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Language：English   Publishing type：Research paper (scientific journal)  

Context Pheochromocytoma (PHEO) and paraganglioma (PGL) (PHEO and PGL: PPGLs), catecholamine-producing tumors, represent an emerging cause of secondary osteoporosis. However, despite decreased bone mineral density (BMD), vertebral fracture (VF) is not associated with BMD in PPGLs. OBJECTIVE: To evaluate whether deteriorated bone quality is involved in the development of osteoporosis in PPGLs. PARTICIPANTS: Trabecular bone score (TBS), used to assess trabecular bone quality, was examined in 56 patients with PPGLs and 52 with non-functional adrenal tumors (AT). Radiograph of the spine was carried out in 35 patients with PPGLs, and TBS was analyzed in 18 patients with PPGLs at follow-up. Main outcome measure TBS and BMD at the lumbar spine in patients with PPGLs with and without VF. RESULTS: PPGLs had a lower TBS (n=56, 1.338 [1.294-1.420]) than non-functional AT (n=52, 1.394 [1.342-1.444]; p=0.033). Among those with PPGLs, patients with VF (n=14, 1.314 [1.289-1.346]) had a lower TBS than those without VF (n=21, 1.383 [1.324-1.426]; p=0.046), despite no significant difference in BMD at the lumbar spine between the two groups (p=0.501). An optimal cut-off level of TBS for diagnosing VF in PPGLs was 1.323, and its area under the curve was 0.702. The severity of catecholamine excess and maximal size of tumor were associated with decreased TBS in PPGLs patients (p=0.016 and p=0.020, respectively). Surgical resection of PPGLs improved TBS at follow-up, with 2.5% increase (p=0.007). CONCLUSIONS: This study provides evidence for the importance of deteriorated bone quality rather than decreased bone mass in the development of VF in PPGLs.

DOI： 10.1016/j.bone.2020.115607

Language：Others   Publishing type：Research paper (scientific journal)  

© 2020, International Osteoporosis Foundation and National Osteoporosis Foundation. Summary: Osteoporosis and atherosclerosis frequently coexist in patients with pheochromocytoma. The presence of osteoporosis may predict that of atherosclerosis and vice versa in patients with PHEO. These findings have implications for the long-term management of the pheochromocytoma and its potential chronic complications. Introduction: Pheochromocytoma (PHEO), a catecholamine-producing tumor, is often found incidentally, and it may be present for years before it is diagnosed. However, long-term exposure to catecholamines excess may induce chronic complications, such as osteoporosis and atherosclerosis. We aimed to evaluate concomitant osteoporosis and atherosclerosis in patients with PHEO. Methods: Fifty-one patients with PHEO and 51 patients with a non-functional adrenal tumor were compared radiographically for the prevalence of vertebral fracture (VF), a typical osteoporotic fracture, and abdominal aortic calcification (AAC). Results: In patients with PHEO, the prevalence of AAC was higher in those with VF (58&#37;) than in those without (6&#37;, p < 0.001). AAC was associated with VF after adjusting for age and sex (odds ratio, 1.53; 95&#37; confidence interval, 1.07–2.46; p = 0.003) in patients with PHEO. The degree of catecholamine excess correlated with the presence of VF and AAC (p = 0.007). The prevalence of VF was higher in patients with PHEO (37&#37;) than those with non-functional AT (12&#37;, p = 0.005), but the prevalence of AAC was comparable between the two groups (25&#37; and 19&#37;, p = 0.636). VF and AAC more frequently coexisted in patients with PHEO (22&#37;) than in those with non-functional AT (2&#37;, p = 0.003). Conclusion: This study represents the first demonstration that osteoporosis and atherosclerosis frequently coexist in patients with PHEO. The presence of osteoporosis may predict that of atherosclerosis and vice versa in patients with PHEO. These findings have implications for the long-term management of the PHEO and its potential chronic complications.

DOI： 10.1007/s00198-020-05527-5

Language：Others   Publishing type：Research paper (scientific journal)  

DOI： 10.1016/j.bone.2020.115221

Language：English   Publishing type：Research paper (scientific journal)  

CONTEXT: The current clinical guidelines suggest that confirmatory tests for primary aldosteronism (PA) may be excluded in some of patients who have elevated plasma aldosterone concentration (PAC) under plasma renin suppression. However, this has low-priority evidence and is under debate in use of serum potassium. OBJECTIVE: This study aimed to investigate an appropriate setting for sparing confirmatory tests in PA. DESIGN AND SETTING: A retrospective cross-sectional study in a single referral center. PARTICIPANTS: This study included 327 patients who had hypertension under plasma renin suppression and underwent the captopril challenge test (CCT) between January 2007 and April 2019. CCT results were used to diagnose PA. MAIN OUTCOME MEASURE: Diagnostic value of PAC and serum potassium in confirmation of PA. RESULTS: Of the studied patients, 252 of 327 (77&#37;) were diagnosed with PA. All 61 patients with PAC > 30 ng/dL were diagnosed with PA. In patients with PAC between 20 and 30 ng/dL, 44 of 55 (80&#37;) were diagnosed with PA, while all 26 with PAC between 20 to 30 ng/dL who had spontaneous hypokalemia were diagnosed with PA. The proportion of unilateral PA determined by adrenal vein sampling (AVS) was higher in patients who had PAC > 30 ng/dL or those with spontaneous hypokalemia who had PAC between 20 and 30 ng/dL than those who did not meet the criteria (76&#37; vs. 17&#37;, P < .001). CONCLUSION: Confirmatory tests in PA could be spared in patients who have typical features of PA and these patients had a high probability of unilateral PA on AVS.

DOI： 10.1210/clinem/dgz148

Language：English   Publishing type：Research paper (scientific journal)  

CONTEXT: Primary aldosteronism (PA) is known to increase vertebral fracture (VF), although the detailed mechanism remains to be elucidated. We hypothesized that the PA subtype is associated with VF. OBJECTIVE: To evaluate whether unilateral PA is associated with the prevalence of VF. DESIGN: This was a retrospective cross-sectional study in a single referral centre. PATIENTS: We identified 210 hypertensive patients whose clinical data were available for case-detection results. One hundred and fifty-two patients were diagnosed with PA using captopril challenge tests. MEASUREMENTS: We measured the prevalence of VF, according to PA subtype. RESULTS: One hundred thirteen patients with PA were subtype classified by adrenal vein sampling. Of these, 37 patients had unilateral PA, 76 patients had bilateral PA, 58 patients had non-PA; 39 patients with PA were not subtype-classified. Patients with PA had a higher prevalence of VF (29&#37;, 44/152) than those with non-PA (12&#37;, 7/58; P = .011). Moreover, unilateral PA had a higher prevalence of VF (46&#37;, 17/37) than bilateral PA (20&#37;, 15/76; P = .021). There was no significant difference in the prevalence of VF between bilateral PA and non-PA. Unilateral PA was an independent risk factor for VF after adjusting for age and sex (OR: 3.16, 95&#37; confidence interval: 1.12-8.92; P = .017). Among patients with unilateral PA, serum cortisol concentrations after 1-mg dexamethasone suppression test were higher in those with VF (1.32 ± 0.67 g/dL) than those without (0.96 ± 0.33 g/dL; P = .048). CONCLUSIONS: Unilateral PA is an independent risk factor for VF.

DOI： 10.1111/cen.14145

Publisher：Proceedings of the National Academy of Sciences of the United States of America  

Aldosterone-producing adenomas (APA), a major endocrine tumor and leading subtype of primary aldosteronism, cause secondary hypertension with high cardiometabolic risks. Despite potentially producing multiple steroid hormones, detailed cellular mechanisms in APA remain insufficiently studied. Our multiomics analysis focusing on APA with KCNJ5 mutations, which represent the most common genetic form, revealed marked cellular heterogeneity. Tumor cell reprogramming initiated from stress-responsive cells to aldosterone-producing or cortisol-producing cells, with the latter progressing to proliferative stromal-like cells. These cell subtypes showed spatial segregation, and APA exhibited genomic intratumor heterogeneity. Among the nonparenchymal cells, lipid-associated macrophages, which were abundant in APA, might promote the progression of cortisol-producing and stromal-like cells, suggesting their role in the tumor microenvironment. Intratumor cortisol synthesis was correlated with increased blood cortisol levels, which were associated with the development of vertebral fractures, a hallmark of osteoporosis. This study unveils the complex cellular ecosystem with clinical relevance in APA with KCNJ5 mutations, providing insights into tumor biology that could inform future clinical approaches.

DOI： 10.1073/pnas.2421489122

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Molecular Metabolism  

OBJECTIVE: The human adrenal cortex comprises three functionally and structurally distinct layers that produce layer-specific steroid hormones. With aging, the human adrenal cortex undergoes functional and structural alteration or "adrenal aging", leading to the unbalanced production of steroid hormones. Given the marked species differences in adrenal biology, the underlying mechanisms of human adrenal aging have not been sufficiently studied. This study was designed to elucidate the mechanisms linking the functional and structural alterations of the human adrenal cortex. METHODS: We conducted single-cell RNA sequencing and spatial transcriptomics analysis of the aged human adrenal cortex. RESULTS: The data of this study suggest that the layer-specific alterations of multiple signaling pathways underlie the abnormal layered structure and layer-specific changes in steroidogenic cells. We also highlighted that macrophages mediate age-related adrenocortical cell inflammation and senescence. CONCLUSIONS: This study is the first detailed analysis of the aged human adrenal cortex at single-cell resolution and helps to elucidate the mechanism of human adrenal aging, thereby leading to a better understanding of the pathophysiology of age-related disorders associated with adrenal aging.

DOI： 10.1016/j.molmet.2024.101954

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Background: The human adrenal cortex consists of three functionally and structurally distinct layers; zona glomerulosa, zona fasciculata (zF), and zona reticularis (zR), and produces adrenal steroid hormones in a layer-specific manner; aldosterone, cortisol, and adrenal androgens, respectively. Cortisol-producing adenomas (CPAs) occur mostly as a result of somatic mutations associated with the protein kinase A pathway. However, how CPAs develop after adrenocortical cells acquire genetic mutations, remains poorly understood. Methods: We conducted integrated approaches combining the detailed histopathologic studies with genetic, RNA-sequencing, and spatially resolved transcriptome (SRT) analyses for the adrenal cortices adjacent to human adrenocortical tumours. Findings: Histopathological analysis revealed an adrenocortical nodular structure that exhibits the two-layered zF- and zR-like structure. The nodular structures harbour GNAS somatic mutations, known as a driver mutation of CPAs, and confer cell proliferative and autonomous steroidogenic capacities, which we termed steroids-producing nodules (SPNs). RNA-sequencing coupled with SRT analysis suggests that the expansion of the zF-like structure contributes to the formation of CPAs, whereas the zR-like structure is characterised by a macrophage-mediated immune response. Interpretation: We postulate that CPAs arise from a precursor lesion, SPNs, where two distinct cell populations might contribute differently to adrenocortical tumorigenesis. Our data also provide clues to the molecular mechanisms underlying the layered structures of human adrenocortical tissues. Funding: KAKENHI, The Uehara Memorial Foundation, Daiwa Securities Health Foundation, Kaibara Morikazu Medical Science Promotion Foundation, Secom Science and Technology Foundation, ONO Medical Research Foundation, and Japan Foundation for Applied Enzymology.

DOI： 10.1016/j.ebiom.2024.105087

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Endocrinology United States  

Pancreatic islet inflammation plays a crucial role in the etiology of type 2 diabetes (T2D). Macrophages residing in pancreatic islets have emerged as key players in islet inflammation. Macrophages express a plethora of innate immune receptors that bind to environmental and metabolic cues and integrate these signals to trigger an inflammatory response that contributes to the development of islet inflammation. One such receptor, Dectin-2, has been identified within pancreatic islets; however, its role in glucose metabolism remains largely unknown. Here we demonstrated that mice lacking Dectin-2 exhibit local inflammation within islets, along with impaired insulin secretion and β-cell dysfunction. Our findings indicate that these effects are mediated by pro-inflammatory cytokines, such as IL-1α and IL-6, which are secreted by macrophages that have acquired an inflammatory phenotype because of the loss of Dectin-2. This study provides novel insights into the mechanisms underlying the role of Dectin-2 in the development of islet inflammation.

DOI： 10.1210/endocr/bqad181

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Quantitative information on blood metabolites can be used in developing advanced medical strategies such as early detection and prevention of disease. Monitoring bioactive lipids such as steroids, bile acids, and PUFA metabolites could be a valuable indicator of health status. However, a method for simultaneously measuring these bioactive lipids has not yet been developed. Here, we report a LC/MS/MS method that can simultaneously measure 144 bioactive lipids, including steroids, bile acids, and PUFA metabolites, from human plasma, and a sample preparation method for these targets. Protein removal by methanol precipitation and purification of bioactive lipids by solid-phase extraction improved the recovery of the targeted compounds in human plasma samples, demonstrating the importance of sample preparation methods for a wide range of bioactive lipid analyses. Using the developed method, we studied the plasma from healthy human volunteers and confirmed the presence of bioactive lipid molecules associated with sex differences and circadian rhythms. The developed method of bioactive lipid analysis can be applied to health monitoring and disease biomarker discovery in precision medicine.

DOI： 10.1016/j.jlr.2023.100492

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Abstract

Quantitative information on blood metabolites has the potential to be utilized in medical strategies such as early disease detection and prevention. Monitoring of bioactive lipids, such as steroids, bile acids, and polyunsaturated fatty acid (PUFA) metabolites, could be a valuable indicator for health status. However, a method for simultaneous measurement of these bioactive lipids has not been reported at present. Here, we report a liquid chromatography tandem mass spectrometry (LC/MS/MS) method that can simultaneously measure more than 140 bioactive lipids, including steroids, bile acids, and PUFA metabolites, from human plasma, and a sample preparation method for these targets. Protein removal in methanol precipitation and purification operations of bioactive lipids by solid-phase extraction improved the recovery of targeted compounds in human plasma samples, demonstrating the importance of sample preparation methods in a wide range of bioactive lipid analyses. Using the developed method, we measured plasma from healthy human volunteers and confirmed the presence of bioactive lipid molecules associated with sex differences and circadian rhythms. The practical bioactive lipid analysis method developed is expected to be applied to health monitoring and disease biomarker discovery for precision medicine.

DOI： 10.1101/2023.04.13.536679

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Clinical Endocrinology  

OBJECTIVE: The clinical practice guideline for primary aldosteronism (PA) places a high value on confirmatory tests to sparing patients with false-positive results in case detection from undergoing adrenal venous sampling (AVS). However, it is unclear whether multiple types of confirmatory tests are more useful than a single type. To evaluate whether the machine-learned combination of two confirmatory tests is more useful in predicting subtypes of PA than each test alone. DESIGN: A retrospective cross-sectional study in referral centres. PATIENTS: This study included 615 patients with PA randomly assigned to the training and test data sets. The participants underwent saline infusion test (SIT) and captopril challenge test (CCT) and were subtyped by AVS (unilateral, n = 99; bilateral, n = 516). MEASUREMENTS: The area under the curve (AUC) and clinical usefulness using decision curve analysis for the subtype prediction in the test data set. RESULTS: The AUCs for the combination of SIT and CCT, SIT alone and CCT alone were 0.850, 0.813 and 0.786, respectively, with no significant differences between them. The AUC for the baseline clinical characteristics alone was 0.872, whereas the AUCs for these combined with SIT, combined with CCT and combined with both SIT and CCT were 0.868, 0.854 and 0.855, respectively, with no significant improvement in AUC. The additional clinical usefulness of the second confirmatory test was unremarkable on decision curve analysis. CONCLUSIONS: Our data suggest that patients with positive case detection undergo one confirmatory test to determine the indication for AVS.

DOI： 10.1111/cen.14854

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Scientific Reports  

Unilateral subtype of primary aldosteronism (PA) is a common surgically curable form of endocrine hypertension. However, more than half of the patients with PA who undergo unilateral adrenalectomy suffer from persistent hypertension, which may discourage those with PA from undergoing adrenalectomy even when appropriate. The aim of this retrospective cross-sectional study was to develop machine learning-based models for predicting postoperative hypertensive remission using preoperative predictors that are readily available in routine clinical practice. A total of 107 patients with PA who achieved complete biochemical success after adrenalectomy were included and randomly assigned to the training and test datasets. Predictive models of complete clinical success were developed using supervised machine learning algorithms. Of 107 patients, 40 achieved complete clinical success after adrenalectomy in both datasets. Six clinical features associated with complete clinical success (duration of hypertension, defined daily dose (DDD) of antihypertensive medication, plasma aldosterone concentration (PAC), sex, body mass index (BMI), and age) were selected based on predictive performance in the machine learning-based model. The predictive accuracy and area under the curve (AUC) for the developed model in the test dataset were 77.3% and 0.884 (95% confidence interval: 0.737-1.000), respectively. In an independent external cohort, the performance of the predictive model was found to be comparable with an accuracy of 80.4% and AUC of 0.867 (95% confidence interval: 0.763-0.971). The duration of hypertension, DDD of antihypertensive medication, PAC, and BMI were non-linearly related to the prediction of complete clinical success. The developed predictive model may be useful in assessing the benefit of unilateral adrenalectomy and in selecting surgical treatment and antihypertensive medication for patients with PA in clinical practice.

DOI： 10.1038/s41598-022-09706-8

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Language：Japanese   Publisher：(公財)大和証券ヘルス財団  

骨粗鬆症の早期診断法を開発するため、骨量正常にもかかわらず脆弱性骨折を引き起こす骨質劣化型骨粗鬆症に着目し、副腎由来ホルモンにおける骨粗鬆症への病態生理学的意義を検討した。副腎由来ホルモン過剰モデルであるヒト副腎腫瘍を対象とした観察研究、健常人を対象としたゲノムワイド関連研究を用いたメンデルランダム化研究、健常人の血液検体を対象とした網羅的ステロイドミクス解析を行った。その結果、副腎由来ホルモンは骨質制御に重要な役割を担っていることが明らかになった。さらに、生理的濃度の副腎由来ホルモンの変動も骨粗鬆症の進展に影響すること、健常人において副腎由来ホルモンに個人差を認めることも明らかになった。副腎由来ホルモンは有用な骨質サロゲート指標になり得ると考えられた。

Language：English   Publishing type：Research paper (scientific journal)   Publisher：Frontiers in Endocrinology  

Whole transcriptome profiling is a promising technique in adrenal studies; however, whole transcriptome profiling of adrenal disease using formalin-fixed paraffin-embedded (FFPE) samples has to be further explored. The aim of this study was to evaluate the utility of transcriptome data from FFPE samples of adrenocortical tumors. We performed whole transcriptome profiling of FFPE and fresh frozen samples of adrenocortical carcinoma (ACC, n = 3), aldosterone-producing adenoma (APA, n = 3), and cortisol-producing adenoma (CPA, n = 3), and examined the similarity between the transcriptome data. We further examined whether the transcriptome data of FFPE samples could be used to distinguish tumor types and detect marker genes. The number of read counts was smaller in FFPE samples than in fresh frozen samples (P < 0.01), while the number of genes detected was similar (P = 0.39). The gene expression profiles of FFPE and fresh frozen samples were highly correlated (r = 0.93, P < 0.01). Tumor types could be distinguished by consensus clustering and principal component analysis using transcriptome data from FFPE samples. In the differential expression analysis between ACC and APA-CPA, known marker genes of ACC (e.g., CCNB2, TOP2A, and MAD2L1) were detected in FFPE samples of ACC. In the differential expression analysis between APA and CPA, known marker genes of APA (e.g., CYP11B2, VSNL1, and KCNJ5) were detected in the APA of FFPE samples. The results suggest that FFPE samples may be a reliable alternative to fresh frozen samples for whole transcriptome profiling of adrenocortical tumors.

DOI： 10.3389/fendo.2022.808331

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：Journal of Clinical Endocrinology and Metabolism  

PURPOSE: Prolonged exposure to pathological cortisol, as in Cushing's syndrome causes various age-related disorders including sarcopenia. However, it is unclear whether mild cortisol excess, for example, accelerates sarcopenia due to aging or chronic stress. We performed a Mendelian randomization (MR) analysis to assess whether cortisol was causally associated with muscle strength and mass. METHODS: Three single nucleotide polymorphisms associated with plasma cortisol concentrations in the CORtisol NETwork consortium (n = 12,597) were used as instrumental variables. Summary statistics with traits of interest were obtained from relevant genome-wide association studies. For the primary analysis, we used the fixed-effects inverse-variance weighted analysis accounting for genetic correlations between variants. RESULTS: One standard deviation (SD) increase in cortisol was associated with SD reduction in grip strength (estimate, -0.032; 95&#37; confidence interval [CI] -0.044 ~ -0.020; P = 3e-04), whole-body lean mass (estimate, -0.032; 95&#37;CI, -0.046 ~ -0.017; P = 0.004), and appendicular lean mass (estimate, -0.031; 95&#37;CI, -0.049 ~ -0.012; P = 0.001). The results were supported by the weighted-median analysis, with no evidence of pleiotropy in the MR-Egger analysis. The association of cortisol with grip strength and lean mass was observed in women but not in men. The association was attenuated after adjusting for fasting glucose in the multivariable MR analysis, which was the top mediator for the association in the MR-Bayesian model averaging analysis. CONCLUSION: This MR study provides evidence for the association of cortisol with reduced muscle strength and mass, suggesting the impact of cortisol on the development of sarcopenia.

DOI： 10.1210/clinem/dgab862

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PURPOSE: Dehydroepiandrosterone sulfate (DHEAS) from the adrenal cortex substantially decreases with age, which may accelerate osteoporosis. However, the association of DHEAS with bone mineral density (BMD) and fracture is inconclusive. We conducted a Mendelian randomization (MR) analysis to investigate the role of DHEAS in age-related changes in BMD and fracture risk. METHODS: Single nucleotide polymorphisms (SNPs) associated with serum DHEAS concentrations were used as instrumental variables (4 SNPs for main analysis; 4 SNPs for men and 5 SNPs for women in sex-related analysis). Summary statistics were obtained from relevant genome-wide association studies. RESULTS: A log-transformed unit (μmol/L) increase in serum DHEAS concentrations was associated with SD increase in estimated BMD at the heel (estimate, 0.120; 95&#37; confidence interval [CI], 0.081-0.158; P = 9 × 10 -10), and decreased fracture (odds ratio [OR], 0.989; 95&#37;CI, 0.981-0.996; P = 0.005), consistent with dual-energy X-ray absorptiometry-derived BMD at the femoral neck and lumbar spine. Their associations remained even after adjusting for height, body mass index, testosterone, estradiol, sex hormone-binding globulin, and IGF-1. The association of DHEAS with fracture remained after adjusting for falls, grip strength, and physical activity but was attenuated after adjusting for BMD. The MR-Baysian model averaging analysis showed BMD was the top mediating factor for association of DHEAS with fracture. The association between DHEAS and BMD was observed in men but not in women. CONCLUSION: DHEAS was associated with increased BMD and decreased fracture. DHEAS may play a protective role in decreasing fracture risk, mainly by increasing bone mass.

DOI： 10.1210/clinem/dgab459

Language：English   Publishing type：Research paper (scientific journal)  

PURPOSE: Dehydroepiandrosterone sulfate (DHEAS) from the adrenal cortex substantially decreases with age, which may accelerate osteoporosis. However, the association of DHEAS with bone mineral density (BMD) and fracture is inconclusive. We conducted a Mendelian randomization (MR) analysis to investigate the role of DHEAS in age-related changes in BMD and fracture risk. METHODS: Single nucleotide polymorphisms (SNPs) associated with serum DHEAS concentrations were used as instrumental variables (4 SNPs for main analysis; 4 SNPs for men and 5 SNPs for women in sex-related analysis). Summary statistics were obtained from relevant genome-wide association studies. RESULTS: A log-transformed unit (µmol/L) increase in serum DHEAS concentrations was associated with an SD increase in estimated BMD at the heel (estimate, 0.120; 95&#37; CI, 0.081-0.158; P = 9 × 10-10), and decreased fracture (odds ratio, 0.989; 95&#37; CI, 0.981-0.996; P = 0.005), consistent with dual-energy X-ray absorptiometry-derived BMD at the femoral neck and lumbar spine. Their associations remained even after adjusting for height, body mass index, testosterone, estradiol, sex hormone-binding globulin, and insulin-like growth factor 1. The association of DHEAS with fracture remained after adjusting for falls, grip strength, and physical activity but was attenuated after adjusting for BMD. The MR-Bayesian model averaging analysis showed BMD was the top mediating factor for association of DHEAS with fracture. The association between DHEAS and BMD was observed in men but not in women. CONCLUSION: DHEAS was associated with increased BMD and decreased fracture. DHEAS may play a protective role in decreasing fracture risk, mainly by increasing bone mass.

DOI： 10.1210/clinem/dgab459

Language：English   Publishing type：Research paper (scientific journal)  

Primary aldosteronism (PA) is associated with an increased risk of cardiometabolic diseases, especially in unilateral subtype. Despite its high prevalence, the case detection rate of PA is limited, partly because of no clinical models available in general practice to identify patients highly suspicious of unilateral subtype of PA, who should be referred to specialized centers. The aim of this retrospective cross-sectional study was to develop a predictive model for subtype diagnosis of PA based on machine learning methods using clinical data available in general practice. Overall, 91 patients with unilateral and 138 patients with bilateral PA were randomly assigned to the training and test cohorts. Four supervised machine learning classifiers; logistic regression, support vector machines, random forests (RF), and gradient boosting decision trees, were used to develop predictive models from 21 clinical variables. The accuracy and the area under the receiver operating characteristic curve (AUC) for predicting of subtype diagnosis of PA in the test cohort were compared among the optimized classifiers. Of the four classifiers, the accuracy and AUC were highest in RF, with 95.7&#37; and 0.990, respectively. Serum potassium, plasma aldosterone, and serum sodium levels were highlighted as important variables in this model. For feature-selected RF with the three variables, the accuracy and AUC were 89.1&#37; and 0.950, respectively. With an independent external PA cohort, we confirmed a similar accuracy for feature-selected RF (accuracy: 85.1&#37;). Machine learning models developed using blood test can help predict subtype diagnosis of PA in general practice.

DOI： 10.1038/s41598-021-88712-8

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副腎皮質腫瘍を対象として、液体クロマトグラフィータンデム質量分析(LC/MS/MS)によるメタボロミクスを基盤とした腫瘍組織の統合解析から、副腎皮質腫瘍における代謝特性の多様性の成因を明らかにすることを目的とした。アルドステロン産生腫瘍、顕性コルチゾール産生腫瘍、不顕性コルチゾール産生腫瘍、非副腎皮質腫瘍を対象として、LC/MS/MSを用いて組織中のアルドステロン、コルチゾールの定量を行った。アルドステロンについては、アルドステロン産生腫瘍においてのみ有意な上昇がみられたが、コルチゾールにおいては、興味深いことにアルドステロン産生腫瘍は不顕性コルチゾール産生腫瘍と同定度のコルチゾール過剰分泌がみられた。アルドステロン産生腫瘍における、腫瘍内コルチゾール合成の局在を評価する目的で、代謝産物の可視化法として、最新技術であるイメージング質量顕微鏡を用いた解析を行った。免疫組織学染色のコルチゾール合成酵素(CYP11B1)の局在と一致して、コルチゾール合成が腫瘍内で均一的に行われることを同定した。アルドステロン産生腫瘍およびコルチゾール分泌が緩徐である、不顕性コルチゾール産生腫瘍を対象として、RNA-seqを施行した。315遺伝子に発現変動が確認され、予想通りAPAにおいてアルドステロン合成に関連するパスウェイがエンリッチされた。一方で、steroid metabolic processパスウェイ(27遺伝子)もエンリッチされていたが、コルチゾール合成に関連する遺伝子発現は両腫瘍において差異は検出されなかった。

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<title>Abstract</title>
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<title>Context</title>
Current clinical guidelines recommend confirmation of positive result in at least one confirmatory test in the diagnosis of primary aldosteronism (PA). Clinical implication of multiple confirmatory tests has not been established, especially when patients show discordant results.


</sec>
<sec>
<title>Objective</title>
The aim of the present study was to explore the role of two confirmatory tests in subtype diagnosis of PA.


</sec>
<sec>
<title>Design</title>
Retrospective cross-sectional study.


</sec>
<sec>
<title>Setting</title>
The study was conducted at two referral centers.


</sec>
<sec>
<title>Participants and Method</title>
We identified 360 hypertensive patients who underwent both captopril challenge test (CCT) and saline infusion test (SIT) and exhibited at least one positive result. Among them, we studied 193 patients with PA whose data were available for subtype diagnosis based on adrenal vein sampling (AVS).


</sec>
<sec>
<title>Main Outcome Measure</title>
The prevalence of bilateral subtype on AVS according to the results of the confirmatory tests.


</sec>
<sec>
<title>Results</title>
Of patients studied, 127 were positive for both CCT and SIT (double-positive), while 66 were positive for either CCT or SIT (single-positive) (n = 34 and n = 32, respectively). Altogether, 135 were diagnosed with bilateral subtype on AVS. The single-positive patients had milder clinical features of PA than the double-positive patients. The prevalence of bilateral subtype on AVS was significantly higher in the single-positive patients than in the double-positive patients. (63/66 [95.5&#37;] vs. 72/127 [56.7&#37;], P &amp;lt; 0.01). Several clinical parameters were different between CCT single-positive and SIT single-positive patients.


</sec>
<sec>
<title>Conclusion</title>
Patients with discordant results between CCT and SIT have a high probability of bilateral subtype of PA on AVS.


</sec>

DOI： 10.1210/clinem/dgaa812

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© 2020 John Wiley & Sons Ltd Context: The success rate of cannulation of the right adrenal vein is limited. The aldosterone gradient within the same adrenal vein branch is specific for aldosterone-producing adenoma. Objective: This study was performed to investigate whether the absolute aldosterone gradient within the left adrenal vein (left-AV absolute aldosterone gradient) indicates unilateral excess aldosterone. Design and setting: A retrospective cross-sectional study in a single referral centre. Patients and methods: In total, 123 consecutive patients with primary aldosteronism who had successful adrenal vein sampling (AVS) data were examined. The left-AV absolute aldosterone gradient was considered significant when a gradient of >4:1 in the aldosterone-to-cortisol ratio between the common trunk vein and central vein was found. Main outcome measure: The prevalence of the unilateral subtype in patients with a significant left-AV absolute aldosterone gradient. Results: The prevalence of the unilateral subtype was higher in patients with than without a significant left-AV absolute aldosterone gradient (88.2&#37; [15/17] vs 21.7&#37; [23/106], P <.001). Of 60 patients with spontaneous hypokalemia, left unilateral disease on computed tomography, or both, a significant left-AV absolute aldosterone gradient was present only in patients with the unilateral subtype on AVS (42.9&#37; [15/35]), but not in those with the bilateral subtype (0.0&#37; [0/25]). These data were validated in an external cohort. Conclusion: The presence of a significant left-AV absolute aldosterone gradient can be used to diagnose the left unilateral subtype of primary aldosteronism on AVS in patients with spontaneous hypokalemia, left unilateral disease on computed tomography or both.

DOI： 10.1111/cen.14320

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Objective Glucose-lowering drug-induced hypoglycemia is a serious complication and there have been a few reports of seasonal variations in hypoglycemia in patients with type 2 diabetes. The aim of the present study was to examine the association between severe drug-induced hypoglycemia and seasonal variations, and to elucidate the contributing factors. Methods This retrospective, single center clinical study, analyzed the cases of 125 patients who required emergency hospitalization for severe drug-induced hypoglycemia between January 1, 2001 and December 31, 2014. The period from November to April was defined as the cold season. Results Severe hypoglycemia occurred more often in the cold season than in the warm season. In the cold season, 62 of 9,981 (0.6&#37;) emergency department visits involved patients who required hospitalization for drug-induced hypoglycemia. In contrast, in the warm season, 27 of 8,649 (0.3&#37;) visits involved patients who required hospitalization for drug-induced hypoglycemia (p=0.002). The proportion of patients treated with sulfonylurea (SU) in the cold season was higher than that in the warm season. Even the use of low-dose SU caused hypoglycemia in the cold season. In the SU-treated group, the proportion of patients with white blood cell and/or C-reactive protein elevation was higher in the cold season than in the warm season (p=0.04). Conclusion Severe glucose-lowering drug-induced hypoglycemia occured more frequently in the cold season than in the warm season, and was associated with an inflammatory state in patients treated with SU.

DOI： 10.2169/internalmedicine.1360-18

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Objectives: The aim of this study was to investigate the impact of adrenal venous sampling (AVS) lateralization cutoffs on surgical outcomes. Patients and Methods: Cosyntropin-stimulated AVS was used to guide surgical management of 377 patients with primary aldosteronism (PA) who were evaluated 6 months after surgery. Main Outcome Measures: The proportion of patients that achieved clinical benefit and complete biochemical success based on the AVS aldosterone lateralization index (LI) was determined. Results: Clinical benefit was achieved in 29 of 47 patients with an LI between 2 and 4, in 66 of 101 with an LI between 4 and 10, and in 158 of 203 with an LI > 10 (P < 0.01 for trend). Complete biochemical success was achieved in 27 of 42 with an LI between 2 and 4, in 60 of 76 with an LI between 4 and 10, and in 127 of 155 with an LI > 10 (P = 0.024 for trend). After adjustment for confounders and using those patients with an LI between 2 and 4 as a reference, a clinical benefit was associated only with those with an LI > 10 (OR, 2.30; 95&#37; CI, 1.03 to 5.16), whereas complete biochemical success was associated with those with an LI between 4 and 10 (OR, 2.83; 95&#37; CI, 1.14 to 7.01) or LI > 10 (OR, 3.55; 95&#37; CI, 1.47 to 8.55). Conclusions: Difference of clinical outcome was relatively small when strict LI diagnostic threshold was used; biochemical cure was sufficiently achieved when an LI > 4 was used. Our study by standardized outcome measures validated that an LI > 4 may be appropriate for determining unilateral disease in PA.

DOI： 10.1210/js.2018-00055

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Differentiation of unilateral from bilateral aldosterone hypersecretion is the essential step in the clinical practice of primary aldosteronism (PA). Although adrenal venous sampling (AVS) has been established as the most standard test recommended by the guideline, its invasive and technically difficult nature has facilitated the approach to develop non-invasive functioning imaging as an alternative test. Compared to the conventional adrenocortical scintigraphy with cholesterol derivatives as tracer, the first-generation imaging, both of (11) C-MTO/PET and (123) I-IMTO/SPECT/CT, the second-generation imaging, bind with high specificity and affinity to CYP11B enzymes and have advantages in shortening the time for obtaining specific images, reducing the radiation exposure to the patient, and resolution of the images. Because of very short half-life of (11) C-MTO, (123) I-IMTO has a potential for a wider application than (11) C-MTO. Sensitivity of identifying an adenoma smaller than 1cm in diameter is still a common limitation of these new functional imaging methods. The new functional imaging could be supplementary to AVS in lateralization of PA when the results of AVS are not conclusive. To be a substitute for AVS, however, it should fulfill various conditions including high selectivity and binding affinity to CYP11B2, high sensitivity in detecting small adenoma, high resolution image, reduction of radiation exposure, and general versatility. Considering the potential number of patients, cost-effectiveness of the subtype testing in the clinical practice of PA could be one of the issues of the medical expenses. Thus, development of a new non-invasive functional imaging will have a significant impact on the clinical practice of PA and hypertension.

DOI： 10.1055/s-0043-120672

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Advanced Glycation End Product 3 (AGE3) Increases Apoptosis and the Expression of Sclerostin by Stimulating TGF-beta Expression and Secretion in Osteocyte-Like MLO-Y4-A2 Cells
Advanced glycation end products (AGEs) cause bone fragility due to deterioration in bone quality. We previously reported that AGE3 induced apoptosis and inhibited differentiation via increased transforming growth factor (TGF)-beta signaling in osteoblastic cells. Additionally, we demonstrated that AGE3 increased apoptosis and sclerostin expression and decreased receptor activator of nuclear factor-kappa B ligand (RANKL) expression in osteocyte-like cells. However, it remains unclear whether TGF-beta signaling is involved in the effects of AGEs on apoptosis and the expression of sclerostin and RANKL in osteocytes. Effects of AGE3 on apoptosis of mouse osteocyte-like MLO-Y4-A2 cells were examined by DNA fragmentation ELISA. Expression of TGF-beta, sclerostin, and RANKL was evaluated using real-time PCR, Western blotting, and ELISA kits. To block TGF-beta signaling, we used SD208, a TGF-beta type I receptor kinase inhibitor. AGE3 (200 A mu g/mL) significantly increased apoptosis and mRNA expression of Sost, the gene encoding sclerostin, and decreased Rankl mRNA expression in MLO-Y4-A2 cells. AGE3 significantly increased the expression of TGF-beta. Co-incubation of SD208 with AGE3 significantly rescued AGE3-induced apoptosis in a dose-dependent manner. Moreover, SD208 restored AGE3-increased mRNA and protein expression of sclerostin. In contrast, SD208 did not affect AGE3-decreased mRNA and protein expression of RANKL. These findings suggest that AGE3 increases apoptosis and sclerostin expression through increasing TGF-beta expression in osteocytes, and that AGE3 decreases RANKL expression independent of TGF-beta signaling.

DOI： 10.1007/s00223-017-0243-x

Language：English   Publishing type：Research paper (scientific journal)  

Clinical studies have shown that hyperhomocysteinemia is associated with bone fragility. Homocysteine (Hey) induces apoptosis of osteoblastic cell lineage by increasing oxidative stress, which may contribute to Hcy-induced bone fragility. Statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, ameliorate oxidative stress by regulating oxidant and anti-oxidant enzymes. However, the effects of statins on Hcy-induced apoptosis of osteocytes are unknown. This study was thus aimed to investigate whether or not statins prevent Hcy-induced apoptosis of osteocytic MLO-Y4 cells and regulate NADPH oxidase (Nox) expression. TUNEL staining showed that 5 mM Hcy induced apoptosis of MLO-Y4 cells, and that co-incubation of 10(-9) or 10(-8) M simvastatin significantly suppressed the apoptotic effect. Moreover, we confirmed the beneficial effect of simvastatin against Hcy's apoptotic effect by using a DNA fragment ELISA assay. However, TUNEL staining showed no significant effects of pravastatin, a hydrophilic statin, on the Hcy-induced apoptosis. Real-time PCR showed that Hcy increased the mRNA expressions of Nox1 and Nox2, whereas simvastatin inhibited the stimulation of Nox1 and Nox2 expressions by Hcy. In contrast, neither Hcy nor simvastatin had any effect on Nox4 expression. These findings indicate that simvastatin prevents the detrimental effects of Hey on the apoptosis of osteocytes by regulating the expressions of Nox1. and Nox2, suggesting that statins may be beneficial for preventing Hey-induced osteocyte apoptosis and the resulting bone fragility.

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Activation of AMP-activated protein kinase decreases receptor activator of NF-kappa B ligand expression and increases sclerostin expression by inhibiting the mevalonate pathway in osteocytic MLO-Y4 cells
Background: AMP-activated protein kinase (AMPK) plays important roles in bone metabolism; however, little is known about its role in osteocytes. This study investigated the effects of AMPK activation on the expression of receptor activator of NF-kappa B ligand (RANKL) and sclerostin in osteocytes.
Results: Real-time PCR showed that AMPK activation by 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) significantly decreased the expression of Rankl in a dose- and time-dependent manner and significantly increased the expression of Sost, the gene encoding sclerostin, in osteocytic MLO-Y4 cells. Western blotting confirmed that AICAR decreased RANKL protein levels and increased sclerostin levels. In addition, suppression of AMPK alpha 1 by siRNA significantly increased the expression of Rankl on 4 days after the transfection of siRNA, while Sost expression was not changed. Simvastatin, an inhibitor of HMG-CoA reductase, significantly decreased Rankl expression and increased Sost expression in MLO-Y4 cells. Supplementation with mevalonate or geranylgeranyl pyrophosphate, which are downstream metabolites of HMG-CoA reductase, significantly reversed the effects of AICAR.
Conclusion: These findings indicated that AMPK regulated RANKL and sclerostin expression through the mevalonate pathway in osteocytes. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bbrc.2015.12.072

Language：English   Publishing type：Research paper (scientific journal)  

Background: Elevated plasma homocysteine (Hcy) level is associated with the risk of osteoporotic fracture. While Hcy increases oxidative stress, AMP-activated protein kinase (AMPK) activation ameliorates it. This study aimed to investigate whether Hcy induces apoptosis of osteocytic MLO-Y4 cells through regulating expressions of oxidant and anti-oxidant enzymes and determine the effects of AMPK activation by 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) and metformin on the Hcy-induced apoptosis of the cells.
Results: DNA fragment ELISA and TUNEL staining assays showed that Hcy treatments (0.1-5.0 mM) induced apoptosis of MLO-Y4 cells in a dose-dependent manner. The detrimental effect of Hcy was partly but significantly reversed by an antioxidant (N-acetylcysteine) and NADPH oxidase (Nox) inhibitors (apocynin and diphenyleneiodonium). In addition, treatment with AICAR (0.05-0.1 mM) and metformin (10-100 mu M) ameliorated Hcy-induced apoptosis of the cells. The favorable effect of metformin on Hcy-induced apoptosis was completely canceled by an AMPK inhibitor Ara-A. Hcy increased the expression levels of Nox1 and Nox2, while it had no effects on the expressions of Nox4 or the anti-oxidant enzymes, superoxide dismutase 1 and 2. Hcy-induced increases in the expressions of Nox1 and Nox2 decreased significantly by treatments with AICAR.
Conclusion: These findings suggest that Hcy induces apoptosis of osteocytes by increasing the expressions of Noxl and Nox2, and AMPK activation by AICAR and metformin effectively prevents the detrimental reactions. Thus, AMPK activation may be a potent therapeutic candidate for preventing Hcy-induced osteocyte apoptosis and the resulting bone fragility. (C) 2015 Elsevier Inc. All rights reserved.

DOI： 10.1016/j.bone.2015.04.025

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骨粗鬆症の早期診断法を開発するため、骨量正常にもかかわらず脆弱性骨折を引き起こす骨質劣化型骨粗鬆症に着目し、副腎由来ホルモンにおける骨粗鬆症への病態生理学的意義を検討した。副腎由来ホルモン過剰モデルであるヒト副腎腫瘍を対象とした観察研究、健常人を対象としたゲノムワイド関連研究を用いたメンデルランダム化研究、健常人の血液検体を対象とした網羅的ステロイドミクス解析を行った。その結果、副腎由来ホルモンは骨質制御に重要な役割を担っていることが明らかになった。さらに、生理的濃度の副腎由来ホルモンの変動も骨粗鬆症の進展に影響すること、健常人において副腎由来ホルモンに個人差を認めることも明らかになった。副腎由来ホルモンは有用な骨質サロゲート指標になり得ると考えられた。

Language：Japanese   Publisher：(一社)日本内分泌学会  

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腫瘍細胞性と粘液性の特徴を有する副腎皮質腫瘍の1症例(A case of adrenocortical tumor with oncocytic and myxoid feature)

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6年間の経過で病型診断が変化した原発性アルドステロン症の1例

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6年間の経過で病型診断が変化した原発性アルドステロン症の1例

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TRAb値とTSAb値に乖離を認めた高齢男性の甲状腺眼症の1例

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原発性アルドステロン症診療の標準化 コンセンサス・ステートメントについて

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原発性アルドステロン症、サブクリニカルクッシング症候群を合併したAdrenocortical oncocytomaの一例

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【原発性アルドステロン症診療の進歩】 わが国の原発性アルドステロン症の診療に関するコンセンサス・ステートメント
原発性アルドステロン症(PA)は高血圧における頻度が高く、治癒可能である一方、適切な診断・治療の遅れは治療抵抗性高血圧、種々の標的臓器障害の原因となることから、診療水準の向上と標準的医療の普及は重要な臨床的課題である。日本内分泌学会は日本高血圧学会、日本内分泌外科学会と協力して、診療の主要なクリニカルクエッションに対するクリニカルアンサーを、客観的なエビデンスに基づいたステートメントとして発表した。要点は(1)PA高頻度の高血圧患者での積極的なスクリーニング実施、(2)ARR>200とPAC>120pg/mlの場合にスクリーニング陽性と判断、(3)機能確認検査:カプトプリル試験、生食負荷試験、フロセミド立位試験、経口食塩負荷試験の中から少なくとも1種類の陽性を確認、(4)副腎腫瘍の確認のためthin sliceでの副腎SDCTを実施、(5)手術適応を考慮する場合は原則AVSを実施。ただし、35歳以下の典型的PAではAVSの省略も考慮、(6)局在判定の指標:ACTH負荷後Lateralized ratio(LR)>4かつContralateral ratio(CR)>1を推奨。結果が乖離した場合は総合判定、(7)片側性病変では副腎摘出術、両側性病変や手術不能な場合はMR拮抗薬を第一選択とする薬物治療、などである。しかしながら、わが国独自のエビデンスは不十分で、今後、現在進行中のAMED難治性疾患実用化研究JPASの結果を踏まえた改訂が必要と考えられる。(著者抄録)

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Prognosis and QOL of pheochromocytoma/paraganglioma

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