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Korean J Gastroenterol Vol. 64 No. 3, 133-141 http://dx.doi.org/10.4166/kjg.2014.64.3.133 pissn 1598-9992 eissn 2233-6869 REVIEW ARTICLE 기능성소화불량증의최근동향 박종규, 허규찬 1, 신철민 2, 이혁 3, 윤영훈 4, 송경호 1, 민병훈 3, 최기돈 ; 대한소화기기능성질환ㆍ운동학회 울산대학교의과대학, 건양대학교의과대학 1, 서울대학교의과대학 2, 성균관대학교의과대학 3, 연세대학교의과대학 4 내과학교실 Current Issues in Functional Dyspepsia Jong Kyu Park, Kyu Chan Huh 1, Cheol Min Shin 2, Hyuk Lee 3, Young Hoon Yoon 4, Kyung Ho Song 1, Byung-Hoon Min 3 and Kee Don Choi; The Korean Society of Neurogastroenterology and Motility Departments of Internal Medicine, University of Ulsan College of Medicine, Seoul, Konyang University College of Medicine, Daejeon 1, Seoul National University College of Medicine, Seongnam 2, Sungkyunkwan University School of Medicine, Seoul 3, Yonsei University College of Medicine, Seoul 4, Korea Functional dyspepsia is one of the most common gastrointestinal disorders encountered in clinical practice. Functional dyspepsia is currently defined by Rome III criteria as the chronic dyspeptic symptoms (postprandial fullness, early satiety, epigastric pain or burning) in the absence of underling structural or metabolic disease that readily explain the symptoms. According to the Rome III consensus, functional dyspepsia can be subdivided into postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS). Although the Rome III criteria have been published more than 8 years ago, not much effort has been put into validating these criteria and direct scientific evidence supporting the validity of the subdividing functional dyspepsia into PDS and EPS are lacking. This article is intended to review the validity of the Rome III criteria on the subdivisions of functional dyspepsia, i.e. PDS and EPS. The impact of sleep disorder, Helicobacter pylori-associated dyspepsia, and the emerging drug therapies in functional dyspepsia will also be discussed in this article. (Korean J Gastroenterol 2014;64:133-141) Key Words: Functional dyspepsia; Diagnosis; Sleep disorder; Helicobacter pylori 서론 기능성소화불량증은가장흔한상복부위장관증상중하나이며, 반복되는증상의호전과악화로삶의질을떨어뜨리고사회경제적손실을초래하는만성질환이다. 1-4 로마기준 III 에근거한기능성소화불량증이란지난 3개월간만성적인소화불량증상이있었고, 이러한증상이적어도진단 6개월전부터발생하였으며, 상부위장관내시경검사등으로이러한증상을설명할수있는기질적질환이나대사성및전신적원인이없는경우로정의된다. 5 로마기준 III에서소화불량증으로정의된증상은불쾌한식후포만감, 조기만복감, 명치부위통증혹은쓰림의네가지증상이다. 이네가지증상중하나 이상인경우로정의되며, 명치통증증후군 (epigastric pain syndrome, EPS) 과식후고통증후군 (postprandial distress syndrome, PDS) 의두가지아형으로분류된다. 그러나증상에근거한아형의분류를뒷받침하는명확한과학적근거가아직없다. 5 로마기준 III는 2006년개정되었음에도이진단기준에대한유효성의평가는지금까지거의이루어지지않았으나, 최근유효성을평가한연구결과들이발표되었다. 6,7 많은연구에서위식도역류질환이나과민성장증후군에서수면장애가흔히동반되는것으로보고하였다. 8,9 이에비해기능성소화불량증에서는수면장애에대한연구가아직많지않으며최근일본에서소규모의연구이지만기능성소화불량증에서수면장애에대하여보고하였다. 10 기능성소화불량증의초기 CC This is an open access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/ by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 교신저자 : 허규찬, 302-812, 대전시서구관저동로 158, 건양대학교병원소화기내과 Correspondence to: Kyu Chan Huh, Department of Internal Medicine, Konyang University Hospital, 158 Gwanjeodong-ro, Seo-gu, Daejeon 302-812, Korea. Tel: +82-42-600-8838, Fax: +82-42-600-9090, E-mail: kchuh2020@hanmail.net Financial support: None. Conflict of interest: None. Korean J Gastroenterol, Vol. 64 No. 3, September 2014 www.kjg.or.kr

134 박종규등. 기능성소화불량증의최근동향 진단으로 Helicobacter pylori 검사를시행하여양성인경우제균치료를시행하는방법은경험적산분비억제제투여와비교할때 1년후증상호전율이높기때문에, 서구와아시아의진료지침에서 H. pylori 검사및치료 방법이권장되고있다. 11,12 최근에기능성소화불량증에서 H. pylori와관련된다양한병태생리적기전들이밝혀지고있어, H. pylori 연관소화불량증 (H. pylori-associated dyspepsia) 을기능성소화불량증과구별하여다른질병단위로간주하려는움직임이있다. 13 이번고찰에서는최근이슈화된이러한연구결과를토대로기능성소화불량증에서로마기준 III의유효성을알아보고, 기능성소화불량증의아형을 PDS와 EPS로분류한로마기준 III의타당성을역학적, 임상적, 병태생리적측면에서알아보고자한다. 또한기능성소화불량증에서수면장애, H. pylori 연관소화불량증, 그리고최근에발표된새로운약물치료에대해알아보고자한다. 본론 1. 기능성소화불량증에서로마기준 III의유효성기능성소화불량증의로마기준 II에서는상복부통증이소화불량증의주증상이었고, 나머지 7개의증상 ( 상복부포만감, 조기만복감, 팽만감, 구역, 상복부쓰림, 트림, 구토 ) 은 불편감 이란용어로그룹화되었다. 14 그러나통증과불편감의구분이어려웠으며, 소화불량증이있는환자에서대부분한가지이상의증상이동반되었고, 환자들의증상표현도제각각이었다. 14 따라서로마 III 위원회에서는소화불량증의증상을위와십이지장에서기인한것으로생각되는네가지의증상으로국한하였고, 이외의증상은그원인이나기원이위가아닐가능성을고려하여제외하였다. 5 하지만이러한기준과분류의적절성에대한임상적연구결과는아직은미미하다. 로마기준 III 설문지를이용한말레이시아연구에서로마기준 III의기질적원인을배제할수있는양성예측도가 84% 로높게나타났으나 19명의기능성소화불량증의환자를대상으로한연구여서제한점이많은연구였다. 6 또한 191명의파키스탄의기능성소화불량증환자에서로마기준 III의기질적원인을배제할수있는양성예측도는 71% 로나타났는데, 15 이는로마기준 II를이용한기능성소화불량증환자 2,700명중 23% 에서내시경후기질적질환이있었다는보고에비해양성예측도가높지만연구에포함된환자수가많지않았다. 16 3차의료기관을내원한환자를대상으로한우리나라연구에서로마기준 III를이용하여기질적원인을배제할수있는민감도와특이도는각각 60% 와 53% 로보고되어로마기준 III가우리나라에서기능성위장장애의진단에비교적유용하게사용될수있음을보여주었다. 17 로마기준 III의한국어설문지가최근 발표되었는데높은신뢰도와수렴타당도를보여한국인에서임상및연구평가에유용하게적용될수있음을보여주었다. 18 최근위장관증상으로외래에내원한 1,452명의환자를대상으로한큰규모의전향적연구에서기능성소화불량증의로마기준 III와로마기준 II의정확도를비교하였다. 7 기능성소화불량증을진단하는데있어서로마기준 III의민감도와특이도는각각 60.7% 와 68.7% 였고, 로마기준 II의민감도와특이도는각각 71.4% 와 55.6% 였다. 로마기준 II보다로마기준 III의민감도가낮고, 특이도가높은것은아마도로마기준 III가로마기준 II보다진단기준에서더엄격하기때문일것이다. 그러나두로마기준간의곡선아래면적 (area under curve) 값은통계적차이를보이지않아, 로마기준 III가로마기준 II보다기능성소화불량증을진단하는데있어정확도가더높은진단기준은아니었다. 또한기능성소화불량증으로진단된환자에서가장많은기질적원인은미란성식도염이었는데, 로마기준 III, 넓은의미의로마기준 III, 그리고로마기준 II로진단된기능성소화불량증환자에서미란성식도염의동반율은각각 11.2%, 11.2% 와 11.8% 였다. 이러한소견은기능성소화불량증의진단기준만으로는기질적원인을배제하기어렵다는것을보여주는것이라할수있겠다. 따라서소화불량증환자에서기질적원인을배제하기위해서는결국위내시경을시행해야한다는것을보여준것이다. 2. 기능성소화불량증의로마기준 III에서 PDS와 EPS 분류의타당성로마기준 III는기능성소화불량증에서증상의특이도를증가시키기위해위십이지장에서기인하는네가지의증상만으로국한하였다. 그러나기능성소화불량증은여러가지병태생리가관여되는이질적질환의집합체이다. 5 따라서로마기준 III의정의와그아형의분류가이러한다양한병태생리적기전들을반영할수있을지에대한타당성을알아볼필요가있다. 로마기준 II에서는주증상이통증인지불편감인지에따라기능성소화불량증을두개의아형으로분류하였다. 그러나시간에따라환자의주증상이변하는경우가있어이러한분류의지속성이결여되었으며, 각각의병태생리적기전과의연관성도결여되었다. 19-21 체계적연구에서소화불량증은대부분의환자에서식사에의해유발되거나악화되었고, 일부에서는식사와상관없이증상을호소하였다. 22,23 따라서이러한결과를토대로로마기준 III에서는식사와증상의연관성에따라 PDS와 EPS로구분하였는데, PDS의주증상은식후포만감과조기만복감으로정의하였고 EPS는식사와무관하게발생하는상복부통증과쓰림으로정의하였다. 5 기능성소화불량증의아형을 EPS와 PDS로분류한로마기준 III의타당성을평가하기위해많은역학연구들이이루어 The Korean Journal of Gastroenterology

Park JK, et al. Current Issues in Functional Dyspepsia 135 져왔다. 스웨덴에서시행된일반인 3,000명을대상으로한역학연구에서연구에직접참여한 1,001명의환자중소화불량증증상은참여자의 20% 에서있었고, 그중내시경에서기저질환이없는기능성소화불량증환자는 15.7% 였고, 기능성소화불량증의아형으로는 PDS가 12.2%, EPS가 5.2% 였으며, 중복되는경우는단지 1.7% 뿐이었다. 4 이탈리아에서시행된일반인 1,533명을대상으로한역학연구에서는연구에참여한 1,033명중소화불량증과기능성소화불량증은각각 15% 와 11% 였으며, 기능성소화불량증환자중에 67.5% 가 PDS, 48.2% 가 EPS였으며, 중복되는경우는 15.8% 였다. 24 최근우리나라에서로마기준 III를이용한인구-기반, 단면적연구가발표되었다. 25 20세에서 69세의일반인 5,000명을대상으로한전화인터뷰조사에서검사되지않은소화불량증 (uninvestigated dyspepsia) 의유병률은 7.7% 였고, PDS와 EPS가각각 5.6%, 4.2% 였다. PDS와 EPS가중복되는경우는검사되지않은소화불량증환자중 27.1% 로다른역학연구에비해높게나타났다. 그러나이연구에서는소화불량증환자에서상부위장관내시경검사가시행되지않았기때문에기질적원인이배제되지못하였고, 전화인터뷰를이용한설문조사여서그한계가있었다. 우리나라의검사되지않은소화불량증의역학연구에서는 PDS 와 EPS가중복되는경우가비교적높게나타났으나, 위와같은역학연구들은기능성소화불량증의아형을 PDS와 EPS로분류한로마기준 III의타당성을보여준것이라할수있다. 반대로소화불량증으로내원한환자를대상으로한연구에서는일반인을대상으로한역학연구보다 PDS나 EPS의아형으로분류하는것이어렵다는것을보여주었다. 상부위장관증상이있으나내시경에서기질적원인이없는 912명을대상으로한네덜란드연구에서참여자의 44% 가 EPS, 42% 가 PDS였으며, 중복되는경우가 26% 였고, 40% 의환자가로마기준 III에의해분류되지않았다. 26 소화기내과외래를내원한 3,014명을대상으로한타이완연구에서 20.2% 가기능성소화불량증으로진단되었고, 이들중 63% 가 EPS, 63% 가 PDS였으며, 중복되는경우는 26% 였다. 27 소화불량증으로내원한 272명의환자를대상으로한사우디아라비아연구에서도기능성소화불량증환자의 54% 가 EPS, 9% 가 PDS였으며, 31% 가중복되었다. 15 만성적인위장관증상으로내원한환자 391명을대상으로한우리나라연구에서기능성소화불량증환자 180명중 74.4% 가 PDS, 5.0% 가 EPS였으며, 2.2% 가중복되었고, 18.3% 는두아형으로분류되지않았다. 28 우리나라연구는 PDS와 EPS가중복되는경우가낮기는하였으나두아형으로분류되지않는경우가많았고, 위의연구들을종합해볼때외래로내원한기능성소화불량증환자에서 PDS 와 EPS로의분류가쉽지않았다. 이러한것은외래로내원한환자에서식사와관련된불편감과상복부통증이나쓰림이같 이동반되는경우가흔함을보여주는것이고, 따라서외래로내원한환자에서는기능성소화불량증의아형을 PDS와 EPS 로분류한로마기준 III의타당성이낮음을보여주는것이다. 기능성소화불량증에서로마기준 III에근거한병태생리연구는로마기준 II에근거한연구보다많이보고되지는않았다. 기능성소화불량증 110명을대상으로한독일연구에서위배출지연에있어 EPS와 PDS 아형간의차이는보이지않았다. 29 일본연구에서는 EPS보다 PDS 아형에서위배출지연이의미있게관찰되었고, 이것은 ghrelin의낮은혈중농도와관련이있었다. 30 초음파를이용한위벽의긴장도를측정한노르웨이의예비연구에서식전이나식후에도 PDS보다 EPS에서전정부의방사상긴장도가의미있게더높았다. 31 기능성소화불량증에서 PDS의아형이면역기능의비정상적인활성화와십이지장의호산구증가와관련되어있다고보고되고있다. 위내시경을시행받은 1,001명을대상으로한스웨덴연구에서대조군에비해 PDS 아형에서의미있게십이지장내호산구가증가되어있었지만, EPS에서는증가되어있지않았다. 32 155명을대상으로한영국연구에서조기만복감과십이지장내호산구증가가의미있는상관관계를보였으며, PDS 환자의 47% 에서십이지장내호산구증가증을보였다. 33 이러한소견은인구학적특성이다른나라의연구에서도일관되게관찰되고있어서 PDS가기능성소화불량증에서 EPS와분명하게구분되는별개의아형임을보여주고있는것이다. 34,35 로마기준 III에따른유전자다형성에대한연구들을보면, 일본연구에서는 EPS가 PDS에비해 G-protein 3 (GN 3) subunit의유전자다형성 (825TT) 과통계적으로의미있게연관되어있었으며, 36 반대로다른연구에서는 GN 3 825CC 유전자형이 EPS에비해 PDS와의미있게관련되어있었다. 37 우리나라의연구에서는 GN 3 825T 유전자다형성의빈도는 CC, CT, TT의경우각각 25%, 29%, 45.8% 였고, 건강대조군과비교시유전자형의빈도차이는없었으며, 각아형에따른차이도보이지않았다. 38 기능성소화불량증 167명을대상으로한우리나라의다른연구에서도 GN 3 C825T 유전자다형성의빈도는대조군과차이를보이지않았으나, 39 102명의소아환자를대상으로한연구에서는 CC 유전자형이기능성소화불량증과관련되어있음을보여주었다. 40 그러나이두연구에서는소화불량증의아형에따른차이를제시하지는않았다. 우리나라의유전자다형성연구에서는두아형간의의미있는차이를보이지않았으나다른병태생리적연구들은위배출지연, 위벽의긴장도, 십이지장내호산구증가등에서 EPS와 PDS의아형간에의미있는차이를보여주었고, 따라서로마기준 III의타당성을보여주는결과들이다. 기능성소화불량증의치료에서 EPS 환자에서는위산분비억제제가, PDS 환자에서는위장관운동촉진제가우선적으로추천되지만, 41,42 로마기준 III를이용한각각의아형에따른치료반 Vol. 64 No. 3, September 2014

136 박종규등. 기능성소화불량증의최근동향 응정도를평가한양질의연구는아직부족하다. 기능성소화불량증에서프로톤펌프억제제와히스타민수용체길항제에대한공개연구들에서 EPS와 PDS의아형간에치료효과에서차이를보이지는않았다. 43-45 또한 H. pylori 제균치료후소화불량증의호전정도도 EPS와 PDS 환자간에차이를보이지않았다. 46 기능성소화불량증의치료를위해개발된 acotiamide는무스카린수용체길항작용과아세틸콜린분해효소를억제하여위장관의신경원에서아세틸콜린의분비를촉진하여위배출과위순응을호전시키는약제로, EPS에서는그효과가분명하지는않았으나, PDS에서탁월한효과를보였다. 47,48 종합해볼때인구학적역학연구와병태생리적연구들은로마기준 III에서기능성소화불량증의아형을 EPS와 PDS로분류하는것에대한타당성을보여주고있지만, 소화불량증으로내원한환자를대상으로한연구에서는 EPS와 PDS가중복되는경우가많았고, acotiamide를제외한치료에대한반응에서도각각의아형에따라큰차이를보이지않았다. 따라서 EPS와 PDS의아형에따라각각다른방법으로치료적접근을해야하는지에대해서는아직까지는불분명하다. 양질의연구가부족하기때문에향후각각의아형에따라치료반응을평가하는더많은무작위대조연구들이필요하다. 3. 기능성소화불량증에서수면장애기능성소화불량증에서불안증이나우울증과의연관성에대해서는많은연구들이이루어져왔으며, 2003년시행된메타분석은기능성소화불량증에서불안증및우울증의높은유병률을보여주었다. 49 하지만로마기준 III를이용한큰규모의인구-기반단면적연구에서는불안증은기능성소화불량증과 PDS와관련성을보였으나, 우울증은소화불량증과관련성을보이지않았다. 4 수면장애는흔한내과적문제로위식도역류질환이나과민성장증후군같은기능성위장질환에서수면장애가빈번하게나타나는것은잘알려져있다. 8,9,50,51 그러나기능성소화불량증에서의수면장애에대한연구는많지않다. 로마기준 III의기능성소화불량증 131명의환자를대상으로한연구에서경증의환자나건강인에비해중등도이상의소화불량증을갖는환자에서피츠버그수면질지수 (Pittsburgh Sleep Quality Index) 와불면증지수 (Insomnia Severity Index) 가의미있게높았다. 52 최근일본에서시행된두개의연구를보면 94명의로마기준 III를적용한연구에서기능성소화불량증환자가건강인에비해피츠버그수면질지수가의미있게높았으며, 소화불량증의중증도와수면장애의정도가일치함을보여주었다. 10 또한 nizatidine 투여후에기능성소화불량증환자에서증상의호전과함께수면장애도의미있는호전을보였다. 다른연구에서도 79명의로마기준 III의기능성소화불량증환자가건강인에비해의미있 는수면장애를보였으나, 3개의소화불량증아형간에는수면장애의차이가없었다. 53 이상최근 3개의연구를통해기능성소화불량증과수면장애의밀접한연관성을알수있었으나, 대부분소규모의연구여서향후더많은연구가필요하다. 국내에서는아직까지기능성소화불량증에서수면장애의유병률에대해보고된바가없으며, 현재전향적다기관연구가진행되고있다. 4. H. pylori 연관소화불량증과기능성소화불량증로마기준 III에의하면소화불량증을설명할만한기질적원인이없어야기능성소화불량증으로정의할수있다. 따라서위내시경에서미란성식도염, 악성종양및소화성궤양등이발견되면실제로이러한기질적원인이소화불량증을유발했는지와상관없이기능성소화불량증으로정의할수없다. 그러나소화성궤양이있는환자의절반정도가증상이없으며, 대부분의조기위암환자도증상이없다. 54,55 또한소화성궤양이나미란성식도염이호전된이후에도지속적으로소화불량증을호소하는경우기능성소화불량증으로진단할수있는지에대해로마기준 III로는알수가없다. 로마기준 III에서 H. pylori 감염은기질적원인이아니기때문에기능성소화불량의배제기준이아니다. 그러나 H. pylori 감염은명백하게위점막의육안적, 현미경적변화를유발하여위암으로발전할수있는위축성위염과장상피화생의원인이된다. 56,57 H. pylori 감염이주로위전정부에발생하는경우소마토스타틴감소와가스트린증가에의해위산분비를증가시키는데이러한위산분비의변화가소화불량증의주요원인으로간주되고있다. 58 최근메타분석에서위장관감염후기능성소화불량증이약 2배정도증가하는것으로나타났으며, 59 염증-면역학적회로 (inflammation-immunological circuit) 가기능성소화불량증의발생에중요한역할을한다고제안하였다. 60 H. pylori 감염은위십이지장염증의주원인이며, 위점막의사이토카인과케모카인을활성화시킨다. 61 따라서 H. pylori 감염이소화불량증의병인중하나로여겨지고있다. Ghrelin은식욕을촉진하고위배출과산분비를자극하는것으로잘알려져있다. 62,63 H. pylori 감염에의한위점막의위축은혈중 ghrelin의농도를감소시켜식욕을떨어뜨리고위운동장애를유발하였다. 64,65 따라서 H. pylori 감염에의한혈중 ghrelin의감소가기능성소화불량증발생에관여할것으로여겨진다. 실제로기능성소화불량증환자에서혈중 ghrelin의농도가감소되어있었으며, 특히운동이상형소화불량증에서는의미있게 ghrelin의농도가감소되어있었다. 63,66 그러나기능성소화불량증환자에서 ghrelin의농도가증가되어있었다는반대의결과도보고된다. 67 H. pylori 감염과연관된위운동장애에서 microrna의역할을본, 쥐를이용한동물실험에서만성적인 H. pylori 감염은근육- The Korean Journal of Gastroenterology

Park JK, et al. Current Issues in Functional Dyspepsia 137 특이 microrna의발현을억제하였으며, histone deacetylase 4와 serum response factor의발현을증가시켰다. 68 결과적으로위근육층의비대를유발하였고위배출이상, 특히위순응장애에의한위배출을항진시켰다. 인간을대상으로한연구가더필요하지만, 이러한소견은 H. pylori 감염과관련된위운동장애에대해분자적수준에서새로운병태생리를보여준것이라할수있고, H. pylori와연관된소화불량증의기질적측면을보여준것이다. 따라서다양한병태생리적기전으로 H. pylori는위십이지장에만성적인염증을유발하는병인이되고, 위십이지장의운동및자각능력에이상을초래하여소화불량을유발하기때문에일부전문가들은 H. pylori를소화불량증의기질적원인으로간주해야하고, 더이상기능성소화불량증으로분류하지말아야한다고주장한다. 13,69 H. pylori가관여하는다양한병태생리의기전에서일부는가역적일수있고, 다른일부는비가역적일수있다. 따라서제균치료가모든 H. pylori와관련된기능성소화불량증환자에서효과적이지는않고, 그중일부에서만효과가있다. 소화성궤양으로기능성소화불량증의진단에서배제되었던환자가소화성궤양의호전후에도여전히소화불량증을호소하는경우이때의소화불량증은소화성궤양에의한것이아니라기능성소화불량증이중복된것으로간주해야할것이다. 마찬가지로 H. pylori에감염된환자에서소화불량증을호소하는경우일부는제균치료에의해증상이호전될수있으며, 일부는증상이지속될수있다. 따라서일부전문가들은 H. pylori에감염된소화불량증을처음부터기능성소화불량증으로진단하는것대신, 먼저 H. pylori에대한제균치료후증상의호전을보이면 H. pylori 연관소화불량증으로정의하고, 제균치료후에도소화불량증의증상이지속되는경우기능성소화불량증으로간주하도록하고있다. 70 그러나 H. pylori 연관소화불량증을기능성소화불량증에서분리해야하는지에대한더많은연구가필요한실정이다. 기능성소화불량증에서 H. pylori 제균치료의유용성에대한우리나라의연구들은일관된소견을보이지않는다. 71 또한우리나라는 H. pylori의유병률이높고, 제균치료에의한부작용과항생제내성균주가증가할수있어우리나라진료지침에서는낮은권고수준으로 H. pylori 양성인기능성소화불량증에서제균치료는일부환자에서도움을줄수있다고되어있다. 72 따라서우리나라에서는기능성소화불량증에서 H. pylori 제균치료를적극적으로권장하고있지않기때문에, H. pylori를기질적원인으로간주하여진단초기부터적극적으로 H. pylori 제균치료를시행하도록하는 H. pylori 연관소화불량증에대해우리나라실정에맞는더많은연구가필요하겠다. 5. 기능성소화불량증의새로운약물치료 1) 위장관운동촉진제기능성소화불량증에서새로운위장관운동촉진제에대한최근연구들은성공적인결과를보여주지못하였다. 5-HT 4 작용제인 mosapride 는이중맹검, 무작위대조연구에서위약에비해효과가없었으며, 73 도파민-2 수용체길항제이며콜린에스테라제억제제인 itopride는 2상연구에서소화불량증의증상호전에효과적이었으나, 3상연구에서는효과를보이지못했다. 74,75 5-HT 4 작용제인 tegaserod는기능성소화불량증이있는여성환자를대상으로한 3상연구에서일부효과를보였으나임상적중요성은불분명하였다. 76 모틸린작용제인 erythromycin에대한소규모연구에서기능성소화불량증의증상호전에효과를보여주지못했다. 77 또한 erythromycin과구조적으로유사한 motilides 라불리는모틸린작용제들도위약에비해더좋은치료효과를보이지는못했다. 78 당뇨병성위마비환자를대상으로한 ghrelin 작용제에대한연구에서도위약에비해의미있는차이를보이지못하였다. 79 2) 위저부이완제위저부이완장애는기능성소화불량증의중요한병태생리중하나이다. 기능성소화불량증환자의 40% 에서식후위저부의이완장애를보이며조기포만감, 체중감소가나타난다는결과가보고되고있다. 80 5-HT 1A 수용체작용제인 buspirone은콜린성긴장을억제하여위의근위부를확장시키는약제로, 소규모의위약대조군연구에서위약에비해기능성소화불량증의증상을의미있게호전시켰으며, 이러한효과는식후위이완기능향상에의한것이었다. 81 다른 5-HT 1A 수용체작용제인 tandospirone도이중맹검, 위약대조군연구에서위약에비해의미있는증상의호전을보였고, 이러한효과는항불안, 항우울작용에의한것은아니었다. 82 Acotiamide는무스카린수용체 M1과 M2의길항작용과콜린에스터라제의억제작용으로아세틸콜린의분비를촉진하여위장운동을촉진시키고, 위저부를이완시키는작용을한다. 위약대조연구에서 acotiamide가소화불량증의증상호전에더효과적인것으로보고되었고, 이러한효과의기전은초음파를이용하여근위부위의단면적의변화를측정한연구에서위이완기능향상과, 위배출작용증가에의한것으로확인되었다. 47,83 2상연구에서는소화불량증증상중주로식후불편감, 조기포만감과복부팽만감개선에효과를나타냈는데이는 acotiamide가로마기준 III의아형중 PDS에더효과적으로작용한다는것을나타낸다. 84 3상연구에서는 4주간의 acotiamide 치료후위약에비해증상호전에있어 17.4% 더효과적임을보여주었다. 48 3) 정신작용제체계적문헌고찰에서항불안제와항우울제가기능성소화 Vol. 64 No. 3, September 2014

138 박종규등. 기능성소화불량증의최근동향 불량증에일부효과가있음이보고되었다. 85 그러나대부분의연구가소규모이고양질의연구가아니었으며출판편향을배제할수없었다. 최근 160명의기능성소화불량증환자에서세로토닌 / 노르아드레날린재흡수억제제 (serotonin/noradrenaline reuptake inhibitor, SNRI) 인 venlafaxine에대한이중맹검, 무작위위약대조연구에서위약에비해더나은효과를보이지못했고, 약제에대한내성이낮았다. 86 Amitriptyline은 38명의기능성소화불량증환자를대상으로한이중맹검, 무작위위약대조연구에서위약에비해임상증상점수와구역증상을의미있게호전시켰지만소규모연구라는제한점이있다. 87 4) 내장과감각억제제내장과감각억제를위한주요약물로는뉴로키닌수용체길항제와 κ-오피오이드수용체작용제이다. κ-오피오이드작용제인 fedotozine은기능성소화불량증에서증상완화에효과를보였으나, 후발연구에서효과가없는것으로나타났다. 88 다른 κ-오피오이드작용제인 asimadoline은소규모의예비연구에서기능성소화불량증의증상완화에도움을주지못하였다. 89 결론 기능성소화불량증의로마기준 III는로마기준 II보다민감도가낮고특이도가높은것으로나타났으나, 두기준간의곡선아래면적값과기질적원인을배제하는데있어차이를보이지않아기능성소화불량증을진단하는데있어로마기준 III가로마기준 II보다정확도가더높은진단기준은아니었다. 로마기준 III에서기능성소화불량증의아형을 PDS와 EPS로분류하는것은역학연구와병태생리연구에서는타당성이인정되었으나, 외래기반연구에서는두아형간에구분되지않는경우가많았으며, 약물치료반응을본연구들에서는 acotiamide를제외한두아형간에의미있는차이가없었다. 따라서 PDS와 EPS의아형에따라다른치료전략이필요한지에대해서는아직불분명하다. 향후각아형간의치료에대한반응을평가하는무작위대조연구가필요하다. 다른기능성위장관장애처럼기능성소화불량증에서도일반인에비해수면장애가많이동반되었고, 소화불량증호전후수면장애도호전을보여기능성소화불량증과수면장애의긴밀한연관성을알수있었다. H. pylori 감염은다양한병태생리적기전으로위십이지장에만성적인염증을유발하고운동및자각능력에이상을초래하기때문에 H. pylori 감염을소화불량증의기질적원인으로간주할수있다. 따라서최근 H. pylori 감염에의한소화불량증은기능성소화불량증과다른질병범위인 H. pylori 연관소화불량증으로간주해야한다고제시되고있다. 우리나라에서는기능성소화불량증에서제균치료를적극권장하고있 지않기때문에 H. pylori 연관소화불량증과관련한논의와연구가필요하다. 기능성소화불량증의새로운치료약제중위장관운동촉진제, 정신작용제및내장과감각억제제는증상의호전을보여주지못하였다. Buspirone, tandospirone은위저부의이완기능을향상시켜증상호전에도움을주었으며, acotiamide 는위저부이완기능을향상시키고위배출작용을증가시켜소화불량증을호전시켰고, 특히 PDS에더효과적으로작용하는것으로나타났다. 우리나라에서 acotiamide에대한연구는아직까지보고된바가없어향후국내에서도 acotiamide 의유용성에대한평가가필요하겠다. 여러차례의개정에도불구하고기능성소화불량증의로마기준 III는아직만족할만한수준은아니며, 효과적인치료약제또한부족하다. 따라서이러한문제점을보완하기위한더많은연구들이필요하며, 특히인종이나지역에따라차이를보일수있어우리나라사람들을대상으로한연구가더욱필요하다. 향후발표될로마기준 IV에서는이제까지제기된문제점들을극복하는진단기준이나오기를기대한다. REFERENCES 1. Drossman DA, Li Z, Andruzzi E, et al. U.S. householder survey of functional gastrointestinal disorders. Prevalence, sociodemography, and health impact. Dig Dis Sci 1993;38:1569-1580. 2. El-Serag HB, Talley NJ. Health-related quality of life in functional dyspepsia. Aliment Pharmacol Ther 2003;18:387-393. 3. Nyrén O, Lindberg G, Lindström E, Marké LA, Seensalu R. Economic costs of functional dyspepsia. Pharmacoeconomics 1992;1:312-324. 4. Aro P, Talley NJ, Ronkainen J, et al. Anxiety is associated with uninvestigated and functional dyspepsia (Rome III criteria) in a Swedish population-based study. Gastroenterology 2009;137:94-100. 5. Tack J, Talley NJ, Camilleri M, et al. Functional gastroduodenal disorders. Gastroenterology 2006;130:1466-1479. 6. Lee YY, Wahab N, Mustaffa N, et al. A Rome III survey of functional dyspepsia among the ethnic Malays in a primary care setting. BMC Gastroenterol 2013;13:84. 7. Ford AC, Bercik P, Morgan DG, Bolino C, Pintos-Sanchez MI, Moayyedi P. The Rome III criteria for the diagnosis of functional dyspepsia in secondary care are not superior to previous definitions. Gastroenterology 2014;146:932-940.e1. 8. Goldsmith G, Levin JS. Effect of sleep quality on symptoms of irritable bowel syndrome. Dig Dis Sci 1993;38:1809-1814. 9. Kusano M, Kouzu T, Kawano T, Ohara S. Nationwide epidemiological study on gastroesophageal reflux disease and sleep disorders in the Japanese population. J Gastroenterol 2008;43: 833-841. 10. Futagami S, Yamawaki H, Izumi N, et al. Impact of sleep disorders in Japanese patients with functional dyspepsia (FD): nizatidine improves clinical symptoms, gastric emptying and sleep dis- The Korean Journal of Gastroenterology

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