Primary aldosteronism patients with previous cardiovascular and cerebrovascular events have high aldosterone responsiveness to ACTH stimulation.

Aldosterone secretion in primary aldosteronism (PA) is often regulated by adrenocorticotropic hormone (ACTH) in addition to its autonomous secretion. However, the clinical characteristics and risk of cardiovascular and cerebrovascular (CCV) events in PA patients with aldosterone responsiveness to ACTH stimulation remain unclear. This study aimed to investigate the prevalence of CCV events in PA patients with high aldosterone responsiveness to ACTH stimulation. A retrospective cross-sectional study was conducted as part of the Japan Primary Aldosteronism Study/Japan Rare Intractable Adrenal Disease project. PA patients with adrenal venous sampling (AVS) between January 2006 and March 2019 were enrolled. The ACTH-stimulated plasma aldosterone concentration (PAC) of the inferior vena cava during AVS was used to evaluate aldosterone responsiveness to ACTH. We analyzed the relationship between responsiveness and previous CCV events. Logistic regression analysis demonstrated that the ΔPAC (the difference between the PAC measurements before and after ACTH stimulation) significantly increased the odds of previous CCV events in PA patients after adjusting for classical CCV event risk factors, baseline PAC and duration of hypertension (relative PAC: odds ratio [OR], 2.896; 95% confidence interval [CI], 0.989-8.482; ΔPAC: OR, 2.344; 95% CI, 1.149-4.780; ACTH-stimulated PAC: OR, 2.098; 95% CI, 0.694-6.339). This study clearly demonstrated that aldosterone responsiveness to ACTH is closely related to previous CCV events. The responsiveness of the PAC to ACTH could be useful in predicting CCV event risk.Registration Number in UMIN-CTR is UMIN000032525.

Do multiple types of confirmatory tests improve performance in predicting subtypes of primary aldosteronism?

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.

Impact of a change to a novel chemiluminescent immunoassay for measuring plasma aldosterone on the diagnosis of primary aldosteronism.

In Japan, the standard method for measuring plasma aldosterone concentration (PAC) for primary aldosteronism (PA) diagnosis was changed from radioimmunoassay (RIA) to a novel chemiluminescent enzyme immunoassay (CLEIA). The purpose of this study is to simulate the possible impact of the change on PA diagnosis. This retrospective study assessed 2,289 PA patients. PACs measured by conventional RIA were transformed to estimated PACs (CLEIA) as follows: RIA (pg/mL) = 1.174 × CLEIA (pg/mL) + 42.3. We applied the estimated PAC (CLEIA) to the conventional cut-off of aldosterone-to-renin activity ratio ≥200 for screening and captopril challenge test (CCT) and PAC ≥60 pg/mL for saline infusion test (SIT). Application of the estimated PAC to screening and confirmatory tests decreased the number of PA diagnoses by 36% (743/2,065) on CCT and 52% (578/1,104) on SIT (discrepant cases). Among the discrepant cases, 87% (548/628) of CCT and 87% (452/522) of SIT were bilateral on adrenal venous sampling (AVS). Surgically treatable aldosterone-producing adenomas (APAs) were observed in 6% (36/579) and 5% (23/472) of discrepant cases on CCT and SIT, respectively; most were characterized by hypokalemia and/or adrenal nodule on CT imaging. Application of the PAC measured by the novel CLEIA to conventional cut-offs decreases the number of PA diagnoses. Although most discrepant cases were bilateral on AVS, there are some APA cases that were characterized by hypokalemia and/or adrenal tumor on CT. Further studies which evaluate PACs measured by both RIA and CLEIA for each patient are needed to identify new cut-offs for PAC measured by CLEIA.

Aldosterone-to-Renin Ratio Is Associated with Diabetic Nephropathy in Type 2 Diabetic Patients: A Single-Center Retrospective Study.

BACKGROUND It is well established that primary aldosteronism (PA) and aldosterone-to-renin ratio (ARR) are associated with kidney disease. The aim of this study was to retrospectively investigate the relationship between ARR, urinary albumin excretion (UAE), and estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes from a single center. MATERIAL AND METHODS We included 70 patients with type 2 diabetes, UAE ≤100 mg/day, not taking renin-aldosterone system inhibitors, did not meet the diagnostic criteria for PA, and had an ARR <20. The patients were divided into 3 groups: the normal low (NL) group (33 patients) with a UAE <10 mg/day, the normal (N) group (22 patients) with a UAE of 10-29 mg/day, and the microalbuminuria (M) group (15 patients) with a UAE of 30-100 mg/day. The ARR, plasma renin activity (PRA), and plasma aldosterone (PAC) were compared among groups. RESULTS The ARR was highest in group M (10.1±4.6), 6.5±0.3 in group NL, and 7.0±2.7 in group N. The PRA and PAC were significantly lower in group M (P<0.001). The ARR showed a significant positive correlation with log UAE (r=0.37, P<0.001) and a significant negative correlation with eGFR (r=-0.33, P<0.01). CONCLUSIONS High levels of aldosterone relative to renin, which did not fulfill confirmatory criteria for PA, may be one of the risk factors for the development of diabetic nephropathy in patients with diabetes. The present results are supported by previous research showing that an increased ARR without PA was a risk factor for kidney disease.

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.

Obesity predicts persistence of resistant hypertension after surgery in patients with primary aldosteronism.

OBJECTIVE: Primary aldosteronism (PA) is considered a major cause of resistant hypertension (RHT). The prevalence of RHT has been recently reported to reach 18% in general hypertension. However, little is known about the prevalence and the outcomes after adrenalectomy of RHT in PA. Therefore, we aimed to clarify the prevalence and surgical outcomes in patients with both PA and RHT. PATIENTS AND DESIGN: Among 550 patients who underwent adrenalectomy for unilateral PA in the Japan PA Study, RHT was defined as an uncontrolled blood pressure (≥140/90 mm Hg) despite treatment with at least any three antihypertensives or hypertension controlled with at least four drugs. Surgical outcome was assessed by the biochemical and clinical outcome. RESULTS: Although 40 (7.3%) patients fulfilled the criteria for preoperative RHT, this should be underestimated because only 36% of patients with postoperative RHT were classified as having preoperative RHT. The prevalence of preoperative RHT was approximately 20% when estimated using the total number of patients with postoperative RHT and the ratio of postoperative RHT in patients with preoperative RHT. Although an improvement in hypertension was achieved in approximately 80% of patients with preoperative RHT, 20% of these exhibited persistent RHT. These patients were more obese than those for whom RHT improved after surgery. Notably, body mass index of ≥25 kg/m2 was an independent predictor of postoperative RHT. CONCLUSIONS: The prevalence of RHT in PA was lower than expected even with the adjustment for underestimation. Furthermore, obesity is an independent factor predicting the postoperative persistence of RHT.

Efficacy of dapagliflozin versus sitagliptin on cardiometabolic risk factors in Japanese patients with type 2 diabetes: a prospective, randomized study (DIVERSITY-CVR).

BACKGROUND: Few prospective studies have compared the cardiovascular benefits of sodium-glucose cotransporter-2 (SGLT2) inhibitors and dipeptidyl peptidase 4 (DPP-4) inhibitors. We aimed to clarify the efficacy of dapagliflozin versus sitagliptin for modulating cardiometabolic risk factors including high glycated hemoglobin (HbA1c) levels, hypoglycemia, and body weight. METHODS: This prospective, randomized, open-label, blinded-endpoint, parallel-group trial enrolled 340 Japanese patients with early-stage type 2 diabetes receiving metformin alone or no glucose-lowering agents, who were randomized to receive dapagliflozin or sitagliptin for 24 weeks. The primary endpoint was the proportion of patients who achieved the composite endpoint of HbA1c level maintenance < 7.0% (53 mmol/mol), avoidance of hypoglycemia (maintenance of sensor glucose ≥ 3.0 mmol/L or ≥ 54 mg/dL), and ≥ 3.0% body weight loss from baseline. Secondary endpoints included components of the primary endpoint, other metabolic indices, and glucose variability indices measured using flash glucose monitoring. RESULTS: Clinical characteristics of patients were age, 58.1 ± 12.2 years; known duration of diabetes, 5.8 ± 6.1 years; body weight, 74.7 ± 14.2 kg; body mass index, 27.9 ± 4.1 kg/m2; and HbA1c level, 7.8 ± 0.8% at baseline. The achievement ratio of primary endpoint was significantly higher in the dapagliflozin group than in the sitagliptin group (24.4% vs. 13.8%, P < 0.05). While the rates of HbA1c level maintenance < 7.0% (53 mmol/mol) and avoidance of hypoglycemia were comparable between the groups (49.4 vs. 50.0% and 88.7 vs. 92.3% for dapagliflozin vs. sitagliptin, respectively), body weight loss of ≥ 3.0% was significantly achieved in the dapagliflozin group (54.4 vs. 19.6%, P < 0.001). Moreover, dapagliflozin was superior to sitagliptin regarding several secondary endpoints that modulate cardiometabolic risk, namely reducing fasting plasma glucose, insulin, uric acid, increasing high-density lipoprotein cholesterol, and suppressing the increase in serum creatinine and the decrease in estimated glomerular filtration rate. On the other hand, sitagliptin was superior to dapagliflozin in suppressing glucose variability. CONCLUSIONS: Compared to sitagliptin, dapagliflozin was significantly more effective at improving cardiometabolic risk factors, suggesting that SGLT2 inhibitors might be more suitable than DPP-4 inhibitors for preventing cardiovascular events in patients with early-stage but inadequately controlled type 2 diabetes. Trial registration Trial number, UMIN000028014; registered on June 30, 2017.

A nationwide survey of adrenal incidentalomas in Japan: the first report of clinical and epidemiological features.

The aim of this study was to reveal clear epidemiologic and clinical characteristics of incidentally discovered adrenal masses, termed adrenal incidentalomas (AIs), and to establish appropriate managemental and therapeutic regimens in Japan. This study had been originally carried out as a project of a research proposed on behalf of the Japanese Ministry of Health, Labour and Welfare, from 1999 to 2004. This nationwide multicenter study on AIs included 3,672 cases with clinically diagnosed AIs, involving 1,874 males and 1,738 females, with mean age 58.1 ± 13.0 years (mean ± SD). In the present study, we focused on the investigation of the real prevalence of various adrenal disorders with AI. The mean nodule size of AI based on computed tomography was 3.0 ± 2.0 cm. Compared to non-functioning adenomas (NFAs), tumor diameters were significantly larger in adrenocortical carcinomas (ACCs), pheochromocytomas, cortisol-producing adenomas (CPAs), myelolipomas, metastatic tumors, cysts, and ganglioneuromas (p < 0.01). Endocrinological evaluations demonstrated that 50.8% of total AIs were non-functioning adenomas, while 10.5%, including 3.6% with subclinical Cushing's syndrome, were reported as CPAs, 8.5% as pheochromocytomas, and 5.1% as aldosterone-producing adenomas. ACCs were accounted for 1.4% (50 cases) among our series of AIs. In conclusion, while almost 50 % of AIs are non-functional adenomas, we must be particularly careful as AIs include pheochromocytomas or adrenal carcinomas, because they may be asymptomatic. To our knowledge, this is the first and the largest investigation of AI, thus providing basic information for the establishment of clinical guidelines for the management of AI.

Accuracy of adrenal computed tomography in predicting the unilateral subtype in young patients with hypokalaemia and elevation of aldosterone in primary aldosteronism.

CONTEXT: The current Endocrine Society Guideline suggests that patients aged <35 years with marked primary aldosteronism (PA) and unilateral adrenal lesions on adrenal computed tomography (CT) scan may not need adrenal vein sampling (AVS) before proceeding to unilateral adrenalectomy. This suggestion is, however, based on the data from only one report in the literature. OBJECTIVE: We sought to determine the accuracy of CT findings in young PA patients who had unilateral adrenal disease on CT with hypokalaemia and elevation of aldosterone. DESIGN AND PATIENTS: We retrospectively studied 358 PA patients (n = 30, aged <35 years; n = 39, aged 35-40 years; n = 289, aged ≥40 years) with hypokalaemia and elevation of aldosterone and unilateral disease on CT who had successful AVS. MAIN OUTCOME MEASURE: Accuracy of CT findings is determined by AVS findings and/or surgical outcomes in patients aged <35 years. RESULTS: Concordance of the diagnosis between CT and AVS was 90% (27/30) in patients aged <35 years, 79% (31/39) in patients aged 35-40 years and 69% (198/289) in those aged ≥40 years (trend for P < .01). Surgical benefit was confirmed in three patients aged <35 years and in three patients aged 35-40 years with the available surgical data who had discordance between CT and AVS findings. Collectively, the diagnostic accuracy of CT findings was 100% (30/30) if aged <35 years and 87% (34/39) if aged 35-40 years. CONCLUSION: Primary aldosteronism patients aged <35 years with hypokalaemia and elevation of aldosterone and unilateral disease on adrenal CT could be spared AVS.

New diagnostic criteria of adrenal subclinical Cushing's syndrome: opinion from the Japan Endocrine Society.

New diagnostic criteria and the treatment policy for adrenal subclinical Cushing's syndrome (SCS) are proposed on behalf of the Japan Endocrine Society. The Japanese version has been published, and the essential contents are presented in this English-language version. The current diagnostic criteria for SCS have elicited two main problems: (i) the relatively low reliability of a low range of serum cortisol essential for the diagnosis by an overnight 1-mg dexamethasone suppression test (DST); (ii) different cutoff values for serum cortisol after a 1-mg DST compared with those of other countries. Thus, new criteria are needed. In the new criteria, three hierarchical cortisol cutoff values, 5.0, 3.0 and 1.8 µg/dL, after a 1-mg DST are presented. Serum cortisol ≥5 µg/dL after a 1-mg DST alone is considered sufficient to judge autonomous cortisol secretion for the diagnosis of SCS, and the current criterion based on serum cortisol ≥3 µg/dL after a 1-mg DST can continue to be used. Clinical evidence suggests that serum cortisol ≥1.8-2.9 µg/dL after a 1-mg DST is not always normal, so cases who meet the cutoff value as well as a basal adrenocorticotropic hormone (ACTH) level <10 pg/mL (or poor ACTH response to corticotropin-releasing hormone (CRH)) and nocturnal serum cortisol ≥5 µg/dL are proposed to have SCS. We suggest surgery if cases show serum cortisol ≥5 µg/dL after a 1-mg DST (or are disheartened by treatment-resistant problems) or suspicious cases of adrenal cancer according to tumor imaging.

Reassessment of the cosyntropin stimulation test in the confirmatory diagnosis and subtype classification of primary aldosteronism.

OBJECTIVE: Although corticotropin is a representative secretagogue of aldosterone, the utility of the cosyntropin stimulation test (C-ST) in diagnosing primary aldosteronism (PA) has not been elucidated. Aim of the study was to evaluate the clinical utility of C-ST for confirmatory testing and subtype classification of PA. DESIGN, SETTING AND PATIENTS: In this retrospective study, we identified patients with hypertension and positive case-detection results for PA who underwent C-ST and saline infusion testing (SIT) between 2006 and 2013 at eight referral centres in Japan. PA and essential hypertension (EH) were distinguished based on SIT results. PA subtype classification was determined by adrenal venous sampling (AVS). Plasma aldosterone concentration (PAC) was measured before and 30 and 60 min after intravenous cosyntropin administration. The ability of C-ST to distinguish PA from EH and to distinguish unilateral from bilateral disease was assessed by the area under the receiver operating characteristic curve. RESULTS: Of 205 patients with hypertension and positive case-detection results, 139 (68%) had PA based on SIT results. Eighteen patients in whom AVS was unsuccessful were excluded from analysis. The baseline PAC before C-ST was significantly higher (P < 0·01) in patients with PA than in those with EH. However, the degree of difference in PAC between patients with PA and EH was not enhanced by the administration of cosyntropin. In addition, the administration of cosyntropin did not improve the distinction between bilateral and unilateral PA subtypes. CONCLUSIONS: C-ST has no utility as a confirmatory and subtype testing of PA when the diagnosis of PA is based on the positive results in SIT.

Bilateral aldosterone suppression and its resolution in adrenal vein sampling of patients with primary aldosteronism: analysis of data from the WAVES-J study.

CONTEXT: In adrenal vein sampling (AVS) for patients with primary aldosteronism, the contralateral ratio of aldosterone/cortisol (A/C) between the nondominant adrenal vein and the inferior vena cava is one of the best criteria for determining lateralized aldosterone secretion. Despite successful cannulation in some patients, the A/C ratios in the adrenal veins are bilaterally lower than that in the inferior vena cava (bilateral aldosterone suppression; BAS). OBJECTIVES: To investigate the prevalence of BAS in AVS and how to resolve this condition. DESIGN AND SETTING: Retrospective study involving nine referral centres. PATIENTS: Four hundred and ninety-one patients who were confirmed as having primary aldosteronism and had an AVS between January 2006 and December 2013. MEASUREMENTS: The prevalence of BAS before and after ACTH stimulation was compared. In addition, we investigated other methods for overcoming BAS. RESULTS: In 304 patients with successful AVS before ACTH stimulation, BAS was observed in 29 (9·5%). BAS was resolved after ACTH stimulation in 22 patients. In 276 patients with successful AVS both before and after ACTH stimulation, the frequency of BAS was significantly reduced after ACTH (8·7% vs 2·5%, P < 0·01). In a few patients, BAS was also resolved by adding a sampling point at the common trunk of the left adrenal vein and by an alternative drainage vein from the adrenal tumour. CONCLUSIONS: BAS sometimes occurs in AVS without ACTH stimulation. ACTH stimulation significantly reduces BAS with a single AVS procedure.

Optimum position of left adrenal vein sampling for subtype diagnosis in primary aldosteronism.

CONTEXT: Although adrenal vein sampling (AVS) is the standard method for subtype diagnosis in primary aldosteronism (PA), protocol details including the sampling position in the adrenal vein are not standardized. OBJECTIVE: To establish the optimum sampling position in the left adrenal vein based on postoperative outcome in PA patients. DESIGN AND SETTING: Retrospective study in nine referral centres. PARTICIPANTS: Of 496 consecutive PA patients who underwent AVS between 2006 and 2013, 217 with successful AVS under cosyntropin stimulation, and with concomitant data from two positions: proximal (common trunk) and distal (central vein) to the junction with the inferior phrenic vein, were included. MAIN OUTCOME MEASURES: Discordant rate of subtype diagnosis between common trunk and central vein, and postoperative outcomes in patients with discordant results. RESULTS: Subtype diagnosis using common trunk and central vein was discordant in 10 (4·6%) of the 217 patients (κ = 0·87, P < 0·05). Of these 10 patients, eight with left unilateral subtype and two with bilateral subtype using common trunk data showed bilateral subtype and unilateral subtype, respectively, using central vein data. Five patients with left unilateral subtype and one with bilateral subtype by common trunk data underwent unilateral adrenalectomy. All six patients were cured of PA after adrenalectomy, resulting in false-negative rates of 17% (1/6) by common trunk data, and 83% (5/6) by central vein data. CONCLUSION: In view of its better potential diagnostic accuracy, technical ease, lower cost and lower risk of vein rupture, blood sampling from the common trunk of the left adrenal vein may be preferable as the standard method of AVS in patients with PA, although additional studies in a larger number of cases are required.

Importance of contralateral aldosterone suppression during adrenal vein sampling in the subtype evaluation of primary aldosteronism.

OBJECTIVES: Adrenal vein sampling (AVS) is the standard criterion for the subtype diagnosis in primary aldosteronism (PA). Although lateralized index (LI) ≥4 after cosyntropin stimulation is the commonly recommended cut-off for unilateral aldosterone hypersecretion, many of the referral centres in the world use LI cut-off of <4 without sufficient evidence for its diagnostic accuracy. AIM: The aim of the study was to establish the diagnostic significance of contralateral (CL) aldosterone suppression for the subtype diagnosis in patients with LI <4 in AVS. DESIGN AND PATIENTS: A retrospective multicentre study was conducted in Japan. Of 124 PA patients subjected to unilateral adrenalectomy after successful AVS with cosyntropin administration, 29 patients with LI < 4 were included in the study. The patients were divided into Group A with CL suppression (n = 16) and Group B (n = 13) without CL suppression. Three outcome indices were assessed after 6 months postoperatively: normalization/significant improvement of hypertension, normalization of the aldosterone to renin ratio (ARR) and normalization of hypokalaemia. RESULTS: The normalization/significant improvement of hypertension was 81% in Group A and 54% in Group B (P = 0·2). The normalization of ARR was 100% in Group A and 46% in Group B (P = 0·004). Hypokalaemia was normalized in all patients of both groups. The overall cure rate of PA based on meeting all the three criteria was 81% in Group A and 31% in Group B (P = 0·01). CONCLUSIONS: In patients with PA, where the LI is <4 on AVS, CL suppression of aldosterone is an accurate predictor of a unilateral source of aldosterone excess. CL suppression data should be interpreted in conjunction with computed tomographic adrenal imaging findings to guide surgical management.

Assessing Lateralization Index of Adrenal Venous Sampling for Surgical Indication in Primary Aldosteronism.

BACKGROUND: Clinical practice guidelines recommend the Lateralization Index (LI) as the standard for determining surgical eligibility in primary aldosteronism (PA). Our goal was to identify the optimal LI cut-offs in adrenal venous sampling (AVS) for diagnosing PA that is amenable to surgical cure. METHODS: We conducted a retrospective international cohort study across 16 institutions in 11 countries, including 1,550 patients with PA who underwent AVS, with and/or without ACTH stimulation. The establishment of optimal cut-offs was informed by a survey of 82 PA patients in Japan, aimed at determining the LI cut-off aligned with patient expectations for a surgical cure rate. RESULTS: The survey revealed that a median cure rate expectation of 80% would motivate PA patients towards undergoing adrenalectomy. The optimal LI cut-offs achieving an adjusted positive predictive value (PPV) of 80% were identified as 3.8 for unstimulated AVS and 3.4 for ACTH-stimulated AVS. Furthermore, a contralateral ratio of less than 0.4 and the detection of an adrenal nodule on CT imaging were identified as independent predictors of surgically curable PA. Incorporating these factors with the optimal LI cut-offs, the adjusted PPV increased to 96.6% for unstimulated AVS and 89.6% for ACTH-stimulated AVS. No clear differences in predictive ability between unstimulated and ACTH-stimulated LI were found. CONCLUSIONS AND RELEVANCE: The present study clarified the optimal LI cut-offs for without and with ACTH stimulation. The presence of contralateral suppression and adrenal nodule on CT imaging seems to provide additional available information besides LI for surgical indication.

A Case of Acute-Onset Type 1 Diabetes Mellitus with Diabetic Ketoacidosis Triggered by COVID-19.

BACKGROUND It is well known that diabetes mellitus contributes to COVID-19 severity. Recently, there have been reports of an increase in the number of children with type 1 diabetes after the COVID-19 pandemic. CASE REPORT A 52-year-old woman presented to the Emergency Department with disturbance of consciousness, accompanied by a 1-day history of thirst, a fever of 38°C, and breathlessness. She had a positive coronavirus antigen test. Her initial vital signs assessment showed a heart rate of 120 beats per minute, blood pressure 90/50 mmHg, temperature 37.3°C, and respiratory rate 30 breaths/minute with an oxygen saturation of 100% with 10 L oxygen inhalation. Her initial laboratory test results showed a blood glucose level of 1507 mg/dl, HbA1c of 10.1%, ketone 2+, and blood gas pH 7.113. The patient was diagnosed with diabetic ketoacidosis (DKA). There were mild inflammatory findings with blood CRP 0.14 mg/dl and a white cell count of 12 400/µL, but no pneumonia on a chest CT scan. Therefore, the patient was diagnosed with COVID-19 and DKA. The patient was positive for anti-glutamic acid decarboxylase (anti-GAD antibody) and had markedly low levels 24-h urine C-peptide (CPR). She was diagnosed with acute-onset type 1 diabetes mellitus, as her blood examination showed a postprandial blood glucose level of 100 mg/dl and HbA1c of 5.7% 2 months before admission. After admission, fluid replacement and continuous intravenous insulin infusion therapy were started, and blood glucose and blood gas pH improved over 10 h. CONCLUSIONS There have been reports of cases of type 1 diabetes consequences of COVID-19, but the mechanism has not been elucidated.

A hyperaldosteronism subtypes predictive model using ensemble learning.

This study aimed to develop a machine-learning algorithm to diagnose aldosterone-producing adenoma (APA) for predicting APA probabilities. A retrospective cross-sectional analysis of the Japan Rare/Intractable Adrenal Diseases Study dataset was performed using the nationwide PA registry in Japan comprised of 41 centers. Patients treated between January 2006 and December 2019 were included. Forty-six features at screening and 13 features at confirmatory test were used for model development to calculate APA probability. Seven machine-learning programs were combined to develop the ensemble-learning model (ELM), which was externally validated. The strongest predictive factors for APA were serum potassium (s-K) at first visit, s-K after medication, plasma aldosterone concentration, aldosterone-to-renin ratio, and potassium supplementation dose. The average performance of the screening model had an AUC of 0.899; the confirmatory test model had an AUC of 0.913. In the external validation, the AUC was 0.964 in the screening model using an APA probability of 0.17. The clinical findings at screening predicted the diagnosis of APA with high accuracy. This novel algorithm can support the PA practice in primary care settings and prevent potentially curable APA patients from falling outside the PA diagnostic flowchart.

Sex Difference in the Association of Osteoporosis and Osteopenia Prevalence in Patients with Adrenal Adenoma and Different Degrees of Cortisol Excess.

Objective: Osteoporosis and osteopenia (OS/OP) are frequent in patients with adrenal adenomas associated with cortisol excess (CE). However, the relationship between OS/OP and CE severity considering sex differences is unknown. Design: A cross-sectional observational study from January 2006 to December 2015. Patients. 237 patients with adrenal adenoma associated with CE, including Cushing's syndrome and mild autonomous cortisol secretion (MACS), diagnosed in 10 referral centers in Japan. MACS was defined by 1 mg overnight dexamethasone suppression test (DST) cortisol level >1.8 µg/dL. Measurements. Prevalence of fragility fractures, medication for osteoporosis, and bone mineral density. Results: In total, 112 of 237 patients, who were predominantly female (P < 0.001) and had lower BMI (P=0.013), had OS/OP. Patients with OS/OP was significantly affected by CE (P < 0.01) than those without. The adjusted odds ratio (OR) for predicting OS/OP was obtained in multivariate logistic regression analysis. Clinical measures of CE, 1 mg DST cortisol levels, were positively associated with OS/OP in total cases (OR 1.124, 95% CI: 1.070-1.181, P < 0.001) and the cases with MACS (OR 1.156, 95%CI: 1.046-1.278, P=0.005). A cutoff value of 1 mg DST cortisol level >5.0 µg/dL was associated with OS/OP differently between men and women. OS/OP risk in men with MACS was significantly affected only by 1 mg DST cortisol levels. However, OS/OP risk in women with MACS was significantly affected by 1 mg DST cortisol levels and age. Conclusions: CE severity in adrenal adenoma is positively associated with OS/OP. However, the associated factors of OS/OP in the patients with MACS are different between men and women.

Machine learning-based models for predicting clinical outcomes after surgery in unilateral primary aldosteronism.

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.

Primary aldosteronism with mild autonomous cortisol secretion increases renal complication risk.

Objective: In primary aldosteronism (PA), renal impairment has been identified as an important comorbidity. Excess cortisol production also may lead to renal damage; thus, concomitant mild autonomous cortisol secretion (MACS) may predispose PA patients to renal disorders. However, there is limited evidence to support this claim. Therefore, this study aimed to determine whether the concurrence of MACS and PA increases the risk of renal complications. Design: This study is a retrospective cross-sectional study. Methods: A total of 1310 patients with PA were stratified into two groups according to 1 mg dexamethasone suppression test (DST) results (cut-off post-DST serum cortisol 1.8 µg/dL): MACS (n = 340) and non-MACS (n = 970). The prevalence of renal complications was compared between the group. We also performed multiple logistic regression analysis to determine factors that increase the risk for renal complications. Results: The prevalence of lowered estimated glomerular filtration rate (eGFR) and proteinuria was nearly twice higher in the MACS group than in the non-MACS group. Not only plasma aldosterone concentration (PAC) but also the presence of MACS was selected as independent factors that were associated with the two renal outcomes. The risk of lower eGFR or proteinuria in patients who had MACS and higher levels PAC was several folds higher than in those who had an absence of MACS and lower levels of PAC. Conclusions: MACS is an independent risk factor for renal complications in patients with PA, and MACS concomitant with higher aldosterone secretion in PA patients causes an increase in the risk of developing renal complications.