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.
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.
Phaeochromocytomas (PHEO) and paragangliomas are rare catecholamine-producing tumours. Although 10-30% of these tumours metastasise, histopathological criteria to discriminate malignant from benign ...tumours have not been established; therefore, reliable histopathological markers predicting metastasis are urgently required. A total of 163 tumours, including 40 metastatic tumours, collected by the Phaeochromocytoma Study Group in Japan (PHEO-J) were analysed using a system called grading system for adrenal phaeochromocytoma and paraganglioma (GAPP). The tumours were scored based on GAPP criteria as follows: histological pattern, cellularity, comedo-type necrosis, capsular/vascular invasion, Ki67 labelling index and catecholamine type. All tumours were scored from 0 to 10 points and were graded as one of the three types: well-differentiated (WD, 0-2 points), moderately differentiated (MD, 3-6 points) and poorly differentiated (PD, 7-10 points). GAPP scores of the non-metastatic and metastatic groups were 2.08±0.17 and 5.33±0.43 (mean±s.e.m., P<0.001) respectively. There was a significant negative correlation between the GAPP score and the interval until metastasis (r=-0.438, P<0.01). The mean number of years until metastasis after the initial operation was 5.5±2.6 years. The study included 111 WD, 35 MD and 17 PD types. The five-year survival of these groups was 100, 66.8 and 22.4% respectively. In addition, negative immunoreactivity for succinate dehydrogenase gene subunit B (SDHB) was observed in 13 (8%) MD or PD tumours and ten of the 13 (77%) had metastases. Our data indicate that a combination of GAPP classification and SDHB immunohistochemistry might be useful for the prediction of metastasis in these tumours.
To assess the efficacy, safety, and pharmacokinetics of metyrosine (an inhibitor of catecholamine synthesis) in patients with pheochromocytoma/paraganglioma (PPGL), we conducted a prospective, ...multi-center, open-label study at 11 sites in Japan. We recruited PPGL patients aged ≥12 years requiring preoperative or chronic treatment, receiving α-blocker treatment, having baseline urinary metanephrine (uMN) or normetanephrine (uNMN) levels ≥3 times the upper limit of normal values, and having symptoms associated with excess catecholamine. Metyrosine treatment was started at 500 mg/day and modified according to dose-adjustment criteria up to 4,000 mg/day. The main outcome measure was the proportion of patients who achieved at least 50% reduction in uMN or uNMN levels from baseline. Sixteen patients (11 males/5 females) aged 12–86 years participated. After 12 weeks of treatment and at the last evaluation of efficacy, the primary endpoint was achieved in 31.3% of all patients, including 66.7% of those under preoperative treatment and 23.1% of those under chronic treatment. Sedation, anemia, and death were reported in 1 patient each as serious adverse drug reactions during the 24-week treatment. Metyrosine was shown to be tolerated and to relieve symptoms by reducing excess catecholamine in PPGL patients under both preoperative and chronic treatment.
A 79-year-old woman with type 2 diabetes receiving insulin was rushed to our hospital due to severe hypoglycemia. Glucose was administered, and the consciousness disturbance was promptly improved. A ...few hours later, conjugate deviation of the eyes to the right and left hemiplegia occurred at a normal glucose level. Cerebral magnetic resonance imaging (MRI) showed hyperintensities of the right posterior limb of the internal capsule and the medial thalamus on diffusion-weighted imaging sequences. However, the changes observed using MRI disappeared completely on the third day, and her symptoms subsequently improved. This may have been a case of glucose reperfusion injury.
Although adrenalectomy (ADX) is an established treatment for unilateral primary aldosteronism (uPA), the influence of age on the surgical outcomes is poorly understood. Therefore, we aimed to ...elucidate how age affects the clinical outcomes after treatments. We analyzed 153 older (≥ 65 years) and 702 younger patients (< 65 years) with uPA, treated either with ADX or mineralocorticoid receptor antagonist (MRA) in the Japan PA Study, and compared the estimated glomerular filtration rate (eGFR) or blood pressure over a 36-month period after treatments. ADX-treated patients showed severer biochemical indicators than MRA-treated patients. During 6 and 36 months, the eGFR decreased more prominently in older but not in younger patients with ADX than in those with MRA, which remained significant after adjustment with the inverse probability of treatment weighting (IPTW). There was a significant interaction between the age-groups and the treatment choices in the change of the eGFR with IPTW-adjusted analysis. The post-treatment dose of antihypertensive medication was lower in younger and higher in older patients with ADX than those with MRA. The clinical benefit of ADX differed between younger and older patients with uPA. These findings indicate the need for further validation on whether ADX can benefit older patients with uPA.
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.
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.
Context:
Although primary aldosteronism (PA) is the most common cause of endocrine hypertension, histopathological methods to reveal the presence and sites of aldosterone overproduction remain to be ...established.
Objective:
The objective of the study was to investigate the significance of immunohistochemical staining to detect CYP11B2 and CYP11B1 in adrenal tissue of patients with PA.
Design and Patients:
Thirty-two patients with PA who underwent unilateral adrenalectomy were studied. Immunohistochemical staining was performed using anti-CYP11B2 and anti-CYP11B1 antibodies on paraffin-embedded sections. We analyzed the expression of each enzyme semiquantitatively by scoring staining intensity and correlating it with clinical findings.
Results:
Twenty-two patients showed positive CYP11B2 immunostaining in their tumors (aldosterone producing adenoma, APA). Four patients with CYP11B2-negative unilateral adenomas and 4 patients without tumors on computed tomography showed aldosterone-producing cell clusters (APCCs) with CYP11B2 immunostaining in the zona glomerulosa (multiple APCCs). The remaining 2 patients had unilateral multiple adrenocortical micronodules and diffuse adrenocortical hyperplasia, respectively. In APA, CYP11B2 score adjusted for tumor volume was positively correlated with plasma aldosterone and negatively correlated with serum potassium. The APA group was divided into 3 subgroups based on relative CYP11B2 and CYP11B1 immunostaining levels. The CYP11B2/CYP11B1-equivalent and CYP11B1-dominant APA groups showed significantly higher serum cortisol after 1 mg dexamethasone and larger tumor size than the CYP11B2-dominant APA group.
Conclusions:
The present study clearly demonstrates that CYP11B2 immunostaining is a powerful tool for histopathological diagnosis of aldosterone overproduction in PA and for subtype classification of APA, multiple APCCs, unilateral multiple adrenocortical micronodules, and diffuse hyperplasia.
ABSTRACT
Aims/Introduction
Diabetes is associated with poor clinical outcomes of coronavirus disease 2019 (COVID‐19). However, the impact of newly diagnosed diabetes on prognosis has not been ...clarified. The objective of this study was to show the features and outcome of COVID‐19 patients with newly diagnosed diabetes in Japan.
Materials and Methods
We retrospectively analyzed 62 patients with diabetes hospitalized for COVID‐19 between 1 April and 18 August 2021 at the National Center for Global Health and Medicine in Tokyo, Japan. We evaluated the worst severity of COVID‐19 and plasma blood glucose levels in patients with newly diagnosed diabetes or pre‐existing diabetes.
Results
This study included 62 confirmed COVID‐19 patients with diabetes, including 19 (30.6%) patients with newly diagnosed diabetes and 43 (69.4%) patients with pre‐existing diabetes. Patients with newly diagnosed diabetes significantly progressed to a critical condition more frequently during hospitalization than patients with pre‐existing diabetes (52.6% vs 20.9%, P = 0.018). In addition, patients with newly diagnosed diabetes had significantly higher average plasma blood glucose levels for the first 3 days after admission than those with pre‐existing diabetes.
Conclusions
Our study suggests that the proportion of COVID‐19 patients who are newly diagnosed with diabetes is high, and they have an increased risk of developing severe disease than those with pre‐existing diabetes. It might be advisable that at the point of COVID‐19 diagnosis, blood glucose and glycated hemoglobin levels be assessed in all patients.
We retrospectively analyzed 62 patients with diabetes hospitalized for coronavirus disease 2019 at the National Center for Global Health and Medicine in Japan. Our study showed that patients with newly diagnosed diabetes had a higher severity of coronavirus disease 2019 and had difficulty in managing glycemic control compared with patients with pre‐existing diabetes.
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