今日の臨床サポート

原発性アルドステロン症

著者: 吉本貴宣 東京都立広尾病院 糖尿病内分泌科

監修: 平田結喜緒 公益財団法人 兵庫県予防医学協会 健康ライフプラザ

著者校正/監修レビュー済:2021/02/10
参考ガイドライン:
  1. 日本内分泌学会日本内分泌外科学会:わが国の原発性アルドステロン症の診療に関するコンセンサス・ステートメント
  1. 日本高血圧学会高血圧治療ガイドライン作成委員会編:高血圧治療ガイドライン2019
患者向け説明資料

概要・推奨   

  1. 国内外多施設からの報告より原発性アルドステロン症PAの罹患率は高血圧の約10%であり、高血圧ではPAの鑑別を考慮して診療にあたるべきである(推奨度1)
  1. PAは年齢、性別、罹病期間、血圧レベルが同程度の本態性高血圧と比較して、脳卒中、心筋梗塞、心肥大、不整脈、腎障害を高率に合併することから、早期に診断し治療することが重要である(推奨度1)
  1. ①中等症以上の高血圧(JSH2019でII度以上)、②治療抵抗性高血圧、③低カリウム血症を伴う高血圧(利尿薬誘発性も含む)、④高血圧を伴う副腎偶発腫瘍、⑤40歳以下の脳血管障害既往例、⑥若年者の高血圧、⑦睡眠時無呼吸を伴う高血圧、はPA罹患のハイリスク群である(推奨度2)
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  1. 閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要となります。閲覧にはご契約が必要
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
吉本貴宣 : 特に申告事項無し[2021年]
監修:平田結喜緒 : 特に申告事項無し[2021年]

改訂のポイント:
  1. 定期レビューを行い、エサキセレノンについて一部加筆、修正を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 原発性アルドステロン症(PA)の診断は、高血圧において副腎からのアルドステロンの自律的過剰産生を確認することである。
  1. PAは、高血圧の約5~10%と高頻度で、同程度の 本態性高血圧症 と比べ心血管合併症が高頻度であり、早期診断・治療が重要である。
  1. PAスクリーニングには、血漿アルドステロン濃度(PAC:pg/mL)/血漿レニン活性(PRA)比>200かつ一定値以上のPAC(> 120 pg/mL)でPAを疑う。採血条件、内服中の降圧薬の影響について留意する。 低カリウム血症 の合併のない例も多い。
  1. PAスクリーニング陽性例に対し、少なくとも1種類以上の機能確認検査陽性で診断を確定する。
  1. 引き続き、副腎からのアルドステロン過剰産生部位が片側性か両側性かをCTおよび選択的副腎静脈サンプリング(AVS)にて診断し、治療方針(手術治療 or 薬物治療)を決定する。
  1. 原発性アルドステロン症診断のアルゴリズム:アルゴリズム
 
PAにおける副腎CT画像

副腎造影CT画像を示す。
(a)片側PAの一例:右副腎に径15mmの腺腫病変を認める。AVSで同側のアルドステロン過剰産生が証明され、片側APAと診断。
(b)両側性PAの一例:左右の副腎は形態上正常である。AVSで両側のアルドステロン過剰産生が証明された(CT、AVSの情報からは両側過形成病変か両側性の微小APAかは診断できない点に留意)。

出典

img1:  著者提供
 
 
 
  1. PAは年齢、性別、罹病期間、血圧レベルが同程度の本態性高血圧と比較して、脳卒中、心筋梗塞、心肥大、不整脈、腎障害を高率に合併することから、早期に診断し治療することが重要である(推奨度1)
  1. 研究背景:国内外に多数の観察研究結果が示されている[1][2]
  1. 研究事例: わが国のPAレジストリ(2,582例)研究でも、PAでは年齢、性別、血圧をマッチさせた本態性高血圧に比べ複合心血管イベント、脳卒中、蛋白尿の発現が多いことが示されており[2]同様の結果は多施設より報告されている。
  1. 結論:PAでは同程度の本態性高血圧と比べて、高率に心血管合併症を発症することから、早期発見・治療することが重要である。
  1. 追記:PAで心血管合併症が多い原因として、アルドステロンによる直接的な心血管障害作用が基礎研究レベルで報告されている[3]
病歴・診察のポイント  
  1. PAスクリーニングの対象者を選別する。

これより先の閲覧には個人契約のトライアルまたはお申込みが必要です。

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文献 

著者: Silvia Monticone, Fabrizio D'Ascenzo, Claudio Moretti, Tracy Ann Williams, Franco Veglio, Fiorenzo Gaita, Paolo Mulatero
雑誌名: Lancet Diabetes Endocrinol. 2018 Jan;6(1):41-50. doi: 10.1016/S2213-8587(17)30319-4. Epub 2017 Nov 9.
Abstract/Text BACKGROUND: There is conflicting evidence, relying on heterogeneous studies, as to whether aldosterone excess is responsible for an increased risk of cardiovascular and cerebrovascular complications in patients with primary aldosteronism. We aimed to assess the association between primary aldosteronism and adverse cardiac and cerebrovascular events, target organ damage, diabetes, and metabolic syndrome, compared with the association of essential hypertension and these cardiovascular and end organ events, by integrating results of previous studies.
METHODS: We did a meta-analysis of prospective and retrospective observational studies that compared patients with primary aldosteronism and essential hypertension, to analyse the association between primary aldosteronism and stroke, coronary artery disease (as co-primary endpoints), atrial fibrillation and heart failure, target organ damage, metabolic syndrome, and diabetes (as secondary endpoints). We searched MEDLINE and Cochrane Library for articles published up to Feb 28, 2017, with no start date restriction. Eligible studies compared patients with primary aldosteronism with patients with essential hypertension (as a control group) and reported on the clinical events or endpoints of interest. We also compared primary aldosteronism subtypes, aldosterone-producing adenoma, and bilateral adrenal hyperplasia.
FINDINGS: We identified 31 studies including 3838 patients with primary aldosteronism and 9284 patients with essential hypertension. After a median of 8·8 years (IQR 6·2-10·7) from the diagnosis of hypertension, compared with patients with essential hypertension, patients with primary aldosteronism had an increased risk of stroke (odds ratio [OR] 2·58, 95% CI 1·93-3·45), coronary artery disease (1·77, 1·10-2·83), atrial fibrillation (3·52, 2·06-5·99), and heart failure (2·05, 1·11-3·78). These results were consistent for patients with aldosterone-producing adenoma and bilateral adrenal hyperplasia, with no difference between these subgroups. Similarly, primary aldosteronism increased the risk of diabetes (OR 1·33, 95% CI 1·01-1·74), metabolic syndrome (1·53, 1·22-1·91), and left ventricular hypertrophy (2·29, 1·65-3·17).
INTERPRETATION: Diagnosing primary aldosteronism in the early stages of disease, with early initiation of specific treatment, is important because affected patients display an increased cardiovascular risk compared with patients with essential hypertension.
FUNDING: None.

Copyright © 2018 Elsevier Ltd. All rights reserved.
PMID 29129575  Lancet Diabetes Endocrinol. 2018 Jan;6(1):41-50. doi: 1・・・
著者: Youichi Ohno, Masakatsu Sone, Nobuya Inagaki, Toshinari Yamasaki, Osamu Ogawa, Yoshiyu Takeda, Isao Kurihara, Hiroshi Itoh, Hironobu Umakoshi, Mika Tsuiki, Takamasa Ichijo, Takuyuki Katabami, Yasushi Tanaka, Norio Wada, Yui Shibayama, Takanobu Yoshimoto, Yoshihiro Ogawa, Junji Kawashima, Katsutoshi Takahashi, Megumi Fujita, Minemori Watanabe, Yuichi Matsuda, Hiroki Kobayashi, Hirotaka Shibata, Kohei Kamemura, Michio Otsuki, Yuichi Fujii, Koichi Yamamoto, Atsushi Ogo, Shintaro Okamura, Shozo Miyauchi, Tomikazu Fukuoka, Shoichiro Izawa, Takashi Yoneda, Shigeatsu Hashimoto, Toshihiko Yanase, Tomoko Suzuki, Takashi Kawamura, Yasuharu Tabara, Fumihiko Matsuda, Mitsuhide Naruse, Nagahama Study, JPAS Study Group
雑誌名: Hypertension. 2018 Mar;71(3):530-537. doi: 10.1161/HYPERTENSIONAHA.117.10263. Epub 2018 Jan 22.
Abstract/Text There have been several clinical studies examining the factors associated with cardiovascular disease (CVD) in patients with primary aldosteronism (PA); however, their results have left it unclear whether CVD is affected by the plasma aldosterone concentration or hypokalemia. We assessed the PA database established by the multicenter JPAS (Japan Primary Aldosteronism Study) and compared the prevalence of CVD among patients with PA with that among age-, sex-, and blood pressure-matched essential hypertension patients and participants with hypertension in a general population cohort. We also performed binary logistic regression analysis to determine which parameters significantly increased the odds ratio for CVD. Of the 2582 patients with PA studied, the prevalence of CVD, including stroke (cerebral infarction, cerebral hemorrhage, or subarachnoid hemorrhage), ischemic heart disease (myocardial infarction or angina pectoris), and heart failure, was 9.4% (stroke, 7.4%; ischemic heart disease, 2.1%; and heart failure, 0.6%). The prevalence of CVD, especially stroke, was higher among the patients with PA than those with essential hypertension/hypertension. Hypokalemia (K+ ≤3.5 mEq/L) and the unilateral subtype significantly increased adjusted odds ratios for CVD. Although aldosterone levels were not linearly related to the adjusted odds ratio for CVD, patients with plasma aldosterone concentrations ≥125 pg/mL had significantly higher adjusted odds ratios for CVD than those with plasma aldosterone concentrations <125 pg/mL. Thus, patients with PA seem to be at a higher risk of developing CVD than patients with essential hypertension. Moreover, patients with PA presenting with hypokalemia, the unilateral subtype, or plasma aldosterone concentration ≥125 pg/mL are at a greater risk of CVD and have a greater need for PA-specific treatments than others.

© 2018 American Heart Association, Inc.
PMID 29358460  Hypertension. 2018 Mar;71(3):530-537. doi: 10.1161/HYPE・・・
著者: Gian Paolo Rossi, Anna Belfiore, Giampaolo Bernini, Giovambattista Desideri, Bruno Fabris, Claudio Ferri, Gilberta Giacchetti, Claudio Letizia, Mauro Maccario, Francesca Mallamaci, Massimo Mannelli, Gaetana Palumbo, Damiano Rizzoni, Ermanno Rossi, Enrico Agabiti-Rosei, Achille C Pessina, Franco Mantero, Primary Aldosteronism Prevalence in Italy Study Investigators
雑誌名: Hypertension. 2007 Aug;50(2):424-31. doi: 10.1161/HYPERTENSIONAHA.107.091827. Epub 2007 Jun 25.
Abstract/Text We performed a prospective head-to-head comparison of the accuracy of the captopril test (CAPT) and the saline infusion test (SAL) for confirming primary aldosteronism due to an aldosterone-producing adenoma (APA) in patients with different sodium intake. A total of 317 (26.9%) of the 1125 patients screened in the Primary Aldosteronism Prevalence in Italy Study underwent both CAPT and SAL. They were composed of the patients with a high aldosterone/renin ratio baseline and 1 every 4 patients without such criterion. The accuracy of post-CAPT or post-SAL plasma aldosterone values for diagnosing APA was estimated with the area under the receiver operator characteristics curves. Primary aldosteronism was found in 120 patients, of which 46 had an APA. No untoward effect occurred with either test. The area under the receiver operator characteristics curve of plasma aldosterone for both tests was higher (P<0.0001) than that under the diagonal, but the between-test difference was borderline significant (P=0.054). The optimal aldosterone cutoff value for identifying APA was 13.9 and 6.75 ng/dL for the CAPT and SAL, respectively. Even at these cutoffs, sensitivity and specificity were moderate because of overlap of values between patients with and without APA. When examined in relation to sodium intake, the accuracy of the SAL surpassed that of the CAPT in the patients with a sodium intake 7.6 g per day, the SAL offers no advantage over the easier-to-perform CAPT.

PMID 17592070  Hypertension. 2007 Aug;50(2):424-31. doi: 10.1161/HYPER・・・
著者: T Nishikawa, M Omura
雑誌名: Biomed Pharmacother. 2000 Jun;54 Suppl 1:83s-85s.
Abstract/Text We studied 1,020 patients with hypertension visiting our outpatient clinic during a five-year period, from 1995 until 1999. Those subjects were screened by determining plasma renin activity (PRA) and plasma aldosterone concentration (PAC) after testing routine laboratory examinations in order to differentiate secondary hypertension from essential hypertension. All patients with low-reninemic hypertension were examined by furosemide plus the upright test. This led to an increase in diagnoses of primary aldosteronism (PA) (confirmed by captopril-loading test). Our studies demonstrated that the incidence of PA is 5.4%, and also that the plasma potassium level is not always beneficial for suspecting the presence of PA, because 28% of the patients with PA show only hypokalemia. We would like to emphasize that adrenal venous sampling plays a critical role in establishing the optimal management for patients with PA, because CT imaging is limited to detection of adrenal masses.

PMID 10914999  Biomed Pharmacother. 2000 Jun;54 Suppl 1:83s-85s.
著者: John W Funder, Robert M Carey, Franco Mantero, M Hassan Murad, Martin Reincke, Hirotaka Shibata, Michael Stowasser, William F Young
雑誌名: J Clin Endocrinol Metab. 2016 May;101(5):1889-916. doi: 10.1210/jc.2015-4061. Epub 2016 Mar 2.
Abstract/Text OBJECTIVE: To develop clinical practice guidelines for the management of patients with primary aldosteronism.
PARTICIPANTS: The Task Force included a chair, selected by the Clinical Guidelines Subcommittee of the Endocrine Society, six additional experts, a methodologist, and a medical writer. The guideline was cosponsored by American Heart Association, American Association of Endocrine Surgeons, European Society of Endocrinology, European Society of Hypertension, International Association of Endocrine Surgeons, International Society of Endocrinology, International Society of Hypertension, Japan Endocrine Society, and The Japanese Society of Hypertension. The Task Force received no corporate funding or remuneration.
EVIDENCE: We searched for systematic reviews and primary studies to formulate the key treatment and prevention recommendations. We used the Grading of Recommendations, Assessment, Development, and Evaluation group criteria to describe both the quality of evidence and the strength of recommendations. We used "recommend" for strong recommendations and "suggest" for weak recommendations.
CONSENSUS PROCESS: We achieved consensus by collecting the best available evidence and conducting one group meeting, several conference calls, and multiple e-mail communications. With the help of a medical writer, the Endocrine Society's Clinical Guidelines Subcommittee, Clinical Affairs Core Committee, and Council successfully reviewed the drafts prepared by the Task Force. We placed the version approved by the Clinical Guidelines Subcommittee and Clinical Affairs Core Committee on the Endocrine Society's website for comments by members. At each stage of review, the Task Force received written comments and incorporated necessary changes.
CONCLUSIONS: For high-risk groups of hypertensive patients and those with hypokalemia, we recommend case detection of primary aldosteronism by determining the aldosterone-renin ratio under standard conditions and recommend that a commonly used confirmatory test should confirm/exclude the condition. We recommend that all patients with primary aldosteronism undergo adrenal computed tomography as the initial study in subtype testing and to exclude adrenocortical carcinoma. We recommend that an experienced radiologist should establish/exclude unilateral primary aldosteronism using bilateral adrenal venous sampling, and if confirmed, this should optimally be treated by laparoscopic adrenalectomy. We recommend that patients with bilateral adrenal hyperplasia or those unsuitable for surgery should be treated primarily with a mineralocorticoid receptor antagonist.

PMID 26934393  J Clin Endocrinol Metab. 2016 May;101(5):1889-916. doi:・・・
著者: William F Young, Anthony W Stanson, Geoffrey B Thompson, Clive S Grant, David R Farley, Jon A van Heerden
雑誌名: Surgery. 2004 Dec;136(6):1227-35. doi: 10.1016/j.surg.2004.06.051.
Abstract/Text BACKGROUND: The aim of this study was to determine the effect of adrenal venous sampling (AVS) on the management of patients with primary aldosteronism.
METHODS: From September 1990 through October 2003, 203 patients with primary aldosteronism (mean age, 53 years; range, 17-80; 163 men) were selected prospectively for AVS on the basis of degree of aldosterone excess, age, desire for surgical treatment, and computed tomographic (CT) findings.
RESULTS: Both adrenal veins were catheterized in 194 patients (95.6%). Notable among the 110 patients (56.7%) with unilateral aldosterone hypersecretion were 24 (41.4%) of 58 patients with normal adrenal CT findings, 24 (51.1%) of 47 with unilateral micronodule (< or =10 mm) apparent on CT (7 had unilateral aldosterone hypersecretion from the contralateral adrenal), 21 (65.6%) of 32 with unilateral macronodule (>10 mm) apparent on CT (1 had unilateral aldosterone hypersecretion from the contralateral adrenal), 16 (48.5%) of 33 with bilateral micronodules, and 2 (33%) of 6 with bilateral macronodules.
CONCLUSIONS: On the basis of CT findings alone, 42 patients (21.7%) would have been incorrectly excluded as candidates for adrenalectomy, and 48 (24.7%) might have had unnecessary or inappropriate adrenalectomy. AVS is an essential diagnostic step in most patients to distinguish between unilateral and bilateral adrenal aldosterone hypersecretion.

PMID 15657580  Surgery. 2004 Dec;136(6):1227-35. doi: 10.1016/j.surg.2・・・
著者: Fiemu E Nwariaku, Barbra S Miller, Richard Auchus, Shelby Holt, Lori Watumull, Bart Dolmatch, Shawna Nesbitt, Wanpen Vongpatanasin, Ronald Victor, Frank Wians, Edward Livingston, William H Snyder
雑誌名: Arch Surg. 2006 May;141(5):497-502; discussion 502-3. doi: 10.1001/archsurg.141.5.497.
Abstract/Text HYPOTHESIS: Adrenal vein sampling is superior to computed tomography for subtype differentiation of primary hyperaldosteronism.
DESIGN: Retrospective review.
SETTING: University medical center.
PATIENTS: Forty-eight patients (32 men and 16 women) with biochemically confirmed primary hyperaldosteronism.
MAIN OUTCOME MEASURES: We compared demographic factors, results of biochemical and imaging studies (computed tomography and adrenal vein sampling), therapy, and patient outcomes.
RESULTS: Mean +/- SEM adrenal nodule size was 1.54 +/- 0.2 cm. Adrenal vein sampling was performed in 41 (85%) of 48 patients, and it was successful in 39 (95%) of those 41 patients. Concordance between computed tomography and adrenal vein sampling was observed in 22 (54%) of the 41 patients. Thirty-two patients underwent successful laparoscopic adrenalectomy. There was 1 complication and no deaths. All 32 patients were cured of hypokalemia.
CONCLUSION: Adrenal vein sampling is superior to image-based techniques for subtype differentiation of primary hyperaldosteronism.

PMID 16702522  Arch Surg. 2006 May;141(5):497-502; discussion 502-3. d・・・
著者: W F Young, G G Klee
雑誌名: Endocrinol Metab Clin North Am. 1988 Jun;17(2):367-95.
Abstract/Text The regulation of mineralocorticoid secretion and the pathophysiology of primary aldosteronism are reviewed. For conceptual and practical purposes, the diagnostic evaluation of primary aldosteronism is discussed as two series of studies. The first series involves the studies necessary to confirm the diagnosis. The second series of studies guides the therapeutic approach by distinguishing unilateral from bilateral adrenal disease.

PMID 3042391  Endocrinol Metab Clin North Am. 1988 Jun;17(2):367-95.
著者: Gian Paolo Rossi, Marlena Barisa, Bruno Allolio, Richard J Auchus, Laurence Amar, Debbie Cohen, Christoph Degenhart, Jaap Deinum, Evelyn Fischer, Richard Gordon, Ralph Kickuth, Gregory Kline, Andre Lacroix, Steven Magill, Diego Miotto, Mitsuhide Naruse, Tetsuo Nishikawa, Masao Omura, Eduardo Pimenta, Pierre-François Plouin, Marcus Quinkler, Martin Reincke, Ermanno Rossi, Lars Christian Rump, Fumitoshi Satoh, Leo Schultze Kool, Teresa Maria Seccia, Michael Stowasser, Akiyo Tanabe, Scott Trerotola, Oliver Vonend, Jiri Widimsky, Kwan-Dun Wu, Vin-Cent Wu, Achille Cesare Pessina
雑誌名: J Clin Endocrinol Metab. 2012 May;97(5):1606-14. doi: 10.1210/jc.2011-2830. Epub 2012 Mar 7.
Abstract/Text CONTEXT: In patients who seek surgical cure of primary aldosteronism (PA), The Endocrine Society Guidelines recommend the use of adrenal vein sampling (AVS), which is invasive, technically challenging, difficult to interpret, and commonly held to be risky.
OBJECTIVE: The aim of this study was to determine the complication rate of AVS and the ways in which it is performed and interpreted at major referral centers.
DESIGN AND SETTINGS: The Adrenal Vein Sampling International Study is an observational, retrospective, multicenter study conducted at major referral centers for endocrine hypertension worldwide.
PARTICIPANTS: Eligible centers were identified from those that had published on PA and/or AVS in the last decade.
MAIN OUTCOME MEASURE: The protocols, interpretation, and costs of AVS were measured, as well as the rate of adrenal vein rupture and the rate of use of AVS.
RESULTS: Twenty of 24 eligible centers from Asia, Australia, North America, and Europe participated and provided information on 2604 AVS studies over a 6-yr period. The percentage of PA patients systematically submitted to AVS was 77% (median; 19-100%, range). Thirteen of the 20 centers used sequential catheterization, and seven used bilaterally simultaneous catheterization; cosyntropin stimulation was used in 11 centers. The overall rate of adrenal vein rupture was 0.61%. It correlated directly with the number of AVS performed at a particular center (P = 0.002) and inversely with the number of AVS performed by each radiologist (P = 0.007).
CONCLUSIONS: Despite carrying a minimal risk of adrenal vein rupture and at variance with the guidelines, AVS is not used systematically at major referral centers worldwide. These findings represent an argument for defining guidelines for this clinically important but technically demanding procedure.

PMID 22399502  J Clin Endocrinol Metab. 2012 May;97(5):1606-14. doi: 1・・・
著者: K Nomura, K Kusakabe, M Maki, Y Ito, M Aiba, H Demura
雑誌名: J Clin Endocrinol Metab. 1990 Oct;71(4):825-30. doi: 10.1210/jcem-71-4-825.
Abstract/Text Dexamethasone-suppression (DS) adrenal scintigraphy localizes an aldosteronoma, but with false-negative results, i.e. 2 of 19 cases in our study. Our aim was to clarify the clinical meaningfulness of this test. Adrenal iodomethyl-norcholesterol (NP-59) uptake on the adenoma side correlated with the estimated adenoma volume (n = 15, r = 0.843, P less than 0.001). Accordingly, the uptake ratio on the adenoma side to that on the opposite side depended on the adenoma volume (r = 0.683, P less than 0.01). This explains the false-negative results (uptake ratio less than 2) in two cases with small adenomas. The NP-59 uptake correlated weakly with the plasma aldosterone level (r = 0.516, P less than 0.05). This result indicates the low correlation between NP-59 uptake and the ability to secrete aldosterone. NP-59 accumulation in the surgically removed gland was analyzed by autoradiography in six cases where DS scintigraphy was done just before surgery. The density was higher in the adenoma cells than in the adjacent cortical cells in five cases, but the difference was rather small, i.e., within a 2-fold difference in four cases. In one case, almost the same density was observed in both types of cells. Thus, the laterality of NP-59 uptake primarily depends on the adenoma volume although NP-59 uptake somewhat reflects the adenoma's ability to secrete aldosterone or the adenoma cell's activity in accumulating NP-59. Care must be taken in interpreting the findings from DS scintigraphy where the adenoma is small or adrenal uptake is low.

PMID 2401712  J Clin Endocrinol Metab. 1990 Oct;71(4):825-30. doi: 10・・・
著者: Kiichiro Hiraishi, Takanobu Yoshimoto, Kyoichiro Tsuchiya, Isao Minami, Masaru Doi, Hajime Izumiyama, Hironobu Sasano, Yukio Hirata
雑誌名: Endocr J. 2011;58(7):543-51. Epub 2011 Apr 27.
Abstract/Text Primary aldosteronism (PA), an autonomous aldosterone hypersecretion from adrenal adenoma and/or hyperplasia, and subclinical Cushing syndrome (SCS), a mild but autonomous cortisol hypersecretion from adrenal adenoma without signs or symptoms of Cuhing's syndrome, are now well-recognized clinical entities of adrenal incidentaloma. However, the clinicopathological features of PA associated with SCS (PA/SCS) remain unknown. The present study was undertaken to study the prevalence of PA/SCS among PA patients diagnosed at our institute, and characterize their clinicopathlogical features. The prevalence of PA/SCS was 8 of 38 PA patients (21%) studied. These 8 PA/SCS patients were significantly older and had larger tumor, higher serum potassium levels, lower basal plasma levels of aldosterone, ACTH and DHEA-S as well as lower response of aldosterone after ACTH stimulation than those in 12 patients with aldosterone-producing adenoma without hypercortisolism. All 8 PA/SCS patients showed unilateral uptake by adrenal scintigraphy at the ipsilateral side, whereas the laterality of aldosterone hypersecretion as determined by adrenal venous sampling varied from ipsilateral (3), contralateral (2), and bilateral side (2). 6 PA/SCS patinets who underwent adrenalectomy required hydrocortisone replacement postoperatively. Histopathological analysis of the resected adrenal tumors from 5 PA/SCS patients revealed a single adenoma in 3, and double adenomas in 2, with varying degrees of positive immunoreactivities for steroidgenic enzymes (3β-HSD, P450(C17)) by immunohistochemical study as well as CYP11B2 mRNA expression as measured by real-time RT-PCR. In conclusion, PA/SCS consists of a variety of adrenal pathologies so that therapeutic approach differs depending on the disease subtype.

©The Japan Endocrine Society
PMID 21521926  Endocr J. 2011;58(7):543-51. Epub 2011 Apr 27.
著者: Georgios P Piaditis, Gregory A Kaltsas, Ioannis I Androulakis, Aggeliki Gouli, Polyzois Makras, Dimitrios Papadogias, Konstantina Dimitriou, Despina Ragkou, Athina Markou, Kyriakos Vamvakidis, Georgios Zografos, Georgios Chrousos
雑誌名: Clin Endocrinol (Oxf). 2009 Dec;71(6):772-8. doi: 10.1111/j.1365-2265.2009.03551.x. Epub 2009 Feb 18.
Abstract/Text OBJECTIVES: Previous studies based on standard endocrine testing have shown a variable incidence of autonomous cortisol secretion (ACS) or autonomous aldosterone secretion (AAS) in patients with single adrenal adenomas (SAA). We tested whether the use of appropriate controls and modification of standard testing, aiming at eliminating interference from endogenous ACTH, reveals previously undetected subtle ACS and AAS by SAA.
DESIGN: Case control study. Patients We investigated 151 patients with SAA and 72 matched controls with normal adrenal computerized tomography.
MEASUREMENTS: All participants had arterial blood pressure recorded, and serum cortisol and aldosterone measured before and after intravenous administration of 250 mug of ACTH, and following dexamethasone administration. Eighty-three patients and all the controls had serum aldosterone and renin measured before and after saline infusion, and after a second saline infusion following dexamethasone administration.
RESULTS: Using the mean + 2 SD values obtained from controls after dexamethasone administration and saline infusion following dexamethasone administration, normal cut-off values for cortisol (30.11 nM), aldosterone (67.59 pM), and aldosterone/renin ratio (9.74 pM/mU/l) were developed. Using these cut-off values, the estimated incidence of ACS and AAS in patients with SAA was 56.63% and 24.10%, respectively, whereas 12.05% had autonomous secretion of both cortisol and aldosterone. Systolic and diastolic arterial blood pressure correlated significantly with the aldosterone/renin ratio following AlphaCTH stimulation (P < 0.0002 and P < 0.001, respectively), and after saline infusion following dexamethasone administration (P < 0.003 and P < 0.002, respectively).
CONCLUSIONS: By applying new cut-offs, ACS and AAS in patients with a SAA is very common, and aldosterone secretion correlates with arterial blood pressure.

PMID 19226269  Clin Endocrinol (Oxf). 2009 Dec;71(6):772-8. doi: 10.11・・・
著者: D A Harris, I Au-Yong, P S Basnyat, G P Sadler, M H Wheeler
雑誌名: Eur J Surg Oncol. 2003 Jun;29(5):467-74.
Abstract/Text AIMS: To evaluate the investigation and surgical management of primary hyperaldosteronism. Retrospective case note analysis of thirty-three patients who underwent adrenalectomy for primary hyperaldosteronism between 1982 and 2001 and a current relevant literature review.
METHODS: The records of twelve male and twenty-one female patients, age range 18 to 81 (mean 48 years) were reviewed. Eleven operations were performed by an open approach and twenty-two laparoscopically. Preoperative investigations included computed tomography (CT), magnetic resonance imaging (MRI), selective venous sampling and seleno-cholesterol isotope scanning, along with biochemical and hormonal assays. Twenty-six benign adenomas, three nodular hyperplastic lesions, one primary adrenal hyperplasia and three functional carcinomas were excised. Mean follow up was 12 months.
RESULTS: Patients had a mean blood pressure of 185/107 mmHg for 6.2 years mean duration. The mean severity of hypokalaemia was 2.7 mmol/l. Sensitivity of CT scanning was 85%, and of MRI 86%. Fifty percent of seleno-cholesterol scans were accurate. Mean operating time was 158 min for laparoscopic adrenalectomy whilst open surgery took 129 min (p=0.2, NS). Two cases commenced laparoscopically required open access for control of primary haemorrhage whilst one other bleed was managed via the operating ports. Mean postoperative stay was significantly shorter for the laparoscopic group (3 days compared with 7.9 days, p<0.0001). Thirty day mortality was zero. There were three infective complications in the open group (two chest, one wound) with no postoperative complications in the laparoscopic group. All patients were cured of hypokalaemia, whilst 62% cure of hypertension was achieved. Of those patients whose blood pressure was improved preoperatively by spironolactone 78% were cured by adrenalectomy. Adrenalectomy led to an overall reduction in the mean number of anti-hypertensive medications (2.3 drugs preoperative to 0.6 postoperative, p<0.0001). Of those not cured, 58% had improved blood pressure control requiring less medication on average (1.6 drugs compared with 2.6 drugs, p=0.08). Mean age of patients not cured by surgery was 55 years, whilst those cured was 44 years (p=0.03).
CONCLUSIONS: Primary hyperaldosteronism is a rare but important cause of hypertension. Selective venous sampling is a useful tool where investigations are inconclusive and fail to lateralise secretion. Patients with primary hyperaldosteronism enjoy lower complication rates and earlier discharge with the advent of laparoscopic surgery. Most patients will be cured of their hypertension and all of hypokalaemia. Laparoscopic adrenalectomy is now the accepted method of surgery for benign hyperaldosteronism. Those with bilateral disease due to idiopathic hyperaldosteronism (IHA) are not candidates for surgery and should be treated medically.

PMID 12798753  Eur J Surg Oncol. 2003 Jun;29(5):467-74.
著者: P O Lim, R T Jung, T M MacDonald
雑誌名: Br J Clin Pharmacol. 1999 Nov;48(5):756-60.
Abstract/Text AIMS: Aldosterone/renin ratio is an index for inappropriate aldosterone activity, and it is increasingly being used to screen for primary aldosteronism within the hypertensive population. It may also be a good index to help predict the response to spironolactone. To assess the blood pressure response to oral spironolactone in hypertensive patients with primary aldosteronism identified with raised aldosterone to renin ratio.
METHODS: We conducted a prospective cohort study of hypertensive patients with raised aldosterone/renin ratio, who failed to suppress plasma aldosterone with salt loading and fludrocortisone suppression test. These patients were treated with spironolactone and were followed-up for a period of up to 3 years.
RESULTS: We studied 28 (12 male) subjects with a mean age of 55 (s.d. 10) years who were followed up for a mean period of 12.9 (7) months. At baseline, the patients were taking a mean of 2.1 (1.2) antihypertensive drugs, but despite this 16/28 (57%) had diastolic BP >90 mmHg, 39% with systolic BP >160 mmHg. After commencing spironolactone, three patients complained of breast tenderness but continued treatment and one patient was intolerant of spironolactone and had to stop treatment. Of the remaining 27 patients, the mean number of antihypertensive drugs used dropped to spironolactone plus 0.7 (s.d. 0.9). All but one patient (96%) achieved a diastolic BPCONCLUSIONS: Spironolactone was a highly effective antihypertensive agent in hypertensive patients who had a raised aldosterone/renin ratio. As a raised ratio was highly predictive of nonsuppression of plasma aldosterone suggesting primary aldosteronism, it might be worthwhile using spironolactone in this subgroup of hypertensive patients with raised aldosterone/renin ratios, provided that adrenal adenomas are excluded with imaging techniques.

PMID 10594479  Br J Clin Pharmacol. 1999 Nov;48(5):756-60.
著者: X Jeunemaitre, G Chatellier, C Kreft-Jais, A Charru, C DeVries, P F Plouin, P Corvol, J Menard
雑誌名: Am J Cardiol. 1987 Oct 1;60(10):820-5.
Abstract/Text The long-term efficacy and tolerance of spironolactone in essential hypertension was evaluated among 20,812 patients referred to the Broussais and St. Joseph systemic hypertension clinics between 1976 and 1985 by using information prospectively collected in the computerized ARTEMIS data bank. In 182 patients (51 men, 131 women) treated with spironolactone alone during a mean follow-up period of 23 months, a mean dose of 96.5 mg decreased systolic and diastolic blood pressure (BP) by 18 and 10 mm Hg, respectively, below pretherapeutic levels. The BP decrease was greater with doses of 75 to 100 mg (12.4% and 12.2%) than with doses of 25 to 50 mg (5.3 and 6.5%, p less than 0.001), but no additional decrease was found with doses above 150 mg. Plasma creatinine level increased modestly (8.3 mumol/liters), as did plasma potassium level (0.6 mmol/liters) (both p less than 0.001); uric acid level increased, but not significantly (10.5 mumol/liter). Fasting blood glucose and total cholesterol levels did not change, triglyceride levels increased slightly (0.1 mmol/liter, p less than 0.05). These changes were similar in both sexes and were not influenced by length of follow-up. Among the 699 men prescribed spironolactone alone or in association with another antihypertensive treatment, 91 cases of gynecomastia developed (13%). Gynecomastia was reversible and dose-related; at doses of 50 mg or less the incidence was 6.9%, but 52.2% for doses of 150 mg or higher. Despite limitations inherent in the interpretation of data banks, it is concluded that spironolactone administered in daily practice reduced BP without inducing adverse metabolic adverse effects and that in patients with essential hypertension, doses should be kept below 100 mg.

PMID 3661395  Am J Cardiol. 1987 Oct 1;60(10):820-5.
著者: Fumitoshi Satoh, Sadayoshi Ito, Hiroshi Itoh, Hiromi Rakugi, Hirotaka Shibata, Atsuhiro Ichihara, Masao Omura, Katsutoshi Takahashi, Yasuyuki Okuda, Setsuko Iijima
雑誌名: Hypertens Res. 2020 Nov 16;. doi: 10.1038/s41440-020-00570-5. Epub 2020 Nov 16.
Abstract/Text Mineralocorticoid receptor (MR) blockers are very beneficial for patients with hypertension and primary aldosteronism (PA). We investigated the efficacy and safety of a newly available nonsteroidal MR blocker, esaxerenone, in Japanese patients with hypertension and PA. A multicenter, open-label study was conducted in Japan between October 2016 and July 2017. Patients with hypertension and PA received 12 weeks of treatment with esaxerenone, initiated at 2.5 mg/day and escalated to 5 mg/day during week 2 or 4 of treatment, based on individual response. The only other permitted antihypertensive therapies were stable dosages of a Ca2+ channel blocker or α-blocker. The primary efficacy outcome was a change in sitting systolic and diastolic blood pressure (SBP/DBP) from baseline to the end of treatment. Forty-four patients were included; dose escalation to 5 mg/day was implemented for 41 of these patients. Significant decreases in SBP and DBP were observed (point estimates [95% confidence interval] -17.7 [-20.6, -14.7] and -9.5 [-11.7, -7.3] mmHg, respectively; both p < 0.0001 at the end of treatment). Significant BP reductions were evident from week 2 and continued through to week 8; BP remained stable until week 12. The antihypertensive effect of esaxerenone on SBP was significantly greater in females and in patients receiving monotherapy. The major drug-related adverse events were serum K+ increase and estimated glomerular filtration rate decrease (both 4.5%, n = 2); no gynecomastia or breast pain was observed. We conclude that esaxerenone is a potent MR blocker with favorable efficacy and safety profiles in patients with hypertension and PA.

PMID 33199881  Hypertens Res. 2020 Nov 16;. doi: 10.1038/s41440-020-00・・・
著者: Gregory L Hundemer, Gary C Curhan, Nicholas Yozamp, Molin Wang, Anand Vaidya
雑誌名: Lancet Diabetes Endocrinol. 2018 Jan;6(1):51-59. doi: 10.1016/S2213-8587(17)30367-4. Epub 2017 Nov 9.
Abstract/Text BACKGROUND: Mineralocorticoid receptor (MR) antagonists are the recommended medical therapy for primary aldosteronism. Whether this recommendation effectively reduces cardiometabolic risk is not well understood. We aimed to investigate the risk of incident cardiovascular events in patients with primary aldosteronism treated with MR antagonists compared with patients with essential hypertension.
METHODS: We did a cohort study using patients from a research registry from Brigham and Women's Hospital, Massachusetts General Hospital, and their affiliated partner hospitals. We identified patients with primary aldosteronism using International Classification of Disease, 9th and 10th Revision codes, who were assessed between the years 1991-2016 and were at least 18 years of age. We excluded patients who underwent surgical adrenalectomy, had a previous cardiovascular event, were not treated with MR antagonists, or had no follow-up visits after study entry. From the same registry, we identified a population with essential hypertension that was frequency matched by decade of age at study entry. We extracted patient cohort data and collated it into a de-identified database. The primary outcome was an incident cardiovascular event, defined as a composite of incident myocardial infarction or coronary revascularisation, hospital admission with congestive heart failure, or stroke, which was assessed using adjusted Cox regression models. Secondary outcomes were the individual components of the composite cardiovascular outcome, as well as incident atrial fibrillation, incident diabetes, and death.
FINDINGS: We identified 602 eligible patients with primary aldosteronism treated with MR antagonists and 41 853 age-matched patients with essential hypertension from the registry. The two groups of patients had comparable cardiovascular risk profiles and blood pressure throughout the study. The incidence of cardiovascular events was higher in patients with primary aldosteronism on MR antagonists than in patients with essential hypertension (56·3 [95% CI 48·8-64·7] vs 26·6 [26·1-27·2] events per 1000 person-years, adjusted hazard ratio 1·91 [95% CI 1·63-2·25]; adjusted 10-year cumulative incidence difference 14·1 [95% CI 10·1-18·0] excess events per 100 people). Patients with primary aldosteronism also had higher adjusted risks for incident mortality (hazard ratio [HR] 1·34 [95% CI 1·06-1·71]), diabetes (1·26 [1·01-1·57]), and atrial fibrillation (1·93 [1·54-2·42]). Compared with essential hypertension, the excess risk for cardiovascular events and mortality was limited to patients with primary aldosteronism whose renin activity remained suppressed (<1 μg/L per h) on MR antagonists (adjusted HR [2·83 [95% CI 2·11-3·80], and 1·79 [1·14-2·80], respectively) whereas patients who were treated with higher MR antagonist doses and had unsuppressed renin (≥1 μg/L per h) had no significant excess risk.
INTERPRETATION: The current practice of MR antagonist therapy in primary aldosteronism is associated with significantly higher risk for incident cardiometabolic events and death, independent of blood pressure control, than for patients with essential hypertension. Titration of MR antagonist therapy to raise renin might mitigate this excess risk.
FUNDING: US National Institutes of Health.

Copyright © 2018 Elsevier Ltd. All rights reserved.
PMID 29129576  Lancet Diabetes Endocrinol. 2018 Jan;6(1):51-59. doi: 1・・・
著者: Gregory L Hundemer, Gary C Curhan, Nicholas Yozamp, Molin Wang, Anand Vaidya
雑誌名: JAMA Cardiol. 2018 Aug 1;3(8):768-774. doi: 10.1001/jamacardio.2018.2003.
Abstract/Text Importance: Primary aldosteronism (PA) is an ideal condition to evaluate the role of the mineralocorticoid receptor (MR) in the pathogenesis of atrial fibrillation (AF).
Objective: To investigate whether MR antagonist therapy or surgical adrenalectomy in PA influence the risk for incident AF.
Design: This cohort study included patients aged 18 years and older. Patients with PA and age-matched patients with essential hypertension were identified via electronic health records. Patients with a history of AF, myocardial infarction, congestive heart failure, or stroke were excluded. Data were collected between 1991 and the end of 2016 in an academic medical center, with a mean follow-up duration of approximately 8 years.
Exposures: Patients with PA treated with MR antagonists or surgical adrenalectomy were compared with patients with essential hypertension. Patients with PA who were treated with MR antagonists were categorized by whether their plasma renin activity remained suppressed (< 1 ng/mL/h) or substantially increased (≥ 1 ng/mL/h), as proxies for insufficient or sufficient MR blockade.
Main Outcomes and Measure: Incident AF.
Results: A total of 195 patients with PA who were treated with MR antagonists and 201 patients with PA treated with surgical adrenalectomy were included, as well as 40 092 age-matched patients with essential hypertension. Despite similar blood pressure at study entry and throughout follow-up, patients with PA who were treated with MR antagonists whose renin remained suppressed had a higher risk for incident AF than patients with essential hypertension (adjusted HR, 2.55 [95% CI, 1.75-3.71]). They also had an adjusted 10-year cumulative AF incidence difference of 14.1 (95% CI, 6.7-21.5) excess cases per 100 persons compared with patients with essential hypertension. In contrast, patients with PA who were treated with MR antagonists and whose renin increased and patients with PA who were treated with surgical adrenalectomy had no statistically significant difference in risk for incident AF compared with patients with essential hypertension.
Conclusions and Relevance: When compared with patients with essential hypertension, patients with PA treated with MR antagonists such that renin remained suppressed (as a proxy for insufficient MR blockade) had a significantly higher risk for incident AF; however, treatment of PA with MR antagonists to substantially increase renin (suggesting sufficient MR blockade), or with surgical adrenalectomy (to remove the source of aldosteronism), was associated with no significant difference in risk for developing AF. These findings add to the growing body of evidence suggesting that MR blockade may be a potential therapy to decrease the incidence of AF.

PMID 30027227  JAMA Cardiol. 2018 Aug 1;3(8):768-774. doi: 10.1001/jam・・・

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