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1 대한내과학회지 : 제 80 권부록 1 호 2011 개원의연수강좌 쉽고도어려운과민성장증후군 원광대학교의과대학내과학교실, 소화기질환연구소 류한승 최석채 서론과민성장증후군은기능성장질환중흔한질환으로복통및복부불편감과함께배변습관의변화등이주증상이다. 유병률은서구에서 3-15% 로흔하며 [1], 국내에서도 % 로보고하고있다 [2-4]. 본질환은높은유병률과만성재발성경과를가지기에자주병원에방문하고사회경제적문제및환자의삶의질을저하시킨다. 진단은증상을기초로한로마기준을적용하며유사한증상을나타낼수있는기질적질환에대한배제진단이필요하지만일차진료기관에서정밀한검사를시행하기에는어려움이있다. 치료는환자와의좋은관계형성부터다양한약제들이사용되지만효과는다양하고새로운약제의개발등이이루어지고있다. 본고에서는과민성장증후군의병태생리및증상을알아보고, 임상에적용가능한적절한진단과정및치료방법에대해논하고자한다. 병태생리 의염증매개물질이관여함을제시하였다. 과민성장증후군환자의일부에서소장내세균과증식 (small intestinal bacterial overgrowth, SIBO) 이동반되는경우가있으며 4-78% 로다양하게보고하고있다 [12,13]. 병인으로서장내세균변화의연관성에대한이견이있지만비흡수성항생제치료는효과적이었다 [14]. 스트레스가대장운동에영향을줄수있음은과민성장증후군의병태생리연구의초기부터알려져왔으며내장과민성 (visceral hypersensitivity) 에기여하여통증의한기전으로설명하고있다 [15]. 또한 positron emission tomography (PET) 와 functional MRI (fmri) 등을이용하여뇌기능에대한영향을영상학적으로증명하고있다 [16,17]. 스트레스에대한반응호르몬인 corticotropin-releasing hormone (CRH) 는장관운동에영향을미칠수있으며수용체차단제를이용한연구등이진행중이다 [18]. 이외에염증및신경전달과정에관여하는물질들에대한여러후보유전자 (candidate gene) [19] 및음식과의연관성연구가이루어지고있다 [20,21]. 과민성장증후군의병인에대한개념적모델은유전적소인과가정환경등의초기요인을바탕으로스트레스및개인의심리상태등의정신사회적요인이작용하고장관및전신의생리적변화가동반되며, 이과정에신경계의상호작용이질병발생에관여할수있다 [5]. 염증과의관련성은급성위장관염후호전된 6-17% 의환자에서과민성장증후군이발생할수있는데 [6], 이러한감염후과민성장증후군 (post-infectious irritable bowel syndrome) 에서대장점막에경도의염증및다양한염증세포가침윤되어지속적인증상을유발할수있다. 병태생리기전들로는환자의직장내림프구, 장크롬친화세포 (enterochromaffin cell), 비만세포 (mast cell) 등이증가되는변화가발견되었으며 [7,8], IL-4, 13 [9], serotonin [10], histamine 및 tryptase [11] 등 증상본질환의진단을내리는주증상은만성재발성복통과불편감이다. 증상의기간은최소 6개월이상의기간을가져야하는데, 이유는감염성질환의경우일과성증상이고, 암의경우는증상발현 6개월내에대부분진단이되기때문이다 [22]. 부가증상으로배변횟수, 대변형태, 배변후의증상의소실여부에대한문진을해야한다. 만일복통의주증상이없이변비또는설사가오랜기간재발성으로불편감을주는경우는기능성변비또는기능성설사일가능성이높다. 두질환의차이점으로는과민성장증후군은기능성변비에비해여자에많고, 변비의지속기간이길며, 위장관이외증상과삶의질이저하된다. 또한배변습관의변화나다른장증상 - S 17 -

2 - 대한내과학회지 : 제 80 권부록 1 호 이없이보다심한복통을지속적으로호소하는경우는기능성복통증후군 (functional abdominal pain syndrome) 을의심해야하며치료는정신과적접근이반드시필요하므로전문가의도움을얻어야한다 [23]. 대변의형태는로마기준에서설사, 변비, 혼합형으로쉽게분류할수있는중요한기준이지만스트레스에의해빈번한배변과동시에대변의형태가변화하는경우진단에주의를요한다 [22]. 일부의환자에서는상부위장관의기능성질환의증상과중복되는경우가종종발견되며국내연구에서과민성장증후군환자의 21% 에서위식도역류질환, 14% 에서소화불량증이동반되었다 [2]. 변비형은설사형에비해상하부복통과복부팽만감등의상부위장관증상의중복이많다 [24]. 위장관이외의증상으로는두통, 피로감, 요통, 근육통, 성교통, 배뇨장애, 어지러움등다양하다 [25]. 만성피로증후군 (chronic fatigue syndrome), 섬유근육통 (fibromyalgia), 측두하악장애 (temporomandibular disorder) 환자에서과민성장증후군이동반되는경우가흔하다 [26]. 신체증상을보다많이호소하는환자는기분장애, 불안, 신경증 (neuroticism) 의빈도가높다 [27]. 자연경과에대한유럽의한연구에서는 7년후까지지속되는경우가 55%, 증상이다소호전되는경우가 21%, 완전관해는 13% 였다 [28]. 이처럼증상의지속기간이길고잦은재발을하고 1년에 29% 이상에서설사형이변비형으로바뀔수있기때문에 [29] 오랜기간동안증상의변화에대한관심을가져야한다. 결론적으로현재의로마기준즉증상을근간으로진단을내리기때문에자세한병력의청취는진단을내리는방향을결정하는중요한정보를제공한다. 진단진단을위한생물학적표지자는없고증상을바탕으로한로마 III 기준이이용된다 (Table 1). 이러한증상들은기질적질환이있는경우에도호소할수있기에경고증상 (Table 2) [30] 이있는경우는추가적인평가가필요하다. 하지만경고증상이없는환자에서로마기준의정확도에대한메타분석에서민감도 67%, 특이도 92% 로 [31] 비교적정확하기에모든환자에대한배제진단을위한검사는불필요하다. 한연구에서본질환에서최소 1.65개의경고증상을호소하고이 Table 1. Rome III diagnostic criteria used to define irritable bowel syndrome. From Longstreth GF, et al [63] Diagnostic Criteria a) for Irritable Bowel Syndrome. Recurrent abdominal pain or discomfort b) at least 3 days per month in the last 3 months associated with 2 or more of the following: 1. Improvement with defecation 2. Onset associated with a change in frequency of stool 3. Onset associated with a change in form (appearance) of stool a) Criteria fulfilled for the last 3 months with symptom onset at least 6 months prior to diagnosis. b) Discomfort means an uncomfortable sensation not described as pain. In pathophysiology research and clinical trials, a pain/ discomfort frequency of at least 2 days a week during screening evaluation for subject eligibility. Table 2. Alarm signs and symptoms. From Videlock EJ & Chang L [30] Age 50 Unintentional weight loss Family history of GI malignancy Severe unrelenting large-volume diarrhea Fevers, chills, recent travel to endemic region Nocturnal symptoms Hematochezia Relevant findings on physical examination (arthritis, skin lesions, lymphadenopathy, abdominal mass) - S 18 -

3 - 류한승외 1 인. 쉽고도어려운과민성장증후군 - 중야간에복통의증상발생과나이 50세이상의경우는기질적질환의가능성을염두에두어야한다 [32]. 진단을위한검사법으로는혈액검사, 대변검사, 호기수소검사, 복부및대장영상검사등을이용할수있지만경우에따라서더많은검사가필요할수도있다. 대변검사는감염성질환이많이발생하는지역을여행한경우에서시행하며, 대변기생충검사는경고증상이없는환자에서양성률은 0-1.6% 로진단적유용성은적다 [33,34]. 대장내시경은 50세이상에서대장암등의기질적질환발생이많기에추천된다. 경고증상이없는경우는변비형을제외한과민성장증후군환자 466명을대상으로한연구에서대장암이있는경우는없었으며기질적질환의빈도가건강대상자와차이가없었다 [35]. 설사형에서는대장내시경이정상인경우에도 70세이상의 20% 에서현미경적대장염이있기에 [36] 설사의원인이설명되지않는경우에는적극적인조직검사가필요하다. 유당불내성 (lactose intolerance) 이과민성장증후군으로오인되는경우가있으며국내한연구에서과민성장증후군이의심되는환자에서 25 g의 lactose를이용한호기수소검사에서는설사가주증상인환자의 66.6% 가유당불내성으로진단되었다 [37]. 따라서문진시환자에게유당섭취여부와증상과의연관성을확인할필요가있다. 소장의세균과증식은본질환을유발하는원인일수있으며검사방법은 lactulose 호기수소검사등을이용한다 [38]. 하지만제한된연구기관에서주장하고있고장기치료의효과에대한추가연구가필요하다. 결론적으로진단의과정은각검사법들에대해요약한근거 (Table 3) [22] 를바탕으로각환자마다증상에따라적용할수있다. 치료 1. 일반적치료과민성장증후군은만성재발성경과를보이며삶의질의저하를가져오기에의사와환자간의좋은관계를형성하는것이중요하다. 환자는질병에대한이해부족과암에대한불안및빈번한재발로인한불편감을가질수있다. 의사는약물치료에앞서충분한설명을통해질환의이해도를높이고치료계획에대한상담을하여야한다. 3차의료기관에서진단된과민성장증후군환자에대한전향적연구에서정신사회력의청취, 원인인자에대한문진, 진단에대한설명과환자와검사결과및질병에대한토의, 불필요한침습적검사를줄이는것이증상으로인한재방문을줄일수있다 [39]. 과민성장증후군에대한아시아합의 [40] 에서는가능한원인인자에대한자세한병력청취, 적절한비유를통한병인의설명, 중증질환이아님을주지하여안심시키기, 합리적인생활습관변화및약물치료에동참하도록유도함으로써좋은의사- 환자관계를형성할것을권유하였다. 이때정신사회적평가를병행하여적절한치료계획을수립하는데도움이될수있다. 일차진료에서는환자가충분한설명에도진단및질병에대해불안해하거나진단이불확실한경우및경고증상이있다면상급의료기관으로의전원을 Table 3. Summary of the recommendations for investigating irritable bowel syndrome. From Spiller R, et al [22] Intervention Quality of evidence Benefit/harm Strength of recommendation Take a symptom history Low Net benefit Definitive Assess psychosocial factors Low Net benefit Definitive Physical examination Low Net benefit Definitive Check for alarm symptoms Moderate Net benefit Definitive Investigations Full blood count Moderate Net benefit Definitive Endomysial antibodies Moderate Trade-offs Qualified Lactose breath hydrogen test Moderate Net benefit Qualified Colonoscopy Moderate Trade-offs Qualified Abdominal ultrasound Low Trade-offs Qualified - S 19 -

4 - 대한내과학회지 : 제 80 권부록 1 호 고려해보아야한다 [22]. 임상에서경험적으로환자의증상과특정음식과의관련성을중요시하여식이조절을하는경우가있을수있지만, 음식과본질환의연관성은결론을내리기어렵다. 증상유발가능성이있는음식에대한제한식이 (exclusion diet) 로 % 까지장증상이감소되었다는긍정보고는있지만 [41] 잘계획된환자- 대조군연구는부족하다. 2. 전통적약제치료약제치료는복통, 변비, 설사등의환자의증상에따라시도해보지만다양한복합증상을동시에치료할수있는약제는없는실정이다. 증상에따라사용가능한약제는 Table 4에기술한바와같다. 복통의경우는진경제, 변비는식이섬유나부피형성하제, 설사는지사제를사용하여왔다. 이에대한새로운연구는없으며과거연구들에대한메타분석은개별연구의대상환자수가적고진단기준이현 Table 4. Agents available to treat irritable Bowel syndrome by predominant symptom. From Videlock EJ & Chang L [30] Constipation Drug class Generic name Dose Bulking agents Psyllium 1-3 Tbsp qd First-line treatment for mild-moderate constipation. Start with 4 g/d, gradually increase over 2-3 weeks to g/d Methylcellulose 1-3 Tbsp qd Polycarbophil 2-4 tablets qd Laxatives Osmotic Milk of magnesia 1-2 Tbsp qd to bid Magnesium citrate 6-12 oz Sodium phosphate 1 tspn in 8 oz fluid Lactulose 1-2 Tbsp qd-bid Polyethylene glycol 17 g in 8 oz fluid Sorbitol 1-2 Tbsp qd-bid Stimulants Cascara sagrada 325 mg or 1 tspn qhs Senna 187-mg tablets; 1-2 tablets qhs Riconleic acid 1-2 Tbsp qd Diphenylmethane derivatives 10 mg 1-2 tablets qhs or 1 suppository qhs Emollients Docusates 100 mg; 1-3 tablets qhs Mineral oil 1 tsp-1 Tbsp qhs 5-HT 4 agonist Tegaserod 6 mg bid Available only through restricted-use program Diarrhea Drug class Generic name Antidiarrheals Loperamide 1 tablet qid Use prophylactically (start at 1 per day but can use up to 8 per day) Diphenoxylate 1-2 tablets tid Binding agents Cholestyramine 1 g bid to qid 5-HT 3 antagonist Alosetron 0.5 mg-1 mg qd-bid For women with severe IBS-D who have failed conventional therapy. Available only through restricted-use program. - S 20 -

5 - 류한승외 1 인. 쉽고도어려운과민성장증후군 - Tricyclic Amitriptyline mg qhs Very sedating antidepressants Doxepin mg qhs Very sedating Imipramine mg qhs Clomipramine mg qhs Trimipramine mg qhs Desipramine mg qhs Most empiric evidence for efficacy. Less sedation and constipation Nortriptyline mg qhs Least sedating Pain/Bloating Antispasmodics Hyoscamine sulfate mg sl/po qid prn, mg po bid Dicyclomine 10 mg po bid Propantheline 15 mg tid a.c. and 30 mg qhs hydrochloride Clidinium mg tid-qid chlordiazepoxide Hyoscamine+ scopolamine+ atropine +phenobarbital 1-2 tablets tid-qid TCAs See above See above SSRIs Fluoxetine mg qd Long half-life; less withdrawal effects Citalopram 20 mg qd Less side effects and drug interactions Paroxetine mg qd Short half-life; more likely withdrawal effects. Greater anticholinergic effect; use in IBS-D Sertraline mg qd Requires dose ranging Escitalopram 10 mg qd Less side effects and drug interactions SNRIs Venlafaxine mg bid-tid Duloxetine mg qd FDA approved for depression and diabetic neuropathy. Unlabeled uses include chronic pain syndromes, fibromyalgia, stress incontinence. Ongoing open labeled trial for IBS. 5-HT4 agonist Tegaserod See above Antibiotics Rifaximin 400 mg tid Probiotics Bifidobacterium infantis 1 tablet qd VSL # 3 1 packet bid Abbreviations: a.c., before meals; bid, twice daily; g, grams; mg, milligrams; oz, ounces; qd, daily; qhs, at night; qid, four times daily; Tbsp, tablespoon; tid, three times daily; tspn, teaspoon. 재와달라해석에주의를요한다. 최근의한메타분석에서는다양한종류의진경제가위약에비해증상이지속될비교위험도가 0.65 (95% CI: ), NNT (number needed to treatment) 는 5로효과적이며, 부피형성하제중차전자피 (psyllium) 는비교위험도 0.78 (95% CI: ), NNT 는 6으 로유의한효과를나타내었다 [42]. 차전자피는밀기울 (wheat bran) 에대한무작위환자- 대조군연구에서도차전자피를사용한환자에서만유의한증상호전을보였다 [43]. 지사제중 loperamide는소수의환자를대상으로한단기간의위약대조군연구들에서배변형태와배변횟수및급박감의호전을 - S 21 -

6 - 대한내과학회지 : 제 80 권부록 1 호 보였으나장기간의치료효과나안전성에대한연구가부족하다 [44]. 전통적약제는효과에대한잘계획된연구가부족하지만, 증상에따라개별약제의부작용을감안하여단기간사용할수있으며 [44,45], 비교적안전하고비용이상대적으로저렴하여일차약물치료로고려할수있다 [40]. 3. 새로운약제개발의임상적용새로운약제의개발은최근발전하는분자생물학적기법과신경계와의관련성연구를근간으로다양한약제의임상적용이활발하게이루어지고있으며, 임상적용이가능할것으로예상되는약제를중심으로서술하고자한다. 1) 세로토닌수용체관련약물 (1) 설사형 Alosetron 은 5-HT 3 수용체길항제로심한변비와허혈성대장염의부작용으로 2000년도에 FDA에서사용중단된후 2002년도에통상적인치료에반응하지않는 6개월이상지속되는, 설사형, 여성과민성장증후군환자에서제한적으로사용이허가되었다. 최근의메타분석에서는상대위험도 0.79 (95% CI: ), NNT 는 8로효과적이었으며 [46], 8개의대규모연구에대한메타분석에서도성별에관계없이효과적인증상호전을보이고이중허혈성대장염 (0.16%), 변비 (0.08%) 등의합병증은드물었다 [47]. 미국소화기학회가이드라인에서는중증의합병증 ( 허혈성대장염 ) 발생이가능하기에선별된환자에서신중히사용할것을권고하고있다 [45]. Ramosetron 은 5-HT 3 수용체길항제로 1996년부터일본에서항암제투여시발생하는구토를조절하기위해사용된약제이다. 2008년도에 2상임상시험및일본에서시행된대규모 3상연구에서 alosetron 에서보였던허혈성대장염등의중증합병증없이남, 여설사형과민성장증후군환자에서증상호전에좋은효과를보고하였다 [48,49]. 향후다양한인종에대한적용및국내임상시험에대한좋은결과를기대해볼수있다. (2) 변비형 Tegaserod 는 5-HT 4 수용체작용제로심혈관계부작용때문에 2007년 FDA에서일반적인사용을규제하였으며 55세 이하의여자인경우제한적사용만을허용하고있다. 최근 100개의료기관에서시행한미국및유럽의대규모연구에서여성에서변비형과교대형과민성장증후군환자에서좋은효능을보였으며 [50], 11개무작위대조군연구들에대한메타분석에서도비교위험도 0.85 (95% CI: ) 로증상조절에효과적이었다 [46]. 최근까지도이약제에대한연구가진행되고있는것은이약제를대체할약제가없는것도하나의이유일수있다. 2) 비흡수성경구용항생제과민성장증후군의한병인으로 SIBO 가제시된바있으나, 증상발생과관련성은모호하며장내세균이병태생리에어떻게작용하는지는명확하지않다. 하지만, SIBO 의치료제로비흡수성경구용항생제인 rifaximin 을 10일간투여한이중맹검연구에서는위약군에비해증상이유의하게호전되었다 [51]. 특히최근미주에서시행된대규모의이중맹검연구에서는 1,260명의변비형을제외한환자에서 rifaximin 550 mg을하루세번 2주간투여하였을때전반적인장증상이대조군과비교하여유의하게호전되었다 [14]. 향후약물의기전에대한실험실및임상연구가필요하며약제의국내임상시험결과및적용을기대할수있을것이다. 3) 생균제 (probiotics) 장내세균조성의변화가과민성장증후군의가능한기전으로제시되었는데, 임상연구결과는사용된균종에따라다르며 Bifidobacterium 및동일균종을포함한복합균종에대한긍정적보고가있다 [52,53]. 그러나대규모임상연구가없고연구마다사용된균주가다양하고균의농도가표준화되어있지않아약제의이상적제형을제시하기어려우며, 일반적인임상적용은권고되고있지않다 [22,44,45]. 4) 염소통로활성제 (chloride channel activator) Lubiprostone은선택적염소통로활성제로 2006년에 FDA 에서만성변비치료제로허가를받았다. 작용기전은위장관상피세포에존재하는제 2형염소통로를활성화시켜많은전해질이포함된수분을분비한후소장으로들어가장관의운동을증가시킨다. 과민성장증후군에서는 FDA에서 18세이상, 여성의변비형환자에서사용하도록 2008년 4월허가하였다. 이후발표된잘계획된 2상및 3상임상시험결과변비형과민성장증후군환자에서의미있는증상의호전을 - S 22 -

7 - 류한승외 1 인. 쉽고도어려운과민성장증후군 - 보였다 [54,55]. 하지만효능에대한연구결과가부족하고장기간사용시안정성문제및남성에서의효과에대한연구가추가적으로이루어져야만한다. Guanylate cyclase-c는장관세포에존재하는수용체로염소통로의하나인 cystic fibrosis transmembrane conductance regulator (CFTR) 를활성화시켜장내분비를촉진한다. Linaclotide 는 guanylate cyclase-c의작동제로, 최근진행된대규모의 3상임상시험에서긍정적효과와비교적적은부작용을나타내고있어추후임상적사용이기대된다. 정신과적치료및항우울제 ( 삼환계항우울제및선택적세로토닌재흡수억제제 ) 에대한메타분석에서증상호전에유의한효과가있었다 (NNT = 4) [62]. 국내및미국의가이드라인에서는인지-행동요법 (cognitive behavioral therapy), 역동정신요법 (dynamic psychotherapy), 최면요법 (hypnotherapy) 을포함하는정신과적치료및항우울제사용을권고하고있다 [44,45]. 요약 5) 기타 Opioid 수용체는장관세포에존재하여중추신경계로전달되는통증을조절하는경로이다. 이중말초에작용하는수용체가내장과민성에관여하여약제표적으로유용하다. Asimadoline은말초성 kappa-opioid 작동제로과민성장증후군의통증의조절에대한연구가진행되었다. 596명을대상으로 12주간치료한 2상연구에서는교대형, 설사형의통증에긍정적인측면을보고하였다 [56]. 2010년부터 3상임상시험이미국에서진행중이다. Corticotropin releasing hormone (CRH) 은 1형과 2형의수용체가있고스트레스와연관된장운동, 내장과민성, 자율신경계의반응을조절하는호르몬이다. CRH를과민성장증후군환자에게주면대장의운동을악화시키고, ACTH 분비를증가시킨다 [57]. 길항제인 alpha-helical CRH ( 비선택적 CRH 수용체길항제 ) 를환자에게투여한결과복통및불안정도가감소하고 [58], 뇌전도의파형을정상화시키는긍정적인결과를보고하였다 [59]. 그러나설사형과민성장증후군환자에서경구 CRH 1 수용체차단제를사용한무작위이중맹검연구에서는장관운동과관계가없었다 [18]. Dextofisopam은정신과에서불안, 스트레스관련자율신경질환치료에사용되는벤조다이아제핀계약물로동물연구에서위장관운동과내장감각기능을변화시킬수있다. 이러한이론을토대로설사형과교대형환자를대상으로 12주간치료한결과위약에비하여좋은효능을보고한단일연구가있다 [60]. 4. 정신과적치료및항우울제과민성장증후군환자는불안및우울등의기분장애를가지는경우가많으며, 3차의료기관에내원한환자의 40~90% 환자에서다양한정신과적질병이있을수있다 [61]. 과민성장증후군은다양하고복합적인증상을호소하는만성재발성질환이다. 환자는질병에대한이해부족으로인한불안및반복되는증상으로삶의질이저하된다. 서구와국내에서유병률및사회적비용이증가되고있고병태생리는다양하다. 진단은로마기준을적용하며세심한진료를통해적절한검사와배제진단을하여야한다. 환자의치료에있어충분한설명을통한좋은의사- 환자관계를수립하는것은현재에도유용하며, 충분한대화를통해정신사회적문제와치료또한고려해야한다. 약물치료는증상의조절을목적으로한고식적인약제치료를시도하지만최근에는병태생리에근거한새로운약제들의임상적용및연구가활발히진행되고있다. REFERENCES 1. Choung RS, Locke GR, 3rd. Epidemiology of IBS. Gastroenterol Clin North Am 2011;40: 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: Park DW, Lee OY, Shim SG, et al. The Differences in Prevalence and Sociodemographic Characteristics of Irritable Bowel Syndrome According to Rome II and Rome III. J Neurogastroenterol Motil 2010;16: 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: Drossman DA. The functional gastrointestinal disorders and the Rome III process. Gastroenterology 2006;130: Spiller RC. Role of infection in irritable bowel syndrome. J Gastroenterol 2007;42(Suppl 17): Dunlop SP, Jenkins D, Neal KR, Spiller RC. Relative importance of enterochromaffin cell hyperplasia, anxiety, and depression in - S 23 -

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