2008 년도대한췌담도학회춘계학술대회 Session II: Korean Guideline for Chronic Pancreatitis 만성췌장염의진단기준및한국에서의진단현황 성균관대학교의과대학삼성서울병원내과학교실 이종균 서론만성췌장염은췌장에지속적인염증과섬유화로인해비가역적인구조적, 기능적손상을초래하는질환이다. 이와같은만성췌장염의정의와진단은조직소견에근거하지만실제적으로임상에서진단목적의조직검사는흔히행해지지않는다. 진행된만성췌장염은임상양상, 영상검사또는기능검사로쉽게진단된다. 그러나영상검사와기능검사는조기단계에서는정상이거나비특이적이다. 조직검사가진단에정작필요한경우는조기단계의만성췌장염이다. 그러나현재조기단계만성췌장염의조직소견에대한정의및분류가명확하지않다. 그리고조기단계에서는소견이불규칙하게분포하여세포검사나작은조직으로는진단이어렵다. 또한만성췌장염을조기발견하여질환을가역적으로돌리거나자연경과를바꿀수있는방법이부족한현재상황에서위험성을안고있는조직검사를시행하는타당성이부족하다. 따라서이와같이진단의표준이되는조직검사를시행한경우가많지않은질환에대하여진단기준을정하는것도어려움이많다. 이러한어려움때문에만성췌장염의분류및진단기준은아직까지도불완전한상태에있다. 만성췌장염이상당히진행된후에는원인에관계없이비슷한소견을보이지만임상경과중에분명히존재하는조기단계의만성췌장염이있는데, 이단계에서는다양한형태와특징을보이고임상양상도다르다. 그러나이러한다양성을명확하게구분하기어려워현재 까지일반적인분류와진단기준을갖는다. 여기서는지금까지의발표된만성췌장염의분류와진단기준을알아보고한국에서만성췌장염진단의현황을조사하여현재상황과한국의실정에맞는만성췌장염진단기준을만드는기초가되고자한다. 만성췌장염의정의및분류 1946년 Comfort 등이 1 만성재발성췌장염을별개의질환으로규정하여발표하였고만성췌장염의정의와진단에대한국제심포지엄이 1963년 Marseilles 에서시작되었다. 이심포지엄에서급성췌장염과만성췌장염의개념을정의하였다 (Table 1). 췌장염을급성췌장염, 재발성급성췌장염, 만성재발성췌장염, 그리고만성무통성췌장염의 4가지로분류하였고만성췌장염은원인이제거된후에도조직변화가지속되어구조적, 기능적손상이지속되는것을의미하였다. 2,3 1983년 Cambridge 분류에서는췌장염을급성과만성으로나누고만성췌장염은계속되는염증성질환으로비가역적인구조적변화와기능의영구적인손실이동반되는것으로정의하였다. 그리고그동안발전된영상과기능검사에의하여중증도를분류하여병원간에자료를비교할수있도록한것이의미있었다. 여기서는주로전산화단층촬영 (CT) 와내시경적역행성담췌관조영술 (ERCP), 췌장기능검사소견에의해등급을분류하였다 (Table 2). 그러나병원마다시행하는검사방법에차이가있고임상적으로만성췌장염이의심되나검사결과가모호한경우에대한해결방법이없는데이는 29
30 2008 년도대한췌담도학회춘계학술대회 Table 1. Classification of acute and chronic pancreatitis Marseille 1963 Cambridge 1983 Marseille 1984 Marseille-Rome 1988 Acute pancreatitis Acute pancreatitis Acute pancreatitis Acute pancreatitis Mild Clinical/morphological Clinical/morphological Severe Relapsing acute pancreatitis Chronic relapsing Chronic pancreatitis Chronic pancreatitis Chronic pancreatitis pancreatitis Clinical/morphological Chronic calcifying pancreatitis Chronic inflammatory pancreatitis Chronic painless pancreatitis Chronic obstructive Chronic obstructive pancreatitis pancreatitis Table 2. Cambridge classification based on ERP findings Main pancreatic duct Abnormal side branches Normal Normal None Equivocal Normal Less than three Mild Normal More than three Moderate Abnormal More than three Marked Abnormal More than three with one or more of: Large cavities (>10 mm) Gross gland enlargement (>2 N) Intraduct filling defects or calculi Duct obstruction, structure or gross irregularity Contiguous organ invasion 현재까지도계속되는문제이다. 1984년에개정된 Marseilles 심포지엄에서는만성췌장염의특징을반복적또는지속적복통에지방변또는당뇨로표현되는췌장기능부전과췌장실질의불규칙한경화와파괴, 다양한정도의췌관확장동반으로규정하였다. 그리고여기서는특수한형태의만성폐쇄성췌장염을별도로구분하여특징을췌관의폐쇄와상부췌관의확장및췌실질의위축, 섬유화로표현하였다. 1988년의 Marseilles-Rome 분류에서는형태에따라좀더세분하여, 만성폐쇄성췌장염외에, 췌 실질의소실과섬유화및염증세포의침윤으로특징짓는만성염증성췌장염, 단백침전물, 플러그, 말기에는췌석이나타나는만성석회성췌장염으로분류하였다. 최근에는원인에따라만성췌장염을정의하고분류하는제안들이있다. Etemad와 Whitcomb은주된원인인자에따라만성췌장염을독성-대사성, 특발성, 유전성, 자가면역성, 재발성및중증급성췌장염후, 폐쇄성으로분류하였다 (Table 3). 4 원인에따라서임상양상, 영상소견, 자연경과가다르기때문에진단기준또한차이가있을수있다. 그러
이종균 : 만성췌장염의진단기준및한국에서의진단현황 31 Table 3. Etiologic risk factors associated with chronic pancreatitis: TIGAR-O classification system Toxic-metabolic Alcoholic Tobacco smoking Hypercalcemia Hyperlipidemia (rare and controversial) Chronic renal failure Medications Toxins Idiopathic Early onset Late onset Tropical Genetic Autosomal dominant Cationic trypsinogen (Codon 29 and 122 mutations) Autosomal recessive/modifier genes CFTR mutations SPINK1 mutations Cationic trypsinogen (codon 16, 22, 23 mutations) Alpha1-antitrypsin deficiency (possible) Autoimmune Isolated autoimmune chronic pancreatitis Syndromic autoimmune chronic pancreatitis Sjögren syndrome-associated chronic pancreatitis Inflammatory bowel disease-associated chronic pancreatitis Recurrent and severe acute pancreatitis Postnecrotic (severe acute pancreatitis) Recurrent acute pancreatitis Vascular diseases/ischemic Obstructive Pancreatic divisum Duct obstruction (e.g., tumor) Posttraumatic pancreatic duct scars 나모든원인별로진단기준을만드는것은충분한연구가필요하며현재로서는무리이다. 다만적어도알코올성과비알코올성을구분하여적용을달리하는시도는필요하리라본다. 만성췌장염의진단기준만성췌장염을진단기준을몇국가또는기관에서발표하였다. 일본에서는위와같은여러번의심포지엄에근거하여만성췌장염의임상적진단기준을제시하였다. 현재사용하고있는진단기준은 일본췌장학회에서 1995년에제정된것을기초로하였으며각종검사 ( 초음파, CT, ERCP, 췌장기능검사, 췌장조직소견 ) 소견을간소화하여어느한항목이라도만족하면진단할수있도록만들어졌다. 따라서영상소견, 기능검사, 조직조견은각각독립적인진단기준을갖는다. 특히 ERCP의역할이중시되어현장에서는만성췌장염진단에유력한진단법으로빈번하게사용되었다. 그러나 ERCP와관련된합병증및사망예가보고되고비침습적인검사법이요구되어 2001년에 MRCP 소견을추가하는부분개정판이지금까지사용되고있
32 2008 년도대한췌담도학회춘계학술대회 다 (Table 4). 5,6 일본진단기준은확진증례 (definite chronic pancreatitis) 와준확진증례 (probable chronic pancreatitis) 로분류하였고상복부통증및혈청췌장효소수치이상등췌장의이상소견이있으나위기준에해당하지않는경우를의심증례 (possible chronic pancreatitis) 로구분하였다. 그리고이런기준에따르지않는만성폐쇄성췌장염, 만성염증성 ( 자가면역 ) 췌장염, 종괴-형성췌장염은제외하였다. 일본진단기준은몇가지문제점을안고있다. 진단기준의제정목적을위양성증례를배제하고확실한만성췌장염을진단하는데두었기때문에조기단계의만성췌장염의진단은배제되었다. 7 그리고현실적으로췌장조직을얻기가쉽지않고췌장기능검사도극히일부기관에서만시행되고있어대부분의경우진단은영상검사에의존하게되는데, 조직조견과영상소견이조기단계에서는잘맞지않는다. 일본기준에는열거된검사중에 Table 4. Diagnostic criteria for the diagnosis of chronic pancreatitis by the Japan Pancreas Society in 2001 The following criteria can be applied primarily to patients with symptoms and findings suggestive of chronic pancreatitis. Diagnosis of chronic pancreatitis is established when one or more of the following criteria are fulfilled. Although the diagnostic criteria listed below are arranged in the sequence in which the tests should be performed in routine practice, the criteria are independent of each other. Definite chronic pancreatitis 1a. Ultrasonography (US). Pancreatic stones evidenced by intrapancreatic hyperreflective echoes with acoustic shadows posteriorly. 1b. Computed tomography (CT). Evidence of intrapancreatic calcifications. 2. Endoscopic retrograde cholangiopancreatography (ERCP). Presence of one of the following findings; (i) irregular dilatation of pancreatic duct branches of variable degree with scattered distribution, or (ii) irregular dilatation of the main pancreatic duct or branches proximal to complete or incomplete obstruction of the main pancreatic duct with pancreatic stones or protein plugs. 3. Secretin test. Abnormally low bicarbonate concentration combined with either low enzyme output or low secretory volume, or both. 4. Histopathological examination. Fibrosis with destruction and loss of exocrine parenchyma in tissue specimens obtained at biopsy, surgery, or autopsy. The areas of fibrosis exhibit irregular and patchy distribution in the interlobular spaces. Intralobular fibrosis alone is not specific for chronic pancreatitis. In addition, protein plugs, pancreatic stones, dilatation of pancreatic duct, hyperplasia and metaplasia of ductal epithelium, and cyst formation are observed. Probable chronic pancreatitis 1a. US. More than one of the following findings; (i) intrapancreatic coarse hyperreflectivities, (ii) irregular dilatation of pancreatic ducts, and (iii) pancreatic deformities of irregular contour. 1b. CT. Pancreatic deformity with irregular contour. 2. Magnetic resonance cholangiopancreatography (MRCP). (i) Irregular dilatation of pancreatic duct branches of variable degree with scattered distribution throughout the entire pancreas, or (ii) irregular dilatation of the main pancreatic duct and branches proximal to complete or incomplete obstruction of the main pancreatic duct. 3. ERCP. One of the following findings; (i) irregular dilatation of the main pancreatic duct alone, (ii) intraductal filling defects suggestive of noncalcified pancreatic stones, or (iii) protein plugs. 4a. Secretin test. (i) Abnormally low bicarbonate concentration alone, or (ii) low enzyme outputs plus low secretory volume. 4b. Tubeless tests. Simultaneous abnormalities in the bentiromide-paraaminobenzoic acid (BT-PABA) test and fecal chymotrypsin test, observed at two different time points several months apart. 5. Histopathological examination. One of the following findings; (i) intralobular fibrosis with loss of exocrine parenchyma, (ii) isolated islets of Langerhans, or (iii) pseudocysts.
이종균 : 만성췌장염의진단기준및한국에서의진단현황 33 서어느한가지만합당한소견을보여도진단할수있도록간편화하기위해대신각항목의기준을분명한소견으로한정하였다. 따라서상당수의환자는기준에부합되지못하는경우가있다. 실제로조직소견과췌장석회외에는어느한가지검사만으로만성췌장염을진단할수는없다. 또한반대로한가지소견만을진단기준으로하였는데, 특히췌장기능검사는만성췌장염이아닌췌장기능부전과의감별에혼돈을줄수있다. 이러한단점을보완하기위해서 2차 Marseilles 심포지엄에서는췌장기능검사와영상검사가서로상호보완적이며혼합된등급체계가진단에유리할수있다고하였다. 점수화진단체계를이용한만성췌장염진단기준은 Mayo Clinic과 Larkisch 등에의해제안되었다 (Table 5). 8,9 이기준에따르면조직학적소견이나췌장의석회외에는어느한가 지소견만으로는만성췌장염을진단할수없도록하였다. 최근에는 Mayo Clinic에서좀더간단한진단기준을제시하였는데반복적췌장염이있으면서다음사항중하나이상을만족할때로하였다. 10 1. 조직소견에서만성췌장염에특징적인소견 2. 췌관조영술에서 Cambridge II 또는 III 의소견 3. 췌장석회 4. EUS 에서만성췌장염의 5가지이상의소견 5. 췌장기능의현저한저하그리고위기준에만성폐쇄성췌장염과자가면역췌장염은예외로하였다. 그러나 EUS는급성췌장염, 췌장염을동반하지않은알코올중독자, 고령에서도비슷한소견을보일수있어주위를요한다. 중국소화기학회에서도만성췌장염의진단기준을제시하는데, 췌장암의배제한상태에서다음소 Table 5. Diagnosis of chronic pancreatitis by scoring systems Parameter Mayo Clinic score Lüneburg score Morphological examinations Postmortem diagnosis of chronic pancreatitis 4 Histology 4 4 Intraoperative findings characteristic of 4 chronic pancreatitis Pancreatic calcifications, shown by any 4 4 imaging procedure Exocrine pancreatic function tests Abnormal secretin pancreozymin test 2 3 Abnormal pancreolauryl test 2 Abnormal fecal chymotrypsin level 2 Abnormal fecal elastase 1 level 2 Steatorrhea 2 1 Imaging procedures Abnormal ultrasound 3 Abnormal endoscopic ultrasound 3 Abnormal computed tomography 3 Abnormal ERCP 3 3 Four or more points, chronic pancreatitis; 3 points, chronic pancreatitis possible, follow-up necessary. Chronic pancreatitis is diagnosed based on the results of imaging procedures and pancreatic function tests. With the exception of histological diagnosis and pancreatic calcifications demonstrated in any imaging procedure, the diagnosis of chronic pancreatitis is impossible on the basis of one examination only In addition, two points were given for more than two previous attacks of acute pancreatitis and another point for diabetes mellitus.
34 2008 년도대한췌담도학회춘계학술대회 견을기준으로하였다. 11 1. 복통, 외분비췌장기능부전과같은특징적인임상양상 2. 만성췌장염의병리학적변화 3. 만성췌장염의변화를보이는췌담도영상소견 4. 췌장외분비기능부전의증거를보이는검사실소견여기서 1항목은필수사항이고, 2항목이동반될때확진, 3항목이동반될때임상적진단, 그리고 4항목이동반될때를의증으로정의하였다. 위에서살펴본바와같이몇가지국가또는기관에서사용하는진단기준은있으나아직까지국제적인진단기준이나이에대한합의는없었다. 그것은다양한원인과형태의만성췌장염을모두만족하고조기또는경증의증례를정확하게진단하는기준이현재의진단방법으로는매우어렵다는것을의미한다. 향후원인에따른특성과자연경과를좀더이해하고비침습적이면서좀더예민하고특이적인검사방법의개발이숙제로남아있다. 한국에서만성췌장염진단의현황만성췌장염의진단은각국가나병원마다시행하는방법이현실적으로차이가있고그동안영상기술의발전과선호하는방법의변화가있었다. 따라서과거에만들어진외국의진단기준을현재의 한국에서그대로적용하는것은현실에맞지않는다. 최근에는전산화단층촬영의많은부분이재래식에서 multi-detector CT로바뀌었고진단목적의췌관조영술은 ERCP 대신 MRCP가많이시행되고있으며 EUS 및 EUS를통한세침흡인또는생검이점차늘고있다. 반면에췌장기능검사중에서직접검사는호르몬의가격이비싸고시행하기번거로워연구목적이아닌임상에서는전세계적으로도시행하는병원이극히일부이다. 그리고간접기능검사는그민감도가낮고영상검사에비해발전이더디다. 따라서현재주로시행되는진단방법을좀더세밀하게평가하고한국의현실에맞는진단기준을설정할필요가있다. 만성췌장염의한국진단기준을만들기에앞서이에대한기초자료를위해한국에서만성췌장염을임상에서어떻게진단하고있는지에대한현황을조사하였다. 전국에서 13개대학병원이참여하였다. 각병원에서 2008년 3월조사시점부터과거로일련의임상적만성췌장염환자 50명씩을등록하여총 650명을대상으로하였고환자들의평가시점은 2000년부터 2008년 3월까지분포하였다. 임상적만성췌장염이란의무기록및상병명을조회하여임상적으로만성췌장염을주상병으로진단하고경과관찰하는경우로정하였다. 환자들의임상적특성, 검사소견등에대하여의무기록및검 Table 6. Causes of chronic pancreatitis in Korea Cause No. of patients % Fig. 1. Diagnostic tools used for the evaluation of chronic pancreatitis in Korea. Alcohol 465 72.5 Idiopathic 133 20.7 Anomaly 15 2.5 Post-SAP* 8 1.9 Trauma 5 0.8 Autoimmune 3 0.5 Infection 3 0.5 Hereditary 2 0.5 Metabolic 2 0.5 Total 650 100 *Post-severe acute pancreatitis.
이종균 : 만성췌장염의진단기준및한국에서의진단현황 35 사자료를후향적으로분석하였고일부의무기록이부실한경우에는전화설문을하였다. 만성췌장염을진단하기위해사용한방법으로대부분의환자에서 CT가이용되었고 (96.9%), 다음으로 ERCP, US, MRCP, EUS, 조직검사순이었다 (Fig. 1). 조사한병원중에는세크레틴자극검사를임상적진단방법으로사용하는병원은없었다. 총 650 명의환자중에서알코올이가장많은원인 (72.5%) 을차지하였고, 다음으로는특발성이었으며 (20.7%) 그외여러가지소수원인들이있었다 (Table 6). 이는기존에알려진만성췌장염의원인분포와크게차이가없었다. 증례들을일본진단기준으로분류하였을때, 확진예가 81.5%, 준확진예가 15.2% 이었고기준에 맞지않는예가 3.2% 였다 (Fig. 2). 비교적보수적으로만든일본진단기준에적용하여도한국에서만성췌장염을주로확실한경우에함을알수있었다. 그러나병원간에적용기준에차이가있어확진예가적은병원은 58%, 많은병원은 100% 였다 (Fig. 3). 이는한국에서병원간의의견교환이나다기관연구를위해서도진단기준의제정이필요한이유가되겠다. 확진예를진단하게된검사방법으로는 CT (84.7%), ERCP (44.3%), US (19.4%) 순이었고, 주소견인췌장석회는 71.4% 에서존재하였다. 준확진 Fig. 2. Application of Japanese criteria in patients with clinical chronic pancreatitis diagnosed in Korea. N/A: not applicable. Fig. 4. Diagnostic tools which showed positive findings for definite and probable chronic pancreatitis. Fig. 3. Proportion of Japanese diagnostic criteria in patients with clinical chronic pancreatitis diagnosed in Korea s hospitals.
36 2008 년도대한췌담도학회춘계학술대회 예를진단한방법은 CT (50.5%), US (33.3%), ERCP (27.3%), MRCP (22.2%) 순이었다 (Fig. 4). 일본진단기준에포함된췌장의직접또는간접기능검사는시행한병원이없었다. 원인에따른진단기준과임상적특성을비교하였다. 소수의원인을별도로분석하기는어려워크게알코올성과비알코올성으로나누어비교하였다. 확진예가알코올성에서는 83%, 비알코올성에서는 77% 이었다 (Fig. 5). 알코올성에서확진예가좀더많은이유는알코올성에서석회가더많이동반되기때문으로보인다. 비알코올성에비해알 코올성에서남자, 흡연자, 통증, 체중감소, 지방변, 췌장석회, 당뇨의빈도가많았다 (Table 7). 알코올성에서좀더진행된상태의만성췌장염소견을보인다고할수있다. 췌장염또는통증발작횟수는원인에따라차이가없었고진단기준의분포와도관계가없었다 (Fig. 6). 그리고통증횟수와진행된만성췌장염소견인석회, 당뇨, 지방변의빈도등과도연관성이없었다 (Fig. 7). 이는통증이병의진행단계와는무관하다는것을의미한다. Fig. 5. Proportion of Japanese diagnostic criteria in alcoholic and non-alcoholic chronic pancreatitis. Fig. 6. Proportion of Japanese diagnostic criteria according to the number of pancreatitis attacks. *continued; more than 6 months. Table 7. Comparison of clinical characteristics in patients with alcoholic and non-alcoholic chronic pancreatitis Alcoholic Non-Alcoholic Total P-value No. of patients 464 (71.4%) 186 (28.6%) 650 Male 432 (93.5%) 120 (64.5%) 553 (84.95%) 0.000 Age 51.5±11.0 49.5±16.8 51.0±12.9 NS No. of pancreatitis attack NS 0 210 (45.2%) 31 (16.7%) 241 (37.0%) 1 or 2 180 (38.7%) 84 (45.2%) 264 (40.6%) 3 or more 224 (48.2%) 71 (38.2%) 295 (45.3%) Smoking 364 (78.3%) 63 (33.9%) 427 (65.6%) 0.000 Pain 338 (72.7%) 119 (64.0%) 457 (70.2%) 0.022 Wt.loss 143 (30.8%) 43 (23.1%) 186 (28.6%) 0.041 Steatorrhea 79 (17.0%) 7 (3.8%) 86 (13.2%) 0.000 Calcification 345 (74.2%) 120 (64.5%) 465 (71.4%) 0.014 Diabetes 259 (55.7%) 61 (32.8%) 320 (49.2%) 0.000
이종균 : 만성췌장염의진단기준및한국에서의진단현황 37 Fig. 7. Manifestations for late-stage chronic pancreatitis according to the number of pancreatitis attacks. *continued; more than 6 months. 결 만성췌장염에대한이해의발전에도불구하고현재의분류나진단기준이다양한원인이나형태의만성췌장염을모두만족하지못하며특히조기단계의만성췌장염에대해서는진단의한계가여전히존재한다. 향후원인에따른특성과자연경과를더많이이해하고비침습적이고좀더예민하고특이적인검사방법의개발이필요하다. 또한한국에서도만성췌장염환자의특성과현재주로사용하고있는검사방법에의거하여한국의현실에맞는진단기준의제정이필요하다. 이는환자의진료뿐만아니라병원간의의견교환과학문의발전을위해서도절실하다. 론 relapsing pancreatitis. A study of twenty-nine cases without associated disease of the biliary or gastrointestinal tract. Gastroenterology 1946; 6: 239-85, 376-408. 2. Banks PA: Classification and diagnosis of chronic pancreatitis. J Gastroenterol 2007; 42(Suppl XVII): 148-151. 3. Kloppel G: Toward a new classification of chronic pancreatitis. J Gastroenterol 2007; 42(Suppl XVII): 55-57. 4. Etemad B, Whitcomb DC. Chronic pancreatitis: Diagnosis, Classification and New Genetic Developments. Gastroenterology 2001; 120: 682-707. 5. The Criteria Committee for Chronic Pancreatitis of the Japan Pancreas Society: Clinical diagnostic criteria of chronic pancreatitis (in Japanese). Suizou (J Jpn Panc Soc) 2001; 16: 560-561. 6. Otsuki M: Chronic pancreatitis in Japan: Epidemiology, prognosis, diagnostic criteria, and future problems. J Gastroenterol 2003; 38: 315-326. 7. Otsuki M: Chronic pancreatitis; The problems of diagnostic criteria. Pancreatology 2004; 4: 28-41. 8. Layer P, Yamamoto H, Kalthoff L, Clain JE, Bakken LJ, DiMagno EP: The different courses of early- and late-onset idiopathic and alcoholic chronic pancreatitis. Gastroenterology 1994; 107: 1481-1487. 9. Lankisch PG, Assmus C, Maisonneuve P, Lowenfels AB: Epidemiology of pancreatic diseases in Lüneburg county. Pancreatology 2002; 2: 469-477. 10. Chari ST: Chronic pancreatitis: classification, relationship to acute pancreatitis, and early diagnosis. J Gastroenterol 2007; 42[Suppl XVII]: 58-59. 11. Pancreas Study Group, Chinese Society of Gastroenterology. Guidelines for the diagnosis and treatment of chronic pancreatitis (Nanjing 205). Chinese J Dig Dis 2005; 6: 198-201. 참고문헌 1. Comfort MW, Gambill EE, Baggenstoss AH: Chronic