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1 Korean J Gastroenterol Vol. 66 No. 2, pissn eissn REVIEW ARTICLE 난치성위식도역류질환의원인및치료 이광재 아주대학교의과대학소화기내과학교실 Underlying Mechanisms and Management of Refractory Gastroesophageal Reflux Disease Kwang Jae Lee Department of Gastroenterology, Ajou University School of Medicine, Suwon, Korea The prevalence of gastroesophageal reflux disease (GERD) in South Korea has increased over the past 10 years. Patients with erosive reflux disease (ERD) shows better response to proton pump inhibitors (PPIs) than those with non-erosive reflux disease (NERD). NERD is a heterogeneous condition, showing pathological gastroesophageal reflux or esophageal hypersensitivity to reflux contents. NERD patients with pathological gastroesophageal reflux or hypersensitivity to acid may respond to PPIs. However, many patients with esophageal hypersensitivity to nonacid or functional heartburn do not respond to PPIs. Therefore, careful history and investigations are required when managing patients with refractory GERD who show poor response to conventional dose PPIs. Combined ph-impedance studies and a PPI diagnostic trial are recommended to reveal underlying mechanisms of refractory symptoms. For those with ongoing reflux-related symptoms, split dose administration, change to long-acting PPIs or PPIs less influenced by CYP2C19 genotypes, increasing dose of PPIs, and the addition of alginate preparations, prokinetics, selective serotonin reuptake inhibitors, or tricyclic antidepressants can be considered. Pain modulators, selective serotonin reuptake inhibitors, or tricyclic antidepressants are more likely to be effective for those with reflux-unrelated symptoms. Surgery or endoscopic per oral fundoplication may be effective in selected patients. (Korean J Gastroenterol 2015;66:70-74) Key Words: Gastroesophageal reflux; Hypersensitivity; Heartburn; Proton pump inhibitors 서론 1990년대에우리나라를포함한아시아권국가에서위식도역류질환은주요관심질환이아니었고, 따라서유병률에대한연구도매우적었다. 2000년대에들어서면서위식도역류질환에대한관심이증가하였는데이는이질환의유병률이증가하는것과관련이있다. 2000년대초에발표된우리나라일반인구집단에서의위식도역류질환증상의유병률은 3.5% 였으나 년도에발표된유병률은 8.5% 로증가되었으며, 2 내시경에서발견되는역류성식도염의유병률도 2013년도에 7.6% 로발표되고있어서우리나라에서증가하고있음을알수있다 (Fig. 1). 3 위식도역류질환에는양성자펌프억제제가가장효과적인치료약물로간주되고있으나표준용량을투여하여도증상의호전이없거나반응이불완전한경우에어떤치료를더해야할지에대해서는결정하기힘든경우가많다. 특히내시경에서미란성병변이없는비미란성위식도역류질환은미란성위식도역류질환에비해양성자펌프억제제가듣지않는경우가더많기때문에, 내시경에서미란성식도염이없으면서역류가의심되는증상을호소하며양성자펌프억제제가효과없는환자들에게적합한접근법에대해서는논의가필요한부분이많다. 최근에발표된국내논문을보면비미란성위식도역류질환을가진환자 28.5% 에서양성자펌프억제제표준용량 4주투여에대해반응이없었다고보고하고있다. 4 이에이 CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright Korean Society of Gastroenterology. 교신저자 : 이광재, 16499, 수원시영통구원천동월드컵로 164, 아주대학교병원소화기내과 Correspondence to: Kwang Jae Lee, Department of Gastroenterology, Ajou University Hospital, 164 Worldcup-ro, Yeongtong-gu, Suwon 16499, Korea. Tel: , Fax: , kjleemd@hotmail.com Financial support: None. Conflict of interest: None. Korean J Gastroenterol, Vol. 66 No. 2, August

2 Lee KJ. Underlying Mechanisms and Management of Refractory GERD 71 한후에치료에대한반응을평가하는것이권장되고있다. 3. 양성자펌프억제제의빠른대사형 Fig. 1. The prevalence of gastroesophageal reflux disease (GERD) or reflux esophagitis in South Korea. 종설에서는양성자펌프억제제가효과없는난치성위식도역류질환의원인및치료에대해살펴보고자한다. 본 론 1. 양성자펌프억제제의부적절한투여시간및나쁜순응도 위식도역류질환환자는증상이호전되면임의로약을중단하거나규칙적으로복용하지않는경향이있다. 그런경우에증상이재발하게되면약이별로효과가없다고착각할수가있다. 위식도역류로인한증상은일반적으로만성적으로반복되는질환이기때문에이런질환의특성을환자에게설명하고, 증상이자주나타나는경우에는규칙적으로약을복용할것을권유하는것이좋다. 일반적으로양성자펌프억제제가최대의위산분비억제효과를내기위해서는식전에복용하는것이권장된다. 5 대개는아침식전 30분에서 60분사이, 저녁식전에복용한다면저녁식전 30분에서 60분사이에복용하게한다. 특히우리나라는많은수의환자들을짧은시간에보는진료환경이어서이런설명들이잘이루어지지않을가능성이많다. 2. 불충분한양성자펌프억제제투여기간 양성자펌프억제제의투여기간이불충분해서치료에대한반응이부족한경우도있을수있는데특히비전형적인증상을호소하는위식도역류질환환자에서이런요인을고려해볼수있다. 실제로비심인성흉통을호소하는환자에서양성자펌프억제제를아침저녁으로 1주간투여한경우에는위식도역류질환연관군과비연관군간에반응률차이가없었으나 2주째에는위식도역류질환연관군이비연관군에비해유의하게반응률이높아지는것을확인할수있다. 6 인후두역류증상이의심이되는경우에도일반적으로 2개월이상투여 유전적으로양성자펌프억제제가빨리대사되는 CYP2C19 의빠른대사형을가진환자들은양성자펌프억제제의효과가상대적으로떨어질수있다. 아시아인들은백인들에비해상대적으로느린대사형이많고빠른대사형이적지만, 아시아국가들에서도빠른대사형이일반인구의 25-40% 정도를차지하고있으므로상대적으로양성자펌프억제제에나쁜반응을보이는경우에원인으로고려해볼수있다. 7 실제로빠른대사형은양성자펌프억제제에대한치료반응률이다른형에비해낮다. 이런경우에는 CYP2C19 효소활성도의영향을비교적적게받는양성자펌프억제제로교체해보는것도한가지방법이될수있다. 또다른방법으로양성자펌프억제제의투여횟수를늘리면빠른대사형에의한영향을극복할수있다. 실제로같은용량이라도하루한번보다하루두번으로나누어서복용하면빠른대사형과느린대사형간의효과의차이를줄여줄수있다 야간위산분비억제의실패양성자펌프억제제를투여하면주간의위산분비는효과적으로잘억제되지만야간의위산분비는잘억제되지않아서, 위내산도가 4 미만으로한시간이상유지되는현상을볼수있다. 이런경우는야간에나타나는역류증상의원인이될수있으나아침식전에하루한번투여하게되면대부분의양성자펌프억제제가야간의위산분비억제에한계를보이게된다. 따라서야간증상이있는경우에는아침식전과저녁식전으로두번나누어서투여하는것이효과적이다. 9 그래도야간의위산분비로인한야간역류증상을막을수없는경우에는최근출시되고있거나출시예정인, 작용시간이상대적으로긴양성자펌프억제제가좀더도움이될수있을것이다. 5. 산포켓의형성식후에위에서분비되는위산들이음식물과섞이지않고음식물에의해중화되지않은상태로음식물의상층에위치하면서위산층을형성하게되는데, 이를산포켓 (acid pocket) 이라고한다. 10 산포켓은식후의위산역류로인해나타나는증상들의중요한원인이될수있으며, 특히열공허니아가있는경우에는산포켓에의한역류가증가하게된다. 산포켓은양성자펌프억제제치료에도불구하고식후에나타나는역류증상의원인이될수있으며, alginate-antacid 복합제의투여가치료효과에도움을줄수있다. Vol. 66 No. 2, August 2015

3 72 이광재. 난치성위식도역류질환의원인및치료 6. 식도과민성또는기능성가슴쓰림가슴쓰림을호소하는환자로내시경에서미란성식도염이관찰되지않지만 24시간식도산도임피던스검사에서병적인역류가관찰되는경우를진정한비미란성위식도역류질환이라고할수있다. 반면에병적인역류는없으나역류와증상의연관성이있는경우에는식도과민성이있다고볼수있다. 병적인역류도없고, 역류와증상간의상관성도음성이지만양성자펌프억제제에반응이있으면 24시간식도산도임피던스검사가위음성일수있기때문에이또한비미란성위식도역류질환의범주에넣을수있으며, 양성자펌프억제제에반응이없으면최종적으로기능성가슴쓰림으로진단이된다 (Fig. 2). 11,12 식도과민성은산에대한과민성이있는경우에는고용량의양성자펌프억제제에효과가있을수있으나산이외의자극에대해서과민성이있는경우에는양성자펌프억제제에효과가없다. 기능성가슴쓰림도양성자펌프억제제에반응이없는원인이며, 낮은용량의삼환계항우울제, 선택적세로토닌재흡수억제제와같은내장진통효과가있는약물이도움이될수있다 양성자펌프억제제로조절이안되는역류 24시간식도산도임피던스검사를통해서조절되지않는증상들이역류와관련이있음을확인한경우, 특히약산역류나비산역류가증상과관련이있으면양성자펌프억제제의효과가적다. 이런경우에는위산보다는역류자체를줄여주어야하므로일시적하부식도괄약근이완을줄여주는약물을투여하는것이좋겠지만, 이런목적으로개발되어온약물들중 에현재사용이가능한약물은없다. 대신에기존에근이완제로사용되어온 GABAB 수용체작용제 baclofen을사용해볼수있으나부작용으로인해활발하게사용하고있지는않다. 역류가약물치료로잘조절되지않는경우에는수술혹은내시경을통한위저부성형술을고려해볼수있다. 복강경하위저부성형술은병적인위식도역류가확인된경우나증상이역류와관련있다고확인된경우에는좋은결과를보일수있으나, 그렇지않은경우에는결과가좋지못하기때문에대상환자를세심하게선별할필요가있다. 14 또한삼킴곤란이나위내가스가배출이안되는등의부작용도있을수있으므로경험이있는전문가가시술할것이권장된다. 그밖에비수술적치료법으로고주파에너지를이용한 Stretta 치료법이우리나라에최근에소개가되었으나효과와안전성및적합한적응증에대해서는향후사용경험에대한추가정보가필요하다. 8. 다른질환이원인이거나동반되어있는경우경피증식도의경우처럼식도운동이심하게저하된경우에는표준용량의양성자펌프억제제하루한번의투여로는위산역류가잘조절되지않는경우가흔하며, 이런경우에는저녁식전에한번더양성자펌프억제제를투여해주는것이필요하다. 또한위장관운동촉진제를같이투여해주는것이효과적일수있다. 위배출지연이나위마비가동반된경우에도위장관운동촉진제가도움이될수있다. 양성자펌프억제제에증상의호전이없는환자에서삼킴곤란증상이동반되어있으면식도내압검사를실시해서이완불능증 (achalasia) 여부를확인해보는것이권장된다. 이완불능증은위의내용물이역류하는것이아니라식도에고여있는내용물로인해역류증상이유발될수있다. 이완불능증은국 Fig. 2. The classification of subgroups causing heartburn according to the Rome III criteria. GER, gastroesophageal reflux; NERD, non-erosive reflux disease; PPI, proton pump inhibitor. The Korean Journal of Gastroenterology

4 Lee KJ. Underlying Mechanisms and Management of Refractory GERD 73 Fig. 3. Approach to refractory symptoms to standard dose of proton pump inhibitors (PPIs). GERD, gastroesophageal reflux disease; SI, symptom index; SAP, symptom association probability; EoE, eosinophilic esophagitis; NERD, nonerosive reflux disease. 내의유병률이 10만명당 7.8명으로보고되어있다. 15 호산구성식도염도삼킴곤란증상과양성자펌프억제제에호전이없는역류증상이있는경우에고려할수있는질환이다. 임상적으로의심이되면내시경식도조직검사를실시해서호산구의수가증가되어있음을확인하여 ( 15/HPF) 진단할수있다. 16 그렇지만호산구성식도염은아직우리나라에는흔하지않은질환이다. 9. 표준용량의양성자펌프억제제에호전이없는경우의접근순서표준용량의양성자펌프억제제에듣지않는증상에대해서는우선환자가제대로적합한시간에약을복용하고있는지점검이필요하고, 표준용량을하루두번으로나누어서복용하게하거나 CYP2C19 효소에덜의존적인양성자펌프억제제로약을교체해서투여해본다. 그래도호전이없으면단기간동안에표준용량하루두번으로용량을증량해서시험적투여를해보고, 호전이없으면환자가호소하는증상이역류에의한증상이맞는지를확인하는 24시간식도산도임피던스검사를시행하는것이권장된다. 증상이위식도역류에의한것임을전에확인한적이있으면양성자펌프억제제를사용하면서검사를해도되고, 그렇지않으면양성자펌프억제제를중단한상태에서검사를시행한다. 이런검사를통해서진정한비미란성위식도역류질환인지, 식도과민성인지, 기능성가슴쓰림인지구분을할수있으며, 각각에맞는치료법을시도해야한다. 삼킴곤란이동반된경우에는이완불능증이나호산구성식도염이아닌지를확인하는것이필요하다 (Fig. 3). 결 론 위식도역류질환으로의심되는증상들이최근 10년동안우리나라에서증가하고있다. 특히내시경에서미란성식도염소견을보이지않으면서양성자펌프억제제투여에증상의호전이없는환자들을어떻게치료할것인가에대해서는정립된접근법이필요하다. 호소하는증상이같아도증상을유발하는원인들은다양하고이질적일수있기때문에, 증상을유발하는기저질환이나기전을파악해서적합한치료법을선택해야할것이다. REFERENCES 1. Cho YS, Choi MG, Jeong JJ, et al. Prevalence and clinical spectrum of gastroesophageal reflux: a population-based study in Asan-si, Korea. Am J Gastroenterol 2005;100: Lee SY, Lee KJ, Kim SJ, Cho SW. Prevalence and risk factors for overlaps between gastroesophageal reflux disease, dyspepsia, and irritable bowel syndrome: a population-based study. Digestion 2009;79: Lee D, Lee KJ, Kim KM, Lim SK. Prevalence of asymptomatic erosive esophagitis and factors associated with symptom presentation of erosive esophagitis. Scand J Gastroenterol 2013; 48: Kim SE, Kim N, Oh S, et al. Predictive factors of response to proton pump inhibitors in korean patients with gastroesophageal reflux disease. J Neurogastroenterol Motil 2015;21: Hatlebakk JG, Katz PO, Camacho-Lobato L, Castell DO. Proton pump inhibitors: better acid suppression when taken before a meal than without a meal. Aliment Pharmacol Ther 2000;14: Kim JH, Rhee PL. Recent advances in noncardiac chest pain in Korea. Gut Liver 2012;6: Yamada S, Onda M, Kato S, et al. Genetic differences in CYP2C19 Vol. 66 No. 2, August 2015

5 74 이광재. 난치성위식도역류질환의원인및치료 single nucleotide polymorphisms among four Asian populations. J Gastroenterol 2001;36: Sugimoto M, Shirai N, Nishino M, et al. Comparison of acid inhibition with standard dosages of proton pump inhibitors in relation to CYP2C19 genotype in Japanese. Eur J Clin Pharmacol 2014;70: Hammer J, Schmidt B. Effect of splitting the dose of esomeprazole on gastric acidity and nocturnal acid breakthrough. Aliment Pharmacol Ther 2004;19: Kahrilas PJ, McColl K, Fox M, et al. The acid pocket: a target for treatment in reflux disease? Am J Gastroenterol 2013;108: Savarino V, Savarino E, Parodi A, Dulbecco P. Functional heartburn and non-erosive reflux disease. Dig Dis 2007;25: Lee KJ, Kwon HC, Cheong JY, Cho SW. Demographic, clinical, and psychological characteristics of the heartburn groups classified using the Rome III criteria and factors associated with the responsiveness to proton pump inhibitors in the gastroesophageal reflux disease group. Digestion 2009;79: Scarpignato C. Poor effectiveness of proton pump inhibitors in non-erosive reflux disease: the truth in the end! Neurogastroenterol Motil 2012;24: Jung HK, Hong SJ, Jo YJ, et al; Korean Society of Neurogastroenterology and Motility. Updated guidelines 2012 for gastroesophageal reflux disease. Korean J Gastroenterol 2012;60: Kim E, Lee H, Jung HK, Lee KJ. Achalasia in Korea: an epidemiologic study using a national healthcare database. J Korean Med Sci 2014;29: Park H. An overview of eosinophilic esophagitis. Gut Liver 2014; 8: The Korean Journal of Gastroenterology

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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