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1 대한내과학회지 : 제 80 권제 6 호 2011 종설 (Review) 한국의비심인성흉통의진단및치료의고유한특징 건국대학교의학전문대학원내과학교실, 건국대학교병원소화기병센터 김정환 Distinct Characteristics of Noncardiac Chest Pain in Korea Jeong Hwan Kim Department of Internal Medicine, Digestive Disease Center, Konkuk University School of Medicine, Konkuk University Medical Center, Seoul, Korea Gastroesophageal reflux disease (GERD) is the most common cause of noncardiac chest pain (NCCP) and was reported to cause 41% of cases of NCCP in a recent study of Korea. Typical reflux symptoms were reported to be frequent in Korean patients suffering from NCCP. Therefore, a careful history of the symptoms is relatively indicative of GERD diagnosis in Korea. In Korea, contrasting Western countries, patients with NCCP but present no alarm features should undergo to exclude gastric cancer or peptic ulcer. In a primary care setting, PPI test is sufficient for the presumptive diagnosis of GERD. Specifically in Korea, the optimal duration of PPI test may be at least 2 weeks because of less frequent or atypical GERD symptoms. In patients diagnosed with GERD-related NCCP, the initial long term therapy (more than 2 months) followed to the maintenance therapy is required to alleviate symptoms. Esophageal dysmotility is relatively uncommon, and pain modulators seem to offer significant improvement in chest pain control in non GERD-related NCCP. Unfortunately, the majority of traditionally available tricyclics or heterocyclics have many undesirable effects. Therefore, newer drugs with fewer side effects may be needed, such as the serotonin-norepinephrine reuptake inhibitors. (Korean J Med 2011;80: ) Keywords: Noncardiac chest pain; Gastroesophageal reflux disease; Esophagogastroduodenoscopy; Proton pump inhibitor 서론흉통을호소하는환자들은관상동맥질환의임상적중요성때문에관상동맥조영술및운동부하검사등을통해환자의증상이심인성인지의여부를먼저평가받게된다. 이러한검사결과심장의이상이없이반복적으로흉통을호소하는경우를비심인성흉통 (noncardiac chest pain, NCCP) 이라하며 [1-3] 일반인에서그빈도가약 30% 까지이르는것으로알려져있다 [3,4]. 이처럼 NCCP는비교적드물지않게접할수 있는임상증상이며그예후는비교적좋다 [5]. 하지만 NCCP 환자는지속적인통증및불안감으로인해업무를수행하지못하거나, 일상생활에지장을받거나, 혹은반복하여병원을찾는것으로알려져있다 [6]. 이들은심장에대한검사를실시하여심장질환에의한흉통이배제되었음에도불구하고특별한원인이밝혀지지않을경우흉통의원인에대해상당히불안감을가지게되며따라서필요없는의료이용을증가시켜의료비를상승시킨다. 그러므로 NCCP의원인및그기전을밝히는것이매우중요하다고할수있다. 지속적 * This work was supported by the Konkuk University Medical Center Research Grant

- The Korean Journal of Medicine: Vol. 80, No. 6, 2011 - 증에대한감각역치가저하되어있는과민성이관련있는것으로알려져있다. 이외에자율신경계, 위심장억제반사, 정신질환 ( 공항장애, 불안, 우울증 ), 심리적인요인등이흉통의발생기전으로지적되고있다 [1,14].

2 - The Korean Journal of Medicine: Vol. 80, No. 6, 증에대한감각역치가저하되어있는과민성이관련있는것으로알려져있다. 이외에자율신경계, 위심장억제반사, 정신질환 ( 공항장애, 불안, 우울증 ), 심리적인요인등이흉통의발생기전으로지적되고있다 [1,14]. 본고에서는 NCCP의진단및치료를위해다양한방법및고려해야할사항들에대해살펴보고우리나라에서의고유한상황및특징을토대로하여앞으로나아가야할방향등에대해그간의경험과자료를중심으로알아보고자한다. 진 단 Figure 1. Upper gastrointestinal evaluation. GERD-related NCCP was found in 24 (41%) of 58 subjects on EGD and/or ambulatory 24 h esophageal ph monitoring. Esophageal motility disorder was found in 24 subjects (41%) including 18 with ineffective esophageal motility, 4 with nutcracker esophagus, one with hypertensive LES, and one with achalasia. non GERD, non GERD-related NCCP; Hyper LES, hypertensive LES; Nutcracker, nutcracker esophagus; IEM, ineffective esophageal motility. 인 NCCP를호소하는환자에서흉통의원인질환을규명해줌으로써환자는심리적불안을덜고적절한치료를통해보다안정된생활을영위할수있을것이다 [7,8]. NCCP를일으키는질환은다양하며, 미세혈관협심증, 근골격계질환, 정신과적질환, 종격동및늑막질환, 결체조직질환, 그리고담도및위장관질환등여러원인이관여하며 [9,10], 최근그원인으로식도질환이중요시되고있고그중위식도역류질환 (gastroesophageal reflux disease, GERD) 이가장흔한원인으로알려져있다 [1,11,12]. 최근국내에서시행된전향적인연구에따르면 NCCP의원인중약 40% 가 GERD임이보고되었고 (Fig. 1) [13], 이와같이국내에서도그원인으로 GERD가가장중요하다고할수있다. GERD 이외에 NCCP의중요한원인이되는식도질환으로써내장신경과민증, 식도운동질환등이비교적빈번한빈도를차지한다. NCCP의기전은명확히규명되어있지않다. 식도질환에의한흉통은식도가심장과공통신경지배를받고있어위산, 펩신, 담즙등이식도를자극할때식도상피세포에있는화학적수용체가자극되거나, 식도의확장이나경련등에의하여물리적자극수용체의자극, 혹은온도수용체를통한자극등에의해서도일어난다고알려져있으며, 또한통 NCCP 의가장흔한원인질환으로는 GERD 를들수있으며, 서양에서는그빈도가 60% 에까지이르는것으로보고되고있다 [15]. 한편, GERD 와관계없는 NCCP (non GERD-related NCCP) 환자중약 30-40% 는식도운동질환으로부터, 나머지는식도의통증의과감각, 즉내장과민성으로부터나타난다고여겨진다. 따라서 NCCP의식도관련병태생리는 GERD, 식도운동질환그리고내장과감각으로정리할수있다. 그러나 NCCP의병태생리를명확히규명하여임상적으로적용하는일은쉽지않다. 심장질환에의한흉통이배제된 NCCP 환자들에서식도질환의가능성을염두에둘때, 현재까지잘알려진검사로는상부위장관내시경 (esophagogastroduodenoscopy, EGD), 식도내압검사 (manometry), 24시간보행성식도 ph 검사및프로톤펌프억제제 (proton pump inhibitor, PPI) 를투여하고증상의변화를관찰하는 PPI 검사가있으나 [16], NCCP의원인질환에대한 gold standard는없는실정으로그상황에따라위의검사들을복합적으로사용할수있다. 최근에는다채널강내임피던스 -ph 검사 (multichannel intraluminal impedance-ph metry, MII-pH), 고해상도식도내압검사 (high resolution manometry, HRM) 등이소개되어임상에서이용되고있다. 비심인성흉통과전형적인위식도역류질환증상 NCCP 환자들이호소하는증상은다양한양상으로나타날수있으며, 흉통이외에가슴쓰림 (heartburn), 산역류 (acid regurgitation) 증상및속쓰림, 소화불량등의위장관증상외에인두불편감, 호흡곤란등의다양한형태로나타날수있다. 따라서그증상에대한분석은매우중요하다고할수있다. 전형적인 GERD 증상이라고하면, heartburn과 acid

3 - Jeong Hwan Kim. Distinct characteristics of noncardiac chest pain in Korea - regurgitation을들수있으며, 서양및동양의일부연구결과를보면그증상과원인질환과의연관성에대해이견이있으며 [12,15], 실제로증상과원인질환과의관계를직접적으로분석한연구도드문실정이다. 저자등은 NCCP 환자를대상으로설문지및인터뷰를통해그증상의양상에따라 heartburn과 acid regurgitation등전형적인 GERD 증상을가지는군과그렇지않은군으로나누었고, 두증상군에서 EGD 와 24시간식도 ph를통해진단된 GERD와연관된 NCCP (GERD-related NCCP) 의예측도를조사하였다. 그결과전형적인 GERD 증상을가지는군에서 GERD-related NCCP의양성예측도및민감도가 65-70% 였다 [13]. 이연구는이전에보고되었던증상과그원인질환과의연관성에대한여러이견에대해국내에서시행된연구로서 NCCP 환자들이호소하는증상에대한분석의중요성을나타내었으며우리나라현실에서일차의료기관에서도 NCCP 환자의원인질환을예측하는데도움이될것으로보인다. 비심인성흉통환자에서상부위장관내시경검사의필요성 NCCP 환자의 EGD 결과에서비정상적인결과, 즉역류성식도염 (reflux esophagitis) 으로진단되는경우는전세계적으 로약 5-35% 로비교적낮게보고되어왔다 [12,16-19]. 따라서 NCCP 환자에서 EGD의진단적역할에대해의문을가지게된다. 우리나라에서는대체로심장질환에의한흉통이배제된환자들에대해 EGD를먼저시행하는경향이있으나서양의 guideline에서는 NCCP 환자중경고증상이있는경우에만 EGD를먼저시행할것을권고하고있다 [14]. 최근저자등은 NCCP 환자의 EGD 결과, reflux esophagitis으로진단되는경우가 20% 였고그리높지않은수치임에도불구하고 EGD를먼저시행할것을권고하였다 [13]. EGD 는식도및위, 십이지장의구부를육안적으로직접관찰할수있는유일한검사로서 reflux esophagitis 진단의역할이외에그로인한합병증을확인하고, 특히위암이나소화성궤양등상부위장관의다른병변을감별하기위하여필요한검사이다 [20]. 따라서위암이나소화성궤양등의빈도가높은우리나라에서는경고증상이없는경우라하더라도, EGD 는필요한검사라고할수있다. 비심인성흉통에서 PPI 검사의기간은 1주로충분한가? PPI 검사는강력한위산분비억제제인 PPI를투여하고증상의변화를관찰하는방법으로서현재서양에서는 GERD Table 1. PPI test performance summaries in noncardiac chest pain Study N PPI, Dose, Duration Fass Omeprazole, 60 mg, 1 wk Bautista Lansoprazole 90 mg, 1 wk Fass Rabeprazole 40 mg, 1 wk Pandak 2002 Squillace Omeprazole, 80 mg, 2 wk 17 Omeprazole 80 mg, 1 day Xia Lansoprazole 30 mg, 4 wk Chambers 1998 Dickman Omeprazole 40 mg, 6 wk 35 Rabeprazole 40 mg, 1 wk Study Design parallel group GERD Responder Reference standard (s) 62 >50% ph-metry, 45 >50% ph-metry, 60 >50% ph-metry, 53 >50% ph-metry, Sensitivity Specificity PPV NPV LR+ LR >50% ph-metry >50% ph-metry Open label 17 No a priori definition 35 >50% ph-metry, ph-metry PPI, proton pump inhibitor; randomized controlled trial; PPV, positive predictive value; NPV, negative predictive value; LR+, positive likelihood ratio; LR, negative likelihood ratio.

4 - 대한내과학회지 : 제 80 권제 6 호통권제 610 호 진단에있어서일차적으로사용되고있는경향이다. PPI 검사는간편하고, 비침습적이며, 비용이절감되고, 민감도가높으며, 치료효과의예측이직접가능하다. 반면에특이도가낮고, 결과해석이통일되지않는등의단점도가지고있어일부보고에서는그진단적가치가과장되었다고평가하기도하지만, 최근보고된메타분석등을통해보았을때역시 PPI 검사는현재로서는 GERD 및 NCCP의일차적인진단방법으로인정되는추세이다 (Table 1) [21,22]. PPI 검사의이론적근거를살펴보면, 위산은 GERD의증상유발에주된작용을하며 PPI는강한위산분비억제작용을한다 [23]. 따라서 PPI는 GERD의증상호전에탁월한효과를보이고, 부작용이거의없고안전한것으로알려져있다. PPI 검사에서 PPI 투여용량은보통치료용량의두배가고려되나, PPI 검사의적정기간에대해서는다소이견이있다 [24,25]. Fass 등은 NCCP 환자를대상으로한이중맹검연구에서 PPI 검사의진단적유용성을처음보고하였는데, PPI 투여후증상호전에서위약군과확연한차이를보여민감도와특이도가각각 78.3%, 85.7% 로높았다고보고하였으며 PPI 투여기간으로는 7일이면충분하다고하였다 [16]. 그이후로많은연구에서 PPI 검사의유용성이입증되어왔으며 [21, 26-29], 국내에서도 Jung 등이다기관연구를통해 PPI 검사가전형적인증상을가지는 GERD에대해 79% 의민감도를나 타낸다고보고하였다 [30]. 최근저자등은 EGD와 24시간식도 ph 검사를통해 GERD-related NCCP로진단된환자를예측함에있어서 PPI 검사가 83% 의민감도를보였고, 따라서국내에서도 NCCP 의진단에 PPI 검사가유용함을입증하였다. 하지만우리나라의경우, 일반적으로비전형적인증상이동반되는경우가흔하고, NCCP 의빈도가서양만큼빈번하지않는점등을고려하여 [31-33], 서양과는달리, 7일로는충분하지않고 14일의기간이적정함을보고하였다 (Figs. 2 and 3) [34]. 다른검사들의임상적유용성식도내압검사 GERD 에서하부식도괄약근 (lower esophageal sphincter, LES) 의역할이매우중요하며, GERD 와비효과적식도운동 (ineffective esophageal motility) 이직접적또는간접적으로연관관계가있다는것이알려져있으나, GERD 를진단함에있어서단독으로 LES 압력을측정하는것에진단적의의를부여할수는없다. 서양의보고에의하면식도운동질환이 NCCP 환자의 30% 까지차지한다는보고가있으나동양에서그비율은보다낮은것으로여겨진다 [13]. American Gastroenterological A B Figure 2. A comparison of PPI test between GERD-related NCCP and non GERD-related NCCP groups. During the second week of the PPI trial (B), the percent of positive PPI tests was significantly higher in GERD-related NCCP group (81%) than non GERD-related NCCP group (27%) (p = 0.001). However, during the first week of the PPI trial (A), there was no significant difference between the two groups (GERD vs. non GERD = 50% vs. 23%, p = 0.1). Figure 3. Receiver operating characteristics (ROC) curve of PPI test for GERD-related NCCP during the first week (A) and the second week (B). The reduction in chest pain corresponded to 0.78 in the area under ROC with an accuracy of 77.1% during the second week of PPI test. Additionally, there was significant difference between the areas under ROC curves of the first and second week of PPI test (p < 0.05)

5 - 김정환. 한국의비심인성흉통의진단및치료의고유한특징 - Association guideline에보면 NCCP 환자에서처음시행해야할검사로 manometry 를배제하고있다 [2,35]. 최근 HRM이등장하였고, achalasia나 diffuse esophageal spasm 등원발성식도운동질환을평가하는데있어서기존의 manometry 보다유용함이보고되고있으나, NCCP의진단에있어서는향후더많은연구가필요하다. 24시간보행성식도 ph 검사 EGD에서 reflux esophagitis를보이지않는위식도역류의진단에널리사용되고있는검사방법으로 24시간보행성식도 ph 검사가있다. 그동안의연구결과이검사는재현성이있다고확인되었고, 컴퓨터를이용해위식도역류에대한여러정량분석이가능하기때문에 GERD의진단에서유용한검사로여겨졌다 [36,37]. 그러나이검사는환자에게불편감을주고비용효과적이지않아 1차의료기관에서는거의이용되기가어렵다. 한편, 위음성의결과가나오는경우도드물지않으며, 양성으로나오더라도그것은증상과의연관성을의미할뿐인과관계를증명할수는없다는한계점이있다. 따라서현재는그유용성이떨어진다고할수있다 [1,38]. 다채널강내임피던스-pH 검사산의역류를측정하기위한 24시간보행성식도 ph 검사는식도가위산에노출된정도를평가할수있고, 실제산의역류를찾아낼수있으며, 식도의산청소능을간접적으로평가할수있다. 하지만실제로비전형적증상및비미란성위식도역류질환 (nonerosive reflux disease, NERD) 을진단할때 24시간보행성식도 ph 검사는그민감도가낮을뿐만아니라약산또는비산역류및역류중재역류를찾아낼수없다. 최근개발된 MII-pH는여러개로구성된전극중에서각각두전극사이에전류를보내서저항변화에기초한통과물의성질을측정하고, 물질의이동을감지할수있는임피던스의성질과산도를결정하는 ph 검사의조합으로식도의음식물통과와역류의성상을더욱세분화하여분석할수있도록고안되었다. 즉산, 약산, 비산역류나재역류를감별할수있고, 기체상이나액체상등역류된물질의성상까지도구분할수있다 [39,40]. 최근 Kim 등의국내연구는 MII-pH를통해 NCCP의진단률을향상시킬수있다고보고한바있다 [41]. 치료 NCCP의가장흔한원인은 GERD이며따라서이에대한치료는위산분비억제제이다. 한편, non GERD-related NCCP 의경우식도운동질환및내장감각과민성을고려해야한다. GERD-related NCCP의경우 PPI가일차선택약제이다. GERD-related NCCP 에서적절한치료효과를보려면 PPI를 2 개월이상투여하여야하며, 초치료후유지요법이필요하다. 제산제와 H 2 수용체길항제는효과가떨어지며, PPI로초치료에성공한경우라도 H 2 수용체길항제로 step-down 치료를하면증상이재발하기쉽다 [42-44]. Non GERD-related NCCP 중식도운동질환에대한치료로는평활근수축을조절하는약물등이제시되어지나그효과에대한연구보고는드물며, 내장과감각의조절등을위해 trycyclic antidepressants (TCA), trazodone 그리고 serotonin uptake inhibitors (SSRIs) 등이사용될수있는것으로보고되고있다 [45,46]. 최근저자등은기능적인 heartburn을가진젊은연령의환자에서새로운정신작용약제인 selective serotoninnorepinephrine reuptake inhibitor (SNRI) 와위약의효과를비교하는전향적이중맹검연구를시행하였고, SNRI 가효과적임을보고하였다 [47]. SNRI 는기존에사용되던약제에비해부작용이거의없는약제로써, non GERD-related NCCP 뿐만아니라, 기능성위장관질환에있어서향후치료전략을세우는데도움이될것으로여겨진다. 맺음말 : 우리나라에서의비심인성흉통 NCCP는서양뿐만아니라동양에서도비교적흔한질환으로서, 삶의질이의미있게저하된다. 그러므로이에대해서올바르게이해하는것은매우중요하다. NCCP는우리나라에서도흔한질환임에도불구하고아직까지우리의현실에맞는진단및치료에대한지침이없이, 단지서양의진단및치료의기준이도입되어있는현실로써, 이를그대로적용하기어려운경우가있다. 따라서보고된문헌들에따른객관적사실에근거하여우리나라의현실에맞는 NCCP의진단및치료에대해다음과같은기준을제시해본다 (Fig. 4). 첫째, NCCP 의원인중 GERD 가가장흔하며따라서 GERD 의전형적인증상인 heartburn과 acid regurgitation 및비전형적인증상에대해서도신뢰성이높은설문지및적극적인

6 - The Korean Journal of Medicine: Vol. 80, No. 6, Figure 4. Proposed diagnostic evaluation of patients with NCCP in Korea. 인터뷰를통해증상에대한분석이필요하다. 둘째, 위암이나소화성궤양등의빈도가높은우리나라에서는경고증상이없는경우라하더라도, 소수의예외를제외한대부분의환자에서먼저 EGD를시행한다. 셋째, EGD 에서이상이없는경우 PPI 검사를시행하되, 치료용량의두배용량을투여하며, 그적정기간은서양과는달리 2주로한다. 넷째, 24 시간식도 ph 검사및 manometry 는일차적인진단검사로써보다는적응증이되는경우에제한적으로이용한다. 다섯째, NCCP의치료로써 GERD-related NCCP 에는 PPI를 non GERDrelated NCCP에서는식도운동질환이배제된다면새로운정신작용약제인 SNRI 를고려해볼수있다. 중심단어 : 비심인성흉통 ; 위식도역류질환 ; 상부위장관내시경 ; 프로톤펌프억제제 REFERENCES 1. Faybush EM, Fass R. Gastroesophageal reflux disease in noncardiac chest pain. Gastroenterol Clin North Am 2004;33: Eslick GD, Fass R. Noncardiac chest pain: evaluation and treatment. Gastroenterol Clin North Am 2003;32: Eslick GD, Jones MP, Talley NJ. Non-cardiac chest pain: prevalence, risk factors, impact and consulting--a population-based study. Aliment Pharmacol Ther 2003;17: Locke GR 3rd, Talley NJ, Fett SL, Zinsmeister AR, Melton LJ 3rd. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Olmsted County, Minnesota. Gastroenterology 1997;112: Chambers J, Bass C. Chest pain with normal coronary anatomy: a review of natural history and possible etiologic factors. Prog Cardiovasc Dis 1990;33: Eslick GD, Talley NJ. Non-cardiac chest pain: predictors of health care seeking, the types of health care professional consulted, work absenteeism and interruption of daily activities. Aliment Pharmacol Ther 2004;20: Nevens F, Janssens J, Piessens J, Ghillebert G, De Geest H, Vantrappen G. Prospective study on prevalence of esophageal chest pain in patients referred on an elective basis to a cardiac unit for suspected myocardial ischemia. Dig Dis Sci 1991;36: Graves EJ, Gillum BS. Detailed diagnoses and procedures, National Hospital Discharge Survey, Vital Health Stat ;130: Achem SR, DeVault KR. Recent developments in chest pain of undetermined origin. Curr Gastroenterol Rep 2000;2: Van Handel D, Fass R. The pathophysiology of non-cardiac chest pain. J Gastroenterol Hepatol 2005;20 Suppl:S Pandak WM, Arezo S, Everett S, et al. Short course of omeprazole: a better first diagnostic approach to noncardiac chest pain than, manometry, or 24-hour esophageal ph monitoring. J Clin Gastroenterol 2002;35: Wong WM, Lai KC, Lau CP, et al. Upper gastrointestinal evaluation of Chinese patients with non-cardiac chest pain. Aliment Pharmacol Ther 2002;16: Kim JH, Rhee PL, Park EH, Son HJ, Kim JJ, Rhee JC. Clinical usefulness of subgrouping of patients with non-cardiac chest pain according to characteristic symptoms in Korea. J Gastroenterol Hepatol 2007;22: Fass R, Dickman R. Non-cardiac chest pain: an update. Neurogastroenterol Motil 2006;18: Richter JE. Chest pain and gastroesophageal reflux disease. J Clin Gastroenterol 2000;30:S39-S Fass R, Fennerty MB, Ofman JJ, et al. The clinical and economic value of a short course of omeprazole in patients with noncardiac chest pain. Gastroenterology 1998;115: Bautista J, Fullerton H, Briseno M, et al. The effect of an empirical trial of high-dose lansoprazole on symptom response of patients with non-cardiac chest pain-a randomized, double-blind, placebocontrolled, trial. Aliment Pharmacol Ther 2004;19: Frobert O, Funch-Jensen P, Jacobsen NO, et al. Upper in patients with angina and normal coronary angiograms. Endoscopy 1995;27: Dickman R, Mattek N, Holub J, Peters D, Fass R. Prevalence of upper gastrointestinal tract findings in patients with noncardiac chest pain versus those with gastroesophageal reflux disease (GERD)-related symptoms: results from a national endoscopic database. Am J Gastroenterol 2007;102: Kapoor N, Bassi A, Sturgess R, Bodger K. Predictive value of alarm features in a rapid access upper gastrointestinal cancer service. Gut 2005;54: Cremonini F, Wise J, Moayyedi P, Talley NJ. Diagnostic and therapeutic use of proton pump inhibitors in non-cardiac chest

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<B0E6C8F1B4EBB3BBB0FAC0D3BBF3B0ADC1C E687770> 개원의와함께하는임상강좌 2011 역류성식도질환제대로이해하기 Division of Gastroenterology, Department of Internal Medicine, Kyung Hee University College of Medicine, Seoul, Korea Jae-Young Jang, M.D., PhD. 개원의와함께하는임상강좌 2011 109 최신치료