2015 대한간학회추계 Single Topic Symposium 스웨덴코호트에서는경증-중등도섬유화를보이는환자 (stage F1-2) 의경우 13% 가간경변증으로진행하였으나, 이보다진행된형태의 stage F3 의섬유화를보인군에서는 25% 환자가간경변증으로진행하여섬유화정도

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Role of non-invasive diagnosis: Cons 최대희 강원대학교의학전문대학원소화기내과 Nonalcoholic fatty liver disease (NAFLD) is an emerging cause of chronic liver disease.

1 Role of non-invasive diagnosis: Cons 최대희 강원대학교의학전문대학원소화기내과 Nonalcoholic fatty liver disease (NAFLD) is an emerging cause of chronic liver disease. NAFLD encompasses a spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH), and cirrhosis. The classical gold standard for diagnosing and staging NAFLD and assessing fibrosis is liver biopsy (LB). However, it has several limitations that they have real risks of procedure-related complications, sampling error issues and subjectivity in the interpretation. Therefore, to overcome its limitation of LB, several non-invasive methods have been studied in the last decade. However, most methods have been evaluated in small pilot studies without external validation. Also, they have shown suboptimal results for diagnosis of NASH and discrimination of mild, moderate, or severe fibrosis. Therefore, further validation for these noninvasive tests is necessary to refine their clinical significance. Key words: Non-alcoholic fatty liver disease; Non-alcoholic steatohepatitis; fibrosis; liver biopsy; non-invasive diagnosis I. 서론 1. 비알코올성지방간질환의자연경과 비알코올성지방간질환 (Non-alcoholic fatty liver disease, NAFLD) 은국내에서의유병률이 16-33% 로알 려져있는비교적흔한만성간질환이다. 1,2 이질환은비교적양호한예후를갖는단순지방간 (Simple steatosis, SS) 부터염증성간질환인비알코올성지방간염 (Non-alcoholic steatohepatitis, NASH) 을포함하는조직학적스펙트럼을이르며, 특히 NASH는섬유화의정도에따라서로다른자연경과를보일수있다. 2011년발표된메타분석에서는 SS 환자의생존률은일반인과큰차이가없으나, NASH 환자는 SS 환자에비해사망률이높다고보고하였다. 특히 NASH 환자에서의간질환과연관된사망률은 % 로, SS의 % 에비해현저하게높아, 사망의주요인은간질환과연관되어있음을확인하였다 (pooled OR NASH vs. SS: 5.71; 95% CI ;P = ; I2 = 0%)

2 2015 대한간학회추계 Single Topic Symposium 스웨덴코호트에서는경증-중등도섬유화를보이는환자 (stage F1-2) 의경우 13% 가간경변증으로진행하였으나, 이보다진행된형태의 stage F3 의섬유화를보인군에서는 25% 환자가간경변증으로진행하여섬유화정도에따라질환의진행정도가다름을확인하였다. 4 또한경한섬유화를동반한 NASH (stage F0-2) 의경우 SS환자보다간질환연관성사망은현저히높으며 (pooled OR 2.11; 95% CI ; P = 0.02; I2 = 0%), 경한형태의 NASH (stage F0-2) 에비해더한섬유화 (stage F3-4) 를동반한경우는간질환연관성사망은더욱높았다 (pooled OR 10.06; 95% CI ; P = ; I2 = 0%). 3 Ⅱ. 진단 1. 간조직검사의역할 NALFD에서조직학소견에따른분류에따라각각다른자연경과를보이는것은위와같이알려져있는데, 이의진단하기위한표준진단법이간조직검사이다. 간조직검사를통하여간내지방침착, 간세포손상, 염증및섬유화등을평가할수있으며, 특히지방침착과함께간세포풍선변성이관찰되면 SS와 NASH를감별하는중요한단서가된다. 성인 NASH는거대수포성지방증, 간세포손상과혼합염증반응이주로 3구역 (zone 3), 중심소엽에분포하는것을특징으로한다. 특히지방증은이미지방이사라진간경변증을제외하고는 NAFLD 진단의전제조건으로최소 5% 이상의간세포가지방소포를함유하고있어야한다. 간세포손상을반영하는소견은간세포의풍선변성이가장중요한데, 호산체나초점괴사가동반될수도있다. NASH가심하게진행되면간소엽의염증세포침윤과문맥주위염증이나타난다. 섬유화증은 NASH의정의에포함되지않으나동주위섬유화는 NASH의특징적인조직소견중하나로동주위섬유화와문맥섬유화에따라병기를분류한다. 5 NAFLD activity score (NAS) 는가장널리사용하는조직학적 grading, staging system이며, SAF score (Steatosis, Activity, Fibrosis) 또한최근에 NASH를좀더정확하게확인하는방법으로등장하였다 (Table 1). 6,7 NAS는 HE 염색과 Masson s trichrome 염색등으로판독이가능한방법으로, 지방증, 풍선변성, 소엽염증정도의점수를합산하여 5점이상이면 NASH로, 2점이하이면 NASH가아닌것으로판정하였다. 그러나 NAS가 5점이상임에도 16% 정도의환자는 NASH에합당하지않으므로 NAS는 NASH의진단을위한검사라기보다는치료에따른조직소견의변화를확인하는데주로이용된다. 8 간조직검사는침습적이며몇가지제한점이있어모든환자에게진단을위해적용하기는어려운점이역시존재한다. 9 조직검사후합병증으로입원을요하는경우가 1%-3%, 사망률이 0.01% 정도로보고되며, 병리의사간판독의불일치문제, 간총중량의극히일부분 (~1/50,000) 만채취하게되면서발생하는샘플링오류등의제한점이알려져있다. 10 그러므로이를대체할만한비침습적인검사법의진화가지속되고있는실정이다. 62 대한간학회 The Korean Association for study of the Liver

3 최대희 Role of non-invasive diagnosis: Cons Table 1. NAFLD activity score (NAS) 6 Histological feature Score Category definition Steatosis 0 <5% % % 3 >66% Plus Hepatocyte 0 None ballooning 1 Few 2 Many Plus Inflammation 0 None foci per 20 field foci per 20 field 3 >4 foci per 20 field NAS total 0-8 Fibrosis 0 No fibrosis 1a Zone 3 mild perisinusoidal fibrosis 1b Zone 3 moderate perisinusoidal fibrosis 1c Periportal/portal fibrosis only 2 Zone 3+periportal/portal fibrosis 3 Bridging fibrosis 4 Cirrhosis Fibrosis score 0-4 A score of 5 with steatosis and hepatocyte ballooning is generally considered diagnostic of non-alcoholic steatohepatitis (NASH), but patients can still have NASH with lower NAS scores if steatosis and hepatocyte ballooning are present. 2. 비침습적진단방법 1) 지방침착의진단과정량화 NAFLD 환자는임상적으로대개증상이없고증상이있더라도비특이적이며대개의 SS의경우에서는앞서기술한대로중증이간질환으로진행하지않으므로, American Association for the Study of Liver Disease 가이드라인에서는지방침착의유무를스크리닝하는것이권고되지않는다. 또한스크리닝프로그램이비용-효율대비효과적이라는보고도전무한상태이다. 11 현재까지알려진지방침착을예측하고정량화하는다양한비침습적진단방법중복부초음파검사는경한지방침착의경우정확도가떨어지는단점이있기는하나가장널리용이하게이용되는방법이고, 양성자자기공명분광기 (magnetic resonance spectroscopy, MRS) 는매우적은지방의침착도감별할수 있다고알려져있으나고비용및임상적으로널리이용되지못하는단점을가지고있다. 12,13 최근에소개 된 Controlled Attenuation Parameter (CAP) 은지방침착의정도를비교적정확히평가할수있는것으 63

4 2015 대한간학회추계 Single Topic Symposium 로알려져있으나향후많은연구결과가뒷받침되어야한다. 14 NAFLD Liver Fat Score 는민감도, 특이 도가 95% 로네덜란드그룹에서도적용하여확인된검사로임상에서비교적쉽게적용할수있을것으로보인다 (Table 2). 15 Table 2. Non-invasive methods for predicting steatosis Score Calculation Results NAFLD Liver Fat Score * (metabolic syndrome - yes = 1/no = 0) * (type 2 diabetes mellitus - yes = 1/no = 0) * (fasting serum insulin, mu/l) * (AST, IU/L) * (AST/ALT) Lipid Accumulation Product (LAP) 17 Ultrasonograp-hic Fatty Liver Indicator (US-FLI) 18 CT scores 18 Zardi s US score 19 MRI/1H-MRS 12,13 Controlled Attenuation Parameter (CAP) 14 (waist circumference - 65) * triglycerides if men and (waist circumference - 58) * triglycerides if women Brighter liver than kidney, whose intensity in contrast can be graded as mild/moderate (2 points) or severe (3 points). One extra point for each of the following: 1. Posterior attenuation of ultrasound beam, 2. Vessel blurring, 3. Difficult visualization of the gallbladder wall, 4. Difficult visualization of the diaphragm, 5. Areas of focal sparing 1. Liver parenchyma attenuation (CTLP): normal range - 50 to 57 Hounsfield Units (HU) 2. Liver to spleen attenuation difference (CTL-S): normal range - 8 to 10 HU 3. Liver to spleen attenuation ratio (CTL/S) Two parameters: 1. Echo amplitude attenuation scored from 0 if absent, 1 mild and 2 severe, 2. Presence/absence of focal fat sparing AUROC cut-offs, and Se and Sp 95% For each log unit increase, OR for steatosis 4.28 Score 2 - highly indicative of NAFLD Score 4 - predicts NASH: AUROC 0.796, NPV 94%, Se 46% CTLP <40 HU - Se 52%, Sp 100% CTL-S >10 HU - Se 60%, Sp 100% CTL/S >1.1 - Se 82%, Sp 100% Score 1 could - Se 92%, Sp 75% mild steatosis (AUROC > or =0.87) moderate/severe steatosis (AUROC > or =0.89) AUROC were 0.80 for mild, 0.86 for moderate and 0.88 for severe steatosis NAFLD, non-alcoholic fatty liver disease; ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; AUROC, area under receiver operating characteristic; Se, sensitivity; Sp, specificity; PPV, positive predictive value; NPV, negative predictive value; HU, hounsfield units; MRI/1H-MRS, MRI and proton magnetic resonance spectroscopy 2) NASH 예측 NAFLD 환자에서 NASH 환자를감별하고치료하는것은중요한문제이나, SS와 NASH를감별해내기위해임상에서널리유용하게사용할수있는혈액검사또는영상검사는아직정해진바없다 (Table 3). 64 대한간학회 The Korean Association for study of the Liver

5 최대희 Role of non-invasive diagnosis: Cons NASH 에서는발생하는간세포의세포자멸 (apoptosis) 증가를반영하기위해서 cytokeratin-18 fragment 측정또는 matrix turnover 를대변하는 terminal peptide of procollagen Ⅲ (PⅢNP) 의측정등으로 NASH 를예측하거나, 이를조합함으로써예측하려는노력이시도되고있다. 20,21 Table 3. Non-invasive methods for predicting NASH Score Calculation Results Plasma-cleaved CK-18 fragments 20 PⅢNP 21 NASH Test 22 NASH Diagnostics 23 NASH Diagnostic Panel 24 Apoptosis Panel 25 Undisclosed formula incorporating: α2-mg, haptoglobin, apolipoprotein A1, total bilirubin, GGT, ALT, AST, triglycerides, cholesterol, age, gender, height, weight Undisclosed formula incorporating: cleaved and total CK18 (M30 and M65 antigens, respectively), adiponectin, resistin Undisclosed formula incorporating: diabetes mellitus, sex, BMI, triglycerides, M30 and M53 antigens Includes: CK18 fragments, soluble Fas and Fas ligand Nice model 26 Model = e-02 * ALT (IU/L) e-03 * CK 18 fragments (IU/L) * (metabolic syndrome: yes = 1, no = 0) Logarithmic transformation = 1/[1 + Exp(-Nice Model)] 71% sensitive and 85% specific for NASH at a cut-off of 279 U/L NASH/advanced fibrosis (AUROC ) AUROC : F0-2 fibrosis AUROC : F0-3 fibrosis AUROC 0.79 Se 33%, Sp 94%, PPV 66%, NPV 81% combined AUROC 0.90 cut-off Se 72%, Sp 91% AUROC cut-offs, and Se 91%, Sp 92%, PPV 83%, NPV 86% AUROC 0.93 Cut-off Se 88%, Sp 89%, PPV 86%, NPV 91% AUROC Cut-off Se 84%, Sp 86%, PPV 44%, NPV 98% NASH, non-alcoholic steatohepatitis; ALT, alanine aminotransferase; AUROC, area under receiver operating characteristic; Se, sensitivity; Sp, specificity; NAFLD, non-alcoholic fatty liver disease; AST, aspartate aminotransferase; BMI, body mass index; PPV, positive predictive value; NPV, negative predictive value; a2-mg, alpha-2 macroglobin; GGT, gamma-glutamyltranspeptidase; CK18, cytokeratin 18 3) 섬유화예측 NAFLD 환자에서섬유화의유무또는정도를조직검사없이확인하기위한방법으로, 일반적인혈액검사및간세포세포자멸의마커, collagen matrix 재형성과관련된마커, 각종사이토카인등을이용하여이를조합한다양한방법들이연구되고있다 (Table 4). 20 여가지가넘는비침습적검사법중, NAFLD fibrosis score (NFS), BARD, ELF panel, Fibrotest 연구에서는진행된섬유화군을포함하고있고 AUROC 수준의결과를보여준다. 3 특히 NFS는 65

6 2015 대한간학회추계 Single Topic Symposium Table 4. Non-invasive methods for predicting fibrosis Score Calculation Results NAFLD Fibrosis Score * age (yr) * BMI (kg/m2) x IFG/diabetes mellitus (yes = 1, no = 0) * AST/ALT ratio * platelet (* 109/L) x albumin (g/dl) BARD 30 Includes 3 variables: 1. BMI 28 kg/m2 (1 point), 2. AST/ALT ratio 0.8 (2 points), 3. Diabetes mellitus (1 point) FIB-4 31 age (yr) * AST (IU/L)/platelet count (109/L) * ALT1/2 (IU/L) Simplified ELF 32 ELF = [Ln(hyaluronic acid) * 0.681] - [Ln(amino-terminal propeptide of type III collagen) * 0.755] - [Ln(TIMP-1) * 0.494] FibroTest 33 Undisclosed formula incorporating: age, α2-macroglobulin, total bilirubin, GGT and apolipoprotein A1 AUROC 0.84 for advanced fibrosis 2 cut-off: and Se 82%, Sp 98%, PPV 90%, NPV 93% AUROC 0.81 for advanced fibrosis Score PPV 43%, NPV 96% AUROC 0.86 for advanced fibrosis cut-off: 1.3 -Se 85%, Sp 65%, NPV 95% AUROC 0.87 for advanced fibrosis in NASH cut-off Se 91%, Sp 59%, PPV 42%, NPV 95% AUROC for significant fibrosis 2 cut-off: 0.3 and 0.7 -Se 77%, Sp 98%, PPV 90%, NPV 73% Fibroscan 34 AUROCs for the detection of stage 2 fibrosis, stage 3 fibrosis and cirrhosis (0.84, 0.93 and 0.95, respectively) high NPV of 96% for stage 3 fibrosis at a cut-off of 7.9 kpa but only modest PPV (52% at 7.9 kpa and 72% at 9.6 kpa) ARFI 28 AUROC for the diagnosis of stage 3 or 4 fibrosis was 0.97 NAFLD, non-alcoholic fatty liver disease; BMI, body mass index; ALT, alanine aminotransferase; AUROC, area under receiver operating characteristic; Se, sensitivity; Sp, specificity; PPV, positive predictive value; NPV, negative predictive value; TIMP-1, tissue inhibitor of metalloproteinases; NASH, non-alcoholic steatohepatitis; GGT, gamma-glutamyltranspeptidase; IFG, increased fasting glucose; AST, aspartate aminotransferase;arfi, acoustic radiation force impulse 진행된섬유화환자군에대해여러후속연구에서추가로입증이된만큼비교적유용하게사용될수있을것이다. NFS는간섬유화평가에있어두개의기준치 [cut-off value, < (low probability) 와 > (high probability)] 를갖는데, 약 20-58% 의환자에서는두기준치사이값을보여, 진행된간섬유화에대한 high 또는 low probability 어느쪽으로도분류되지못하는분류의경우 (indeterminate probability), 결국간조직검사로확인할수밖에없다. 3 이외영상검사로는간경도측정 (liver stiffness measurement, LSM) 을초음파또는 MR로시행하는방법이있다. 초음파를이용하는 Fibroscan은 AUROC 0.94, 진행된섬유화에서민감도, 특이도가각각 94%, 95% 이며, 후속연구에서도이의정확성과재현성이확인되었으나체질량지수 (body mass index, BMI) 30 kg/m 2 미만의비만환자 5-13% 에서 LSM을측정할수없었다는단점을가지고있다. 비만환자에게사용할새로운 XL probe에대한연구가진행되어측정실패의확률을 35% 에서 6% 까지현저히 66 대한간학회 The Korean Association for study of the Liver

7 최대희 Role of non-invasive diagnosis: Cons 줄였다는보고가있었음에도, 급성간염의동반, 담즙정체, 간울혈을동반하면 LSM을증가시킬수있다. 27 Acoustic radiation force impulse (ARFI) sonoelastography는전통적인 B-mode 초음파검사를이용하여간탄력도를측정할수있는검사이며 54명을대상으로진행한연구에서 stage 3, 4단계의진행된섬유화환자에서 AUROC 0.97이라는지표를보여주었으나, 후속연구및향후후속연구에서의확인이필요한실정이다. 28 Ⅲ. 결론 NAFLD 환자에서진단및특히예후와관련된질환의진행정도를알아보기위해서는간조직검사가표준진단법이다. 그러나간조직검사는몇가지제한점이존재하므로일반적으로 SS를진단하기위한스크리닝목적의검사는추천되지않지만, NASH 감별및섬유화정도를비교적정확히평가하기위해조직검사를시행, 진단하여향후예후를적절히예측하고치료및관리의계획을세우는것은매우중요한일이다. 현재로서는 SS, NASH, 또는섬유화의정도를간조직검사만큼예측할수있는단일검사또는공식은증명되지않았으므로 NAFLD에서간조직검사의역할이타검사로대치될수있다고보기는어렵다. 그러나, 간조직검사의제한점을극복하기위한비침습적검사법들의발전이지속되고있으므로비교적경한예후를보일것으로예측되는대다수의 NAFLD 환자들에대해서는비침습적인검사방법일부를적용함으로써간조직검사를대체할수있을것으로기대된다. REFERENCES 1. Choi SY, Kim D, Kim HJ, Kang JH, Chung SJ, Park MJ, et al. The relation between non-alcoholic fatty liver disease and the risk of coronary heart disease in Koreans. Am J Gastroenterol 2009;104: Bae JC, Cho YK, Lee WY, Seo HI, Rhee EJ, Park SE, et al. Impact of nonalcoholic fatty liver disease on insulin resistance in relation to HbA1c levels in nondiabetic subjects. Am J Gastroenterol 2010;105: Musso G, Gambino R, Cassader M, Pagano G. Meta-analysis: natural history of non-alcoholic fatty liver disease (NAFLD) and diagnostic accuracy of non-invasive tests for liver disease severity. Ann Med 2011;43: Ekstedt M, Franzén LE, Mathiesen UL, Thorelius L, Holmqvist M, Bodemar G, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006;44: Brunt EM. Histopathology of non-alcoholic fatty liver disease. Clin Liver Dis 2009;13: Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41: Bedossa P, Poitou C, Veyrie N, Bouillot JL, Basdevant A, Paradis V, et al. Histopathological algorithm and scoring system for evaluation of liver lesions in morbidly obese patients. Hepatology 2012;56:

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9 최대희 Role of non-invasive diagnosis: Cons 28. Yoneda M, Suzuki K, Kato S, Fujita K, Nozaki Y, Hosono K, et al. Nonalcoholic fatty liver disease: US-based acoustic radiation force impulse elastography. Radiology 2010;256: Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, et al. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007;45: Harrison SA, Oliver D, Arnold HL, Gogia S, Neuschwander-Tetri BA. Development and validation of a simple NAFLD clinical scoring system for identifying patients without advanced disease. Gut 2008;57: McPherson S, Stewart SF, Henderson E, Burt AD, Day CP. Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic fatty liver disease. Gut 2010;59: Guha IN, Parkes J, Roderick P, Chattopadhyay D, Cross R, Harris S, et al. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: Validating the European Liver Fibrosis Panel and exploring simple markers. Hepatology 2008;47: Ratziu V, Massard J, Charlotte F, Messous D, Imbert-Bismut F, Bonyhay L, et al. Diagnostic value of biochemical markers (FibroTest-FibroSURE) for the prediction of liver fibrosis in patients with non-alcoholic fatty liver disease. BMC Gastroenterol 2006;6: Wong VW, Vergniol J, Wong GL, Foucher J, Chan HL, Le Bail B, et al. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology 2010;51:

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<303220C6AFC1FD20B1E8B9AEBFB D E687770> 대한내과학회지 : 제 86 권제 4 호 2014 http://dx.doi.org/10.3904/kjm.2014.86.4.405 특집 (Special Review) - 비알코올지방간질환 비알코올지방간질환의진단 연세대학교원주의과대학내과학교실 김문영 The Diagnosis of Nonalcoholic Fatty Liver Disease Moon Young Kim