대한소화기학회지 2010;55:217-224 DOI: 10.4166/kjg.2010.55.4.217 REVIEW 식도성흉통의진단과치료 순천향대학교의과대학내과학교실 홍수진 Diagnosis and Management of Esophageal Chest Pain Su Jin Hong, M.D., Ph.D. Department of Internal Medicine, Soonchunhyang University School of Medicine, Bucheon, Korea Esophageal pain that manifests as heartburn or chest pain, is a prevalent problem. Esophageal chest pain is most often caused by gastroesophageal reflux disease (GERD), but can also result from inflammatory processes, infections involving the esophagus, and contractions of the esophageal muscle. The mechanisms and pathways of esophageal chest pain are poorly understood. Vagal and spinal afferent pathways carry sensory information from the esophagus. Recently, esophageal hypersensitivity is identified as an important factor in the development of esophageal pain. A number of techniques are available to evaluate esophageal chest pain such as endoscopy and/or proton-pump inhibitor trial, esophageal manometry, a combined impedance-ph study, and esophageal ultrasound imaging. Proton pump inhibitors (PPIs) have the huge success in the treatment of GERD. Other drugs such as imipramine, trazadone, sertraline, tricyclics, and theophylline have been introduced for the control of esophageal chest pain in partial responders to PPI and the patients with esophageal hypersensitivity. Novel drugs which act on different targets are anticipated to treat esophageal pain in the future. (Korean J Gastroenterol 2010;55: 217-224) Key Words: Esophagus; Chest pain 서론식도성흉통은허혈성심장병의통증과매우유사하여, 흉통의본질을구별하는것은진단과치료에있어매우중요한일이다. 식도성흉통은비심장성흉통 (noncardiac chest pain) 의가장흔한원인이되며, 위식도역류질환 (gastroesophageal reflux disease, GERD) 은식도성흉통발생의가장강력한자극이기때문에 1,2 아칼라지아또는미만성식도경련의가능성이낮은환자에있어시험적양성자펌프억제제 (proton pump inhibitor, PPI) 치료는유용한초기접근방식으로여겨진다. 3 위식도역류질환보다빈도는적지만이차성식도근육경련도식도성흉통의주요원인이며, 1 아칼라지아 ( 특히 vigorous achalasia), 미만성식도경련증은통상적인식도내압검사로확인할수있다. 그러나, 식도종주근 (longitudinal muscle) 의경련은식도내압검사로확인이불가능하여별도의검사로확인하기도한다. 4 그외에도폐쇄성병변에의한이차성식도경련, 다른염증성질환들도급성흉통을유발한다. 이글에서는식도성흉통의원인에대한이해 연락처 : 홍수진, 420-853, 경기도부천시원미구중동 1174 순천향대학교의과대학부천병원내과 Tel: (032) 621-5090, Fax: (032) 621-5080 E-mail: sjhong@schbc.ac.kr Correspondence to: Su Jin Hong, M.D. Department of Internal Medicine, Soonchunhyang University School of Medicine, 1174, Jung-dong, Wonmi-gu, Bucheon 420-853, Korea Tel: +82-32-621-5090, Fax: +82-32-621-5080 E-mail: sjhong@schbc.ac.kr
218 대한소화기학회지 : 제 55 권제 4 호, 2010 와적절한치료에대하여문헌고찰을통하여정리하고자한다. 본론 1. 식도성흉통의정의와유병률간혹심한가슴쓰림 (heartburn) 이흉통으로느껴지기도하지만, 일반적으로식도성흉통은마치허혈성심장병의흉통과아주유사한통증을말한다. 식도성흉통의진단은심장성흉통이아님을관상동맥조영술을위시한검사방법들로확인해야하기때문에쉽지않은과정이며, 심장검사들이음성이라도식도성흉통을직접적으로의미하지는않는다. 때로비심장성흉통 (noncardiac chest pain) 이위식도역류질환에대한문헌등에서식도성흉통의의미로사용되는데이는엄밀하게는올바르지않으며, 단지식도성흉통은비심장성흉통의가장흔한원인이라할수있다. 진단과정이쉽지않기때문에식도성흉통의유병률은대략적으로만추정할수있으나상당히높음을간접적으로알수있다. 심장성흉통과유사한증상을가진환자중위식도역류질환의비율은 22% 에서 66% 로보고되었다. 1,2,5 2. 식도성흉통의발생기전산역류에의한강렬한점막통증은식도성흉통을가장빈번하게유발하며이차성식도근육경련의빈도는이보다적다. 1,2 식도종주근의경련은식도내압검사로검출되지않으며, 내강초음파검사를비롯한다른방법으로확인할수있다. 폐색성식도병변에인한이차성경련도빈도는적지만급성심장성통증과유사한통증을일으킬수있다. 전형적인위식도역류질환의증상이있으나, 내시경에서관찰되는식도점막이정상인경우비미란성역류질환 (nonerosive reflux disease, NERD) 으로부른다. 비미란성역류질환으로추정되는환자의 50% 정도에서 24시간식도산도검사는정상소견을보인다. 6 기능성식도질환에대한 Rome II 위원회는기능성가슴쓰림 (functional heartburn) 을정상식도점막과정상 24시간식도산도검사를가진환자군이라정의하고, 이들을다시산역류시점에서증상을보이는그룹과산역류시점과증상이전혀관련이없는그룹으로분류하였다. 이후 Rome III 위원회는산역류시점에서증상을보이는그룹과양성자펌프억제제에반응을보이는환자들을기능성가슴쓰림에서제외하였다. 7 기능성가슴쓰림환자들은식도풍선팽창이나전기적자극에대하여위식도역류질환환자에비하여낮은통증감각역치를나타낸다. 8 실제로기능성가슴쓰림환자의 90% 는식도풍선팽창또는식도산관류검사 (Bernstein test) 에양성을보였다. 9 식도과민성 (esophageal hypersensitivity) 은기능성가슴쓰림의주요한기전으로여겨지고있다. 스트레스, 불안, 우울과같은정신적자극도식도감각을변화시킬수있으며, 10 담즙산의역류 11 와같은화학적자극, 식도확장, 종주근수축, 식도운동의기계적자극 12 이관여한다고믿어진다. 미주및척수구심성경로는식도로부터감각에대한정보를전달하며, 산유발성염증이나손상은식도구심성신경섬유의반응성을변화시킨다. 그러나염증의정도와증상의심한정도는상관성을보이지않는다. 미주구심성경로는수용체의위치에따라 3군으로분류된다. 점막수용체는휴지기에는반응이없다가점막의급성염증이나손상후유리되는 5-HT (5-hydroxytryptamine) 과같은물질에활성화된다. 13 장력수용체 (tension receptor) 는식도벽장력에대하여반응을나타내며이차성연동운동을일으키거나식괴를감지한다. 척수구심성경로는불쾌감이나통증과같은감각을중추신경계로전달한다. 14 식도의편평상피세포는내인성매개체 (endogenous mediators) 분비를담당하는분비성세포가소장등에비하여적은편이다. Table 1은식도상피세포에존재는수용체들을정리하였으며, 식도에작용하는약물의기전의이해에도움이될수있다. 조직손상이나염증은열 (heat), 이온 (K +, H + ), amines (5-HT, histamine), kinins (bradykinin), prostanoids (PGE2), purines (ATP), cytokines (TNF, IL-1, IL-6), 신경성장인자 (nerve growth factor, NGF) 같은여러가지물리적, 화학적, 생물학적인자들의축적을가져오고, 이러한물질들은특정수용체또는세포전령물질 (cellular messengers) 을통하여신경적감작 (sensitization) 을가져온다. 25 염증성과민성 (inflammatory hypersensitivity) 은세포골격의충실여부에따라다르게나타난다. 세포골격이염증에의해손상되면, 유해물질에의한신경적감작이더쉽게일어나게된다. 3. 식도성흉통의진단전략위식도역류질환의유병률이높기때문에양성자펌프억제제는위식도역류질환연관증상이있는경우별도의진단검사없이시도되는경우가있다. 그러나내시경검사를양성자펌프억제제치료이전에시행하여야하는가는현재까지도논쟁거리이다. 내시경검사로는미란성식도염을평가할수있고, 감염성식도염이나약제유발성식도염등을감별해낼수있다. 한편, 내시경검사에뚜렷한소견이없는환자들에서 24시간식도산도검사가양성자펌프억제제치료이전에필요한것인가도논쟁이되고있다. 그러나현재소화기의사들의일반적인합의는합병증이없는가슴쓰림은검사이전에경험적양성자펌프억제제치료를하는것이다. 증상이양성자펌프억제제치료 4주이내에충분한호전을보이면위식도
홍수진. 식도성흉통의진단과치료 219 Table 1. Receptors of Esophageal Afferents Names Locations Related substances Causes of activation Actions Excitatory P2X, P2Y 15 Bradykinin Receptors (B 1-B 5) 16 iglurs (inotropic glutamate receptors) 17 Vanilloid recptor1 (VR1 or TRPV1) 18,19 Inhibitory GABA B, 20,21 Dorsal root Nodose ganglia Neurons Vagal and spinal esophageal afferents ATP (adenosine triphosphate) Cell damage after or during inflammation Direct activation or sensitization of esophageal afferents Bradykinin Tissue damage Contractile response of smooth muscle Vagal afferents Glutamate Peripheral excitatory modulation of vagal afferent mechanosensitivity Vagal and spinal esophageal afferents Variable to species Guinea pignodose ganglia Vanilloids GABA (gammaamino butyrinc acid) Noxious heat and low ph Rise to a burning sensation - Inhibit mechanosensory stimulus response relationships Ferretvagal afferents GALR1, GALR3 22 Vagal afferents Galanin - Inhibit mechanosensory stimulus response relationships mglur2-4,6-8 (metabotropic glutamate receptors) 23 Vagal afferents Nodose ganglia Glutamate - Inhibit mecahnosensory stimulus response relationships Opioid receptors Vagal afferents Opioids - Reduce the sensitivity of (μ and κ) 24 esophageal vagal tension receptors 역류질환과관련된증상이라추정하고치료하게된다. 잘못된진단을피하고, 위식도역류질환의합병증을구별해내려면 경고증상 유무를잘살펴야한다. 감별해야할질환으로는관상동맥질환, 담낭질환, 위및식도의악성종양, 소화성궤양, 호산구성식도염, 감염성식도염, 부식성식도염등이있다. 이중에서허혈성심질환은질환의사망률이높으므로특히유의하여감별해야한다. 경고증상으로는구토, 위장관출혈의증거, 체중감소, 연하곤란, 빈혈, 심와부종물등이있다. 26,27 하루 2회의충분한양성자펌프억제제치료에도반응을보이지않는가슴쓰림또는흉통에서는내시경검사를통하여바렛식도, 협착, 호산구성식도염, 그외다른질환의진단을확인하기위하여내시경검사가필요하다. 연하곤란이있는경우, 식도의폐쇄성질환이없더라도호산구성식도염을확인하기위하여여러위치에서조직생검을얻어야한다. 28 정상내시경소견을보이며양성자펌프억제제치료에도증상이지속되면역류유도성식도확장 (reflux-elicited esophageal distention) 29 또는역류유도성지속적식도수축 (reflux- elicited sustained esophageal contraction) 30 의가능성을생각할수있다. 이런경우역류억제약물이나항역류수술이필요하다. 역류억제약물로는 GABA B 작용제 (agonist) 인 baclofen 이현재사용가능한유일한약제이다. 불행히도 baclofen은때로부작용으로진정 (sedation) 이나타나기때문에이러한부작용을최소화하고유사한약물작용을보이는새로운 baclofen 유사약물을기대하고있다. 식도내압검사는위식도역류질환으로오인된일부의아칼라지아, 미만성식도경련등을감별할수있다. 최근이용되고있는고해상도내압검사 (high-resulotion manometry) 는아칼라지아와미만성식도경련의비전형적예를보다잘진단할수있다. 고해상도내압검사는내시경검사후두번째진단도구로이용하는것이권장된다. 한편, 식도종주근수축은 1-2 mm의가느다란 catheter probe를이용한내강초음파검사로측정이가능하다. 그러나내강초음파검사는간편하고비침습적이라는장점이있지만, 보행성검사가불가능하며, 판독에많은시간과노력이필요하다는단점이있다. 고해상도내압검사는상부및하부식도조임근을명확하게보
220 The Korean Journal of Gastroenterology: Vol. 55, No. 4, 2010 Table 2. Efficacy and Safety of Therapeutic Trials in Esophageal Chest Pain Drugs Study design Study size (n) Mean age F/M Duration Outcome measure Results Safety analysis Clonidine Double-blind, 60 50 40/20 10 weeks Frequency Imipramine Imipramine: 0.01 mg BID placebo of chest pain decreased prolonged or controlled (CPF) CPF QT interval imipramine crossover (p=0.03) 50 mg QHS clonidine or placebo no effect on BID 37 CPF Nifedipine Double-blind 20 50 8/12 14 weeks Distal esophageal Nifedipine Nifedipine 10-30 mg placebo contraction (DEC), decreased >placebo: TID 33 controlled CPF, severity, DEC amplitude facial crossover index (p<0.005), flushing, Daily CPF, edema, severity, index headache similar to lightheadedplacebo ness, nervousness Botulinum Open-label 29 61 24/5 1-18 CPF Botulinu toxin Not reported toxin 100U prospective months reduced chest Injection 35 pain in 62% (p<0.0001), regurgitation and dysphagia Trazadone Double-blind, 29 47.5 21/8 6 weeks Global index Trazadone Sedation 100-150 mg placebo of health (GIH), increased GIH QD or controlled residual distress, (p=0.02), placebo QD 38 manometric decreased changes residual effect on manometry Amitriptyline, Open-label 21 49.7 14/7 Mean 2.7 Chest pain Tricyclic Sedation, imipramine, retrospective years (0.8-8.6) index (CPI), antidepressants anticholinergic nortriptyline, review dstress (TCA) symptoms desipramine 40 decreased CPI (varying doses) and distress (p<0.01) at follow-up Sertraline Double-blind 30 - - 8 weeks Daily pain Sertraline Sertraline: 50-200 mg placebo daries (DPD) decreased nausea, QD or controlled Beck Depression daily pain restlessness, placebo 39 Inventory (BDI), (p<0.02), decreased SF36 no effect libido, on BDI delayed or SF36 ejaculation (all mild) Theopylline Double-blind 25 46 18/7 8 weeks CPF, CPI Theophylline Theophylline: SR 200 mg placebo decreased nausea, BID or controlled CPF (p<0.05) insomnia, placebo and CPI tremor, and lightheadedness; Placebo: palpitations, insomnia
Hong SJ. Diagnosis and Management of Esophageal Chest Pain 221 여주어, 식도길이 (esophageal length) 측정이가능하다. 따라서고해상도내압검사를시행하면, 식도종주근수축과증상과의연관성을관찰할수있으리라생각한다. 내시경검사와식도내압검사이후에세번째진단도구로는고식적 24시간식도산도검사, 임피던스-pH 검사, 또는 wireless ph 검사가있다. 이들검사로써비정상적산노출의양을측정할수있고, 현재와같이양성자펌프억제제가널리사용되는현실에서양성자펌프억제제가실제로효과를발휘하고있는지여부를확인할수있다. 마지막으로식도과민성과관련된기능성가슴쓰림에대한평가를하고, 우울증, 강박증, 신체화장애 (somatization), 불안장애와같은정신질환의유병률이이들환자에서상당히높기때문에이에대한고려가필요하다. 4. 식도성흉통의치료앞서기술한바와같이식도성흉통의가장흔한원인은위식도역류질환이다. 고용량양성자펌프억제제의경험적투여는식도성흉통에대한비용효과가우수한접근방식 이다. Fass 등은하루 60 mg의 omeprazole 1주투여후흉통이 65% 호전됨을보고한바있다. 31 미만성식도경련, 호두까기식도, 아칼라지아, 공피증, 비특이적식도운동장애등과같은여러가지식도운동장애역시식도성흉통의원인으로생각되나, 식도내압검사에서이같은질환이진단된일부환자에서도비정상적식도운동의시기에식도성흉통이동반하여나타나지않는것을볼수있다. 한편식도내강초음파검사에서흉통기간동안에지속적인식도수축이관찰되었지만, 32 이러한현상은일부환자군에서만관찰되며, 일부통증시점에서만나타나는것으로여겨진다. Calcium channel blockers, nitrates와같은평활근이완제뿐아니라보툴리눔독소주입등이흉통의호전을보여주었다. 그러나이러한약물에의한흉통의호전은단지일시적이어서장기적효과를보여주지못하였다. 33-35 불응성증상을가진환자에서 long esophageal myotomy와같은수술적치료를시행하기도한다. 흉강경적수술과복강경적수술방법에는별다른차이가없지만보다중요한것은일부환자에서만수술적치료가효과를보인다는것이다. 36 따 Fig. 1. Diagnostic and treatment strategy of esophageal chest pain. GERD, gastroesophageal reflux disease; TLESR, transient lower esophageal sphincter relaxation.
222 대한소화기학회지 : 제 55 권제 4 호, 2010 라서수술적치료의임상적적용에대해서는잘디자인된임상연구가필요한실정이다. 식도과민성 (esophageal hypersensitivity) 은최근에식도성흉통의중심적병인의하나로인식되고있다. Imipramine, 37 trazadone, 38 sertraline, 39 tricyclics 40 같은약물들이도움을줄수있다. Theophylline도식도성흉통에도움이된다. 41 Theophylline 정주는식도과민성을감소시키고, 식도벽확장능 (esophageal distensibility) 을호전시켰다. 42 Theophylline은내장감각에있어진통효과와평활근이완제의효과를가지며이는 adenosine 수용체길항과 phosphor-diesterase의억제에의해중재되는것으로생각된다. Adenosine은정상인에서식도통각과민을발생시키는것으로보고되어 43 추후선택적 adenosine길항제의개발이기대된다. Table 2는양성자펌프억제제를제외한약물들의치료연구결과들을정리하였다. 최근에는최면요법 (hypnotherapy) 도치료의한방법으로시도되고있다. 44 위와같은약물이외에도식도성흉통의발생기전에근거를둔신약개발이활발하다. 위산분비억제약물이외에도 Motilin4 항진제, 5-HT 4 수용체항진제, GABA B 수용체작용제, mglur5 길항제, 5-HT 3 수용체길항제, TRPV1 길항제, adenosine A1 수용체길항제등이개발중에있다. Fig. 1은식도성흉통의진단과치료과정에대하여설명하고있다. 결론식도성흉통의발생에는위식도역류질환이가장흔한원인적인자로작용하지만, 그외에도식도근육의운동성질환, 염증성질환, 감염성질환등과함께우울증, 강박증, 신체화장애와같은정신과적질환등을감별해야하며, 최근식도과민성이주요병인의하나로인식되고있다. 양성자펌프억제제는식도성흉통을가진환자에서좋은치료적시도로생각되나, 경고증상이있는경우반드시상부위장관내시경검사를통하여점막병소의유무, 병변의특징을평가하여진단하고, 위식도역류질환인경우미란성식도염, Barrett 식도, 협착등의유무를파악하여야한다. 최근개발된고해상도내압검사는기존의고식적인내압검사에비해세밀한관찰이가능하고, 경우에따라식도종주근의수축을반영하는식도길이의단축을관찰할수있어, 식도종주근수축에의한식도성흉통진단이조금은간편해지리라생각된다. 또한 24시간식도산도검사와임피던스검사는양성자펌프억제제불응성위식도역류질환자의진단및치료에도움을줄수있다. 최근여러가지약물이식도성흉통의치료에이용되었고, 기전에바탕을둔새로운약물의개발이기대된다. 향후이러한약물의효능을입증하는수준높은임상연구들의지속적인발표가필요하다하겠다. 참고문헌 1. Fass R, Dickman R. Non-cardiac chest pain: an update. Neurogastroenterol Motil 2006;18:408-417. 2. 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;22:320-325. 3. Kim JH, Sinn DH, Son HJ, Kim JJ, Rhee JC, Rhee PL. Comparison of one-week and two-week empirical trial with a high-dose rabeprazole in non-cardiac chest pain patients. J Gastroenterol Hepatol 2009;24:1504-1509. 4. Balaban DH, Yamamoto Y, Liu J, et al. Sustained esophageal contraction: a marker of esophageal chest pain identified by intraluminal ultrasonography. Gastroenterology 1999;116:29-37. 5. Fruergaard P, Launbjerg J, Hesse B, et al. The diagnoses of patients admitted with acute chest pain but without myocardial infarction. Eur Heart J 1996;17:1028-1034. 6. Martinez SD, Malagon IB, Garewal HS, Fass R. Non-erosive reflux disease (NERD)--acid reflux and symptom patterns. Aliment Pharmacol Ther 2003;17:537-545. 7. Douglas A Drossman. Rome III: The Functional Gastrointestinal Disorders. 3rd ed. McLean, Va: Degnon Associates, Inc., 2006. 8. Fass R, Tougas G. Functional heartburn: the stimulus, the pain and the brain. Gut 2002;51:885-892. 9. Rodriguez-Stanley S, Robinson M, Earnest DL, Greenwood- Van Meerveld B, Miner PB Jr. Esophageal hypersensitivity may be a major cause of heartburn. Am J Gastroenterol 1999;94:628-631. 10. Mayer EA. Spinal and supraspinal modulation of visceral sensation. Gut 2000;47(suppl 4):iv69-72. 11. Tack J, Koek G, Demedts I, Sifrim D, Janssens J. Gastroesophageal reflux disease poorly responsive to single-dose proton pump inhibitors in patients without Barrett s esophagus: acid reflux, bile reflux, or both? Am J Gastroenterol 2004;99: 981-989. 12. Ang D, Sifrim D, Tack J. Mechanisms of heartburn. Nat Clin Pract Gastroenterol Hepatol 2008;5:383-392. 13. Blackshaw LA, Grundy D. Effects of 5-hydroxytryptamine on discharge of vagal mucosal afferent fibres from the upper gastrointestinal tract of the ferret. J Auton Nerv Syst 1993;45: 41-50. 14. Cervero F. Sensory innervationsof the viscera: peripheral basis of visceral pain. Physiol Rev 1994;74:95-138. 15. Page AJ, O Donnell TA, Blackshaw LA. P2X purinoceptorinduced sensitization of ferret vagal mechanoreceptors in oe-
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