA1c, C-peptide and creatinine were significantly correlated with ΔHbA1c. In the multivariate analysis, age (r2 = 0.006), duration of diabetes (r2 = 0.019), HbA1c (r2 = 0.296), and creatinine levels (r2 = 0.024) were independent predictors for the response to DPP4i. Body mass index and insulin resistance were not associated with the response to DPP4i. In conclusion, better response to DPP4i would be expected in Korean patients with type 2 diabetes who have higher baseline HbA1c and creatinine levels with shorter duration of diabetes.

Radiographic Characteristics of Adrenal Masses in Oncologic Patients

Background We aimed to assess the usefulness of pre-contrast Hounsfield unit (HU) and mass size on computed tomography to differentiate adrenal mass found incidentally in oncologic patients. Methods From 2000 to 2012, 131 oncologic patients with adrenal incidentaloma were reviewed retrospectively. Receiver operating characteristic (ROC) curves were applied to determine the optimal cut-off value of the mean HU and size for detecting adrenal metastasis. Results The median age was 18 years, and 80 patients were male. The initial mass size was 18 mm, and 71 (54.2%) of these were on the left side. A bilateral adrenal mass was found in 11 patients (8.4%). Biochemically functional masses were observed in 9.2% of patients. Thirty-six out of 119 patients with nonfunctional masses underwent adrenalectomy, which revealed metastasis in 13. The primary cancers were lung cancer (n=4), renal cell carcinoma (n=2), lymphoma (n=2), hepatocellular carcinoma (n=2), breast cancer (n=1), and others (n=2). The area under the curve for the size and HU for clinically suspicious metastasis were 0.839 (95% confidence interval [CI], 0.761 to 0.900; P<0.001) and 0.959 (95% CI, 0.898 to 0.988; P<0.001), respectively. The cut-off value to distinguish between metastasis and benign masses were 22 mm for size and 20 for HU. Conclusion ROC curve results suggest that pre-contrast HU >20 can be used as a diagnostic reference to suggest metastasis in oncologic patients with adrenal masses.

Adrenocorticotropic Hormone-Independent Cushing Syndrome with Bilateral Cortisol-Secreting Adenomas

A 48-year-old woman was incidentally found to have bilateral adrenal masses, 2.8 cm in diameter on the right, and 2.3 cm and 1.7 cm in diameter on the left, by abdominal computed tomography. The patient had a medical history of hypertension, which was not being controlled by carvedilol, at a dose of 25 mg daily. She presented with signs and symptoms that suggested Cushing Syndrome. We diagnosed adrenocorticotropic hormone (ACTH)-independent Cushing Syndrome based on the results of basal and dynamic hormone tests. Adrenal vein sampling (AVS) was performed to localize a functioning adrenal cortical mass. AVS results were consistent with hypersecretion of cortisol from both adrenal glands, with a cortisol lateralization ratio of 1.1. Upon bilateral laparoscopic adrenalectomy, bilateral ACTH-independent adrenal adenomas were found. The patients signs and symptoms of Cushing Syndrome improved after surgery just as the blood pressure was normalized. After surgery, the patient was started on glucocorticoid and mineralocorticoid replacement therapy.

The Presence of Thyroid-Stimulation Blocking Antibody Prevents High Bone Turnover in Untreated Premenopausal Patients with Graves' Disease.

Osteoporosis-related fractures are one of the complications of Graves’ disease. This study hypothesized that the different actions of thyroid-stimulating hormone receptor (TSHR) antibodies, both stimulating and blocking activities in Graves’ disease patients might oppositely impact bone turnover. Newly diagnosed premenopausal Graves’ disease patients were enrolled (n = 93) and divided into two groups: patients with TSHR antibodies with thyroid-stimulating activity (stimulating activity group, n = 83) and patients with TSHR antibodies with thyroid-stimulating activity combined with blocking activity (blocking activity group, n = 10). From the stimulating activity group, patients who had matched values for free T4 and TSH binding inhibitor immunoglobulin (TBII) to the blocking activity group were further classified as stimulating activity-matched control (n = 11). Bone turnover markers BS-ALP, Osteocalcin, and C-telopeptide were significantly lower in the blocking activity group than in the stimulating activity or stimulating activity-matched control groups. The TBII level showed positive correlations with BS-ALP and osteocalcin levels in the stimulating activity group, while it had a negative correlation with the osteocalcin level in the blocking activity group. In conclusion, the activation of TSHR antibody-activated TSH signaling contributes to high bone turnover, independent of the actions of thyroid hormone, and thyroid-stimulation blocking antibody has protective effects against bone metabolism in Graves’ disease.

DNA methylation profiles in sibling pairs discordant for intrauterine exposure to maternal gestational diabetes

ABSTRACT Intrauterine exposure to hyperglycemia is reported to confer increased metabolic risk in later life, supporting the ‘developmental origins of health and disease’ hypothesis. Epigenetic alterations are suggested as one of the possible underlying mechanisms. In this study, we compared pairwise DNA methylation differences between siblings whose intrauterine exposure to maternal gestational diabetes (GDM) were discordant. Methylation of peripheral blood DNA of 18 sibling pairs was measured using Infinium HumanMethylation450 BeadChip assays. Of the 465,447 CpG sites analyzed, 12 showed differential methylation (false discovery rate <0.15), including markers within genes associated with monogenic diabetes (HNF4A) or obesity (RREB1). The overall methylation at HNF4A showed inverse correlations with mRNA expression levels, though non significant. In a gene set enrichment analysis, metabolism and signal transduction pathways were enriched. In conclusion, we found DNA methylation markers associated with intrauterine exposure to maternal GDM, including those within genes previously implicated in diabetes or obesity.

A Possible Link Between Parathyroid Hormone Secretion and Local Regulation of GABA in Human Parathyroid Adenomas.

CONTEXT γ-Aminobutyric acid-B receptor 1 (GABABR1) forms a heterodimeric complex with calcium-sensing receptor (CaSR) in human brain tissue. However, the expression and implication of GABABR1 in human parathyroid adenoma has not yet been examined. OBJECTIVE The objective of the study was to examine a possible link between GABABR1 and PTH secretion in human parathyroid adenoma Design and Methods: Sixty-five patients who underwent parathyroidectomy for primary hyperparathyroidism (PHPT) and 29 control patients with normal parathyroid glands were retrospectively included. All patients diagnosed with PHPT had parathyroid adenomas. We evaluated the protein expression of GABABR1, glutamic acid decarboxylase 65/67 (GAD65/67), and various factors proposed as regulators of PTH secretion including CaSR, vitamin D receptor (VDR), CYP24A1, CYP27B1, fibroblast growth factor, and α-klotho in parathyroid tissues from patients with parathyroid adenomas using immunohistochemistry. RESULTS Expressions of CaSR, GABABR1, and VDR were significantly lower in PHPT patients than in control subjects (P < .001 for CaSR and GABABR1; P = .006 for VDR). Protein expression of GAD65/67, which indicates local production and regulation of GABAergic pathway, was significantly increased in PHPT (P < .001). There were no significant differences in CYP24A1, CYP27B1, fibroblast growth factor, and α-klotho expression between the two groups. Expression of GAD65/67 was significantly correlated with VDR, CYP24A1, CYP27B1, and α-klotho in PHPT (all P < .01) but not in the control groups. CaSR expression was positively associated with serum phosphorus level (r = 0.274, P = .029) and GAD65/67 was negatively correlated with serum PTH level (r = -0.342, P = .005). CONCLUSIONS Local production and action of GABA may be regulated in human parathyroid adenomas. This suggests a possible link between PTH secretion and local regulation of GABA in parathyroid adenomas.