Japan Endocrine Society Research Articles

6973 Prospective Multicenter Registry-Based Study on Thyroid Storm: The 2016 Guidelines for the Management from the Japan Thyroid Association and Japan Endocrine Society Are Useful

Abstract Disclosure: Y. Furukawa: None. K. Tanaka: None. O. Isozaki: None. A. Suzuki: None. T. Iburi: None. K. Tsuboi: None. M. Iguchi: None. N. Kanamoto: None. K. Minamitani: None. S. Wakino: None. T. Satoh: None. S. Teramukai: None. E. Kimura: None. Y. Miyake: None. T. Akamizu: None. Context: The mortality rate in thyroid storm (TS) has been reported to be higher than 10%. Even when patients survive, some have irreversible damages. In order to improve the prognosis of patients with TS, appropriate management as well as prompt and accurate diagnosis are needed. We created the diagnostic criteria in 2012 and established guidelines for the management of TS in 2016. Objective: We aimed to evaluate the effectiveness of the 2016 guidelines for the management of TS proposed by the Japan Thyroid Association and Japan Endocrine Society. Design: Prospective registry-based study through a secure web platform. Setting: Prospective multicenter registry. Patients and Measurements: Patients with new-onset TS were registered in the Research Electronic Data Capture (REDCap) from May 1, 2018 to April 30, 2022, over four years. On day 30 after admission, clinical information and prognosis of each patient were added to the platform. On day 180, the prognosis was described. The questionnaire consisted of 176 items totally. Results: This study included 110 patients with TS (93 definite and 17 suspected). The median of Acute Physiology and Chronic Health Evaluation (APACHE) II score was 13, higher than the score in the previous nationwide survey, 10 (p=0.001). Nonetheless, the mortality rate at day 30 was 5.5%, approximately half compared with 10.7% in the previous nationwide survey (p=0.13). Lower BMI, lower left ventricular ejection fraction (LVEF) and shock were positively associated with poor prognosis at day 30. The lack of fever ≥ 38°C was surprisingly associated to the outcome. Approximately 80% of doctors followed the guidelines. The mortality rate in patients with an APACHE II score ≥ 12 for whom the guidelines were not followed was significantly higher than the rate in patients for whom the guidelines were followed (50% vs. 4.7%) (p=0.01). Conclusions: Prognosis seemed better than in the previous nationwide survey, even though disease severity was higher. The mortality rate was lower when the guidelines were followed. Thus, the guidelines are useful for managing TS. Presentation: 6/2/2024

Clinical Efficacy of Beta-1 Selective Beta-Blockers Versus Propranolol in Patients With Thyroid Storm: A Retrospective Cohort Study.

Thyroid storm is the most severe manifestation of thyrotoxicosis. Beta-blockers are among the standard treatment regimens for this condition, with propranolol being the historically preferred option. However, 2016 guidelines issued by the Japan Thyroid Association and the Japan Endocrine Society recommend the use of beta-1 selective beta-blockers over nonselective beta-blockers, such as propranolol. Nevertheless, evidence supporting this recommendation is limited. Herein, we aimed to investigate the in-hospital mortality of patients with thyroid storms based on the choice of beta-blockers. Retrospective cohort study. The Diagnosis Procedure Combination database, a national inpatient database in Japan. Patients hospitalized with thyroid storm between April 2010 and March 2022. Propensity-score overlap weighting was performed to compare in-hospital mortality between patients who received beta-1 selective beta-blockers and those who received propranolol. Subgroup analysis was also conducted, considering the presence or absence of acute heart failure. Among the 2462 eligible patients, 1452 received beta-1 selective beta-blockers and 1010 received propranolol. The crude in-hospital mortality rates were 9.3% for the beta-1 selective beta-blocker group and 6.2% for the propranolol group. After adjusting for baseline variables, the use of beta-1 selective beta-blockers was not associated with lower in-hospital mortality (6.3% vs. 7.4%; odds ratio, 0.85; 95% CI, 0.57-1.26). Furthermore, no significant difference in in-hospital mortality was observed in patients with acute heart failure. In patients with thyroid storm, the choice between beta-1 selective beta-blockers and propranolol did not affect in-hospital mortality, regardless of the presence of acute heart failure. Therefore, both beta-1 selective beta-blockers and propranolol can be regarded as viable treatment options for beta-blocker therapy in cases of thyroid storm, contingent upon the clinical context.

Systematic molecular analyses for 115 karyotypically normal men with isolated non-obstructive azoospermia.

Do copy-number variations (CNVs) in the azoospermia factor (AZF) regions and monogenic mutations play a major role in the development of isolated (non-syndromic) non-obstructive azoospermia (NOA) in Japanese men with a normal 46, XY karyotype? Deleterious CNVs in the AZF regions and damaging sequence variants in eight genes likely constitute at least 8% and approximately 8% of the genetic causes, respectively, while variants in other genes play only a minor role. Sex chromosomal abnormalities, AZF-linked microdeletions, and monogenic mutations have been implicated in isolated NOA. More than 160 genes have been reported as causative/susceptibility/candidate genes for NOA. Systematic molecular analyses were conducted for 115 patients with isolated NOA and a normal 46, XY karyotype, who visited our hospital between 2017 and 2021. We studied 115 unrelated Japanese patients. AZF-linked CNVs were examined using sequence-tagged PCR and multiplex ligation-dependent probe amplification, and nucleotide variants were screened using whole exome sequencing (WES). An optimized sequence kernel association test (SKAT-O), a gene-based association study using WES data, was performed to identify novel disease-associated genes in the genome. The results were compared to those of previous studies and our in-house control data. Thirteen types of AZF-linked CNVs, including the hitherto unreported gr/gr triplication and partial AZFb deletion, were identified in 63 (54.8%) cases. When the gr/gr deletion, a common polymorphism in Japan, was excluded from data analyses, the total frequency of CNVs was 23/75 (30.7%). This frequency is higher than that of the reference data in Japan and China (11.1% and 14.7%, respectively). Known NOA-causative AZF-linked CNVs were found in nine (7.8%) cases. Rare damaging variants in known causative genes (DMRT1, PLK4, SYCP2, TEX11, and USP26) and hemizygous/multiple-heterozygous damaging variants in known spermatogenesis-associated genes (TAF7L, DNAH2, and DNAH17) were identified in nine cases (7.8% in total). Some patients carried rare damaging variants in multiple genes. SKAT-O detected no genes whose rare damaging variants were significantly accumulated in the patient group. The number of participants was relatively small, and the clinical information of each patient was fragmentary. Moreover, the pathogenicity of identified variants was assessed only by in silico analyses. This study showed that various AZF-linked CNVs are present in more than half of Japanese NOA patients. These results broadened the structural variations of AZF-linked CNVs, which should be considered for the molecular diagnosis of spermatogenic failure. Furthermore, the results of this study highlight the etiological heterogeneity and possible oligogenicity of isolated NOA. This study was supported by Grants from the Japan Society for the Promotion of Science (21K19283 and 21H0246), the Japan Agency for Medical Research and Development (22ek0109464h0003), the National Center for Child Health and Development, the Canon Foundation, the Japan Endocrine Society, and the Takeda Science Foundation. The results of this study were based on samples and patient data obtained from the International Center for Reproductive Medicine, Dokkyo Medical University Saitama Medical Center, Koshigaya, Japan. The authors have no conflicts of interest to disclose. N/A.

Prospective Multicenter Registry-Based Study on Thyroid Storm: The Guidelines for the Management from Japan are Useful.

The mortality rate in thyroid storm (TS) has been reported to be higher than 10%. We aimed to evaluate the effectiveness of the 2016 guidelines for the management of TS proposed by the Japan Thyroid Association and Japan Endocrine Society. Prospective registry-based study through a secure web platform. Prospective multicenter registry. Patients with new-onset TS were registered in the Research Electronic Data Capture (REDCap). On day 30 after admission, clinical information and prognosis of each patient were added to the platform. On day 180, the prognosis was described. This study included 110 patients with TS. The median of Acute Physiology and Chronic Health Evaluation (APACHE) II score was 13, higher than the score in the previous nationwide epidemiological study, 10 (p = 0.001). Nonetheless, the mortality rate at day 30 was 5.5%, approximately half compared with 10.7% in the previous nationwide survey. Lower body mass index, shock and lower left ventricular ejection fraction were positively associated with poor prognosis at day 30, while the lack of fever ≥ 38℃ was related to the outcome. The mortality rate in patients with an APACHE II score ≥12 for whom the guidelines were not followed was significantly higher than the rate in patients for whom the guidelines were followed (50% vs. 4.7%) (p = 0.01). Prognosis seemed better than in the previous nationwide survey, even though disease severity was higher. The mortality rate was lower when the guidelines were followed. Thus, the guidelines are useful for managing TS.

Impact of coronavirus disease 2019 on medical practice in endocrine and metabolic diseases in Japan: a nationwide surveillance study conducted by the Japan Endocrine Society.

We investigated the impact of the Coronavirus disease 2019 (COVID-19) pandemic on the management of endocrine and metabolic disorders in Japan. We conducted a cross-sectional nationwide questionnaire survey targeting board-certified endocrinologists under the auspices of the Japan Endocrine Society. The questionnaire consisted of multiple-choice questions and open-ended responses. Out of approximately 2,700 specialists, 528 (19.5%) opted to participate, suggesting a high level of interest in COVID-19 management among endocrinologists. The study found that almost half of participants had encountered cases of endocrine and metabolic disorders following COVID-19 infection or vaccination. Conditions related to thyroid diseases, glucose metabolism disorders/diabetes, and hypothalamic-pituitary disorders were particularly prevalent. Diabetes and obesity were identified as having high rates of severe cases or fatalities due to COVID-19. The study also highlighted challenges in routine diagnosis and treatment, emphasizing the potential benefits of combining remote consultations with in-person visits to optimize the frequency of examinations and check-ups during infectious disease outbreak which disrupts access to healthcare providers. The insights obtained from this survey are expected to contribute to ensuring appropriate healthcare provision for patients with endocrine and metabolic disorders by using flexible consultation formats, particularly even in the conditions where medical access may be limited due to future outbreaks of emerging or re-emerging infectious diseases.

Impact of the transition from radioimmunoassay (RIA) to chemiluminescent enzyme immunoassay (CLEIA) for the measurement of plasma aldosterone concentration (PAC) on the diagnosis of primary aldosteronism (PA) via retrospective analyses in Okinawa, Japan.

In Japan, the traditional method for measuring plasma aldosterone concentration (PAC) was radioimmunoassay (RIA), which had several challenges, including poor traceability of certified reference materials and reduced detection sensitivity at low concentrations. To overcome these issues, a chemiluminescent enzyme immunoassay (CLEIA) for PAC measurement was introduced in April 2021 and the Japan Endocrine Society published new guidelines for primary aldosteronism (PA). This study aimed to evaluate the impact of the transition from RIA to CLEIA for PAC measurement on PA diagnosis. Data from 190 patients admitted to the Second Department of Internal Medicine, University of the Ryukyus Hospital, between April 2012 and March 2021 were analyzed. Patients who were diagnosed with PA underwent adrenal venous sampling. The PAC measured by RIA (PAC(RIA)) was converted to the estimated PAC measured by CLEIA (ePAC(CLEIA)) using a conversion formula. The present study evaluated the discordance rates in diagnoses based on screening (SC), captopril challenge test (CCT), saline infusion test (SIT), and diagnosis of PA between results judged by PAC(RIA) according to the previous guidelines and those judged by ePAC(CLEIA) according to the new guidelines. The results revealed discordant diagnosis rates of 6.4% for SC and 10.1% for CCT, with no discordance for SIT. The discordant diagnosis rate for PA was 3.7%. Our study reveals the challenges in establishing appropriate diagnostic criteria for PA using PAC(CLEIA) and highlights the demand for further research on provisionally positive categories.

Celebrating the 100th anniversary of the Japan Endocrine Society and international collaborations.

Celebrating the 100th anniversary of the Japan Endocrine Society and international collaborations.

Epigenetic alterations of 11beta-hydroxysteroid dehydrogenase 1 gene in the adipose tissue of patients with primary aldosteronism.

11Beta-hydroxysteroid dehydrogenase 1 (11β-HSD1) is a key enzyme involved in metabolic syndrome. Transcript-specific epigenetic regulation of the gene encoding 11β-HSD1 (HSD11B1) has been reported. We examined the mRNA level and methylation status of the HSD11B1 promoter region in the adipose tissue of patients with primary aldosteronism (PA). We compared 10 tissue specimens from patients with PA caused by aldosterone-producing adenoma (APA) with 8 adipose tissue specimens from patients with subclinical Cushing's syndrome (SCS) caused by cortisol-producing adenomas, 4 tissue specimens from patients with Cushing's adenoma (Cu), or 7 tissue specimens from patients with non-functioning adrenal adenoma (NFA). PA, SCS, and Cu were diagnosed according to the guideline of the Japan Endocrine Society. The mRNA level of HSD11B1 was quantified using real-time PCR. Isolated DNA was treated with bisulfite and amplified using primers specific to the human HSD11B1 promoter region. The glycohemoglobin level was significantly higher in patients with APA, SCS, or Cu than in those with NFA (p < 0.05). Blood pressure was significantly higher in patients with APA than in those with SCS, Cu, or NFA (p < 0.01). The HSD11B1 mRNA level was significantly increased in the adipose tissues of APA or SCS patients compared with Cu or NFA patients (p < 0.05). The methylation ratio was significantly lower in SCS patients than in APA, Cu, or NFA patients (p < 0.05). HSD11B1 expression is partly controlled by an epigenetic mechanism in human tissues. The pathophysiological role of epigenetic regulation of HSD11B1 expression in adipose tissue requires further study.

FRI136 Adrenal Venous Sampling Criteria For Chemiluminescent Enzyme Immunoassay

Abstract Disclosure: K. Nakai: None. Y. Tsurutani: None. K. Irie: None. K. Teruyama: Employee; Self; Fujirebio Inc. J. Saito: None. M. Omura: None. T. Nishikawa: None. Objective: In primary aldosteronism (PA), plasma aldosterone concentration (PAC) was measured by radioimmunoassay (RIA), but the supply of the RIA kit was discontinued in March 2021 in Japan. The Japan Endocrine Society's 2021 Clinical Practice Guideline for the Diagnosis and Management of PA recommends that PAC measured by chemiluminescent enzyme immunoassay (CLEIA), which yields standardized LC-MS/MS compliant measurements, be used for clinical judgment. Because CLEIA shows a lower PAC than RIA, various cutoff values for PA need to be revised. Although conversion formulas for RIA and CLEIA for various kits have been provided, these conversions were studied mainly using samples representing aldosterone concentrations in peripheral blood; thus, it is unclear whether the same conversion formula can be used for samples obtained by adrenal venous sampling (AVS). In this study, we examined PAC conversion in AVS samples and the criteria for AVS when measured using CLEIA. Methods: PAC of 415 adrenal venous blood samples from AVS (including segmental AVS) from 63 patients with PA, were measured using RIA and CLEIA methods. The established conversion formula for PAC in peripheral blood samples was PAC (CLEIA) = 0.852 × PAC (RIA) − 36.0. PAC and aldosterone/cortisol ratio (A/C ratio) conversion formulas were determined between the two assays for AVS samples. Moreover, the CLEIA conversion value, which corresponds to the AVS criteria of conventional RIA, was obtained. Results: The median [interquartile range] PAC (CLEIA) in the samples was 9823.3 [3659.8-20600.5]. PAC measured using CLEIA was significantly correlated with RIA, and the correlation coefficient was 0.971. The PAC conversion formula determined was PAC (CLEIA) = PAC (RIA) × 0.7723 - 1199 pg/mL. PAC at 14,000 pg/mL in RIA was equivalent to 9,613 pg/mL in CLEIA. The correlation coefficient for the A/C ratio was 0.997, and the conversion formula was A/C (CLEIA) = A/C (RIA) × 0.7864 - 2.427. Discussion: Samples obtained from AVS had a much higher level of PAC than those obtained from peripheral blood. The PAC conversion formula for samples in AVS has a very large intercept compared with those in peripheral blood. Thus, the results of AVS tested by CLEIA should be interpreted with care because of the differences in the conversion formula. A different cut-off value may also be needed when evaluating the lateralization ratio because of the large intercept. Conclusion: PAC conversion formulas for AVS samples using CLEIA and RIA methods were obtained. The study outcomes are useful for interpreting AVS results using the CLEIA. Presentation: Friday, June 16, 2023

PS-C31-1: SIGNIFICANCE OF SCREENING AND DIAGNOSING PRIMARY ALDOSTERONISM (PA) IN GENERAL MEDICINE

Background: Primary aldosteronism (PA) is a frequent secondary hypertension that is more frequently associated with cerebrovascular disease than essential hypertension, and thus requires appropriate diagnosis and treatment. The Japan Endocrine Society has published the new guideline for the diagnosis and treatment of primary aldosteronism, following the change of aldosterone measurement system in 2021. In this presentation, we will discuss a case of PA experienced at a dental school hospital. Case 75 years old male Current medical history: He had been diagnosed as hypertensive more than 10 years ago and had been prescribed antihypertensive medication, but he had stopped taking it. When he visited an oral surgeon for a tooth extraction, hypertension was noted and he was referred to internal medicine. &lt;Physical findings&gt; Blood pressure: 208/120 mmHg, Pulse: 83/min, &lt;Biochemistry&gt; Cre 1.09 mg/dL, Na 139mEq/L, K 3.7mEq/L. &lt;Endocrine metabolism&gt; fT4 0.95ng/dL, TSH 2.58micro-IU/mL, Plasma renin activity: PRA (EIA method) 0.6ng/mL/hr, Plasma aldosterone concentration: PAC (CLEIA method) 130pg/mL. &lt;Abdominal CT&gt; There was a nodule on the right adrenal gland. &lt;Progress and discussion&gt; The patient had a high aldosterone-renin ratio: ARR = PAC/PRA = 130/0.6 = 217 at the time of initial examination, and PA was suspected. CT showed a nodule in the right adrenal gland, raising suspicion of unilateral disease. Because of the high basal plasma aldosterone level and low K level, we referred the patient to a specialized facility because we thought that if PA was confirmed by functional confirmation testing, the case could be aggressively localized and typed by adrenal vein sampling (AVS). In this presentation, we would like to discuss the significance of screening and diagnosis of PA in primary care and general practice settings such as dental school hospitals, based on the results of functional confirmation testing at specialized facilities, and in light of current guidelines.

Discover inspiring stories from the 100-year history of the Japan Endocrine Society; progress toward future successes.

Discover inspiring stories from the 100-year history of the Japan Endocrine Society; progress toward future successes.

My 50 years in adrenal endocrinology coincident with 100 years of the Japan Endocrine Society.

My 50 years in adrenal endocrinology coincident with 100 years of the Japan Endocrine Society.

PS-C21-10: A LC-MS/MS-EQUIVALENT VALUE OF ALDOSTERONE MEASUREMENT BY A NEW CHEMILUMINESCENT ENZYME IMMUNOASSAY USING A TWO-STEP SANDWICH METHOD

Primary aldosteronism (PA) is the most frequent cause of secondary hypertension. Patients with PA have an increased risk of cardiovascular events, such as cerebral infarction, myocardial infarction, and chronic kidney disease, compared to those with essential hypertension, and early diagnosis makes PA a treatable disease. In clinical practice, accurate measurement of plasma aldosterone concentration (PAC) is crucial because entire diagnostic tests critically depend on aldosterone concentrations. Recently, we developed a new chemiluminescent enzyme immunoassay (CLEIA) using a two step sandwich method to measure aldosterone concentrations. We measured PAC in blood samples from patients using a radioimmunoassay (RIA) and the CLEIA (with current and newly improved reagents) as well as liquid chromatography tandem mass spectrometry (LC MS/MS). Based on the results of the Passing Bablok regression analysis, the aldosterone levels measured using CLEIA with the new reagents and those measured by LC MS/MS were found to be significantly correlated. However, aldosterone levels were lower with the improved CLEIA method than with RIA and CLEIA using the current reagent. Since April 2021, the plasma aldosterone concentration has been measured by CLEIA in Japan. As a provisional response due to changes of the measurement method, the Japan Endocrine Society Clinical Practice Guideline for the Diagnosis and Management of Primary Aldosteronism 2021 was announced. This time, we will report on the new measuring method.

Celebrating 100th Anniversary of the Japan Endocrine Society.

Celebrating 100th Anniversary of the Japan Endocrine Society.

JS-HR-9: A NEW ERA OF PROGRESS IN PRIMARY ALDOSTERONISM TREATMENT, A NEW ALDOSTERONE ASSAY, AND A CLINICAL PRACTICE GUIDELINE

Primary aldosteronism (PA), one of the mineralocorticoid receptor (MR)-associated hypertension, is a highly prevalent secondary hypertension that accounts for 5–15% of all hypertension and is a severe hypertension that is prone to cerebrovascular and cardiovascular disease. Therefore, it is expected that the pathophysiology and treatment strategies for PA will be elucidated. In recent years, the major changes in PA have been in treatment and diagnosis in Japan. Bilateral or non-surgical unilateral PA is treated with mineralocorticoid receptor antagonist (MRA). Esaxerenone, a non-steroidal MRA, is now widely used in Japan for hypertension including PA. It has been reported that add-on treatment using esaxerenone with maximal tolerable doses of a renin-angiotensin system inhibitor reduced the urinary albumin creatinine ratio in patients with type 2 diabetes mellitus (ESAX-DN), suggesting a renoprotective effect against diabetic nephropathy. Several clinical studies of another non-steroidal MRA, finerenone(FIDELIO-DKD, FIGARO-DKD, and FIDELITY), have shown its renoprotective effect against diabetic nephropathy as well as cardiovascular events, particularly hospitalization for heart failure in patients with type 2 diabetes and chronic kidney disease. Although there are no reports of clinical studies on finerenone for PA, finerenone may be used in the future for type 2 diabetes patients with PA, as obesity, glucose intolerance, and sleep apnea are common complications in patients with PA. Secondly, radiofrequency ablation of macroscopic adrenal tumors has been reported as an alternative treatment for PA to lower blood pressure and plasma aldosterone levels. This treatment has been covered by health insurance providers in Japan since April 2022, but long-term outcomes need to be validated. In diagnosis, serum and urine aldosterone has been measured in Japan since early 2021 by the two-step sandwich chemiluminescent enzyme immunoassay (CLEIA) method. This new CLEIA method correlates well with LC-MS/MS values and is expected to be more accurate. As CLEIA serum aldosterone levels are lower than those measured with a previous radioimmunoassay, the Japan Endocrine Society issued the 2021 Primary Aldosteronism Clinical Guidelines, which included a provisional positive value for the diagnosis of PA. More than ever, the diagnosis of PA needs to be carefully considered. This CLEIA method is currently available only in Japan. This presentation will cover the latest treatments, diagnostic procedures, and other hot topics in PA as described above.

PS-BPC02-2: CLINICAL IMPACTS OF ENDOTHELIUM-DEPENDENT FLOW-MEDIATED VASODILATION ASSESSMENT ON PRIMARY ALDOSTERONISM

Objective: Primary aldosteronism (PA) is defined as autonomous aldosterone production from the adrenal glands and represents the most common and treatable cause of hypertension. Also, it is well known that the incidence of cardiovascular morbidity is higher among patients with PA than among those with essential hypertension (EH). Histologically, PA is divided into two major subtypes, aldosterone-producing adenoma (APA) and bilateral idiopathic hyperplasia (IHA). However, the nature of vascular function in PA patients remains to be determined. The aim of this study was to determine the vascular function and investigate the implications of vascular function assessments in the patients with PA. Design and Method: All patients were diagnosed with PA according to the guidelines of the Japan Endocrine Society. Flow-mediated dilation (FMD), as an index of endothelial function, and cardio-ankle vascular index (CAVI), as an index of arterial stiffness, were retrospectively compared between 42 patients with APA, 37 patients with IHA, and 42 patients with EH. These values were also compared with background factors, KCNJ5 mutation and clinical outcome in terms of blood pressure reduction after adrenalectomy in the APA group. Results: No differences were found among the three groups (APA, IHA and EH) with regard to age, sex, duration of hypertension, body mass index, blood pressure, renal function and hemoglobin A1c. FMD was significantly lower in the APA group (4.8 ± 2.1%) and IHA group (4.1 ± 1.9%) than in the EH group (5.7 ± 2.1%). CAVI did not differ significantly among APA, IHA and EH groups (7.9 ± 1.3, 7.8 ± 1.0, 7.8 ± 1.1, respectively). Although no significant correlations were seen between FMD and background factors (i.e. age, body mass index, renal function, glucose and lipid metabolic parameters, and hormonal data) in the IHA group, FMD correlated negatively with BMI and plasma aldosterone concentration in the APA group (rs = -0.313, rs = -0.342, respectively). No significant difference in FMD (4.8 ± 1.4%, 4.5 ± 2.1%, respectively) or CAVI (8.1 ± 1.8, 8.0 ± 1.1, respectively) was seen between the KCNJ5-mutant group and the wild-type group. A cut-off FMD of 4.3% was selected for complete clinical success after adrenalectomy, offering 78% sensitivity and 80% specificity. Conclusions: Patients with PA displayed impaired endothelial function. Complete clinical success after adrenalectomy was associated with preserved endothelial function. This study provides a better understanding of FMD assessment in patients with PA.

Clinical characteristics of adrenal insufficiency induced by pembrolizumab in non-small-cell lung cancer.

Immune checkpoint inhibitors have significantly improved the clinical outcomes of many cancer types, but they induce a range of immune-related adverse events (irAEs). Although adrenal insufficiency (AI) is a rare irAE, it can lead to serious consequences. This study aimed to determine the clinical features of patients with advanced non-small-cell lung cancer (NSCLC) who developed AI following pembrolizumab treatment. We retrospectively reviewed and analyzed the clinical data of all patients with NSCLC treated with pembrolizumab at Juntendo University Hospital from February 2017 to December 2020. The diagnosis of AI was established based on the Endocrine Emergency Guidance for the acute management of endocrine complications of checkpoint inhibitor therapy in the UK and the clinical practice guidelines of the Japan Endocrine Society. AI was clinically suspected in 59 out of 186 patients treated with pembrolizumab, and 10 (5.4%) cases were confirmed. The symptoms included hyponatremia (n=9), fatigue (n=8), and loss of appetite (n=6). All patients had low adrenocorticotropic hormone (ACTH) levels, and five patients were diagnosed with isolated ACTH deficiency. All patients completely recovered with corticosteroid replacement. The median time to onset of AI was 8.0 (range 3.8-15.2) months. The median progression-free survival in these patients was 22.4 (95% confidence interval 11.2-not reached) months. The incidence of AI among patients treated with pembrolizumab is more frequent than previously reported. In addition, secondary AI, especially isolated ACTH deficiency, is a major form of AI induced by pembrolizumab.

Clinical guidelines for the diagnosis and treatment of 21-hydroxylase deficiency (2021 revision).

.Congenital adrenal hyperplasia is a category of disorders characterized by impaired adrenocortical steroidogenesis. The most frequent disorder of congenital adrenal hyperplasia is 21-hydroxylase deficiency, which is caused by pathogenic variants of CAY21A2 and is prevalent between 1 in 18,000 and 20,000 in Japan. The clinical guidelines for 21-hydroxylase deficiency in Japan have been revised twice since a diagnostic handbook in Japan was published in 1989. On behalf of the Japanese Society for Pediatric Endocrinology, the Japanese Society for Mass Screening, the Japanese Society for Urology, and the Japan Endocrine Society, the working committee updated the guidelines for the diagnosis and treatment of 21-hydroxylase deficiency published in 2014, based on recent evidence and knowledge related to this disorder. The recommendations in the updated guidelines can be applied in clinical practice considering the risks and benefits to each patient.

Japan Endocrine Society clinical practice guideline for the diagnosis and management of primary aldosteronism 2021.

Primary aldosteronism (PA) is associated with higher cardiovascular morbidity and mortality rates than essential hypertension. The Japan Endocrine Society (JES) has developed an updated guideline for PA, based on the evidence, especially from Japan. We should preferentially screen hypertensive patients with a high prevalence of PA with aldosterone to renin ratio ≥200 and plasma aldosterone concentrations (PAC) ≥60 pg/mL as a cut-off of positive results. While we should confirm excess aldosterone secretion by one positive confirmatory test, we could bypass patients with typical PA findings. Since PAC became lower due to a change in assay methods from radioimmunoassay to chemiluminescent enzyme immunoassay, borderline ranges were set for screening and confirmatory tests and provisionally designated as positive. We recommend individualized medicine for those in the borderline range for the next step. We recommend evaluating cortisol co-secretion in patients with adrenal macroadenomas. Although we recommend adrenal venous sampling for lateralization before adrenalectomy, we should carefully select patients rather than all patients, and we suggest bypassing in young patients with typical PA findings. A selectivity index ≥5 and a lateralization index >4 after adrenocorticotropic hormone stimulation defines successful catheterization and unilateral subtype diagnosis. We recommend adrenalectomy for unilateral PA and mineralocorticoid receptor antagonists for bilateral PA. Systematic as well as individualized clinical practice is always warranted. This JES guideline 2021 provides updated rational evidence and recommendations for the clinical practice of PA, leading to improved quality of the clinical practice of hypertension.

USEFULNESS OF SHORTENED SALINE INFUSION TEST FOR PRIMARY ALDOSTERONISM DIAGNOSTICS

Objective: Primary aldosteronism (PA) is a frequent and remediable cause of endocrine hypertension. Saline infusion test (SIT) is one of the most widely-accepted confirmatory tests for PA, but some patients may not tolerate the standard loading volume of 2 L saline over 4 h. Shortened SIT, loading only 1 L saline over 2 h, has been suggested to be useful and would be more acceptable across wider population if the diagnostic utility proves to be comparable to the standard SIT. Therefore, we compared the diagnostic values of plasma aldosterone concentration after 2 hours of 1 L saline loading (2 h PAC) and those after 4 hours of 2 L saline loading (4 h PAC) for the prediction of unilateral aldosterone hypersecretion and postoperative outcome. Design and method: The retrospective, single-center study involved 555 PA-suspected patients who underwent recumbent SIT, 153 of whom subsequently underwent adrenal vein sampling (AVS). Postoperative blood pressure outcome was also examined in 37 patients. We calculated the defined daily doses (DDD) of anti-hypertensive drugs according to those set by the World Health Organization, and compared the values between before and 1 year after the surgery. Results: The Youden Index of 2 h PAC for receiver operating characteristic (ROC) curves of 4 h PAC &gt; 60 pg/mL (The SIT was considered positive if 4 h PAC was over 60 pg/mL according to the Japan Endocrine Society 2009 guidelines) was 66 pg/mL. The areas under the ROC curves of 2 h and 4 h PAC were comparable (0.80 vs.0.85, 95% CI -0.1035 – 0.0109, P = 0.11) for unilateral aldosterone hypersecretion defined as lateralization index &gt;4. Postoperative reduction of anti-hypertensive drug use and 2 h PAC was significantly correlated (P = 0.04). The areas under the ROC curves of 2 h and 4 h PAC were comparable (0.82 vs.0.78, 95% CI -0.0949 – 0.1706, P = 0.58) for postoperative reduction of anti-hypertensive drug use. Conclusions: Shortened SIT may be similarly useful as standard SIT to select PA patients for AVS and also to predict postoperative blood pressure outcome with reduced burden on patients.