대한소화기학회지 2010;55:308-315 DOI: 10.4166/kjg.2010.55.5.308 REVIEW 과민성장증후군의진단 : 체계적인문헌고찰 성균관대학교의과대학내과학교실, 울산대학교의과대학내과학교실 *, 한림대학교의과대학내과학교실, 연세대학교의과대학내과학교실, 아주대학교의과대학내과학교실 박정호ㆍ변정식 * ㆍ신운건 ㆍ윤영훈 ㆍ천재희 ㆍ이광재 ㆍ박효진 ㆍ대한소화기기능성질환 운동학회 Diagnosis of Irritable Bowel Syndrome: a Systematic Review Jung Ho Park, M.D., Jeong-Sik Byeon, M.D.*, Woon-Geon Shin, M.D., Young Hun Yoon, M.D., Jae Hee Cheon, M.D., Kwang Jae Lee, M.D., Hyojin Park, M.D., and The Korean Society of Neurogastroenterology and Motility Department of Internal Medicine, Sungkyunkwan University School of Medicine, Seoul, Department of Internal Medicine, University of Ulsan College of Medicine*, Seoul, Department of Internal Medicine, Hallym University College of Medicine, Seoul, Department of Medicine, Yonsei University College of Medicine, Seoul, Department of Internal Medicine, Ajou University School of Medicine, Suwon, Korea Irritable bowel syndrome (IBS) is a very common functional gastrointestinal disorder characterized by abdominal discomfort, bloating, and disturbed defecation. Patients with IBS have a tendency to visit physicians more frequently than those without IBS, thus annual economic consequences of IBS in the Western countries are substantial. Therefore, guidelines for the diagnosis and treatment of IBS patients have been designed to give a favored effect on the Department of Gastroenterology s overall performance. A variety of criteria have been developed to identify a combination of symptoms to diagnose IBS, including Manning and Rome I, II, and III criteria. Overall, Manning s criteria had a pooled sensitivity and specificity, 78% and 72%, respectively. In addition, the Rome I criteria had a sensitivity and specificity, 71% and 85%, respectively. However, none described the accuracy of Rome II and III yet. Alarm features such as rectal bleeding and nocturnal pain offer little discriminative value in separating patients with IBS from those with organic diseases. Even though anemia and weight loss have poor sensitivity for organic diseases, they offer very good specificity. Since specific biomarker of IBS is not yet available, diagnostic tests are frequently performed to exclude organic diseases. However, the accuracy of diagnostic tests is disappointing. CBC, chemistry, thyroid function test, stool exam, ultrasonography, hydrogen breath test, erythrocyte sedimentation rate, and C-reactive protein have all very limited accuracy in discriminating IBS from organic diseases. This systemic review is targeted to establish the strategy of IBS treatment, which is very necessary for the current clinical practice. (Korean J Gastroenterol 2010;55:308-315) Key Words: Irritable bowel syndrome; Diagnosis 연락처 : 박효진, 135-720, 서울시강남구언주로 712 강남세브란스병원소화기내과 Tel: (02) 3497-3310, Fax: (02) 3463-3882 E-mail: HJPARK21@yuhs.ac Correspondence to: Hyojin Park, M.D. Department of Internal Medicine, Kangnam Severance Hospital, Yonsei University College of Medicine, 712, Eonguro, Gangnam-gu, Seoul 135-720, Korea Tel: +82-2-3497-3310, Fax: +82-2-3463-3882 E-mail: HJPARK21@yuhs.ac
박정호외 6 인. 과민성장증후군의진단 : 체계적인문헌고찰 309 서 론 2. 문헌검색 과민성장증후군 (Irritable bowel syndrome, IBS) 은기질적이상없이배변습관의변화를동반한복통이나복부불편감을특징으로하는만성기능성위장관질환으로, 스트레스및내장과민성과같은여러원인에의해증상이발생하는것으로생각되고있다. IBS는매우흔한질환중하나로미국과영국에서는여성이좀더많아여성의유병률은 7-24%, 남성은 5-19% 로보고되었으나, 1-3 우리나라의경우에는남자는 7.1%, 여자는 6.0% 로성별에따른유병률차이가없는것이특징이다. 4 IBS의증상은 1차의료기관을방문하는가장흔한원인이되고있으며, IBS 환자들은 IBS 없는사람과비교할때소화기증상뿐만아니라편두통, 섬유근육통 (fibromyalgia) 등소화기와관련이없는증상으로도자주의사를방문하는것으로나타났다. 5,6 따라서 IBS로인한경제적지출은막대할수밖에없는데, 미국의경우매년직접의료비용이 17-100 억달러에이르며, IBS로인한생산성감소및결근등으로인한간접적인비용까지생각하면 100-200억달러의추가비용이들정도로심각한경제적손실을유발하고있다. 7,8 이와같이사회경제적으로큰영향을미치는 IBS에대해미국을비롯한서구에서는일찍이진료지침을개발하여사용해왔다. 우리나라에서는 2005년대한소화기기능성질환ㆍ운동학회에서 IBS 진단및치료에대한진료지침을발표하였으며, 9,10 외국과는다른우리나라의실정에맞는진단및치료의지침을제시하여실제임상에서사용되어왔다. 이번종설에서는그동안의의학적발전을다시정리하고 IBS의합리적인진단및치료를위한근거를마련하며, 앞으로보다발전적인 IBS 진단의가이드라인작성을위해 IBS의진단기준및실제임상에서사용되는검사방법의유용성에대하여체계적인문헌고찰을시행하고자하였다. 대상및방법 1. IBS의정의 1978년 Manning 등 11 에의해처음 IBS의 Manning 기준이제시된이래, 1989년각국의소화기질환전문가들이모여 IBS를포함한다양한기능성위장질환에대해로마기준 I 이라불리는진단기준을만들었으며, 이후 1999년, 2006년 2, 3차개정이이루어져현재에이르고있다. 이번원고에서는 Manning 기준을비롯하여로마기준 I, II, III을바탕으로연구를시행한논문을모두포함하여문헌고찰을시행하였다. 문헌검색은 2010년 3월 1일부터 3월 14일까지실시하였다. 국외문헌검색은미국소화기학회진료지침, 12 영국 IBS 진료지침 (National Institute for Clinical Excellence, NICE), 13 영국소화기학회진료지침, 14 유럽일차진료소화기질환진료지침 (European Society of Primary Care Gastroenterology, ESPCG), 15 2005년개정된 IBS에대한 Cochrane 고찰을검색하였다. 상기작업은 2005년이전에검색된 IBS 진단및치료에관한체계적문헌고찰및메타분석이포함되어있고 2005년부터 2010년 2월사이의새롭게발표된문헌은 Cochrane Library와 MEDLINE 검색엔진을이용하여검색하였다. 국내문헌검색은 2000년 1월부터 2010년 3월까지한국의학논문데이터베이스 (http://kmbase.medric.or.kr/), KoreaMed (http://www. koreamed.org), 국회도서관, Korean studies Information System (http://kiss.kstudy.com/) 을이용하여검색하였다. IBS의진단에관한관찰연구 (observational study) 및무작위통제연구 (randomized controlled trial) 를대상으로고찰하였다. 영문검색에사용한주제어는 Mesh 용어인 irritable bowel syndrome 과 IBS 진단에사용되는다음과같은진단방법을주제어로결과내에서재검색하였다 : Manning 기준, 로마기준 I, II, III, 경고증상들, CBC, TFT, colonoscopy, CRP, stool, hydrogen breath test. 국내문헌검색에서사용한주제어는 과민성장증후군, 과민성장, irritable bowel syndrome, IBS 로검색되는모든문헌을고찰하였다. 이번체계적문헌고찰에포함된문헌선정기준은다음과같다 : 1) 성인을대상으로한연구, 2) 1차진료에서가능한진단방법을이용한 IBS 진단방법을이용한연구, 3) IBS의정의가명시되어있는연구. 연구제외기준은다음과같다 : 1) 생체내혹은생체외실험실연구, 2) 국외연구중영어이외의언어로게재된문헌, 3) 학회초록, 4) 종설, 5) 연구종료점 (outcome) 이비용혹은비용효과분석인연구. 자료추출과 1차문헌선정은초록의제목혹은전문을보고선정하였으며, 독립된 2인의소화기내과전문의가각기시행하여 Endnote와 Exel에정리하여중복된문헌을검색하여제거하였다. 1차에서선정된문헌중두저자가문헌을선택할것인지에대해의견이일치되지않는경우에한해논문의전문을확인한후각각 2차선택을실시하였다 (Fig. 1). 결과 1. IBS 진단에있어서진단기준의유용성 IBS는진단을위한생물학적표지자 (biological marker) 가
310 The Korean Journal of Gastroenterology: Vol. 55, No. 5, 2010 Fig. 1. Flow chart for searching strategy. 없기때문에비슷한증상을갖는여러질환과의감별을통해진단이이루어진다. 따라서이전부터 IBS의특징적인증상에근거하여기준을만들어진단과정을단순화하고표준화하려는노력이이루어져왔으며, 대표적인진단기준으로 manning 기준, 로마 I, II, III 기준이있다 (Table 1). 우선, IBS 각개별증상들이 IBS를진단하는데도움이될것인가, 즉각증상의정확도에대해알아보면, 6개연구 11,16-20 에서대장내시경이나대장조영촬영검사후 manning 및로마 I, II, III 기준에의해 IBS 진단을받았던총 1,077명의환자를대상으로하였을때 IBS 각증상, 즉복통, 복통을동반한묽은변및잦은변, 잔변감 (incomplete evacuation), 점액분비 (mucus per rectum), 복부팽만의양성우도비는각각 1.3, 2.1, 1.3, 1.2, 1.7로, 개별증상은 IBS 진단에있어서정확성이제한적임을알수있었다. Manning 기준 11 은 1978년 32명의 IBS 환자와 33명의기질적복부질환환자를대상으로, 15개의복부증상중 IBS 환자에서보다많이나타나는 6개의증상으로만들어졌다. 이기준은 IBS의진단에처음으로증상에근거한진단기준을제시한데의의가있으나증상의지속기간이나빈도에대한 규정이없었으며, 몇가지이상의증상을나타내는경우 IBS로진단할수있는지명확하지않는제한점이있다. 574 명의환자를대상으로한 4개의연구 18,19,21,22 에서 Manning 기준의 6가지증상중 3가지증상이상이있을때 IBS로진단할경우, 민감도는 78%, 특이도는 72% 였으며, 양성우도비 (positive likelihood ratio (LR)) 는 2.9, 음성우도비 (negative LR) 는 0.29였다. 로마기준은 1988년다국적실행위원회 (multinational working team committee) 가로마에서열린국제소화기병학회에서기능성위장관질환의진단기준을만들었기때문에붙여진이름이다. 지난 22년간총 3차례의개정이있었으며, 로마 III 기준이가장최근인 2006년에발표되었다. 로마기준중로마기준 I은발표된지가장오래되어정확도에대한평가가가장많이이루어졌는데, IBS 진단의민감도는 67-83%, 특이도는 33-85% 였다. 23-25 로마기준 II는민감도 31-65%, 특이도 30-100% 로 23,24,26,27 로마기준 I에비해정확도가낮게나타났으며로마기준 III에대한진단의정확도는아직알려져있지않다.
Park JH, et al. Diagnosis of Irritable Bowel Syndrome: a Systematic Review 311 Table 1. Summary of Diagnostic Criteria Used to Define Irritable Bowel Syndrome Diagnostic criteria Manning (1978) Rome I (1990) Rome II (1999) Rome III (2006) IBS, irritable bowel syndrome. Symptoms, signs, and laboratory investigations included in criteria IBS is defined as the symptoms given below with no duration of symptoms described. The number of symptoms that need to be present to diagnose IBS is not reported in the paper, but a threshold of three positive is the most commonly used: 1. Abdominal pain relieved by defecation 2. More frequent stools with onset of pain 3. Looser stools with onset of pain 4. Mucus per rectum 5. Feeling of incomplete emptying 6. Patient-reported visible abdominal distension Abdominal pain or discomfort relieved with defecation, or associated with a change in stool frequency or consistency, PLUS two or more of the following on at least 25% of occasions or days for three months: 1. Altered stool frequency 2. Altered stool form 3. Altered stool passage 4. Passage of mucus 5. Bloating or distension Abdominal discomfort or pain that has two of three features for 12 weeks (need not be consecutive) in the last one year: 1. Relieved with defecation 2. Onset associated with a change in frequency of stool 3. Onset associated with a change in form of stool Recurrent abdominal pain or discomfort three days per month in the last three months associated with two or more of: 1. Improvement with defecation 2. Onset associated with a change in frequency of stool 3. Onset associated with a change in form of stool 2. IBS 진단에있어서경고증상의유용성경고증상이란직장출혈, 체중감소, 빈혈, 50세이상의고령및대장암, 염증성장질환, 비열대성스프루 (nontropical sprue, celiac sprue) 의가족력을말하는데, 복통과배변습관의변화와같은특징적인 IBS 증상을가진환자들은기질적인질환을동반할경우 경고증상 을같이나타낼수있다. 이와같은개념은 25년전처음제시되었으며 20 이후여러연구에서그유용성이검증된바있다. 16,17,21,26-29 568명의 IBS 환자를대상으로각경고증상의기질적질환의예측정도를알아본연구에서, 증상이시작될때가 50세이상고령일경우기질적질환을가질 odds ratio (OR) 는 2.65 (95% confidence interval 1.4-5.0) 였으며, 화장실휴지에피가묻어날경우의 OR는 2.7 (1.4-5.1) 로의미있는결과를보였다. 17 또한경고증상을가진환자를제외하고로마 I 기준에의한 IBS 진단의정확도를알아본연구들을메타분석을한결과중위값민감도는 67%, 특이도는 92% 였으며, 30 또다른메타분석에서는중위값민감도는 84%, 특이도는 87% 31 로비교적진단기준의민감도및특이도가높게나타났다. 17개연구에서하복부증상을가진 19,189명의환자를대상으로경고증상의대장암진단에대한유용성을알아본연구에서, 직장출혈이있을때대장암진단의통합민감도 (pooled sensitivity) 는 64% (95% CI=55-73%) 였으며, 통합특이도 (pooled specificity) 는 52% (95% CI=42-63%) 였다. 32 마찬가지로 7개연구, 4,404명의하복부증상을가진환자를대상으로빈혈의대장암진단에의유용성을알아본결과통합민감도는 19% (95% CI=5.5-33%), 통합특이도는 90% (95% CI=87-92%) 였으며, 5개연구 7,418명의하복부증상환자를대상으로한체중감소의대장암진단유용성에대한연구결과통합민감도는 22% (95% CI=14-31%), 통합특이도는 89% (95% CI=81-95%) 였다. 32 또한부모형제 (first degree relative) 가대장암, 염증성장질환, 비열대성스프루를앓았던경우대장암의위험성이증가한다는것은입증되었으나, 33-35 야간에발생하는복통 (nocturnal abdominal pain) 은기질적질환환자뿐아니라 IBS 환자에서도마찬가지로발생하기때문에야간증상 (nocturnal symptoms) 이기질적질환을시사하는소견이라말하기는어렵다. 17,27
312 대한소화기학회지 : 제 55 권제 5 호, 2010 종합해보면, 전반적인경고증상의정확도는만족스럽지는않다. 직장출혈및야간증상은 IBS 환자와기질적질환환자를감별하는데큰도움을주지는못한다. 반면에빈혈과체중감소는민감도는낮지만매우높은특이도를갖고있다. 따라서, 환자의증상이 IBS 증상기준에합당하면서환자가빈혈, 체중감소, 대장암및염증성장질환, 비열대성스프루의가족력을갖고있지않은경우 IBS 가능성이높다고할수있겠다. 3. IBS 진단에있어서진단적검사법의유용성 IBS는다양한병태생리를갖는질환으로아직특정한생물학적표지자가없는실정이다. 그러므로대부분의의사들이진단적검사를 IBS와증상이비슷한기질적질환을감별하기위한과정으로생각하고많은비용을투자하고있다. IBS 환자가내원하였을때주로시행하는검사로는 CBC (complete blood count; 전혈구검사 ), 일반화학검사, 갑상선기능검사, C-반응성단백질 (CRP) 과같은염증지표, 흡수장애및소장내세균과증식진단을위한수소호기검사 (hydrogen breath test) 가있으며, 이번장에서는각검사의임상적유용성에대해서알아보고자한다. 진단기준에합당하고경고증상이없는 IBS 환자에서 CBC나일반화학검사가중요한기질적질환을발견할확률은같은검사로정상인에서기질적질환을발견할확률과비슷하다고알려져있으며, 36 5개연구, 총 2,160명의 IBS 환자를대상으로갑상선기능검사의유용성을확인한결과, IBS 환자에서갑상선기능검사이상의유병률은 4.2% (0-5.5%) 로정상인에서와차이가없었다. 더욱이갑상선기능이상을동반한 IBS 환자에서증상과검사결과사이에는상관관계가발견되지않았다. 23,37-40 대변기생충검사역시경고증상이없는 IBS 환자에게진단적유용성이없다는보고가있었는데, 170명의 IBS 환자를대상으로대변기생충검사를하였을때이상소견이전혀없었으며, 38 1,154명의 IBS 환자를대상으로한검사에서도단지 1.6% 의환자에서이상소견이관찰되었으며, 원인기생충치료로증상이호전되었는지여부역시확실치않았다. 39 복부방사선학적검사의 IBS 진단유용성에대한연구는매우제한적이다. 125명의 IBS 환자를대상으로복부초음파검사의유용성을검사하였을때, 22명 (18%) 의환자에서이상소견이관찰되었으며, 가장흔한이상은담석증 (6명, 5%) 이었다. 41 그러나검사결과로 IBS 진단이번복되지는않았기때문에역시경고증상이없는 IBS 환자의진단을위한복부초음파검사의유용성은확실치않다. 유당불내증 (lactose intolerance) 은 IBS 환자에서비교적흔한것으로알려져있다. 7개연구, 42-48 2,149명의환자를대상으로락툴로오스호기검사 (lactose breath test) 를하였을때 유병률은 35% (95% CI 1.27-5.22) 였으며, 3개의환자대조군연구, 총 425명 (IBS환자 251명 ) 을대상으로하였을때정상인보다 IBS 환자에서유당불내증이의미있게많은것으로나타났다 (38 vs. 26%; OR=2.57, 95% CI=1.27-5.22). 이와같이 IBS 환자에서유당불내증의비율이의미있게높으므로환자에게반드시증상과관련하여유당섭취여부를확인하여야하고, 확실치않은경우수소호기검사를시행하는것을생각해볼수있겠다. 최근소장내세균과증식 (small intestinal bacterial overgrowth, SIBO) 이 IBS의중요한발병기전으로주목을받고있으나지금까지락툴로오스및글루코스호기검사로확인된 IBS 환자에서의 SIBO 유병률은결과가매우다르게보고되고있다. 46-48 3개의연구총 432명의환자를대상으로하였을때, 락툴로오스호기검사양성인환자는 65% (95% CI=47-81%) 였고우리나라 IBS 환자 39명을대상으로하였을때락툴로오스호기검사양성은 48.7% 였으나, 49 2개의연구총 208명의환자중글루코스호기검사양성인환자는 36% 였다 (95% CI=29-43%). 50,51 이와같이호기검사방법에따라결과가상이하게나타나는것은 SIBO 진단의최적검사법 (gold standard) 이마땅치않기때문이다. 전통적으로 SIBO 진단의최적검사법은소장흡입액 (jejunal aspirate) 을배양하는것으로, 배양시균의수가 >10 5 CFU/mL일때 SIBO로정의하고있다. 이와같은방법으로 IBS 환자와정상인을비교하였을때 IBS 환자에서소장내세균의의미있는과증식이보고된바있으나, 52 호기검사와흡입액배양검사를동시에시행한다른연구에서는 IBS 환자와정상인사이에뚜렷한차이를발견하지는못하였다. 45 따라서 IBS 환자에게호기검사를시행해야한다는증거는아직부족한실정이다. Erythrocyte sedimentation rate (ESR) 과 CRP는전신염증반응 (systemic inflammation) 의정도를나타내는지표로 IBS 환자 300명에게검사했을때 3명, 즉 1% 의환자에서증가되어있었으며이들환자는이후기질적질환으로진단되었다고하였다. 37 또한대변 serine protease는내장과민성 (visceral hypersensitivity) 의발생에중요한역할을하는 protease activated receptor (PAR) 의활성화와연관이있는데, 최근연구에서설사형 IBS 환자의대변 serine protease의활성도가대조군과설사형이아닌 IBS 환자들보다증가되어있다는보고가있었다. 53 그러나역시이들검사의임상적유용성에대한연구가많지않아보다객관적인근거가필요할것으로생각된다. 마지막으로, 경고증상이없는 IBS 환자에게대장내시경및대장바륨조영술이필요한가에대한최근연구에서, 3개연구총 636명의 IBS 환자를대상으로대장내시경및대장바륨조영술검사를시행한결과단지 1.3% 의환자에서기
박정호외 6 인. 과민성장증후군의진단 : 체계적인문헌고찰 313 질적질환이발견되었으며, 29,38,54 설사형및혼합형 IBS 환자 216명과건강한 416명의환자를대상으로대장내시경검사를시행하였을때두군사이에대장암 (IBS=0%, Controls= 0.2%) 및염증성장질환 (IBS=0.46%, Controls=0%) 의유병률차이는없었고, 오히려선종성용종 (14 vs. 26%, p=0.0004) 및게실 (13 vs. 21%, p=0.01) 이 IBS 환자군에서적게나타났는데, 이는 IBS 환자군들이더젊고 (51 vs. 55 years, p< 0.0001) 여성환자 (69 vs. 42%, p<0.0001) 가많았기때문이라하였다. 55 따라서 50세이상의 IBS 환자들에한해대장내시경및대장바륨조영술검사를받는것이좋다고할수있겠다. 이번고찰은 IBS 진단의가이드라인을제작하기에앞서시행한체계적문헌고찰로주로서구의연구결과를참조하였으며, 아쉽게도우리나라의 IBS 진단에대한연구결과는상당히제한적이어서고찰에많은도움을주지는못하였다. 따라서향후 IBS 환자의진단에실질적인도움이될수있는진단기준이나진단적검사에대한보다체계적인연구가필요할것으로생각되며, 이를위한다기관연구의활성화및학회차원의대규모연구비투자가필요하다고하겠다. 참고문헌 결론 IBS는흔한기능성질환중하나로소화기증상뿐아니라다른동반증상으로도의료기관을이용하는경우가많아막대한경제적손실을유발하고있다. 따라서미국, 유럽등의서구에서는지금까지이뤄진여러연구를기반으로 IBS 진단및치료의가이드라인을제시하여사회적비용을줄이기위한시도를하고있으며, 우리나라도 2005년 IBS 진단및치료의가이드라인을제시한이래현실에맞는지침을만들고자노력하고있다. IBS 진단기준은 Manning 기준을시작으로로마 I, II, III 기준으로발전해왔다. 여러연구결과 Manning 기준의정확성은민감도 78%, 특이도 72% 였으며, 로마 I 기준의민감도는 67-83%, 특이도는 33-85% 로편차가심하였고, 로마 II, III 기준의정확도는아직정확히알려져있지않다. 경고증상은 IBS 증상을갖고있는환자들중기질적인질환을동반할가능성을나타내는증상으로직장출혈, 체중감소, 빈혈, 50세이상의고령및대장암, 염증성장질환, 비열대성스프루 (nontropical sprue, celiac sprue) 의가족력을말한다. 이들경고증상중직장출혈및야간복통증상은 IBS와기질적질환의감별에큰도움이되지못하는반면, 빈혈과체중감소는민감도는낮으나특이도는매우높은것으로알려져있다. 따라서환자의증상이 IBS에합당하면서환자가빈혈, 체중감소, 대장암및염증성장질환, 비열대성스프루의가족력을갖지않는경우 IBS 가능성이높다고할수있겠다. IBS는다양한병태생리를갖는질환으로아직특정한생물학적표지자가없다. 이에많은의사들이 IBS를기질적질환과감별하기위해여러진단적검사를처방하고있지만 CBC, 일반화학검사, 갑상선기능검사, 대변기생충검사, 복부초음파검사, 수소호기검사, ESR, CRP 검사는여러연구결과 IBS를기질적질환과감별하는데큰도움이되지않는것으로나타났으며, 대장내시경검사는 50세이상의 IBS 환자의경우에만도움이될수있다. 1. Drossman DA, Whitehead WE, Camilleri M. Irritable bowel syndrome: a technical review for practice guideline development. Gastroenterology 1997;112:2120-2137. 2. Chey WD, Olden K, Carter E, Boyle J, Drossman D, Chang L. Utility of the Rome I and Rome II criteria for irritable bowel syndrome in U.S. women. Am J Gastroenterol 2002; 97:2803-2811. 3. Sandler RS. Epidemiology of irritable bowel syndrome in the United States. Gastroenterology 1990;99:409-415. 4. Han SH, Lee OY, Bae SC, et al. Prevalence of irritable bowel syndrome in Korea: population-based survey using the Rome II criteria. J Gastroenterol Hepatol 2006;21:1687-1692. 5. Whitehead WE, Palsson O, Jones KR. Systematic review of the comorbidity of irritable bowel syndrome with other disorders: what are the causes and implications? Gastroenterology 2002;122:1140-1156. 6. Azpiroz F, Dapoigny M, Pace F, et al. Nongastrointestinal disorders in the irritable bowel syndrome. Digestion 2000;62: 66-72. 7. Talley NJ, Gabriel SE, Harmsen WS, Zinsmeister AR, Evans RW. Medical costs in community subjects with irritable bowel syndrome. Gastroenterology 1995;109:1736-1741. 8. Sandler RS, Everhart JE, Donowitz M, et al. The burden of selected digestive diseases in the United States. Gastroenterology 2002;122:1500-1511. 9. Lee OY, Yoon CO. Evidence based guideline for diagnosis and treatment: diagnostic guideline for irritable bowel syndrome. Korean J Neurogastroenterol Motil 2005;11:30-35. 10. Park HJ. Evidence based guideline for diagnosis and treatment: therapeutic guideline for irritable bowel syndrome. Korean J Neurogastroenterol Motil 2005;11:36-43. 11. Manning AP, Thompson WG, Heaton KW, Morris AF. Towards positive diagnosis of the irritable bowel. Br Med J 1978;2:653-654. 12. Brandt LJ, Chey WD, Foxx-Orenstein AE, et al. An evi-
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