今日の臨床サポート

クッシング病

著者: 沖隆 医療法人社団 盛翔会 浜松北病院 代謝・内分泌内科

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:2019/09/06
参考ガイドライン:
間脳下垂体機能障害の診断と治療の手引き(平成30年度改訂)
患者向け説明資料

概要・推奨   

  1. クッシング病の1 次スクリーニング検査である少量デキサメタゾン抑制試験(LDDST)において、わが国では0.5mg法を欧米では1mg法を用いている(推奨度1)
  1. クッシング病と異所性ACTH症候群の鑑別に下錐体静脈洞サンプリングは有用である(推奨度2)
  1. 治療の第1選択は手術療法である(推奨度2)
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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:
沖隆 : 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. 間脳下垂体機能障害の診断と治療の手引き平成30年度改訂版に準拠した。
  1. 保険適用外となる検査試薬などは、参考所見・付記となった。
  1. 局在診断としての、MRIの施行条件、下錐体静脈洞サンプリングに加えて海綿静脈洞サンプリングの判定基準を追記した。
  1. 薬物治療として、メチラポン治療について注意点を追記、パシレオチドLARの新規保険適用にともなう追記を行った。

病態、疫学、診察

疾患情報(疫学・病態)  
  1. クッシング病とは、下垂体ACTH産生腫瘍により、副腎より副腎皮質ホルモンを過剰産生することにより発症したクッシング症候群の1つである。
  1. 円形(満月様)顔貌・中心性(体幹)肥満・赤色皮膚線条・水牛様肩・皮膚菲薄化などの特徴的症状を呈する。
  1. 偶発的 下垂体腺腫 の発見や高血圧・糖尿病・脂質異常症・うつ病が発見の契機となることがある。
 
クッシング病の下垂体MRI(T1WI、Gd造影後)

下垂体右側の造影効果に乏しい部位が腺腫

出典

img1:  著者提供
 
 
 
  1. 早朝安静時の血漿中ACTH(副腎皮質刺激ホルモン)およびコルチゾール濃度は正常~高値を呈する。
  1. 尿中遊離コルチゾールは正常~高値を呈する。
  1. 血中コルチゾール濃度の日内変動の消失(深夜血中コルチゾール≧ 5 µg/dl)
  1. CRH(100 µg静注)試験で血漿ACTHの増加反応(1.5倍以上)を認める。
  1. 参考所見として、DDAVP(4 µg静注)で血漿ACTHの増加反応(1.5倍以上)を認める。ただし、DDAVPは保険適用外である。
  1. 一晩少量デキサメタゾン(0.5 mg)抑制試験で、早朝コルチゾール濃度が5 µg/dL以上となる(サブクリニカルクッシング病では一晩少量デキサメタゾン抑制試験で早朝コルチゾール≧3 µg/dl )。3 µg/dL未満の場合、コルチゾール過剰はないと判断するが、コルチゾールの測定値に10%程度の誤差があることを考慮し、慎重に判断する。
  1. 一晩大量デキサメタゾン(8 mg)抑制試験で、早朝コルチゾール濃度が前値の1/2以下となることが多い。
  1. クッシング病は、指定難病であり、その一部(重症度分類で重症)などは、申請し認定されると健康保険の自己負担分の一部が公費負担として助成される。(改訂になりました)
  1.  難病法に基づく医療費助成制度 
病歴・診察のポイント  
  1. 過食の傾向、体重の増加、検診などで血圧や血糖値の上昇はないか、浮腫の出現、気分の変調、無自覚の皮下溢血、易感染性などの病歴聴取

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文献 

著者: Yutaka Oki, Kozo Hashimoto, Yukio Hirata, Yasumasa Iwasaki, Takeshi Nigawara, Masaru Doi, Satoru Sakihara, Kazunori Kageyama, Toshihiro Suda
雑誌名: Endocr J. 2009;56(7):897-904. Epub 2009 Aug 25.
Abstract/Text For the diagnosis of Cushing' s syndrome (CS), the overnight 1 mg dexamethasone suppression test (DST) has been widely used as a standard low-dose DST. However, it is evident that 1 mg DST may not be sensitive enough to detect CS when the cortisol cut-off concentration is 5 microg/dL. Therefore, we developed and validated 0.5 mg DST as a new screening method for diagnosis of ACTH-dependent CS. To compare 0.5 mg DST with 1 mg DST, 110 patients with ACTH-dependent CS were enrolled, including 88 with Cushing' s disease (CD), 8 with subclinical CD and 14 with ectopic ACTH syndrome, as well as 134 control subjects. Subjects were given either 0.5 mg or 1 mg dexamethasone orally at 23:00 on different days, with blood samples collected the following morning between 8:00 and 9:00 to determine plasma cortisol concentration. The area under the receiver operator characteristics curve observing the 0.5 mg DST was higher than that of the 1 mg DST. The most sensitive and specific cut-off value of plasma cortisol concentration using 0.5 mg DST was found to be 3.05 microg/dL with 99.1% sensitivity and 98.4% specificity, identical to the 3 microg/dL cut-off currently used in the Japanese guideline for diagnosis of subclinical CD. In conclusion, 0.5 mg DST is a sensitive and specific screening test for diagnosis of ACTH-dependent CS. We recommend 0.5 mg DST with a cortisol cut-off concentration of 3 microg/dL to be used as the initial step in diagnosing ACTH-dependent CS.

PMID 19706991  Endocr J. 2009;56(7):897-904. Epub 2009 Aug 25.
著者: Lynnette K Nieman, Beverly M K Biller, James W Findling, John Newell-Price, Martin O Savage, Paul M Stewart, Victor M Montori
雑誌名: J Clin Endocrinol Metab. 2008 May;93(5):1526-40. doi: 10.1210/jc.2008-0125. Epub 2008 Mar 11.
Abstract/Text OBJECTIVE: The objective of the study was to develop clinical practice guidelines for the diagnosis of Cushing's syndrome.
PARTICIPANTS: The Task Force included a chair, selected by the Clinical Guidelines Subcommittee (CGS) of The Endocrine Society, five additional experts, a methodologist, and a medical writer. The Task Force received no corporate funding or remuneration.
CONSENSUS PROCESS: Consensus was guided by systematic reviews of evidence and discussions. The guidelines were reviewed and approved sequentially by The Endocrine Society's CGS and Clinical Affairs Core Committee, members responding to a web posting, and The Endocrine Society Council. At each stage the Task Force incorporated needed changes in response to written comments.
CONCLUSIONS: After excluding exogenous glucocorticoid use, we recommend testing for Cushing's syndrome in patients with multiple and progressive features compatible with the syndrome, particularly those with a high discriminatory value, and patients with adrenal incidentaloma. We recommend initial use of one test with high diagnostic accuracy (urine cortisol, late night salivary cortisol, 1 mg overnight or 2 mg 48-h dexamethasone suppression test). We recommend that patients with an abnormal result see an endocrinologist and undergo a second test, either one of the above or, in some cases, a serum midnight cortisol or dexamethasone-CRH test. Patients with concordant abnormal results should undergo testing for the cause of Cushing's syndrome. Patients with concordant normal results should not undergo further evaluation. We recommend additional testing in patients with discordant results, normal responses suspected of cyclic hypercortisolism, or initially normal responses who accumulate additional features over time.

PMID 18334580  J Clin Endocrinol Metab. 2008 May;93(5):1526-40. doi: 1・・・
著者: E H Oldfield, J L Doppman, L K Nieman, G P Chrousos, D L Miller, D A Katz, G B Cutler, D L Loriaux
雑誌名: N Engl J Med. 1991 Sep 26;325(13):897-905. doi: 10.1056/NEJM199109263251301.
Abstract/Text BACKGROUND: Measurement of adrenocorticotropin levels in plasma from the inferior petrosal sinuses of patients with Cushing's syndrome can distinguish adrenocorticotropin-secreting pituitary tumors (Cushing's disease) from other causes of the syndrome, principally ectopic adrenocorticotropin secretion from an occult tumor. However, it is unknown whether such measurement consistently identifies patients with Cushing's disease and whether testing with corticotropin-releasing hormone (CRH) enhances the value of the procedure.
METHODS: We prospectively studied 281 patients with Cushing's syndrome to evaluate the diagnostic efficacy of the procedure. Bilateral sampling was successfully accomplished in 278 patients, with no major morbidity; 262 of these patients underwent sampling before and after administration of ovine CRH. The adrenocorticotropin levels in the samples were used to calculate the ratio of the concentration in plasma from the inferior petrosal sinuses to the concentration in peripheral-blood plasma (the IPS:P ratio).
RESULTS: The diagnosis of 246 patients was confirmed surgically as Cushing's disease in 215, as ectopic adrenocorticotropin syndrome in 20, and as primary adrenal disease in 11. An IPS:P ratio greater than or equal to 2.0 in basal samples identified 205 of the 215 patients with Cushing's disease (sensitivity, 95 percent), with no false positive results (specificity, 100 percent). A peak IPS:P ratio greater than or equal to 3.0 after CRH administration identified all 203 of the patients with Cushing's disease who received CRH (sensitivity, 100 percent), with no false positive results (specificity, 100 percent). The sensitivity was much lower when the adrenocorticotropin concentrations in the samples from one sinus were considered alone. In patients with Cushing's disease a difference of greater than or equal to 1.4-fold between the concentrations in the two sinuses (the adrenocorticotropin gradient) predicted the location of the microadenoma in 68 percent of 104 patients during basal sampling and in 71 percent of 105 patients after CRH administration.
CONCLUSIONS: Simultaneous bilateral sampling of plasma from the inferior petrosal sinuses, with the adjunctive use of CRH, distinguishes patients with Cushing's disease from those with ectopic adrenocorticotropin secretion with high diagnostic accuracy.

PMID 1652686  N Engl J Med. 1991 Sep 26;325(13):897-905. doi: 10.1056・・・
著者: J Newell-Price, P Trainer, M Besser, A Grossman
雑誌名: Endocr Rev. 1998 Oct;19(5):647-72. doi: 10.1210/edrv.19.5.0346.
Abstract/Text
PMID 9793762  Endocr Rev. 1998 Oct;19(5):647-72. doi: 10.1210/edrv.19・・・
著者: B M K Biller, A B Grossman, P M Stewart, S Melmed, X Bertagna, J Bertherat, M Buchfelder, A Colao, A R Hermus, L J Hofland, A Klibanski, A Lacroix, J R Lindsay, J Newell-Price, L K Nieman, S Petersenn, N Sonino, G K Stalla, B Swearingen, M L Vance, J A H Wass, M Boscaro
雑誌名: J Clin Endocrinol Metab. 2008 Jul;93(7):2454-62. doi: 10.1210/jc.2007-2734. Epub 2008 Apr 15.
Abstract/Text OBJECTIVE: Our objective was to evaluate the published literature and reach a consensus on the treatment of patients with ACTH-dependent Cushing's syndrome, because there is no recent consensus on the management of this rare disorder.
PARTICIPANTS: Thirty-two leading endocrinologists, clinicians, and neurosurgeons with specific expertise in the management of ACTH-dependent Cushing's syndrome representing nine countries were chosen to address 1) criteria for cure and remission of this disorder, 2) surgical treatment of Cushing's disease, 3) therapeutic options in the event of persistent disease after transsphenoidal surgery, 4) medical therapy of Cushing's disease, and 5) management of ectopic ACTH syndrome, Nelson's syndrome, and special patient populations.
EVIDENCE: Participants presented published scientific data, which formed the basis of the recommendations. Opinion shared by a majority of experts was used where strong evidence was lacking.
CONSENSUS PROCESS: Participants met for 2 d, during which there were four chaired sessions of presentations, followed by general discussion where a consensus was reached. The consensus statement was prepared by a steering committee and was then reviewed by all authors, with suggestions incorporated if agreed upon by the majority.
CONCLUSIONS: ACTH-dependent Cushing's syndrome is a heterogeneous disorder requiring a multidisciplinary and individualized approach to patient management. Generally, the treatment of choice for ACTH-dependent Cushing's syndrome is curative surgery with selective pituitary or ectopic corticotroph tumor resection. Second-line treatments include more radical surgery, radiation therapy (for Cushing's disease), medical therapy, and bilateral adrenalectomy. Because of the significant morbidity of Cushing's syndrome, early diagnosis and prompt therapy are warranted.

PMID 18413427  J Clin Endocrinol Metab. 2008 Jul;93(7):2454-62. doi: 1・・・
著者: Stephan Petersenn, Albert Beckers, Diego Ferone, Aart van der Lely, Jens Bollerslev, Marco Boscaro, Thierry Brue, Paolo Bruzzi, Felipe F Casanueva, Philippe Chanson, Annamaria Colao, Martin Reincke, Günter Stalla, Stelios Tsagarakis
雑誌名: Eur J Endocrinol. 2015 Jun;172(6):R227-39. doi: 10.1530/EJE-14-0883. Epub 2015 Jan 19.
Abstract/Text OBJECTIVE: A number of factors can influence the reported outcomes of transsphenoidal surgery (TSS) for Cushing's disease - including different remission and recurrence criteria, for which there is no consensus. Therefore, a comparative analysis of the best treatment options and patient management strategies is difficult. In this review, we investigated the clinical outcomes of initial TSS in patients with Cushing's disease based on definitions of and assessments for remission and recurrence.
METHODS: We systematically searched PubMed and identified 44 studies with clear definitions of remission and recurrence. When data were available, additional analyses by time of remission, tumor size, duration of follow-up, surgical experience, year of study publication and adverse events related to surgery were performed.
RESULTS: Data from a total of 6400 patients who received microscopic TSS were extracted and analyzed. A variety of definitions of remission and recurrence of Cushing's disease after initial microscopic TSS was used, giving broad ranges of remission (42.0-96.6%; median, 77.9%) and recurrence (0-47.4%; median, 11.5%). Better remission and recurrence outcomes were achieved for microadenomas vs macroadenomas; however, no correlations were found with other parameters, other than improved safety with longer surgical experience.
CONCLUSIONS: The variety of methodologies used in clinical evaluation of TSS for Cushing's disease strongly support the call for standardization and optimization of studies to inform clinical practice and maximize patient outcomes. Clinically significant rates of failure of initial TSS highlight the need for effective second-line treatments.

© 2015 European Society of Endocrinology.
PMID 25599709  Eur J Endocrinol. 2015 Jun;172(6):R227-39. doi: 10.1530・・・
著者: Martin J Rutkowski, Patrick M Flanigan, Manish K Aghi
雑誌名: Neurosurg Focus. 2015 Feb;38(2):E16. doi: 10.3171/2014.11.FOCUS14703.
Abstract/Text After transsphenoidal surgery, Cushing's disease (CD) shows excellent long-term remission rates, but it may recur and pose a therapeutic challenge. Findings in recent published reports on the treatment of recurrent adrenocorticotropic hormone (ACTH)-secreting tumors suggest that repeat resection, radiation-based therapies such as Gamma Knife surgery and proton-beam radiosurgery, pharmacotherapy, and bilateral adrenalectomy all have important roles in the treatment of recurrent CD. Each of these interventions has inherent risks and benefits that should be presented to the patient during counseling on retreatment options. Radiation-based therapies increasingly appear to have efficacies similar to those of repeat resection in achieving biochemical remission and tumor control. In addition, an expanding retinue of medication-based therapies, several of which are currently being evaluated in clinical trials, has shown some promise as tertiary adjunctive therapies. Lastly, bilateral adrenalectomy may offer durable control of refractory recurrent CD. An increasing number of published studies with long-term patient outcomes highlight the evolving treatment patterns in the management of recurrent CD.

PMID 25639318  Neurosurg Focus. 2015 Feb;38(2):E16. doi: 10.3171/2014.・・・

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