[Show abstract][Hide abstract] ABSTRACT: To examine if a simple biomarker can identify people with diabetes who are at high risk of atrial fibrillation.
A retrospective cohort study was conducted at a single centre in people with Type 2 diabetes referred to our department between January 2000 and December 2007. In 517 consecutive people without any history, signs or symptoms of atrial fibrillation at baseline, the association between baseline B-type natriuretic peptide level and future atrial fibrillation incidence was examined, with adjustments for other potentially confounding factors.
A total of 28 people were diagnosed with new-onset atrial fibrillation during a median 6-year follow-up. When people were categorized into three groups according to B-type natriuretic peptide clinical thresholds (20 and 100 pg/ml), hazard ratios for the development of atrial fibrillation in the middle and highest B-type natriuretic peptide groups were 2.8 and 9.4, respectively, compared with the lowest B-type natriuretic peptide group. Time-dependent receiver-operating curve analysis identified a threshold for B-type natriuretic peptide to detect atrial fibrillation development of 52.8 pg/ml (sensitivity 75.2%, specificity 68.8%). The B-type natriuretic peptide predictive value was independent of and similar to that of left atrial size and ventricular dimension.
In people with Type 2 diabetes, high baseline B-type natriuretic peptide levels were significantly associated with future atrial fibrillation development. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
Diabetic Medicine 07/2015; DOI:10.1111/dme.12856 · 3.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The syndrome of inappropriate secretion of thyrotropin (SITSH) is a hallmark of resistance to thyroid hormone (RTH) due to mutations in the β isoform of the thyroid hormone receptor (TRβ). Here, we report on a family of RTH due to a TRβ mutation (RTHβ) and presenting occasional SITSH. The proband was a 16 year-old girl with a goiter, detected at a school physical examination. She was initially diagnosed as having euthyroid Hashimoto thyroiditis because her thyroid function was normal with a positive anti-thyroglobulin antibody. Follow-up examinations resulted in mild SITSH on some occasions and euthyroid on the other occasions. A magnetic resonance imaging (MRI) revealed a normal pituitary gland. Because her mother also had mild SITSH, genetic analysis was performed and revealed a heterozygous point mutation in TRβ (p.R316C). Previously, the p.R316C had only been found in severe RTH cases with homozygous mutations or with an ectopic thyroid. Her mother with a heterozygous mutation showed variable RTH phenotype on T3 suppression testing. In conclusion, the prevalence of RTHβ might be underestimated and occasional SITSH could also suggest RTHβ. TRβ gene mutation is not always correlated with the RTH phenotype.
[Show abstract][Hide abstract] ABSTRACT: Objective: The objective was to assess involvement of loss the of PRKAR1A gene encoding a type 1α regulatory subunit of cAMP-dependent protein kinase A located on 17q24 in a Carney complex (CNC)-related pituitary adenoma. Design: We investigated aberrations of the PRKAR1A gene in a CNC patient with a GH-producing pituitary adenoma, whose family has 3 other members with probable CNC. Methods: A gene mutation was identified by a standard DNA sequencing method based on PCR. DNA copy number was measured to evaluate allelic loss on 17q24 by quantitative PCR. The breakpoints of deletion were determined by cloning a rearranged region in the deleted allele. Results: A PRKAR1A mutation of c.751_758del8 (p.S251LfsX16) was found in genomic DNA obtained from a pituitary adenoma, but not leukocytes from the patient. Reduced DNA copy number at loci including the PRKAR1A gene on 17q24 was detected in both the tumor and leukocytes, suggesting a deletion at the loci at the germline level. The deletion size was determined to be approximately 0.5 Mb and this large deletion was also found in other 2 family members. Conclusion: This is the first case showing a CNC-related pituitary adenoma with the combination of somatic mutation and a large inherited deletion of the PRKAR1A gene. Biallelic inactivation of PRKAR1A appears to be necessary for the development of CNC-related pituitary adenoma.
European Journal of Endocrinology 10/2014; 172(1). DOI:10.1530/EJE-14-0685 · 4.07 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Context: Proprotein convertase subtilisin/kexin 9 (PCSK9) is known to be a good target to decrease LDL cholesterol (LDL-C) and two forms of PCSK9, mature and furin-cleaved PCSK9, circulate in blood. However, it has not been clarified whether and how the levels of each PCSK9 are affected by LDL-apheresis (LDL-A) treatment, a standard therapy in patients with severe forms of familial hypercholesterolemia (FH). Objective: Our objective was to investigate the differences in LDL-A-induced reduction of mature and furin-cleaved PCSK9 between homozygous and heterozygous FH, and between dextran sulfate (DS) cellulose adsorption and double membrane (DM) columns and to clarify the mechanism of their removal. Design: A sandwich ELISA to measure two forms of PCSK9s using monoclonal antibodies was developed. Using the ELISA, PCSK9 levels were quantified before and after LDL-A with DS columns in 7 homozygous and 11 heterozygous FH patients. A crossover study between the two column types was performed. The profiles of PCSK9s were analyzed after fractionation by gel filtration chromatography. Immunoprecipitation of apolipoprotein B (apoB) in FH plasma was performed. Results: Both mature and furin-cleaved PCSK9s were significantly decreased by 55-56% in FH homozygotes after a single LDL-A treatment with DS columns, and by 46-48% or 48-56% in FH heterozygotes after treatment with DS or DM columns. The reduction ratios of LDL-C were strongly correlated with that of PCSK9 in both FH homozygotes and heterozygotes. In addition, more than 80% of plasma PCSK9s were in the apoB-deficient fraction and a significant portion of mature PCSK9 was bound to apoB, as shown by immunoprecipitation. Conclusions: Both mature and furin-cleaved PCSK9s were removed by LDL-A in homozygous and heterozygous FH either by binding to apoB or by other mechanisms. The ELISA method to measure both forms of plasma PCSK9 would be useful for investigating physiological or pathological roles of PCSK9.
[Show abstract][Hide abstract] ABSTRACT: A questionnaire survey was conducted at local pharmacies in an urban area to investigate awareness and management of cardiovascular risk factors in patients with diabetes. Among respondents, 51, 86, and 94 % stated that they knew their low density lipoprotein (LDL) cholesterol, hemoglobin A1c (HbA1c), and systolic blood pressure levels, respectively. Among patients aware of their risk factor levels, 49 % achieved HbA1c HbA1c 15 years) met all three of these less stringent criteria. Awareness of HbA1c was significantly associated with achievement of systolic blood pressure
Diabetology International 06/2014; 6(2). DOI:10.1007/s13340-014-0183-x
[Show abstract][Hide abstract] ABSTRACT: Aims
Diabetes is a major risk factor for heart failure (HF). We examined whether baseline HbA1c level predicts HF incidence independent of other HF risk factors, including baseline cardiac structural and functional abnormalities.
In patients with type 2 diabetes, multivariable Cox regression models were constructed to examine the independent association between baseline HbA1c and future HF hospitalization.
In 608 subjects (mean age, 66.5 years; men, 68%; mean HbA1c, 9.1% (76 mmol/mol)), 92 were hospitalized for HF during a median follow-up of 6 years. For a 1% (11 mmol/mol) increase in baseline HbA1c, the hazard ratio for HF was 1.23 (95% confidence interval, 1.1–1.7, p < 0.001) with adjustment for age, sex, body mass index, blood pressure and plasma B-type natriuretic peptide (BNP) level. The effect of HbA1c on HF was independent of baseline left ventricular (LV) ejection fraction, the ratio of peak early to late diastolic filling velocity, and prevalent/incident coronary heart disease (CHD), and was more evident in patients with enlarged LV, decreased systolic function, prevalent CHD, or prevalent HF.
In patients with type 2 diabetes, HbA1c significantly predicts future HF hospitalization independent of baseline BNP level or echocardiographic parameters.
Diabetes research and clinical practice 05/2014; 104(2). DOI:10.1016/j.diabres.2014.02.009 · 2.54 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
Multiple endocrine neoplasia type 2B (MEN2B) is the rarest and most aggressive form of MEN2. MEN2B cases usually carry either an M918T or A883T mutation of the RET, but to date, there are 3 atypical MEN2B caused by tandem mutations.
Methods and results:
A 32-year-old woman with no family history of medullary thyroid carcinoma (MTC) presented with a neck tumor and multiple mucosal nodules. She was diagnosed with MEN2B. Genetic analyses of RET revealed that she had 2 mutations, Q781R and V804M. Subclone and genetic analyses revealed that Q781R was on the paternal allele and V804M was a de novo. In silico analysis of the tandem mutations showed a high prediction score.
We describe a novel combination of tandem RET mutations (Q781R/V804M) in a MEN2B-like patient. In silico analysis showed a high prediction score, which was compatible with the clinical phenotype in the present case.
Head & Neck 12/2013; 35(12). DOI:10.1002/hed.23241 · 2.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although IgG4-related disease is characterized by extensive infiltration of IgG4-positive plasma cells and lymphocytes of various organs, the details of this systemic disease are still unclear. We screened serum total IgG levels in the patients with Hashimoto thyroiditis (HT) to illustrate the prevalence of IgG4-related thyroiditis in HT. Twenty-four of 94 patients with HT (25.5 %) had elevated serum IgG levels and their serum IgG4 was measured. Five of the 24 cases had more than 135 mg/dL of IgG4, which is the serum criterion of IgG4-related disease. One was a female patient who was initially treated as Graves' disease and rapidly developed a firm goiter and hypothyroidism. The biopsy of her thyroid gland revealed that follicular cells were atrophic with squamous metaplasia, replaced with fibrosis, which was compatible with the fibrous variant of HT. Immunohistochemical examination revealed diffuse infiltration of IgG4-positive plasma cells, and the serum IgG4 level was 179 mg/dL. The levels of IgG and IgG4 were positively correlated with the titers of anti-thyroglobulin antibody or anti-thyroid peroxidase antibody. In conclusion, at least a small portion of patients with HT with high titers of anti-thyroid antibodies may overlap the IgG4-related thyroiditis.
[Show abstract][Hide abstract] ABSTRACT: Estrogen is suggested to be one of the plausible risk factors for pituitary hemorrhagic apoplexy through pituitary hyperemia. We experienced a 33-year-old woman with pituitary ischemic apoplexy of a nonfunctional macroadenoma under oral contraceptive use. Our case indicates that hypercoagulable state, but not hyperemia, associated with estrogen may promote pituitary ischemic apoplexy.
Journal of stroke and cerebrovascular diseases: the official journal of National Stroke Association 04/2013; 22(8). DOI:10.1016/j.jstrokecerebrovasdis.2013.03.030 · 1.67 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective: Hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome is an autosomal dominant disorder caused by a GATA3 gene mutation. Here we report a novel mutation of GATA3 in a patient diagnosed with HDR syndrome at the age of 58 with extensive intracranial calcification.Methods: A 58-year-old Japanese man showed severe hypocalcemia and marked calcification in the basal ganglia, cerebellum, deep white matter, and gray-white junction on computed tomography. The serum intact parathyroid hormone level was relatively low against low serum calcium concentration. The patient had been diagnosed with bilateral sensorineural deafness in childhood and had a family history of hearing disorders. Imaging studies revealed no renal anomalies. The patient was diagnosed with HDR syndrome, and genetic testing was performed.Results: Genetic analysis of GATA3 showed a novel nonsense mutation at codon 198 (S198X) in exon 3. The S198X mutation leads to a loss of two zinc finger DNA binding domains, and is considered to be responsible for HDR syndrome.Conclusion: We identified a novel nonsense mutation of GATA3 in an adult patient with HDR syndrome who showed extensive intracranial calcification.
Endocrine Practice 11/2012; 19(1):1-15. DOI:10.4158/EP12186.CR · 2.81 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objectives: Saline infusion test (SIT) is useful for confirming primary aldosteronism (PA). Previous study reported bilateral PA (Bil-PA) may frequently have suppression of plasma aldosterone concentration (PAC). In addition, it is noted that SIT should be indicated with caution in patients with uncontrolled hypertension or congestive heart failure. Aims of the study were to clarify 1) the diagnostic criteria for subtype classification and 2) whether SIT is reliable when carried out with a shorter infusion period. Subjects and methods: Thirty two patients with PA were studied. Fourteen were diagnosed with Bil-PA and 18 were diagnosed with unilateral PA (Unil-PA) by CT, adrenal venous sampling and pathology after surgery. SIT was performed by infusing 2 liters of saline over 4 hrs. Blood samples for PAC were obtained at 2hrs (PAC2 h) and 4hrs (PAC4 h). Distinguishing Unil-PA from Bil-PA criteria of SIT were assessed using ROC curve analysis. Results: PAC2 h and PAC4 h in patients with Unil-PA were significantly higher than those with Bil-PA (278 +/- 123 vs. 85 +/- 39 pg/ml; 294 +/- 145 vs. 68 +/- 29pg/m) (p < 0.01). Using the ROC curve analysis, the optimal cutoff value of PAC2hr for distinguishing Unil-PA from Bil-PA was 120pg/ml (sensitivity 85.7%, specificity 100%) and that of PAC4 h was 110pg/ml (sensitivity 100%, specificity 83.3%). AUC of both of them were not significantly different (0.964 for PAC2 h vs. 0.952 for PAC4 h). Conclusions: The SIT is useful for subtype classification of PA. The test can be shortened to 1litter infusion of saline over 2hrs with 120pg/ml as the best cutoff limit.
Journal of Hypertension 09/2012; 30:e191. DOI:10.1097/01.hjh.0000420479.95640.56 · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background: Primary aldosteronism (PA) is a common cause of endocrine hypertension. Although adrenal venous sampling (AVS) is the gold standard for subtype classification, it is available in limited specialized centers. The aim of the study was to investigate the clinical significance of cosyntropin (ACTH) stimulation test for subtype classification in PA. Design and Methods: Sixty patients with PA who underwent ACTH stimulation test were studied. The subjects were diagnosed as having either unilateral (n = 41) or bilateral PA (n = 19) based upon AVS, adrenal scintigraphy, and/or adrenal surgery. We evaluated the diagnostic significance of ACTH stimulation test in differentiating unilateral PA from bilateral PA. Results: Peak PAC (P < 0.01) and peak PAC/cortisol (P < 0.05) after ACTH stimulation were significantly higher in patients with unilateral PA than those with bilateral PA. Peak PAC-basal PAC ([DELTA]PAC) was higher in patients with unilateral PA than those with bilateral PA, although the difference was not statistically significant. Receiver operating characteristic curve analysis for the diagnosis of unilateral PA showed a peak PAC value of 403 pg/ml had a sensitivity of 70.7% and specificity of 79.0%, and a value of 596 pg/ml had a sensitivity of 46.3% and specificity of 100%. A peak PAC/cortisol value of 19.7 (cortisol, mcg/dl) had a sensitivity of 58.5% and specificity of 89.5%, and a value of 30.5 had a sensitivity of 26.8% and specificity of 100%. Conclusions: ACTH stimulation test could discriminate between unilateral and bilateral PA and is useful in selecting the patients who should undergo AVS before surgery.
Journal of Hypertension 09/2012; 30:e187. DOI:10.1097/01.hjh.0000420467.34651.5b · 4.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although confirmatory testing to verify aldosterone excess is a key step in the diagnosis of primary aldosteronism (PA), there is no consensus as to whether it is always needed and which of the tests need to be performed.
The objective of this study was to investigate the diagnostic significance of confirmatory tests in PA.
In group A, 120 hypertensive patients who had positive case detection using the aldosterone to renin ratio (ARR) were subjected to at least one confirmatory test: the captopril challenge test (CCT), furosemide upright test (FUT), or saline infusion test (SIT). Among group A, 57 patients underwent all three confirmatory tests (group B), and 57 patients were differentiated as having either unilateral or bilateral PA based upon adrenal venous sampling, adrenal scintigraphy, and/or adrenal surgery (group C).
The percentages of patients with positive CCT and FUT were 86 and 87% in group A, 88 and 88% in group B, and 96 and 94% in group C, respectively. The percentage of patients with positive SIT results was lower than that with other tests (P < 0.01). The percentage of patients with positive results for the three tests was higher in patients with baseline ARR of at least 1000 or plasma aldosterone concentration (PAC) of at least 250 pg/ml than in those with lower ARR or PAC in all three groups.
Most patients with positive case detection also had positive results on the CCT and FUT, especially when ARR was at least 1000 or PAC was at least 250 pg/ml under renin suppresion. Confirmatory testing for PA may not be needed in all patients with positive case detection.
The Journal of Clinical Endocrinology and Metabolism 03/2012; 97(5):1688-94. DOI:10.1210/jc.2011-2504 · 6.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Toxic adenoma and toxic multinodular goiter (TMNG) are common causes of hyperthyroidism in iodine-deficient regions, but they are relatively rare in iodine-sufficient regions, including Japan. Constitutive activating mutations of the thyroid stimulating hormone receptor (TSHR) gene and adenylate cyclase-stimulating G α protein (GNAS) gene are frequent in these thyrotoxic disorders. Here we report two cases of rare TSHR gene mutations in Japanese thyrotoxicosis patients. In Case 1, we observed multiple toxic nodules with thyrotoxicosis, and in Case 2, we detected a solitary toxic nodule in an 8-year-old girl. In both cases, ultrasonography showed thyroid nodules and scintigraphy revealed increased uptake. Total thyroidectomy was performed for Case 1 and a hemi-thyroidectomy was performed for Case 2. Genetic analysis of the resected tissues revealed an I568F mutation in Case 1 and a S281I mutation in the TSHR gene in Case 2. The I568F mutation was located in the second extracellular loop, and the S281I mutation was located in the N-terminal extracellular domain of the TSH receptor. In Case 1, the mutation was restricted to the largest nodule, and was not detected in other functioning nodules or non-nodule thyroid tissue. Bi-allelic expression of the TSHR gene was confirmed by reverse transcription-polymerase chain reaction in both tumors. Both the I568F and S281I mutations were studied previously in vitro, and were revealed to cause basal activation of the protein kinase A pathway. Case 1 represents the second reported case of an I568F mutation and Case 2 represents the third reported case of an S281I mutation.
[Show abstract][Hide abstract] ABSTRACT: Adrenocorticotropic hormone (ACTH)-secreting pituitary adenomas are sometimes difficult to visualize, even with high-quality
magnetic resonance imaging, due to their small size and variable location. Sampling the cavernous or inferior petrosal sinus
is helpful for confirming the central origin of a tumor, but ectopic corticotroph adenomas in the paraseller region also typically
exhibit a high central/peripheral plasma ACTH ratio. We experienced an extremely rare case of Cushing’s disease caused by
an ACTH-secreting microadenoma located entirely inside the left cavernous sinus attached to the medial wall (ectopic pituitary
adenoma) that was not visible by preoperative MRI. In this case, the microadenoma was completely removed and an endocrinologic
cure was achieved. This case reveals that in addition to meticulous sectioning of the pituitary gland, bilateral periglandular
inspection with visualization of the medial wall of the cavernous sinus and of the diaphragm should always be performed to
detect ectopic parasellar microadenomas when no adenoma is visible by preoperative MRI.
KeywordsCushing’s disease–Ectopic–Intracavernous sinus–Surgery
[Show abstract][Hide abstract] ABSTRACT: To evaluate the prevalence of dyslipidemia in the population of Hashimoto thyroiditis, we reviewed medical records on the consecutive 1181 cases with adult Hashimoto thyroiditis and 830 cases were adopted for the study. First, the serum TSH level increased and serum free T4 level decreased, slightly but significantly, with increasing age. There were significant positive correlations between serum TSH levels and lipid parameters such as total cholesterol (TC), triglyceride (TG), HDL-cholesterol (HDL-C), LDL-cholesterol (LDL-C), non-HDL-C and LDL-C/HDL-C ratio (L/H). In contrast, there were significant negative correlations between serum free T4 levels and all of these lipid parameters. According to the thyroid function, the cases were classified into 4 groups such as thyrotoxicosis (TT), euthyroidism (EU), subclinical hypothyroidism (SH) and overt hypothyroidism (OH). TC, HDL-C, non-HDL-C and LDL-C of TT were significantly lower than those in EU. In contrast, TC, TG, non-HDL-C, LDL-C, L/H and age of OH were significantly higher than those in EU. Interestingly, LDL-C and L/H of SH were significantly higher compared with EU. Thirty-two of SH patients were treated with small doses of levothyroxine and the effects on the lipid profile were examined. The TC, non-HDL-C, LDL-C and L/H were significantly decreased after treatment. In conclusion, the prevalence of dyslipidemia increases along with hypofunction of the thyroid and T4 replacement therapy may improve lipid profile in the cases of SH with Hashimoto thyroiditis.
[Show abstract][Hide abstract] ABSTRACT: It has been estimated that approximately 10% of pheochromocytomas and paragangliomas are part of a hereditary syndrome. Recent studies, however, suggest that the genetic involvement in pheochromocytoma/paraganglioma is actually far more common. Here, we report a case of malignant paraganglioma with no apparent family history. A 59-year-old man was referred to our services because of multiple abdominal masses. Plasma and urine adrenalin and noradrenalin levels were slightly elevated, and plasma dopamine and urine vanillylmandelic acid levels were remarkably elevated. Abdominal and chest computed tomography revealed multiple masses in the para-aortic region and in both lungs. Although (131)I-meta iodobenzylguanidine scintigraphy did not show significant uptake in these tumors, a 6-[(18)F]fluorodeoxyglucose positron emission tomographic scanning study showed multiple areas of uptake corresponding to the tumors. Biopsy of the tumors revealed paraganglioma with chromogranin A-immunopositive cells. Genetic analysis indicated a nonsense mutation at codon 27 of the SDHB gene. As recently described, SDHB mutations may cause extra-adrenal and malignant paragangliomas, such as in the present case.