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1 대한내과학회지 : 제 82 권제 4 호 특집 (Special Review) - 내분비질환에의한이차고혈압의진단과치료 일차성알도스테론증 서울대학교의과대학내과학교실, 서울특별시보라매병원내분비대사내과 김상완 Primary Aldosteronism Sang Wan Kim Department of Internal Medicine, Seoul Metropolitan Government Borame Medical Center, Seoul National University College of Medicine, Seoul, Korea Primary aldosteronism (PA) is characterized by inappropriately high production of aldosterone relatively autonomous from the renin-angiotensin system and no suppression by sodium loading. The prevalence of PA is estimated more than 10% among nonseleted hypertensive patients. PA is clinically very important since patients with PA have higher cardiovascular morbidity and mortality than age- and sex-matched patients with essential hypertension and the same degree of blood pressure elevation. The ratio of plasma aldosterone concentration to plasma renin activity (ARR) has been generally accepted as a first-line screening test. ARR might be affected by patient age, anti-hypertensive drugs, posture and menstrual cycles. Once the ARR is measured, confirmative test should be performed. Although a gold standard confirmative test for PA is not yet identified, intravenous saline loading test is widely used. Adrenal venous sampling (AVS) is a gold standard for differentiation of unilateral from bilateral forms of PA. Since adrenal CT imaging has limitations to accurate diagnosis of PA, AVS is recommended for all patients who wish to pursue surgical treatment. Although unilateral laparoscopic adernalectomy is the optimal treatment for patients with aldosterone producing adenoma or unilateral hyperplasia, strong evidence linking adernalectomy with improved quality of life, morbidity or mortality is not available. Mneralocorticoid receptor antagonists, spironolactone or eplerenone, are recommended for pharmacologic therapy of PA. (Korean J Med 2012;82: ) Keywords: Primary aldosteronism; Ratio of plasma aldosterone concentration to plasma renin activity; Adrenal venous sampling; Unilateral laparoscopic adrenalectomy 서론일차성알도스테론증 (primary aldosteronism, PA) 는알도스테론이레닌- 알도스테론계로부터자동능을가짐으로저레닌, 고알도스테론증을동반한고혈압을나타내며소디움부하등으로억제되지않는질환이다. 1955년미국미시간대학의 Conn 교수에의해처음기술되었는데그환자는 34세의여자로서고혈압, 간헐적마비, 저칼륨혈증을동반하였고부신 Correspondence to Sang Wan Kim, M.D. Department of Internal Medicine, Seoul Metropolitan Government Borame Medical Center, Seoul National University College of Medicine, 20 Boramae-ro 5-gil, Dongjak-gu, Seoul , Korea Tel: , Fax: , swkimmd@snu.ac.kr

2 - Sang Wan Kim. Primary aldosteronism - 선종이제거됨으로완치되었다 [1]. PA의원인으로는 Conn 병으로알려진알도스테론분비종양 (aldosterone producing adeoma, APA), 특발성고알도스테론증 (idiopathic hyperaldosteronism, IHA) 이있으며드물게유전성질환인당류코르티코이드억제성알도스테론증 (glucocorticoid-remediable aldosteronism, GRA) 이있다. 과거에는저칼륨혈증이 PA의필수조건임을감안하여전체고혈압환자의 1% 이하만이 PA라고생각하였으나여러단면연구와전향적연구의결과 PA 의유병률은고혈압환자의 10% 이상으로보고되고있다 [2]. 따라서 PA는완치가가능한고혈압의가장흔한원인이므로임상적으로중요하다. 본론병태생리와임상적중요성알도스테론은주로레닌, 안지오텐신 II에의해부신피질의사구대 (zona glomerulosa) 에서합성되지만부신피질자극호르몬 (adrenocorticotrophin, ACTH), 혈중칼륨, 도파민에의해서도영향을받는다. 알도스테론은핵속에위치한염류코르티코이드수용체에결합하여유전자발현을촉진한다. 신세뇨관상피세포에서알도스테론은소디움의섭취를촉진하여체액용적과심박출량을증가시킨다. 소디움의재흡수는칼슘의배설을동반하므로과거에는저칼륨혈증이 PA에필수적인소견이라생각했었지만대부분의환자들에서혈중칼륨이정상이라는사실이나중에알려지게되었다 [3-5]. 고혈압외에도고알도스테론혈증은산화성스트레스와콜라겐재형성을증가시켜고혈압과독립적으로내피세포의기능이상, 좌심실비후그리고신장및심장과혈관에서의섬유화를초래한다 [6]. 실제본태성고혈압환자보다 PA 환자에서혈압에비의존적으로뇌졸중, 심근경색, 심방세동등의주요심혈관계사건의발생이더흔하다고보고되었다 [7]. 실제로다기관임상연구에서기존의약제에염류코르티코이드수용체차단제를추가하였을때심혈관계합병증의동반된 PA 환자의유병률과사망률을감소시켰다 [8,9]. 그외에도본태성고혈압환자보다 PA 환자에서대사증후군의더흔하다는보고가있으나아직기전은불확실하다 [10]. 진단선별검사가필요한대상다음의경우 PA에대한선별검사가고려되어야한다 [11]. 1) 고혈압에저칼륨혈증이동반되거나저용량의이뇨제투여에도저칼륨혈증이유발되는경우 2) 중증의고혈압 (Joint National Committee 7의 2기고혈압에해당되는경우 ), 즉수축기 160 mmhg 이상이거나이완기 100 mmhg 이상인경우 3) 세가지이상의항고혈압제를필요로하는경우 4) 20세미만의어린나이에고혈압이발견된경우 5) 부신우연종이있는경우 6) 이차성고혈압에대한평가가이루어질때 7) 친척중에 PA 환자가있는고혈압환자선별검사레닌-알도스테론비 (aldosterone: renin ratio, ARR) 가장신뢰도가높은선별검사이나검사실간의측정방법이표준화되어있지않으므로선별검사로만사용되어야한다. 아침기립시에혈장알도스테론 (plasma aldosterone concentration, PAC) 과혈장레닌활성도 (plasma renin activity, PRA) 를동시에측정한다. ARR 20 (PAC: ng/dl, PRA: ng/ml/h) 이상이면서 PAC > 15 ng/dl인경우에알도스테론자율분비가의심되는데 Mayo clinic의보고에의하면외과적으로확진된 APA 환자의 90% 이상에서 ARR (PAC [ng/dl]: PRA [ng/ml/hr]) 가 20 이상이면서 PAC가 15 ng/dl 이상이었다 [12]. ARR 측정조건 ARR은저칼륨혈증을교정하고식염을제한하지않은상태에서측정해야하며아침기상 2시간이경과한후앉은상태에서채혈하는것이좋다. 많은종류의항고혈압약제가 ARR에영향을주기때문에 ARR을측정하기전에현재사용중인항고혈압제를확인해야한다. ARR 해석에영향을미치는항고혈압제 : 염류코르티코이드수용체차단제 (spironolactone, eplerenone), 레닌억제제, 고용량 (> 5 mg/dl) amiloride 등은최소한 4주간중단한다. 안지오텐신전환효소억제제, 안지오텐신수용체차단제, 디하이드로피리딘칼슘통로차단제, 칼륨비보존성이뇨제, 비스테로이드항염제, 베타차단제, 중추성알파 2 작용제등은최소 2주간중단한다. 하지만실제임상에서는 2주이

3 - 대한내과학회지 : 제 82 권제 4 호통권제 620 호 상약제를중단하는것이현실적으로어려울수있다. 더구나 ARR에대한항고혈압제의영향에대해서도논란이있는실정이다. 안지오텐신전환효소억제제, 안지오텐신수용체차단제, 디하이드로피리딘칼슘통로차단제, 칼륨비보존성이뇨제등은 PRA를상승시킬수있으므로오히려이약제를복용하는경우에 PRA가매우낮다면 PA가강력하게의심될수있다 [4]. 베타차단제나중추성알파-2 작용제는상대적으로알도스테론보다상대적으로레닌의분비를더욱억제시키므로 PA가아닌본태성고혈압환자들에서도 ARR이증가되지만이경우에도대개 PAC는 15 ng/dl 이하이므로감별에도움이될수있다 [12]. 이뇨제나염류코르티코이드수용체차단제는 PRA와 PAC 모두증가시키며그중에서도 PRA 증가폭이훨씬크므로 ARR이감소된다. 이약제들은 ARR에가장뚜렷한영향을미치므로최소 4-6주중단후선별검사를시행해야한다. 표 1에서 ARR에영향을거의미치지않는것으로알려진항고혈압제를기술하였다 [2]. 따라서선별검사나확진검사시에이약제들을사용할수있다. 그외 ARR 해석에영향을미치는약제 : 항고혈압제뿐아니라흔히사용되는경구피임약이나항우울제도 ARR에영향을미칠수있다. 에스트로젠은간에서안지오텐시노젠생성을유발하여결과적으로안지오텐신 II를상승시키게되어음성되먹이기기전에의해결과적으로는레닌분비를억제시킨다 [13]. 생리주기가 ARR에영향을미친다는보고가있는데 26명의저레닌혈증을보이는여자고혈압환자들중생리주기 7일째에비해 21일째에환자들의 68% 에서 ARR이증가되며알도스테론이 15 ng/dl 이상증가된다고하였다 [14]. 약제외에도 65세이상의고령환자에서혈중레닌이감소되어 ARR이증가될수있다. 활성형레닌농도 (active renin concentration, ARC) PRA의측정은안지오텐신의생리적농도에영향을받게되며아직검사실간의표준화가되지않았다는문제가있다. 이런문제를극복하기위해단클론항체를통해혈중레닌을직접측정하는방법이개발되었고몇기관에서현재 PRA대신 ARC로레닌을측정하고있다. ARC (ng/l) 를사용할경우검체를냉각하게되면 cryoactivation에의해 ARC가증가될수있으므로검체는실온에보관해야한다 [2]. 아직 PA의진단을위한 PAC:ARC 의기준값에대해서는연구가제한적이며 ng/dl:ng/l 등다양한결과가제시되었으므로 PRA를대체하기위해서는보다큰규모의코호트연구결과가필요하다 [15-17]. 확진검사확진검사는 PA의진단을위해 ARR이상승된환자들에대해반드시시행되어야하지만어떤검사를시행해야하는지는아직논란이있으며여러검사중한가지검사를추천하기에는아직연구결과가부족한실정이다. 확진검사는내분비전문의가있는기관에서시행되는것이원칙이다. 생리식염수부하검사정상인은생리식염수에의한세포외액의증가에의해 PAC가감소하지만 PA 환자는이러한반응을보이지않는데착안하여최소한 30분이상침상안정후앉은상태에서혈액을채취한다음환자가누워있는상태에서 4시간동안생리식염수 2 L를주입펌프를통해정맥주사한후다시혈액을채취하여 PAC를측정한다. 이시간동안환자의활동을최소한으로제한하며특히생리식염수부하후혈액채취직전 30분간은활동을금지한다. 검사가진행되는동안환자의안전을고려하기위해혈압과증상을모니터링해야 Table 1. Medications that have minimal effects on plasma aldosterone levels and can be used to control hypertension during case finding and confirmatory testing for PA [2] Drug Class Usual Dose Comments Verapamil slow-release Non-dihydropyridine calcium channel blocker mg twice daily Use singly or in combination with the other agents listed in this table Hydralazine Vasodilator mg twice daily Commence verapamil slow release first to prevent reflex tachycardia Prazosin α-blocker mg two to three times daily Monitor for postural hypotension Doxazosin α-blocker 1-2 mg once daily Monitor for postural hypotension Terazosin α-blocker 1-2 mg once daily Monitor for postural hypotension

4 - 김상완. 일차성알도스테론증 - 한다. 정상인의경우 PAC가 5 ng/dl 미만으로억제되지만 PA 환자는 PAC가 10 ng/dl 이상으로억제되지않는다. 심기능이감소되어있거나심부전이의심되는경우시행해서는안된다 [2]. 캡토프릴검사최소한 30분이상침상안정후혈액을채취한다음캡토프릴 50 mg을투여한다. 침상안정후 60, 90분후에혈액을채취한다. PA의경우 ARR이계속 20 이상이거나 PAC가 12 ng/dl으로증가되어있다 [18]. 맥관부종이나신혈관성고혈압이있는환자들에서는캡토프릴에의한과도한혈압강하와관련한숔이유발될수있으므로주의해야한다. 원인질환분류 PA의원인질환에따라치료방침이완전히달라지기때문에원인질환을결정하는것이매우중요하다. 부신 CT 일단 PA으로확진되면부신 CT를시행한다. 일반적으로알도스테론분비종양의경우크기가 2 cm 이하의균질한형태를보이며 Hounsfield unit은대개 10 이하이다. PA 환자에서의 CT의제한점은작은알도스테론분비종양과양측성부신증식증과의감별이어렵다는점, 부신우연종의가능성, 실제부신정맥채혈과의일치도가낮다는점등이다 [2,19]. 실제 950명의 PA 환자를검토하였을때 CT나 MRI의진단율은 62% 정도였다 [20]. 따라서 CT나 MRI에만의존하는것 은 PA 환자를부적절하게치료할가능성이있다. 부신정맥채혈 (adrenal venous sampling) 부신정맥채혈은일측성알도스테론과분비를측정하기위한표준검사이며숙련된영상의학전문의에의해수행되어야한다. 2008년미국내분비학회에서제정된임상진료지침은 PA가확진된환자가수술을할의향이있다면부신정맥채혈을하도록권고하고있다 [2]. 하지만아직까지부신정맥채혈의성공률, 안전성, 재현성과검사방법과결과해석의표준화그리고검사의민감도와특이도등여러분야에서 gold standard 에서기대되는요건을제대로충족시키지못하고있다는논란이있다 [21]. 뿐만아니라, 부신정맥채혈이환자의예후에어떤영향을미치는지에대한전향적, 무작위적연구결과는없는실정이다. 부신정맥채혈결과를해석할때가장주의해야할사항은채혈이부신정맥에서선택적으로이루어졌는지확인하는것이다. 특히우측부신정맥은하대정맥으로부터직접분지되므로혈관도자가어려울수있다 [22]. 대개하대정맥에비해코티졸농도가 3배이상높을때선택적채혈이이루어졌다고판단한다. 해부학적변이에따라부신정맥으로횡격막정맥혈이유입되어알도스테론값이희석될수있으므로검사를해석할때는코티졸값으로보정된알도스테론값 (normalized aldosterone) 을사용한다 [23]. 일반적으로양측부신정맥의보정된알도스테론비가 4:1 이상이면서건측부신정맥의보정된알도스테론이하대정맥보다적을때편측화되었다고할수있다 [23]. 양측부신증식증의경우양측부신정맥의보정된알도스테론값이하대정맥의것과 Table 2. Result of bilateral adrenal venous sampling Aldosterone (ng/dl) Cortisol (μg/dl) Normalized aldosterone Rt/Lt normalized aldosterone Rt 25, Nondominant/IVC normalized aldosterone Lt IVC A 54-year-old-man had a 9-year history of hypertension and a 1-year history of hypokalaemia. The case-detection test results for primary aldosteronism were positive, with a plasma aldosterone concentration (PAC) of 68.5 ng/dl and low plasma renin activity (PRA) of less than 0.1 ng/ml per hour. The confirmatory test results for primary aldosteronism were also positive, with suppressed aldosterone of ng/dl on a saline loading test. The adrenal-directed computed tomography scan showed normal adrenal glands. Adrenal venous sampling lateralized aldosterone secretion to the right adrenal and a cortical adenoma measuring 7 mm was found at laparoscopic right adrenalectomy. The postoperative PAC was < 1 ng/dl. Hypokalemia was cured and blood pressure was normalized without antihypertensive medications. Rt, right adrenal vein; Lt, left adrenal vein: IVC, inferior vena cava.

5 - The Korean Journal of Medicine: Vol. 82, No. 4, 같거나크다. 표 2는생리식염수부하검사로 PA가확진된 54세남자환자의부신정맥채혈결과이다. CT상부신은정상소견이었으나부신정맥채혈검사를시행하였을때우측으로편측화되어있는소견이었다. PAC: PRA > 20 ng/ml per ng/ml per hour + PAC 15 ng/dl 치료 수술치료일측성복강경부신절제술은알도스테론분비종양이나일측성부신증식증환자에서적절한치료로추천된다. 수술후환자의 35-60% 정도에서항고혈압제의도움없이혈압이 140/90 mmhg 으로조절된다 [24-26]. 수술후완치와관련된인자로는고혈압의가족력이없는경우, 수술전두가지이하의항고혈압제를사용한경우, 젊은나이, 5년미만의짧은이환기, spironolactone에대한반응, 수술전 ARR이높거나알도스테론의요배설이많은경우등이있다 [27,28]. 복강경부분부신절제술을시행할경우수술시간이짧고정상부신조직을보존하는등의약간의이점은있을수있지만다결절성병변에의해수술후 PA가지속될수있으므로부신전절제술이원칙이다. 아직까지 PA에대한복강경부신절제술의 PA의사망률, 이환율, 삶의질등의결과에대한잘고안된연구결과는없는실정이다. 수술후병리검사로최종진단이이루어지며작은 APA와 IHA의감별진단을위해서는스테로이드합성효소의면역화학염색이도움이된다. IHA 의경우 aldosterone synthetase (CYP11B2) 와 3β-hydroxysteroid dehydrogenase (3β-HSD) 가과증식성사구대에서발현이증가되어있으나 APA의경우종양주변정상사구대에서발현이감소되어있다 [18]. 약물치료 IHA 또는수술하지못하는 APA나일측성증식증환자는 spironolactone이나 eplerenone과같은염류코르티코이드수용체차단제 (mineralocorticoid receptor antagonist, MRA) 를투여해야한다. Spironolactone 은안드로젠과프로제스테론수용체에도결합하여남자에서여성형유방이나성기능감소, 여자에게월경이상등을일으킬수있으므로사용이제한된다. 특히여성형유방의경우하루 spironolactone 50 mg 을복용하는남자의 6.9%, 150 mg을복용하는경우 50% 이상에서보고된다 [29]. 반면에 eplerenone은안드로젠과프로제스테론수용체에대한친화도가매우낮아이러한부작용이매우적지만가격이비싸다. 최근 2,737명의경도의증상을 Figure 1. Algorithm for the screening, confirmation, subtype evaluation, and treatment of primary aldosteronism. PAC, plasma aldosterone concentration, PRA, plasma rennin activity. 보이는수축기심부전환자에게 eplerenone을하루최대 50 mg을 2년정도투여하였을때사망위험과입원위험을개선시켰다는결과가보고되었다 [30]. MRA 를우선적으로사용하고필요하면칼슘차단제를추가할수있다. Spironolactone 은하루 12.5 mg부터사용할수있다. GRA의경우 ACTH를억제하기위해당류코르티코이드를사용하는데의인성쿠싱증후군이발생하지않는최소유효용량을사용해야한다. 당류코르티코이드투여만으로혈압이정상화되지않을경우추가적인 MRA 투여를고려해야하며그외항고혈압제도사용할수있다 [31]. 결 PA는전체고혈압환자의 10% 내외로추정되며완치가가능한고혈압의가장흔한원인이다. 앞에서살펴본내용을중심으로진단및치료에대한알고리듬을그림 1에서제시하였다. 진단을위해서는 ARR의증가와후속적인알도스테론억제검사가요구된다. 원인질환의감별은치료를위해필수적이며부신 CT가진단에제한점이있으므로수술을고려하는환자들에서부신정맥채혈이추천된다. APA 의치료로는일측성복강경부신절제술이적절하며약물학적치료로 MRA의사용이추천된다. 론

6 - Sang Wan Kim. Primary aldosteronism - 중심단어 : 일차성알도스테론증 ; 혈장레닌- 알도스테론비 ; 부신정맥채혈 ; 일측성복강경부신절제술 REFERENCES 1. Conn JW. Presidential address: I. painting background: II. primary aldosteronism, a new clinical syndrome. J Lab Clin Med 1955;45: Funder JW, Carey RM, Fardella C, et al. Case detection, diagnosis, and treatment of patients with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab 2008;93: Fardella CE, Mosso L, Gómez-Sánchez C, et al. Primary hyperaldosteronism in essential hypertensives: prevalence, biochemical profile, and molecular biology. J Clin Endocrinol Metab 2000;85: Mulatero P, Rabbia F, Milan A, et al. Drug effects on aldosterone/plasma renin activity ratio in primary aldosteronism. Hypertension 2002;40: Rossi E, Regolisti G, Negro A, Sani C, Davoli S, Perazzoli F. High prevalence of primary aldosteronism using postcaptopril plasma aldosterone to renin ratio as a screening test among Italian hypertensives. Am J Hypertens 2002;15(10 Pt 1): Brown NJ. Aldosterone and end-organ damage. Curr Opin Nephrol Hypertens 2005;14: Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol 2005;45: Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003; 348: Zannad F, Alla F, Dousset B, Perez A, Pitt B. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES): Rales Investigators. Circulation 2000;102: Fallo F, Veglio F, Bertello C, et al. Prevalence and characteristics of the metabolic syndrome in primary aldosteronism. J Clin Endocrinol Metab 2006;91: Mattsson C, Young WF Jr. Primary aldosteronism: diagnostic and treatment strategies. Nat Clin Pract Nephrol 2006;2: Young WF. Primary aldosteronism: renaissance of a syndrome. Clin Endocrinol (Oxf) 2007;66: Oelkers WK. Effects of estrogens and progestogens on the renin-aldosterone system and blood pressure. Steroids 1996;61: Fommei E, Ghione S, Ripoli A, et al. The ovarian cycle as a factor of variability in the laboratory screening for primary aldosteronism in women. J Hum Hypertens 2009;23: Ferrari P, Shaw SG, Nicod J, Saner E, Nussberger J. Active renin versus plasma renin activity to define aldosterone-torenin ratio for primary aldosteronism. J Hypertens 2004; 22: Olivieri O, Ciacciarelli A, Signorelli D, et al. Aldosterone to Renin ratio in a primary care setting: the Bussolengo Study. J Clin Endocrinol Metab 2004;89: Unger N, Lopez Schmidt I, Pitt C, et al. Comparison of active renin concentration and plasma renin activity for the diagnosis of primary hyperaldosteronism in patients with an adrenal mass. Eur J Endocrinol 2004;150: Nishikawa T, Omura M, Satoh F, et al. Guidelines for the diagnosis and treatment of primary aldosteronism: the Japan Endocrine Society Endocr J 2011;58: Cicala MV, Mantero F. Primary aldosteronism: what consensus for the diagnosis. Best Pract Res Clin Endocrinol Metab 2010;24: Kempers MJ, Lenders JW, van Outheusden L, et al. Systematic review: diagnostic procedures to differentiate unilateral from bilateral adrenal abnormality in primary aldosteronism. Ann Intern Med 2009;151: Stewart PM, Allolio B. Adrenal vein sampling for primary aldosteronism: time for a reality check. Clin Endocrinol (Oxf) 2010;72: Lee JS, Kang MY, Kim SW, Shin CS, Kim SY, Chung JW. The clinical implication and problems of adrenal vein sampling in patients with primary aldosteronism. J Korean Endocr Soc 2007;22: Young WF, Stanson AW. What are the keys to successful adrenal venous sampling (AVS) in patients with primary aldosteronism? Clin Endocrinol (Oxf) 2009;70: Meyer A, Brabant G, Behrend M. Long-term follow-up after adrenalectomy for primary aldosteronism. World J Surg 2005;29: Sawka AM, Young WF, Thompson GB, et al. Primary aldosteronism: factors associated with normalization of blood pressure after surgery. Ann Intern Med 2001;135: Sywak M, Pasieka JL. Long-term follow-up and cost benefit of adrenalectomy in patients with primary hyperaldosteronism. Br J Surg 2002;89: Celen O, O'Brien MJ, Melby JC, Beazley RM. Factors influencing outcome of surgery for primary aldosteronism

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10. Interpretation of diagnostic test.hwp

10. Interpretation of diagnostic test.hwp 대한내과학회지 : 제 92 권제 4 호 2017 https://doi.org/10.3904/kjm.2017.92.4.387 Interpretation of diagnostic test 저칼륨혈증을동반한고혈압환자에대한접근 한림대학교의과대학내과학교실 김윤정 류옥현 Approach to the Patient with Hypertension Accompanied by