Focused Issue J Korean Diabetes 2018;19:160-167 https://doi.org/10.4093/jkd.2018.19.3.160 Vol.19, No.3, 2018 ISSN 2233-7431 당뇨병성자율신경병증의진단및치료 김종화세종병원내분비대사내과 Diagnosis and Management of Diabetic Autonomic Neuropathy Chong Hwa Kim Division of Endocrinology and Metabolism, Department of Internal Medicine, Sejong General Hospital, Bucheon, Korea Abstract Diabetic autonomic neuropathy (DAN) is a serious and common complication of diabetes, although it is often overlooked. Abnormal autonomic function tests are often found in peoples with diabetic peripheral neuropathy. Autonomic neuropathies affect the autonomic neurons (parasympathetic, sympathetic, or both) and are associated with a variety of site-specific symptoms. The symptoms and signs of DAN should be elicited carefully during the medical history and physical examination. Major clinical manifestations of DAN include hypoglycemia unawareness, resting tachycardia, orthostatic hypotension, gastroparesis, constipation, diarrhea, fecal incontinence, erectile dysfunction, neurogenic bladder, and sudomotor dysfunction with either increased or decreased sweating. When a patient has signs and symptoms of DAN, various autonomic function tests should be performed. Recognition and management of DAN may improve symptoms, reduce sequelae, and improve quality of life. Clinically relevant diabetic autonomic neuropathies such as cardiovascular, gastrointestinal, genitourinary, and sudomotor dysfunction should be considered in the optimal care of patients with diabetes. The present review summarizes the latest knowledge regarding clinical presentation, diagnosis, and management of DAN. Keywords: Autonomic neuropathy, Diabetic neuropathy Corresponding author: Chong Hwa Kim Division of Endocrinology and Metabolism, Department of Internal Medicine, Sejong General Hospital, 28 Hohyeon-ro 489beon-gil, Sosa-gu, Bucheon 14754, Korea, E-mail: drangelkr@hanmail.net Received: Jul. 27, 2018; Accepted: Aug. 13, 2018 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/bync/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright c 2018 Korean Diabetes Association 160 The Journal of Korean Diabetes
김종화 서론 본론 당뇨병성자율신경병증 (diabetic autonomic neuropathy) 은여러장기의자율신경계뉴런 ( 부교감신경, 교감신경 ) 에영향을주어발생하는특징적인증상과징후들을포함한다. 그러므로병력청취및신체검사를통하여자율신경계이상에대한증상및징후들을찾아내는것이중요하다. 당뇨병성자율신경병증은당뇨병초기부터발생하며보고자에따라서다양하게보고하고있다 [1]. 위험인자로는나이, 당뇨병유병기간, 혈당조절, 망막증과신증, 그리고심혈관질환등이있다 [1,2]. 증상이있는제2형당뇨병환자는 5% 미만으로당뇨병진단초기부터자율신경기능검사를시행해야하고, 특히말초신경병증으로진단한경우는 50% 에서자율신경병증이동반되기때문에자율신경병증에대한검사를해야한다 [1,2]. 당뇨병성자율신경병증의주요임상증상들은안정시빈맥, 기립저혈압, 위부전마비, 변비, 설사, 변실금, 발기부전, 신경성방광, 저혈당무감지증및발한장애등의증상들이있다. 심혈관계자율신경병증이당뇨병성자율신경병증에서임상적으로가장중요하며위장관장애, 비뇨생식기및발한장애등도당뇨병환자에서최적의치료를위해서는관심을기울여야한다. 또한당뇨병성자율신경병증은이환율과사망률증가, 삶의질감소와일상생활에제한을가져오기때문에조기진단과관리가중요하다. 당뇨병성자율신경병증치료의일반원칙은다른합병증의관리와마찬가지로적절한혈당조절과다요소위험요인의관리가필요하다. 이에더하여개별적인당뇨병성자율신경병증의증상완화를목적으로다양한약물치료가권고되며이는환자의삶의질을향상시킨다. 1. 심혈관계자율신경병증 (cardiovascular autonomic neuropathy) 처음진단된제1형당뇨병환자에서심혈관계자율신경병증의유병률은매우낮지만당뇨병기간에따라유병률이증가하는양상을보이며, DCCT/EDIC (Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications) 연구에서는 20년의당뇨병병력을가진당뇨병환자에서 30% 의심혈관계자율신경병증의유병률을보고하고있다 [3,4]. 제2형당뇨병환자에서도심혈관계자율신경병증의유병률은당뇨병의유병기간에따라증가하는양상을보이며, 15년이상의병력을가진환자에서는 60% 까지유병률을보고하고있다 [3,4]. 또한심혈관계자율신경병증은내당능장애, 인슐린저항성또는대사증후군에서도발생할수있다. 심혈관계자율신경병증은심혈관질환사망률, 부정맥, 무증상심근허혈, 주요한심혈관질환발생, 심근기능이상등에대한독립적인위험인자로작용하므로심혈관계자율신경병증을조기에진단하는것은매우중요하다. 제1형당뇨병환자를대상으로연구한 EURODIAB 전향적코호트연구에서심혈관계자율신경병증은사망률의가장강력한위험요소로보고하고있다 [5]. 당뇨병동반유무와관련하여안정형심장질환을가진 31,531명의환자를 5년간추적관찰한 2개의대규모심혈관질환연구결과에서심혈관계자율신경병증의간접적인척도로사용한심장박동수는심혈관질환의증가와전체사망률의증가의의미있는독립적인연관성을보였다 [6-8]. 또한 8,000명이상의제2형당뇨병환자를대상으로연구한 ACCORD (Action to Control Cardiovascular Risk in Diabetes) 연구에서도심혈관계자율신경병증이동반된환자는모든전통적인심혈관질환발생위험인자와약물복용을포함한다른다양한위험인자를보정한후에도모든원인의심혈관질환사망률은 2.14배로높았다 [9]. www.diabetes.or.kr 161
Focused Issue 당뇨병성자율신경병증의진단및치료 엄격한혈당및혈압관리가심혈관계자율신경병증의징후가있는사람들에서는심혈관계사건의위험을증가시킬수있다는연구결과가있으며, 심혈관계자율신경병증은당뇨병성신증및만성신장질환의진행을독립적으로예측한다 [10-12]. 1) 증상및진단심혈관계자율신경병증의가장흔한증상은기립시발생하는머리가가벼운느낌, 두근거림, 흐릿함, 실신등의증상이있다 [1]. 그러므로의사는진료실에서환자에게이러한증상에대해반드시질문해야한다. 저혈당무감지증에대한스크린을해야하는데심혈관계자율신경병증과동반되어나타나기도한다 [13]. 심혈관계자율신경병증의진단은증상과징후로가능하며, 호흡에따른심박동수변동 (heart rate variability), 발살바조작에따른심박동수변동및기립시혈압의변동검사방법등이포함된다 [1,14,15]. 다른동반된질환이나약물의효과 / 상호작용등이심혈관계자율신경병증의증상또는징후와유사하게나타날수있으므로감별진단하는것이중요하다. 또한, 많은약제의복용은직접또는간접적으로심혈관계자율신경병증에영향을줄수있다. 심혈관계자율신경병증초기단계에는대부분에서무증상일경우가많으며, 심호흡동안심박동수변동감소에의해서만발견될수있다 [1,15]. 심박동수변동검사는 1 환자가앉은자세에서일어나기시작할때심전도검사를하거나 2 1~2분의깊은호흡동안심전도검사를실시하여심박동수변동을계산하는방법으로시행할수있다 [13,15]. 심혈관계자율신경병증이상당히진행된경우에는안정시빈맥 (> 100) 이발생하거나운동불내성이생길수있다 [1,15]. 또한자세변동시심장박동수가적절히증가하지않으면서수축기혈압또는이완기혈압이각각 20 mm Hg 이상또는 10 mm Hg 이상감소되는기립성저혈압이발생할수있다 [16]. 2) 치료심혈관계자율신경병증환자는너무엄격한혈당관리를피하여적정수준으로조절해야하고, 동반된위험요소의관리가매우중요하며수술시주의를요한다. 초기치료는전반적인심혈관계운동기능의향상을목적으로하며운동요법으로초기또는진행성심혈관계자율신경병증의호전을기대할수있다. 기립성저혈압은증상악화와관련이있는약물 (tricyclic anti-depressant [TCA], monoamine oxidase inhibitor, 도파민촉진제, 이뇨제등 ) 중단, 자세의변화를서서히하고, 더운날씨에무리한외부활동, 기침, 도보등을피할것, 몸에적합한탄력붕대나스타킹의착용등으로대비한다 [17,18]. 심한기립성저혈압시염류코르티코이드인플루드로코르티손 (0.1~0.4 mg/ 일 ) 과고염분섭취를적용하기도하나고혈압과말초부종을악화시킬수있어주의를요한다 [17-19]. 또한미도드린 (midodrine, a peripheral, selective, direct a1-adrenoreceptor agonist) 을사용할수있다 [20]. 빈혈이동반된경우, 조혈호르몬 (erythropoietin) 이도움이될수있다 [19]. 2. 위장관자율신경병증 (gastrointestinal autonomic nueropathy) 위장관자율신경병증은식도운동장애, 위무력증 ( 위배출지연 ), 변비, 설사및대변실금등의여러가지위장관기능장애증상을나타내며위장관어떤장기에서도발생할수있다. 위장관자율신경병증의유병률에대한연구는대규모환자를대상으로하는연구보다는선택된집단을위주로하는연구가주된연구이고, 진단방법에따라결과는다양하게보고되고있다 [21]. 유일하게대규모환자를대상으로한연구에서는 10년동안의누적발생빈도는제1형당뇨병환자에서 5% 로제2형당뇨병환자 1%, 대조군 1% 보다높게보고되고있다 [22]. 위장관운동장애는혈당관리 ( 예 : 인슐린또는경구당뇨병약제용량 ) 에영향을줄수있는데, 음식물의흡수와인 162 https://doi.org/10.4093/jkd.2018.19.3.160
김종화 슐린및경구당뇨병약제의약동력학사이에불일치를초래하여혈당조절이힘들어지고예기치않은저혈당발생의원인이될수있다 [23,24]. 1) 증상및진단위장관운동장애는다양한증상과징후로나타날수있다. 당뇨병환자에서병력청취를할때조기포만감, 위장관팽만, 메스꺼움, 구토, 소화불량및복통등과같은증세를확인하는것이중요하다. 하지만대부분의위장관운동장애의증상은임상적으로잘나타나지않을수있으며, 증상또한위장운동지연의중증도와반드시일치하지는않으며위배출이상과도관련이없는경우가많다 [23,24]. 혈당변동폭이심한현상을보이는당뇨병환자는위장운동의변화를초래할수있으며일부약물, 특히아편유사제제, 다른통증조절제및글루카곤유사펩타이드 1 수용체작용제등도이러한증상이나타날수있다 [25,26]. 그러므로위장관운동장애를진단하기위해서는위장운동에영향을줄수있는요소들을배제한후진단해야한다 [27,28]. 위장관운동장애를진단하기위한검사를실시하기전에위내시경등을통한위출구폐쇄질환또는소화성궤양질환유무를먼저확인해야한다. 위장관운동장애를진단하기위한가장좋은방법은소화성고체음식물섭취후 4시간동안 15분간격으로신티그라피를이용한위배출능을측정해야하고검사전혈당을적절하게잘조절하여위양성의결과를피하는것이중요하다 [23]. 2) 치료위마비 (gastroparesis) 의치료는식사요법, 혈당조절, 약물요법과수술적요법등이있다. 저지방, 저섬유소식사를자주, 소량씩하도록권고하며유동식식사요법이나경공장루영양법도시도할수있다. 총경정맥영양법은위장관영양법이불가능한경우에고려한다 [23]. 위장운동의변화를초래할수있으며일부약물들특히아편유사제제, 다른통증조절제및글루카곤유사펩타이드 1 수용체작용제, dipeptidyl peptidase 4 억제제등은피한다 [23,29]. 약물요 법에는메토클로프라마이드, 돔페리돈, 에리스로마이신등을사용한다. 비약물적요법으로위전정부에보툴리눔독소 (botulinum toxin) 주입이나전기자극을시도하며기존치료에불응성인경우수술적치료도고려한다 [29]. 당뇨병성장병증 (diabetic enteropathy) 중설사는로페라마이드 (2~4 mg씩 1일 4회 ), 장운동항진은코데인 (30 mg씩 1일 4회 ), 세균과증식은항생제, 그리고항문직장기능부전은바이오피드백등을고려한다 [29]. 3. 비뇨생식기자율신경병증 (genitourinary autonomic neuropathy) 당뇨병성자율신경병증은성기능장애및방광기능장애를포함한비뇨생식기장애를일으킬수있다. 남성에서는당뇨병성자율신경병증으로인하여발기부전또는역행성사정을유발한다. 발기부전은당뇨병환자에서일반인에비하여 3배정도많이발생한다 [30-32]. 1) 발기부전발기부전은다양한원인에의해발생하므로임상의사는고혈압, 고지혈증, 비만, 흡연, 심혈관질환, 복용하는약물그리고심인성요인과같은다른혈관위험인자도평가해야한다 [31,32]. 성선기능저하를배제하기위해호르몬검사 ( 황체형성호르몬, 테스토스테론, 유리테스토스테론, 프로락틴 ) 가필요할수도있다 [31,32]. 엄격한혈당조절은제1 형당뇨병남성의발기부전발병률을낮추는것과연관성이높지만제2형당뇨병남성에대한증거는부족하다 [33,34]. 혈압조절및고지혈증과같은다른위험인자의조절은많은도움이될수있다 [31]. 발기부전치료는혈당조절의최적화및금주나금연등생활습관개선과함께발기부전을유발할수있는약물들 ( 베타차단제, 이뇨제, TCA 등 ) 에대한평가가필요하다 [31,32]. 금기가없다면일차적으로 phosphodiesterase-5 억제제를사용한다. 이차적치료로주사요법이나수술을고려한다. 남성호르몬부족이동반되면보충요법도고려한다. www.diabetes.or.kr 163
Focused Issue 당뇨병성자율신경병증의진단및치료 정신과적인상담과함께우울증이나불안장애등에대한치료가도움이되며비만환자에서운동요법및체중감소는발기부전을호전시킬수있다. 많아매운음식이나치즈와같은발한유발물질을피하도록한다 [38]. 증상이심한경우 glycopyrrolate와같은약물을시도할수있다 [39]. 2) 하부요로증상과여성의성기능장애하부요로증상은남녀모두에서요실금및방광기능장애 ( 야간빈뇨, 잦은배뇨, 배뇨긴급 ) 로나타나며당뇨병성말초신경병증과동반되어나타나는경우가많다 [35,36]. 여성의성기능장애는당뇨병이없는여성에비해더자주발생하며성욕감소, 성교시통증증가, 성적흥분감소등의증상을호소한다 [36]. 당뇨병환자에서재발성요로감염, 신우신염, 요실금등의증상을호소하거나촉지되는방광의소견을보인다면방광기능평가를해야한다. 당뇨병성방광병증치료는방광배출의호전과요로감염증을예방하는것이치료의목적이다 [34,36]. 일정한시간마다자발성배뇨를하도록교육과함께크레드 (Crede s) 법을병용한다. 베타네콜 (30 mg씩 1일 3회 ) 이나독사조신 (doxazocin) 을투여할수있다. 좀더진행된경우간헐적인도관법을이용하거나, 심한경우에는내괄약근의절제가필요할수도있다. 4. 발한기능장애 (abnormal sweating) 결론 당뇨병성자율신경병증은당뇨병초기부터발생하고, 교감신경과부교감신경모두를포함하는자율신경계에영향을주어자율신경기능부전이불현성또는다양한형태의임상증상으로나타날수있다. 또한당뇨병성자율신경병증은이환율과사망률증가, 삶의질감소와일상생활에제한을가져오기때문에제1형당뇨병환자는진단 5년후부터, 제2형당뇨병환자는당뇨병진단초기부터당뇨병성자율신경병증에대한검사를시행해야한다. 자율신경기능검사에는심혈관계검사인혈압및맥박의변화를포함하여, 위및장운동, 비뇨생식계검사, 땀샘분비및동공수축반사등이있다. 당뇨병성자율신경병증치료의일반원칙은다른합병증의관리와마찬가지로적절한혈당조절과다요소위험요인의관리가필요하며, 다양한당뇨병성자율신경병증증상완화를목적으로다양한약물치료가권고되며이는환자의삶의질을향상시킬수있어조기진단과관리가필요하다. 땀샘기능장애로인하여건조한피부, 무한증, 열불내성등의증상이나타난다 [37,38]. 미각발한장애 (gustatory sweating) 도발생할수있는데음식물을섭취또는경우에따라음식냄새에의해머리와목부위의과도한발한의증상을보일수있다 [37,38]. 또한하지부원위부발한장애 (distal anhidrosis) 도발생하는데, 대부분임상증상은없지만이에대한보상으로체간부와안면부에서땀이많아지는경우도있다. 하지만땀샘기능장애의확실한증상이있어도땀샘기능장애를검사하는것은현재로서는권장되지않는다. 발한기능장애치료는상체의발한증과하체의무한증이특징적인소견으로, 발한증은식사와관련이있는경우가 REFERENCES 1. Spallone V, Ziegler D, Freeman R, Bernardi L, Frontoni S, Pop-Busui R, Stevens M, Kempler P, Hilsted J, Tesfaye S, Low P, Valensi P; Toronto Consensus Panel on Diabetic Neuropathy. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metab Res Rev 2011;27:639-53. 2. Low PA, Benrud-Larson LM, Sletten DM, Opfer- Gehrking TL, Weigand SD, O Brien PC, Suarez GA, Dyck PJ. Autonomic symptoms and diabetic neuropathy: a population-based study. Diabetes Care 2004;27:2942-7. 164 https://doi.org/10.4093/jkd.2018.19.3.160
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