The Japan Endocrine Society (JES) attempted to develop guidelines for the diagnosis and treatment of primary aldosteronism (PA). The Task Force Committee (TFC) was composed of a chair, selected by the JES, and additional experts. Systematic reviews of available evidence for Japanese patients were used to recommend the key treatment and prevention. We have evaluated the methods of screening, confirmatory tests and imaging, plus adrenal vein sampling (AVS). Consensus was guided by systematic review of evidence and discussion during each annual meeting of the JES, plus its related meetings, and by e-mail communication. The drafts prepared by TFC were reviewed successively by the members of Research on Intractable Diseases provided by the Japanese Ministry of Health, Labour and Welfare, and in comments from the JES’s councilors. At each stage of review, TFC received written comments and incorporated suggested changes. In conclusion, all patients with hypertension should be screened for PA, because of the high prevalence of cardiovascular disease and the current low case-detection rate in Japan. Case detection can be performed in hypertensive patients and those with hypokalemia by determining the aldosterone/renin ratio, and the diagnosis of PA can be confirmed by two of three confirmatory tests. The presence of a unilateral aldosterone-producing adenoma should be established/excluded by AVS by an experienced radiologist, optimally followed by laparoscopic adrenalectomy. In contrast, patients with bilateral adrenal hyperplasia, or those unsuitable for surgery, are optimally treated medically with mineralocorticoid receptor antagonists.

Objective: To investigate the effect of KCNJ5 mutations on the cure of hypertension in patients with aldosterone-producing adenoma (APA) after unilateral adrenalectomy. Methods: Our study included 142 patients with APA, who were detected with an endocrinological abnormality and diagnosed with hypertension, as confirmed by pathological analysis. We sequenced KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 from APA tissue samples, and performed a retrospective analysis to determine correlations between wild-type or mutated KCNJ5 and patient clinical characteristics. Results: Somatic KCNJ5 mutations were identified in 106 of 142 patients with APA, 136 of whom had resolution of hyporeninemic-hyperaldosteronemia 1 year after surgery. Of the 136 patients, 81 patients had resolution of hypertension (’Cured group’ vs. ‘Improved group’). We found increased prevalence of KCNJ5 mutations in the Cured group compared to the Improved group (85.2% vs. 60.0%, respectively; P = 0.002), which was associated with younger age, shorter duration of hypertension, fewer antihypertensive medications, lower BMI, higher aldosterone level, higher estimated glomerular filtration rate, and milder vascular complications. In both groups we found that harbouring a KCNJ5 mutation, taking fewer antihypertensive medications, and the duration of hypertension were independently associated with resolution of hypertension by unilateral adrenalectomy. In patients with KCNJ5-mutated APA, left ventricular hypertrophy was significantly decreased by surgical treatment in patients from either Cured or Improved groups, although those patients with wild-type KCNJ5 showed no change. Conclusions: Testing for KCNJ5 mutations in young patients with APA may provide a prognostic indication for resolution of hypertension and severity of vascular complications.

Segmental selective adrenal venous sampling (sAVS) elucidates an intraadrenal aldosterone activity map (IAMap), which allows us to design a novel surgical treatment strategy for patients with primary aldosteronism. We evaluated the usefulness of sAVS by analyzing 278 patients with whom we had prospectively used IAMap using the criteria of sAVS for surgical indication between 2009 and 2015. We evaluated its diagnostic accuracy using pathological and postsurgical biochemical and clinical outcomes. One hundred twenty and 158 patients were diagnosed with unilateral and bilateral disease, respectively, through sAVS. The concordance of lateralization diagnosis with computed tomography imaging was 66.6%. Among the unilateral patients, we performed partial adrenalectomy in 68 patients whose IAMap showed focal aldosterone hypersecretion from computed tomography-detectable tumor in the affected adrenal gland. All of them achieved complete biochemical success 1 year after surgery. Furthermore, 25 of 158 bilateral disease patients underwent surgical resection because they were preoperatively diagnosed as bilateral aldosterone-producing adenomas by IAMap. These cases showed complete or partial biochemical success (28.0% and 72.0%, respectively); 36.0% showed complete clinical success. Pathological studies demonstrated that all 145 resected specimens possessed aldosterone-producing adenoma or multiple nodules (132 and 13 cases, respectively), and none showed diffuse hyperplasia. IAMap accurately diagnosed both bilateral and unilateral aldosterone-producing adenomas and diffuse hyperplasia before surgery. sAVS allows a novel surgical strategy for selected PA patients with favorable outcomes.

We attempted to study the standardization of aldosterone measurement in blood. The serum certified reference material (serum CRM) was established by spiking healthy human serum with pure aldosterone. ID-LC/MS/MS as a reference measurement procedure was performed by using the serum CRM. LC-MS/MS as a comparison method (CM) was routinely used for clinical samples, and the values with and without calibration by the serum CRM were compared. The serum CRM demonstrated similar reactivity with peripheral blood plasma as clinical samples in routine methods (RM) of RIA, ELISA, and CLEIA. In comparison between RM and CM, the results in regression analysis indicated that the range of the correlation coefficient (r) was 0.913 - 0.991, the range of y intercept was 0.9 - 67.3 pg/mL and the range of slope was 0.869 - 1.174. The values by RM in 100 - 150 pg/mL for the diagnostic level, had a significant calibration effect, and the relative difference between calibrated value in RM and result by CM was within ±20%. Furthermore, the calibrated value using the serum CRM was 10,187 pg/mL, which corresponds to measured value of 14,000 pg/mL using RIA for the adrenal venous sampling. Measured values between plasma and serum as a sample for the aldosterone measurement from clinical samples showed no significant differences. In conclusion, we succeeded to prepare the certified reference material of aldosterone for RM. Then, we can accurately calculate corrected values by using our equation for four RMs of determination of aldosterone.

Primary aldosteronism (PA) and subclinical Cushing's syndrome (SCS) are conditions in which the adrenal glands autonomously produce excessive amounts of aldosterone and cortisol, respectively. The conventional adrenal venous sampling (cAVS) method collects blood samples from both adrenal central veins and is useful for identifying the laterality of excess hormone production in a unilateral lesion(s), as documented in PA cases. In cAVS, plasma cortisol concentrations (PCCs) are used to normalize plasma aldosterone concentrations (PACs). A novel "super-selective" adrenal venous sampling (ssAVS) method was developed using a micro-catheter, which collects blood samples from adrenal tributary veins (TVs). PACs in ssAVS samples do not require PCC normalization because samples contain a limited amount of systemic venous blood, if any. The ssAVS method enabled segmental lesion(s) to be detected in both adrenal glands, which may be treated by bilateral adrenalectomy, thereby sparing lesion-free segment(s). Right and left adrenals typically have three TVs each, i.e., the superior, lateral, and inferior TVs in the right adrenal as well as the superior-median, superior-lateral, and lateral TVs in the left adrenal. In the ssAVS method, specific parent catheters and a technique to handle them are required, and have been described herein. Furthermore, ssAVS results from three cases of PA are presented: bilateral aldosterone-producing adenoma (APA) (Case #1), left APA and right possible cortisol-producing adenoma causing SCS (Case #2), and idiopathic hyperaldosteronism in which bilateral adrenal segments produced excessive amounts of aldosterone (Case #3). The ssAVS method is not difficult for expert angiographers, and, thus, is recommended worldwide to treat PA cases for which cAVS does not represent a viable surgical treatment option.