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1 대한내과학회지 : 제 81 권제 3 호 2011 한국인자가면역성간염을진단하기위한 Simplified Scoring Criteria 의가치및유용성 순천향대학교의과대학 1 내과학교실소화기연구소, 2 병리과학교실 이윤나 1 김영석 1 김상균 1 임재희 1 정승원 1 장재영 1 이세환 1 김홍수 1 김부성 1 김희경 2 Diagnostic Value and Utility of the Simplified International Autoimmune Hepatitis Group (IAIHG) Criteria for Autoimmune Hepatitis in Korea Yun Nah Lee 1, Young Seok Kim 1, Sang Gyune Kim 1, Jae Hee Lim 1, Soung Won Jeong 1, Jae Young Jang 1, Se Hwan Lee 1, Hong Soo Kim 1, Boo Sung Kim 1, and Hee Kyung Kim 2 Digestive Disease Center, Departments of 1 Internal Medicine and 2 Pathology, Soonchunhyang University College of Medicine, Bucheon and Seoul, Korea Background/Aims: The diagnostic criteria for autoimmune hepatitis (AIH) were created and revised by the International Autoimmune Hepatitis Group (IAIHG) in Simplified scoring criteria based on four clinical components were recently proposed. The aim of this study was to assess the diagnostic value and usefulness of these simplified criteria in Korea. Methods: We applied the simplified scoring criteria to 22 AIH patients diagnosed according to the original revised scoring criteria proposed in Furthermore, in order to compare the predictive power of these two sets of diagnostic criteria, we included 84 patients with liver diseases [toxic hepatitis (n = 50), nonalcoholic fatty liver disease (n = 18), primary biliary cirrhosis (PBC) (n = 11), and PBC/AIH overlap syndrome (n = 5)] other than AIH. Results: Twenty (90.9%) patients with AIH and five (100%) with PBC/AIH overlap syndrome were diagnosed with AIH according to the simplified scoring criteria. Three (27.3%) patients with PBC were false-positive for AIH according to the simplified scoring criteria. Those patients diagnosed according to the simplified scoring criteria showed an increased frequency of ANA and/or SMA of 1:80 (p = 0.491) and an increased frequency of serum IgG levels at or above the upper normal limit compared to patients with PBC (p = 0.006). The sensitivity and specificity of the simplified scoring criteria for the diagnosis of AIH were 90.9 and 96.2%, respectively. Conclusions: The simplified scoring criteria offer a reliable and simple method for excluding AIH; however, these criteria may have limitations in the diagnosis of patients with atypical features, especially those with low autoantibody and IgG levels. (Korean J Med 2011;81: ) Keywords: Hepatitis, Autoimmune; Diagnosis; Criteria Received: Revised: Accepted: Correspondence to Young Seok Kim, M.D. Institute for Digestive Research, Department of Internal Medicine, Soonchunhyang University College of Medicine, 1174 Jung-dong, Wonmi-gu, Bucheon , Korea Tel: , Fax: , liverkys@schmc.ac.kr

2 - Yun Nah Lee, et al. Diagnostic value of the simplified IAIHG criteria in Korea - 서론자가면역간염 (autoimmune hepatitis, AIH) 은계면간염 (interface hepatitis) 을특징으로하는만성간염형태의조직소견과혈청내자가항체의존재, 고감마글로불린혈증, 그리고면역억제제투여후호전을특징으로하는만성간질환이다 [1]. 1950년대초 Waldenström 에의해처음증례가보고된 [2] 이후연평균북유럽백인 10,000명당 1.9명에서발생하고 [3], 전체간이식의 % 를차지하는것으로알려져있다 [4]. 우리나라의경우알코올성간질환을제외한만성간질환중 B형및 C형바이러스간염이 80-90% 로대부분을차지하고있다. 따라서자가면역간염에대한관심도는상대적으로낮은상태이며, 현재까지정확한국내발병률도조사되지않은상태이다. 자가면역간염은주로여성에서호발하고 [5] 전연령층에서발병할수있다 [6]. 대부분은서서히발병하지만약 40% 는급성발병을보이며 [7] 전격간염으로발현하기도한다 [8]. 또한 1/3에서는증상이없고 [9], 성인환자중 30% 는진단당시간경변이동반되어있다 [10]. 증상의유무는염증의정도및간경변동반과관련이없으며, 경한상태라하더라도 15년내 49% 에서는간경변이동반되고 10% 는간부전으로사망할수있다. 따라서질환의만성여부를확인하기위해 6개월정도를기다리는것은불필요한과정이다 [11]. 그러나자가면역간염은특이적인진단검사법이없고 [12], 비교적특징적인소견으로알려진자가항체가다른간질환에서도발견될수있기때문에다른원인의비알코올성, 비바이러스성간질환과의감별이쉽지않다 [13-15]. 이에 1993년 IAIHG (International Autoimmune Hepatitis Group, IAIHG) 은자가면역간염의진단을위해최소필요지표 (minimum required parameter) 와조직검사결과및치료후반응에따른추가지표 (additional parameter) 를이용한점수체계 (scoring system) 을제시하였고 [16], 이후 1999년개정된점수체계 (original revised scoring criteria) 를발표하였다 (Table 1) [17]. 이점수체계는 15개항목을평가하여의증 (probable) 과확진 (definite) 으로자가면역간염을진단하며담즙정체간질환을확실히배제하기위해 alkaline phosphatase (ALP)/aspartate aminotransferase (AST) 비및조직소견의중요성을부각시켰고, 항미토콘드리아항체 (antimitochondrial antibody, AMA) 양성과약제복용력이있을때감점의폭이가장컸다. 그러나개정된진단체계는지나치게번거로워임상에서의 적용이쉽지않으며, 진단을위해조직검사결과와치료반응이모두포함되어야하기때문에어떤환자에게간조직검사와면역억제제투여를시도해야하는지적응증을제공하지못한다는단점이있다. 또한전반적인특이도가 98.1% 로향상된것에비해, 다른간질환이동반되어있거나, 자가면역간염중복증후군 (AIH overlap syndrome) 일경우, 민감도가 66.7% 와 50% 로낮아지는현상을보였다 [18]. 이를보완하기위해 2008년 Hennes 등 [19] 은자가항체소견, 면역글로불린 G (Immunoglobulin G, IgG), 간조직검사소견, 바이러스성간염여부의네가지기준만으로구성된 simplified scoring criteria을제시하였다 (Table 2). 당시저자들은의증 (probable) 의경우진단의민감도와특이도를각각 88% 와 97% 로, 확진 (definite) 일경우 81% 와 99% 로보고하였다. 자가면역간염은인종에따라발현양상이매우다양하나 [20,21] 우리나라의경우 2004년 172명의환자를대상으로한현황보고외에는대규모연구가시행된바없어서구에서제시된진단체계를한국인에게그대로적용가능한지알수없는상태이다. 이에본연구에서는 simplified scoring criteria를한국인에게적용시켰을때진단적가치및유용성을평가, 비교하고진단체계의간소화에의해발생할수있는문제점을확인하고자하였다. 대상및방법연구대상환자군 2002년 2월부터 2010년 5월까지순천향대학교부천병원에서간조직검사를시행받은제1형자가면역간염 22예와자가면역간염 / 원발성담즙간경변증 (autoimmune hepatitis/ primary biliary cirrhosis, AIH/PBC) 이함께존재하는중복증후군 (overlap syndrome) 5예를후향적으로분석하였다. 제1형자가면역간염의경우치료전 original revised scoring criteria 를적용하여진단하였고, AIH/PBC 중복증후군은 PBC의세가지진단기준인 1) ALP 가정상상한치의 2배이상이거나 gamma-glutamyl transpeptidase (GGT) 가정상상한치의 5배이상인경우, 2) 항미토콘드리아항체 (antimitochondrial antibody, AMA) 양성, 3) 전형적인간조직검사소견 (florid bile duct lesion) 중두가지를만족하고, 자가면역성간염의세가지

3 - 대한내과학회지 : 제 81 권제 3 호통권제 613 호 Table 1. Original revised scoring criteria for the diagnosis of AIH Parameter/Discriminator Score Parameter/Discriminator Score Female sex +2 Drug history ALP:AST (or ALT) ratio Positive -4 < Negative Average alcohol intake > < 25 g/day +2 Serum globulins or IgG above normal > 60 g/day -2 > Liver histology Interface hepatitis Predominantly lymphoplasmacytic infiltrate +2 < Rosetting of liver cells +1 ANA, SMA, or LKM-1 None of the above -5 > 1:80 +3 Biliary changes a +3 1:80 +2 Atypical features b -3 1:40 +1 Other autoimmune disease in patient or first-degree relative +2 < 1:40 0 Optional additional parameters AMA-positive -4 Seropositivity for other defined antibodies +2 Hepatitis viral markers HLA DR3 or DR4 +1 Positive -3 Response to therapy Negative +3 Remission alone +2 Remission with relapse +3 Interpretation of aggregate scores Pretreatment: Post-treatment: Definite AIH > 15 Definite AIH > 17 Probable AIH Probable AIH AIH, autoimmune hepatitis; ALP, alkaline phosphatase; AST, alanine aminotransferase; ALT, aspartate aminotransferase; IgG, immunoglobulin G; ANA, anti-nuclear antibody; SMA, anti-smooth muscle antibody; LKM, anti-liver-kidney microsome antibody; AMA, antimitochondrial antibody; HLA, human leukocyte antigen. a Including destructive cholangitis, nondestructive cholangitis, or ductopenia. b Including steatosis, iron overload consistent with genetic hemochromatosis, alcohol-induced hepatitis, viral features (ground-glass hepatocytes), or inclusions (cytomegalovirus, herpes simplex). Based on the recommendations of the International Autoimmune Hepatitis Group (J Hepatol 1999;31: ). 진단기준인 1) ALT가정상상한치의 5배이상, 2) IgG가정상상한치의 2배이상이거나항평활근항체 (antibody to smooth muscle, SMA) 양성, 3) 전형적인간조직검사소견 ( 계면간염등 ) 중두가지이상을만족한경우로진단하였다 [22]. 대조군 2002년 2월부터 2010년 5월까지부천순천향병원에서간조직검사를시행받은환자중각질환별표준진단기준 (standard diagnostic criteria) [23,24] 에따라독성간염 (toxic hepatitis) 을진단받은 50예와비알코올성지방간 (nonalcoholic fatty liver disease, NAFLD) 18예, PBC 11예를후향적으로분석하였다. 연구방법모든환자군과대조군의성별, 나이, 알코올의남용력, 동반된자가면역질환, 약물복용력은의무기록의후향적검토를통해확인하였다. 그외점수체계에필요한변수인

4 - 이윤나외 9 인. 자가면역성간염진단을위한 simplified scoring criteria 의적정성 - Table 2. Simplified scoring criteria (2008) Variable Cutoff Points ANA or SMA 1:40 1 ANA or SMA 1:80 or LKM 1:40 2 or SLA Positive IgG Upper normal limit 1 > 1.10 times normal limit 2 Liver histology a Compatible with AIH 1 Typical AIH 2 Absence of viral hepatitis Yes 2 Definite H: 7 Probable AIH: 6 ANA, anti-nuclear antibody; SMA, anti-smooth muscle antibody; LKM, anti-liver-kidney microsome antibody; SLA, anti-soluble liver antigen antibody; IgG, immunoglobulin G; AIH, autoimmune hepatitis. a Typical (1) Interface hepatitis, lymphocytic/lymphoplasmacytic infiltrates in portal tracts and extending into the lobule. (2) Emperipolesis (active penetration by one cell into and through a large cell). (3) Hepatic rosette formation. Compatible: Chronic hepatitis with lymphocytic infiltration without features considered typical. Atypical: showing signs of another diagnosis, like NAFLD. Based on the recommendations of the International Autoimmune Hepatitis Group (Hepatology 2008;48: ). 병리소견과항핵항체 (antinuclear antibody, ANA), SMA, AMA, IgG, ALP, 총빌리루빈 (bilirubin), AST, alanineamino-transferase (ALT), HBsAg, anti-hcv를조사하였고, 이를바탕으로 original revised scoring criteria (Table 1) 와 simplified scoring criteria (Table 2) 를이용하여집합점수를산출하였다. 항핵항체와항평활근항체, 항미토콘드리아항체경우역가 1:40 이상을양성으로하였다. 통계분석 측정된모든자료는평균과범위로표시하였고, 통계분석은 SPSS version 12.0 프로그램을이용하였다. 기술통계와교차분석을통하여결과를도출하였으며, 연속변수에대한군간의비교는 Kruskal-Wallis test를사용하였고, 비연속변수의군간비교는 chi-sqaure test 및 Fisher's exact test를사용하였다. 이때 p 값이 0.05 미만인경우를의미있는것으로판단하였다. 결과대상환자의임상적특성총 106명의환자중남자가 30명 (28.3%), 여자가 76명 (71.7%) 이었고, 평균연령은 46.1세 (18-73세) 였다. 모든환자는바이러스성간염이배재된상태였고, 하루 60 g 이상의음주력이있는환자는독성간염을진단받은 2명에서관찰되었고, 25 g 이상, 60 g 미만의음주력은독성간염을포함해서 2명이확인되었다. 독성간염을제외한환자군에서간독성이있을것으로생각되는약물복용력은자가면역간염환자중 3명 (13.6%) 외에없었다. 자가면역성간염환자군의진단당시평균연령은 45.8세 (28-66세) 였고남녀비는 1:21였다. IgG는자가면역성간염군에서 2,478 ml/dl로다른질환군에비해유의하게 (p < 0.01) 높았고, ANA는자가면역성간염환자의 90.5%, AIH/PBC 중복증후군의 100% 에서양성이었으며 PBC 72.7%, NAFLD 36.8%, 독성간염 30% 에서양성을보였다 (p < 0.01, Table 3). Simplified scoring criteria의 sensitivity와 specificity Original revised scoring criteria 에의해 AIH가진단된 22명의환자중 simplified scoring criteria을적용하였을때, 2명 (9.1%) 이 6점미만으로진단에서제외되었다. 대조군중 PBC에서 1명 (9.1%) 이확진으로, 2명 (18.2%) 이의증으로진단되었고, 그외독성간염과 NAFLD 환자는모두 simplified scoring criteria 적용시음성소견을유지하였다 (Table 4). Original revised scoring criteria 에의해 AIH가진단된환자를기준으로산출한 simplified scoring criteria의민감도 (sensitivity) 와특이도 (specificity) 는확진을기준으로할때 77.3% 와 98.7% 였고, 의증이상일경우각각 90.6% 와 96.2% 로확인되었다 (Table 5). 자가면역성간염자가면역성간염환자중 simplified scoring criteria 적용시 2명 (9.1%) 은의증에서음성으로, 2명 (9.1%) 은확진에서의증으로진단이하강하였으며 5명 (22.7%) 의환자는의증에서확진으로진단이상승하였다. 통계적으로유의하지는않으나두군중진단이하강한군에서 ALP/AST 비가 2.6 으로진단이상승된군의 1.8보다높은경향을보였고, ANA 가 1:80 이상으로증가된환자가 50%, IgG가정상상한지보다 1.1배이상증가된환자가 25% 로진단이상승된군의 100 % 와 60% 에비해낮은경향을보였다 (Table 6)

5 - The Korean Journal of Medicine: Vol. 81, No. 3, Table 3. Baseline characteristics and scores by the original revised scoring and simplified scoring criteria of the patients AIH (n = 22) Toxic (n = 50) NAFLD (n = 18) PBC (n = 11) PBC/AIH (n = 5) p value Age (years) 45.8 (28-66) 46.5 (18-73) 41.8 (19-69) 49.9 (38-69) 51.2 (34-63) M:F 1:21 18:32 10:8 1:10 0: AST (IU/L) 366 ( ) 580 ( ) 94.5 (35-200) 87 (26-189) 121 (50-237) <0.01 ALT (IU/L) 428 ( ) 858 ( ) 152 (39-458) 88 (12-218) 190 (42-561) <0.01 ALP/AST ratio 1.0 ( ) 0.77 ( ) 1.1 ( ) 3.8 ( ) 3.4 ( ) <0.01 IgG (mg/dl) 2478 ( ) 1289 ( ) 1322 ( ) 1609 ( ) 1736 ( ) <0.01 Autoantibodies a (n [%]) 19 (90.5%) 15 (30%) 7(36.8%) 8(72.7%) 5 (100%) <0.01 Typical or compatible histology b 21 (95.5%) 1(2.0%) 0 3(27.3%) 5 (100%) <0.01 Original revised c 17.1 (11-25) -3.5 (-9-0) 1.4 (-2-4) -5.5 (-4-6) 7.8 (4-10) <0.01 Simplified d 6.8 (4-8) 2.5 (2-5) 2.6 (2-5) 4.5 (2-8) 6.6 (6-8) <0.01 p values were determined by the Kruskal-Wallis test with the exception of M:F and autoantibodies. p values were determined by the Pearson chi-square test for M:F and autoantibodies. AIH, autoimmune hepatitis; NAFLD, nonalcoholic fatty liver disease; PBC, primary biliary cirrhosis; ALP, alkaline phosphatase; AST, alanine aminotransferase; ALT, aspartate aminotransferase; IgG, immunoglobulin G. a Autoantibodies: anti-nuclear antibody and anti-smooth muscle antibody. b Typical (1) Interface hepatitis, lymphocytic/lymphoplasmacytic infiltrates in portal tracts and extending into the lobule. (2) Emperipolesis (active penetration by one cell into and through a large cell). (3) Hepatic rosette formation. Compatible: chronic hepatitis with lymphocytic infiltration without features considered typical. c Original revised scoring criteria. d Simplified scoring criteria. Table 4. Comparison of scoring diagnoses using each system Diagnosis by scoring system, n (%) Original a Simplified b Original Simplified Original Simplified Definite Probable Non-diagnostic AIH [22] 14 (63.6%) 17 (77.3%) 8 (36.4%) 3 (13.6%) 0 2 (9.1%) Toxic hepatitis [50] (100%) 50 (100%) NAFLD [18] (100%) 18 (100%) PBC [11] 0 1 (9.1%) 0 2 (18.2%) 11 (100%) 8 (72.7%) PBC/AIH [5] 0 2 (40%) 0 3 (60%) 5 (100%) 0 AIH, autoimmune hepatitis; NAFLD, nonalcoholic fatty liver disease; PBC, primary biliary cirrhosis. a Original revised scoring criteria. b Simplified scoring criteria. PBC PBC 환자중 simplified scoring criteria에서위양성을보인군과지속적으로진단에서배제된군을비교하였을때위양성군은모두 ANA가양성이었고, 나머지 PBC 군은 62.5% 에서양성이었다 (p = 0.491). IgG의경우정상상한치보다 1.1배이상으로증가되어있는경우가위양성군은 100% 였으나지속적으로음성을보인환자군에서는관찰되지않아위양성군에서유의하게높았다 (p = 0.006). 자가면역성간염을

6 - Yun Nah Lee, et al. Diagnostic value of the simplified IAIHG criteria in Korea - Table 5. Sensitivity and specificity of the simplified scoring criteria for the diagnosis of AIH (n = 22) Simplified scoring criteria Sensitivity Specificity Definite ( 7) 77.3% 98.7% Overall ( 6) 90.9% 96.2% Table 6. Comparison of demographic, laboratory, and clinical variables between down- and up-graded patients by simplified scoring criteria Down-graded (n = 4) Up-graded (n = 5) p value M:F 0:5 0: ALP (IU/L) ALP/AST ratio ANA or SMA 1:80 (n [%]) 2 (50%) 5 (100%) AMA positive (n [%]) IgG > 1.1 NL (n [%]) 1 (25%) 3 (60%) Florid bile duct lesions 2 (50%) 1 (20%) Compatible or typical histology with AIH a 3 (75%) 5 (100%) Original revised b p values were determined by Fisher s exact test except for ALP, ALP/AST ratio, and original revised scoring criteria. p values were determined by the Kruskal-Wallis test for ALP, ALP/AST ratio, and original revised. ALP, alkaline phosphatase; AST, alanine aminotransferase; ALT, aspartate aminotransferase; ANA, anti-nuclear antibody; SMA, anti-smooth muscle antibody; AMA, anti-mitochondrial antibody; IgG, immunoglobulin G; NL, normal limit; AIH, autoimmune hepatitis. a Original revised scoring criteria. b Typical (1) Interface hepatitis, lymphocytic/lymphoplasmacytic infiltrates in portal tracts and extending into the lobule. (2) Emperipolesis (active penetration by one cell into and through a large cell). (3) Hepatic rosette formation. Compatible: chronic hepatitis with lymphocytic infiltration without features considered typical. 고 찰 시사하는조직학적소견 (p = 1.00) 과담관변화소견 (p = 0.727) 의유무에는통계학적으로유의한차이가없었다 (Table 7). AIH/PBC 중복증후군 AIH/PBC 중복증후군의 ALP/AST 비는평균 3.4로자가면역성간염의 1.0보다유의하게높았다 (p = 0.039). 중복증후군환자는 5명 (100%) 모두가 AMA 양성이었고, PBC에합당한조직학적소견을보이고있었다. IgG가정상상한치의 1.1배이상증가되어있는경우는중복증후군 2명 (40%), 자가면역성간염 13명 (59.1%) 에서관찰되었으나유의하지않았고 (p = 0.628), 자가면역성간염을시사하는조직학적소견은각각 95.5% 와 100% 에서관찰되고있었다 (Table 8). 2008년자가면역성간질환에대한새로운진단기준이제시된이후 Czaja 등은검정과정을통해 simplified scoring criteria가 95% 의민감도와 90% 의특이도를가진다고보고한바있다 [22]. 이는이전진단기준의민감도인 95% 보다는다소낮지만특이도를 73% 에서 90% 까지향상시킨결과이다. 1999년진단기준에포함된 ALP/AST 비, IgG, ANA 수치, 조직검사결과에부여된차등적인점수체계는질환의특성과함께정도가반영되기때문에원인미상의간염이자가면역성간염으로진단될가능성이있었다. 이러한단점을보완하기위해새로운진단기준에서는자가면역성간질환에특이적인네가지검사항목만을포함하여기준을마련하였고이러한변화는특이도를향상시키는결과를보여주었

7 - 대한내과학회지 : 제 81 권제 3 호통권제 613 호 Table 7. Comparison of demographic, laboratory, and clinical variables at presentation between false-positive and true-negative cases of PBC as ascribed by the simplified scoring criteria True-negative (n = 8) False-positive (n = 3) p value M:F 0:8 1: ALP (IU/L) ( ) ( ) AST 78 (26-139) 68 (61-189) ALT 91 (12-218) 80 (46-125) ALP/AST ratio Exclusion of viral hepatitis 9 (100) 3 (100) ANA or SMA 1:80 (n [%]) 5(62.5) 3 (100) AMA positive (n [%]) 7(87.5) 2(66.7) IgG > 1.1 NL (n [%]) 0 3 (100) Florid bile duct lesions 7(87.5) 3 (100) Compatible or typical histology with AIH a 2(25) 1(33.3) Original revised b p values were determined by Fisher s exact test except for ALP, AST, ALT, ALP/AST ratio, and original revised scoring criteria. p values were determined by the Kruskal-Wallis test for ALP, AST, ALT, ALP/AST ratio, and original revised scoring criteria. ALP, alkaline phosphatase; AST, alanine aminotransferase; ALT, aspartate aminotransferase; ANA, anti-nuclear antibody; SMA, anti-smooth muscle antibody; AMA, anti-mitochondrial antibody; IgG, immunoglobulin G; NL, normal limit; AIH, autoimmune hepatitis. a Typical (1) Interface hepatitis, lymphocytic/lymphoplasmacytic infiltrates in portal tracts and extending into the lobule. (2) Emperipolesis (active penetration by one cell into and through a large cell). (3) Hepatic rosette formation. Compatible: chronic hepatitis with lymphocytic infiltration without features considered typical. b Original revised scoring criteria. 다. 그러나 simplified scoring criteria는지나치게기준이간소화되어각각의항목이진단에서차지하는비중이높아, 발병양상이비특이적일경우진단에서누락될가능성이있다. 실제로 Alvarez 등 [17] 은자가면역간염중 ANA, SMA, 항간신마이크로좀 1 항체 (antibody against liver-kidney microsome 1, anti-lkm1) 가모두음성인경우를약 20% 까지보고하였으며, Jung 등 [25] 의연구에서도제 1형자가면역성간염환자 26명중 80.8% 만이자가항체양성이면서고감마글로불린혈증이함께있었다. 따라서자가면역간염환자중자가항체가음성이거나, 감마글로불린의수치가높지않을경우 simplified scoring criteria를통해진단이불가능할수있다. 본연구에서도자가면역성간염환자 22명중 2명 (9.1%) 이새로운진단기준에서위음성을보였고, 이전진단기준에서확진을보였던 2명 (9.1%) 의환자가새로운진단기준에서의증으로하향되었다. 새로운진단기준적용시의증에서확진으로변화된환자 5명 (22.7%) 과앞의 4명의환자를비교해 보았을때진단이하향된군에서 ANA가 1:80 이상인경우가 50% 로진단이상향된군의 100% 보다낮았다. 또한 IgG 가정상상한치의 1.1 이상인환자도 25% 로진단이상향된군의 60% 보다낮은비율을보였다. 이러한결과는통계학적으로유의하지는않았으나 ANA와 IgG의역가가비교적높지않은자가면역성간염에서 simplified scoring criteria 적용시위음성이증가할수있음을예측할수있는소견이다. 1993년처음발표된 IAIHG의점수체계는 % 의민감도를보였지만의증환자의 8-52% 가자가면역성담관염과같은담즙정체간질환이었기때문에낮은특이도를보였다 [18,26-28]. 이를보완하기위해 1999년개정시, ALP/AST 비를추가하였고, 조직검사소견에서담관변화를보이는경우감점을하였다. 그러나 ALP/AST 비는대부분의만성간질환이담즙울체형간손상을보이지않기때문에자가면역성간염을 PBC이나원발경화담관경화 (primary sclerosing cholangitis, PSC) 로부터구별하는데에는도움이되지만자

8 - 이윤나외 9 인. 자가면역성간염진단을위한 simplified scoring criteria 의적정성 - Table 8. Comparison of clinical and scoring diagnoses using the original revised scoring criteria and simplified scoring criteria Pure AIH (n = 22) AIH/PBC (n = 5) p value Age (yr) ALP (IU/L) 120 (54-246) 237 (68-485) AST (IU/L) 366 ( ) 121 (50-237) ALT (IU/L) 428 ( ) 190 (42-561) Bilirubin (mg/dl) 5.2 ( ) 0.8 ( ) INR 1.2 ( ) 1.0 ( ) ALP/AST ratio 1.0 ( ) 3.4 ( ) IgG (mg/dl) 2478 ( ) 1736 ( ) IgG > 1.1 NL (n [%]) 13 (59.1%) 2 (40%) ANA or SMA 1:80 18 (81.8%) 5 (100%) AMA 0 4 (80.0%) <0.001 Compatible or typical histology with AIH a 21 (95.5%) 5 (100%) Biliary changes (n [%]) 7(25.9%) 5 (100%) Original revised b score 17.1 (11-25) 7.8 (4-10) Simplified c score 6.8 (4-8) 6.6 (6-8) p values were determined by the Kruskal-Wallis test for age, ALP, AST, ALT, bilirubin, INR, ALP/AST ratio, IgG, original revised score, and simplified score. p values were determined by the Pearson chi-square test except for age, ALP, AST, ALT, bilirubin, INR, ALP/AST ratio, IgG, original revised score, and simplified score. AIH, autoimmune hepatitis; PBC, primary biliary cirrhosis; ALP, alkaline phosphatase; AST, alanine aminotransferase; ALT, aspartate aminotransferase; IgG, immunoglobulin G; ANA, anti-nuclear antibody; SMA, anti-smooth muscle antibody; AMA, anti-mitochondrial antibody; NL, normal limit. a Typical (1) Interface hepatitis, lymphocytic/lymphoplasmacytic infiltrates in portal tracts and extending into the lobule. (2) Emperipolesis (active penetration by one cell into and through a large cell). (3) Hepatic rosette formation. Compatible: chronic hepatitis with lymphocytic infiltration without features considered typical. b Original revised scoring criteria. c Simplified scoring criteria. 가면역양상을동반한담즙울체형간질환과의감별에있어서는취약하다 [29]. 따라서중복증후군의경우 ALP/AST 비가순수자가면역성간염에비해높고조직검사에서도담관변화를동반하기때문에진단의민감도가 50% 로감소하게되었다 [18]. 이를반영하여 Hennes 등 [19] 은중복증후군을자가면역성간질환으로분류하여 simplified scoring system을제시하였다 [19]. 물론일부중복증후군이시간이경과함에따라순수자가면역성간질환과는전혀다른양상으로진행할수있기때문에 [30] 이러한분류에논란이없는것은아니다. 그러나중복증후군이활동성의자가면역성간염을동반할경우 PBC나 PSC 유무와관계없이치료를요한다는점 을고려하여진단체계를구성하였고, 그결과본연구에서도 5명의 AIH/PBC 중복증후군환자가 1999년진단체계에서는모두위음성이었으나 simplified scoring criteria을적용하였을때자가면역성간염으로진단되고있었다 (Table 8). 중복증후군환자는순수자가면역성간염환자에비해 ALP/AST 비가 3.4 (p = 0.039) 로유의하게높았고, 조직검사에서담관변화를보인경우도유의하게 (100%, p = 0.01) 많았다. 또한 AMA도모두에서양성을보여순수자가면역성간염군 (0%, p < 0.001) 보다유의하게높았다. 그러나 ANA나 IgG, 자가면역성간염을시사하는조직소견에서는유의한차이를보이지않았다. 이러한결과를통해 ALP/AST 비, 조

9 - The Korean Journal of Medicine: Vol. 81, No. 3, 직검사에서의담관변화및 AMA 항목이 1999년진단체계에서중복증후군의자가면역성간염진단의민감도를감소시킨주요인임을확인할수있었다. Simplified scoring criteria가제시된이후발표된검정결과중 Czaja 등 [22] 은새로운진단기준의민감도와특이도를 95% 와 90% 로발표하였고, Yeoman 등 [31] 의연구에서는 90% 와 98% 로발표한바있다. 본연구에서측정된 simplified scoring criteria 의민감도는 90.9% 였으며특이도는 96.2% 로이전에발표된내용들에준하는결과를보여주었다. 이중민감도를감소시킨요인은 2명의자가면역성간질환이위음성으로진단되었기때문이었고, 이들은앞에서설명한바와같이 ANA와 IgG가낮은비특이적인양상의환자들이었다. 특이도에는 PBC 환자 11명중위양성을보인 3명 (27.3%) 이영향을주었다. 이들중 2명은의증이었고, 1명은확진으로분류되었다. 전체 PBC 환자 11명중 8명 (72.2%) 에서 ANA 가 1:80 이상증가되어있었고, 3명 (27.3%) 에서 IgG가정상상한치의 1.1 이상증가되어있었다. 이세명의환자는모두 ANA가 80 이상이었고, 바이러스성간염이배제되어 simplified scoring criteria 적용시자가면역성간염으로진단되었다. 이러한결과는 ANA 와 IgG의비특이성때문이다. ANA의경우 PBC, PSC, 약인성간손상, 바이러스간염, 알코올, NAFLD 등여러간질환에서검출되며, 정상성인에서도 15% 까지양성으로보고된다 [32-34]. 또한 Jung 등 [25] 의연구에따르면만성간질환의 50% 이상에서 IgG가정상상한치이상으로상승되어있었고, 본연구에서도독성간염환자중 2명 (4.0%), NAFLD 중 2명 (11.1%) 에서같은결과를보였다. 이러한비특이성은 simplified scoring criteria을만든의도와는다르게원인미상의간염을자가면역성간염으로오진할수있는원인이될수있다. 그러나 PBC 일부가위양성으로진단된데에는검사의비특이성과함께중복증후군의가능성도고려되어야한다. 현재중복증후군은아직까지진단방법이표준화되어있지못하며, 흔히사용되고있는 Paris criteria [21] 의경우 Kuiper 등 [35] 에의해이루어진후향적, 단일기관연구를통해각각 92% 와 97% 의민감도와특이도가보고되었지만, 적절성을입증하기위한더많은연구가필요한상태이다. 따라서위양성을보인 PBC 환자들이비록 Paris criteria를만족하지는않았지만중복증후군의가능성이완전히배제된것은아니며, 이러한양상을보이는환자에서는지속적으로자가항체와면역글로불린등에대한추적검사 가필요할것이다. 결과적으로한국인에게 simplified scoring criteria는자가면역성간염을진단하는데매우유용하게사용될수있으며, 특히중복증후군의진단에많은향상을가져다주었다. 그러나진단항목의간소화는비특이적양상의자가면역성간염을진단하지못할가능성이있으며, 또이항목들이자가면역성간염에대한특이도가낮기때문에위양성을초래할위험성이있다. 특히자가항체나면역글로불린이의미있게상승한경우면밀한추적관찰을시행하고, 자가면역성간질환의다양한임상경과를이해하는것이중요할것으로생각한다. 본연구에는대조군에비알코올성간질환중가장많은비율을차지하는바이러스성간염환자가포함되어있지않다는점과단일기관에서시행되었다는제한점이있다. 따라서한국인에서 simplified scoring criteria의진단적가치및유용성을평가하기위해더다양하고많은환자를대상으로한대규모연구가필요할것으로생각한다. 요약목적 : 자가면역성간염 (AIH) 을진단하기위한 revised original scoring criteria 는지나치게번거로워임상에서의적용이쉽지않았다. 이러한단점을보안하기위해 2008년 Hennes 등 [19] 에의해 simplified scoring criteria 가발표되었다. 이에저자등은이 criteria를한국인에게적용하였을경우, 진단적가치및유용성을평가하고자연구를시행하였다. 방법 : Original revised scoring criteria 에의해 AIH이진단된 22예와자가면역간염 / 원발성담즙간경변증 (autoimmune hepatitis/primary biliary cirrhosis, AIH/PBC) 중복증후군을진단받은 5예, 그리고대조군으로독성간염 50예, 비알코올성지방간 (NAFLD) 18예, 원발성담즙간경변증 (PBC) 11예를후향적으로분석하였다. 결과 : AIH 중 20명 (90.9%) 과 AIH/PBC 중복증후군 5명모두가 simplified scoring criteria에의해 AIH로진단되었다. 그리고 PBC 중 3명인 27.3% 에서새로운진단기준을적용하였을경우위양성을보였다. AIH 진단에대한 simplified scoring criteria의민감도와특이도는각각 90.9% 와 96.2% 였다. 결론 : 한국인에게 simplified scoring criteria는중복증후군을포함한자가면역성간염을진단하는데유용하게사용될수있을것으로생각한다

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