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1 대한내과학회지 : 제 93 권제 1 호 Roadmap to diagnosis 비알코올성지방간염의진단 순천향대학교의과대학부천병원내과 유정주 김상균 Diagnostic Approach to Nonalcoholic Steatohepatitis Jeong-Ju Yoo and Sang Gyune Kim Department of Internal Medicine, Soon Chun Hyang University Bucheon Hospital, Soon Chun Hyang University College of Medicine, Bucheon, Korea 임상증례 44세남자가건강검진에서발견된간수치이상및지방간소견으로방문하였다. 환자는특별한증상을보이지않았고, 5년전부터고혈압으로약물치료중이었다. 키 173 cm, 체중 89 kg으로다소비만하였으며, 혈압, 맥박, 호흡수는모두정상이었다. 이상심음이나호흡음은청진되지않았고, 흉곽의압통은관찰되지않았다. 혈액검사에서 AST 및 ALT가각각 160 U/L와 192 U/L로상승되어있었고, 이외다른수치는정상범위였다. 복부초음파에서는지방간소견이관찰되었다. 진단의일차단계다른원인의간질환을배제하기위해서병력청취및혈청학적검사를시행하였다. 만성 B형및 C형간염에대한항체검사를시행하였으나만성바이러스간염의증거는관찰되지않았다. 또한알코올, 약제, 건강식품등의복용력을조사하였으나특별한약제복용력은없었다. 혈액검사에서 AST 및 ALT 수치의상승외에는 gamma-gt, alkaline phosphatase, total bilirubin 수치는모두정상범위였다. 대사성증후군의감별을위해당화혈색소, 공복혈당, 지질검사를시행하였으나, 치료를요하는제2형당뇨나고지혈증은진단되지않았다. 복부초음파에서간의에코가신장및비장에비해증가되어있었고, 문맥벽의에코가뚜렷이보이지않았다. 또한간의표면이약간거칠게보였고, 간변연의둔화의심소견이보였다. 복부컴퓨터단층촬영에서는내장지방과다소견및간음영정도 (hounsfield unit) 가비장보다감소한소견을보였다. 최종진단과치료경과초음파및혈액학적소견을바탕으로비알코올성지방간으로진단하고적극적인체중조절및중간강도의운동요법, 탄수화물섭취제한등을한후간효소수치에대한추적검사를하였으나 AST/ALT 102/155 IU/L 로여전히증가된소견을보여지방간염의유무와간섬유화진행정도에대한감별진단을위해간조직검사를시행하였다. 조직검사결과중심 Correspondence to Sang Gyune Kim, M.D., Ph.D. Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Soon Chun Hyang University College of Medicine, 170 Jomaru-ro, Bucheon 14584, Korea Tel: , Fax: , mcnulty@schmc.ac.kr Copyright c 2018 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - The Korean Journal of Medicine: Vol. 93, No. 1, 소엽주변으로 66% 이상에서지방증 (steatosis) 이있었고, 간세포손상을반영하는풍선변성 (ballooning degeneration) 과호산체 (acidophilic body) 가관찰되었다. 또한문맥섬유화 (portal fibrosis) 소견이일부관찰되었다. 이에 F2 간섬유화를동반한비알코올성지방간염으로확진하였다. 진단후영양상담을통한적극적인식이습관교정과체중감량및 vitamin E를하루에 800 IU씩복용하기시작하였고, 1년경과후체중은 80 kg으로감량되고, 간수치는정상범위로호전되었다. 고찰비알코올성지방간염의진단및선별검사비알코올성지방간염은지방침착및간세포손상을반영하는염증소견이동반된질환으로, 간섬유화 (fibrosis) 및간경변증, 간세포암의원인질환이될수있다. 서구식식단변화와함께우리나라에서도매우빠른속도로증가하고있으며, 특히미국의경우 50세미만에서간이식을받게되는가장많은원인으로알려져있다 [1]. 모든비알코올성지방간환자가비알코올성지방간염으로진행하지는않지만, 일단지방간염으로진행할경우간질환및이와관련된합병증으로사망할가능성이높아적극적인검사및치료가필요할수있다 [2]. 비알코올성지방간염환자의약 50% 이상은무증상으로, 본증례에소개된환자처럼건강검진에서우연히간수치이상소견을주소로내원할때가많다 [3]. 그러나간수치의상승정도가질병의중증도와비례하지는않으며, 특히이미 간경변증으로진행된환자의경우 ALT는많게는약 80% 의환자에서정상으로관찰된다 [4]. 비알코올지방간질환의진단을위해서는간내지방변화의확인뿐아니라, 다른원인의간질환을배제하는것이중요하다. 따라서임상적으로만성간질환이의심되는경우나간기능검사에서이상소견이발견되는경우, 우리나라에서만성간질환의중요원인인만성 B형및 C형간염, 알코올간질환, 약물유발간질환, 자가면역간질환, 윌슨병등을배제하기위한병력청취및혈청학적검사를시행해야하며, 아울러간내지방축적을확인하기위하여복부초음파검사등을일차적으로시행한다. 또한인슐린저항성제2형당뇨나대사성증후군 ( 복부비만, 고지질혈증 ) 을동반하는경우가많으므로, 동반질환에대해서도검사가필요하다. 비알코올성지방간염환자에게일차적으로검사가필요한항목에대해서는표 1에정리하였다. 비침습적검사지방증의정도예측복부초음파는지방증정도를알기위해가장많이이용되는검사이다 [5]. 영상학적검사가불가능할경우에는혈청학적바이오마커검사로대체할수있으며, 가장많이검증된검사는 fatty liver index (FLI) 및 SteatoTest 이다 [6]. 본검사는일반인및특히고도비만환자에서인슐린저항성및장기예후예측에도움이되나, 지방증의정도를정량화시키지는못한다. 최근많이사용되는 Fibroscan 검사의 controlled attenuation parameter 가지방증과비례한다고알려져 Table 1. Protocol for a comprehensive evaluation of suspected NAFLD 7 Initial 1. Alcohol intake: < 20 g/day (women), < 30 g/day (men) 2. Personal and family history of diabetes, hypertension and CVD 3. BMI, waist circumference, change in body weight 4. Hepatitis B/Hepatitis C virus infection 5. History of steatosis-associated drugs 6. Liver enzymes (aspartate and alanine transaminases [γ-glutamyl-trans-peptidase]) 7. Fasting blood glucose, HbA1c, OGTT, (fasting insulin [HOMA-IR]) 8. Complete blood count 9. Serum total and HDL-cholesterol, triacylglycerol, uric acid 10. Ultrasonography (if suspected for raised liver enzymes) Extended 1. Ferritin, transferrin saturation 2. Tests for coeliac and thyroid diseases, polycystic ovary syndrome 3. Wilson disease, autoimmune hepatitis, α1-antitrypsin deficiency NAFLD, non-alcoholic fatty liver disease; CVD, cardiovascular disease; BMI, body mass index; HbA1c, hemoglobin A1c; OGTT, oral glucose tolerance test; HOMA-IR, homeostasis model assessment for insulin resistance; HDL, high-density lipoprotein

3 - Jeong-Ju Yoo, et al. Road map to diagnose NASH - 있으나, 조직학적소견과잘일치되지못한다는상반된결과도있다 [7]. 간전체지방증의정량적인예측은 Hydrogen-1 MR spectroscopy로가능하나고가의검사로아직임상에일반적으로적용하기에는시기상조로보인다 [8]. 지방간염의정도예측단순지방증에서비알코올성지방간염으로의발전가능성이높은고위험군은아래와같다 (Table 2). 그러나이외에현재까지생화학적, 영상학적인검사로단순지방증과비알코올성지방간염을구분할수있는비침슴적방법은존재하지않는다. Cytokeratin-18 이비알코올성지방간염을예측한다고알려져있으나, 아직까지검사의민감도 (66% sensitivity) 나특이도 (82% specificity) 가높지않다 [9]. 즉, 간조직검사이외에는비알코올성지방간염을진단할수있는검증된비침습적방법은없는실정이다. 섬유화의정도예측간섬유화는비알코올성지방간염의가장중요한예후예측인자로, 간질환관련사망률과연관이있다 [2]. 많은혈청학적검사가섬유화정도를비교적정확하게예측한다고보고되어있는데, 가장많이이용되고검증된검사는 NAFLD fibrosis score (NFS) 및 fibrosis 4 calculator (FIB-4) 로각각의점수체계에사용되는인자들은표 3과같다 [10]. 이외 enhanced liver fibrosis, FibroTest 도전체사망률및간관련사망률과관련이있다고연구되었고, 현재까지개발된점수체계및항목에대해서는표 3에정리하였다 [10,11]. 영상학적검사중에서최근임상에서가장많이사용되고있는검사는 Fibroscan 이고, 많은연구에서섬유화정도와비례함이잘밝혀져있다 [12]. 다만, 간경변증 (F4) 에대한진단율은비교적우수한예측력을보여주지만그이하의간섬유화 ( F3) 를구별하는데는비교적진단정확도가떨어지는것으로알려져있으며, 체질량지수 (body mass index) 가높거 Table 2. Clinical predictors of NASH Character Advanced age Sex Race Hypertension, central obesity, dyslipidemia, insulin resistance/diabetes AST/ALT ratio > 1 Low platelet Persistently elevated ALT Outcome Greater duration of disease Postmenopausal women experience accelerated disease Prevalence and severity in Hispanic, Asian Prevalence and severity in Black Risk increases with metabolic syndrome, 66% prevalence of bridging fibrosis if older than 50 years of age and obese or diabetic Indicators of advanced fibrosis/cirrhosis in NASH Can be associated with greater risk of disease progression NASH, nonalcoholic steatohepatitis; AST, aspartate aminotransferase; ALT, alanine aminotransferase. Table 3. Clinical predictors and biomarkers for advanced fibrosis Test name Year Marker AUROC validation AST/ALT 1988 AST, ALT Fibrotest 2001 ALT, haptoglobin, alpha- macroglobulin, GGT, apolipoprotein A1, total 0.75 bilirubin APRI 2003 AST, platelets ELF score 2004 HA, TIMP-1, PIIINP 0.90 Fibrometer 2005 Glucose, AST, weight, ferritin, ALT, age, platelets 0.94 FIB-4 a 2006 Age, AST, ALT, platelets 0.86 NFS b 2007 Age, albumin, AST/ALT ratio, hyperglycemia, platelet count, BMI BARD 2008 BMI, DM, AST, ALT AST, aspartate aminotransferase; ALT, alanine aminotransferase; GGT, gamma glutamyl transferase; APRI, AST to platelet ratio index; ELF, enhanced liver fibrosis; HA, hyaluronic acid; TIMP-1, tissue inhibitor of metalloproteinases 1; PIIINP, amino-terminal propeptide of type III procollagen; BMI, body mass index; DM, diabetes mellitus. a b

4 - 대한내과학회지 : 제 93 권제 1 호통권제 680 호 나흉강피부가두꺼울경우검사가어려울수있다 [13]. 특히비만한환자를대상으로할경우 M probe보다는 XL probe 를사용해야진단의정확도를높일수있다 [14]. 침습적검사간조직검사가필요한환자간조직검사는비알코올성지방간염을진단할수있는표준검사방법이다. 그러나간조직검사는검사비용이비싸고, 검사의해석에전문적인의료인력이필요하며, 드물기는하나대량출혈및사망의합병증의보고되고있다. 따라서꼭필요한환자에대해서선별적으로검사를시행하는것이좋다. 특히지방간으로진단된환자중대사성증후군이동반되어있거나 NFS 및 FIB-4 점수, Fibroscan 상에서진행된섬유화나간경변증의가능성이높은환자를대상으로간조직검사를시행할경우진단및치료방향에대해많은도움을받을수있다. 다른원인질환을감별하는것외에도간섬유화의정도를평가할수있고, 예후예측에도움이된다 [6]. 요약비알콜성지방간은최근에우리나라에서도매우급격하게유병률이증가하고있으며, 이중진행된비알코올성지방간염및섬유화가동반되어있을가능성이높은환자를선별하여정밀하게검사하고치료를적용하는것이요구된다. 현재까지비알코올성지방간염을진단할수있는가장정확한표준검사법은간조직검사이지만환자및의사모두에게쉽게선택할수있는검사법이아니기때문에, 간조직검사를대신하여비침습적으로비알코올성지방간염의진단및조직학적중증도를평가하고자하는노력이영상의학검사및생화학검사분야를중심으로진행되고있다. 간과해서는안되는중요한문제는지방간염진단기준이서양에서도입된방식을따라가다보니진단에요구되는여러가지구성요소를유전적, 환경적으로다른우리나라와같은동양인에도획일적으로적용되고있다는점이며조직검사의적절한시기및병리판독자간의일치도, 치료의올바른선택에대하여보다적절한근거가필요한실정이다. 간조직검사의해석성인비알코올성지방간염은지방증 (steatosis), 간세포의풍선변성 (ballooning degeneration), 간소엽의염증세포침윤 (lobular inflammation) 의 3가지병변을특징으로한다 [5]. 특히지방증은이미지방이사라진간경변증을제외하고는반드시필요한전제조건으로최소 5% 이상의간세포가지방소포 (fat droplets) 를함유하고있어야한다. 이외문맥주위염증 (portal inflammation), 다형핵백혈구 (polymorphonuclear infiltrate), 말로리소체 (Mallory-Denk body), 호산체 (acidophilic body) 등이관찰될수있으나비알코올성지방간염진단의필수요소는아니다. 섬유화증은비알코올성지방간염의정의에포함되지않으나, 동주위섬유화 (perisinusoidal fibrosis) 는비알코올성지방간염의특징적인조직소견중하나이며, 동주위섬유화와문맥섬유화 (portal fibrosis) 에따라병기를분류한다. 2002년부터 NAFLD activity score (NAS) 가계산되어비알코올성지방간염의진단에사용되고있으나, 정확도가높지않으므로, NAS는비알코올성지방간염의진단을위한검사라기보다는이미진단이된환자에서질병의중증도나치료에따른조직소견의변화를확인하는데주로사용된다. 중심단어 : 비알코올성지방간염 ; 진단 ; 간조직검사 REFERENCES 1. Quillin RC 3rd, Wilson GC, Sutton JM, et al. Increasing prevalence of nonalcoholic steatohepatitis as an indication for liver transplantation. Surgery 2014;156: Ekstedt M, Hagstrom H, Nasr P, et al. Fibrosis stage is the strongest predictor for disease-specific mortality in NAFLD after up to 33 years of follow-up. Hepatology 2015;61: Daniel S, Ben-Menachem T, Vasudevan G, Ma CK, Blumenkehl M. Prospective evaluation of unexplained chronic liver transaminase abnormalities in asymptomatic and symptomatic patients. Am J Gastroenterol 1999;94: Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004;40: Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of nonalcoholic fatty liver disease: Practice guidance from the American Association for the Study of Liver Diseases. Hepatology 2018;67: Fedchuk L, Nascimbeni F, Pais R, et al. Performance and limitations of steatosis biomarkers in patients with nonalcoholic fatty liver disease. Aliment Pharmacol Ther

5 - 유정주외 1 인. 비알코올성지방간염의진단 ;40: European Association for the Study of the Liver, European Association for the Study of Diabetes, European Association for the Study of Obesity. EASL-EASD-EASO clinical practice guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64: Kaswala DH, Lai M, Afdhal NH. Fibrosis assessment in Nonalcoholic Fatty Liver Disease (NAFLD) in Dig Dis Sci 2016;61: Cusi K, Chang Z, Harrison S, et al. Limited value of plasma cytokeratin-18 as a biomarker for NASH and fibrosis in patients with non-alcoholic fatty liver disease. J Hepatol 2014;60: Guha IN, Parkes J, Roderick P, et al. Noninvasive markers of fibrosis in nonalcoholic fatty liver disease: Validating the European Liver Fibrosis Panel and exploring simple markers. Hepatology 2008;47: McPherson S, Anstee QM, Henderson E, Day CP, Burt AD. Are simple noninvasive scoring systems for fibrosis reliable in patients with NAFLD and normal ALT levels? Eur J Gastroenterol Hepatol 2013;25: Wong VW, Vergniol J, Wong GL, et al. Diagnosis of fibrosis and cirrhosis using liver stiffness measurement in nonalcoholic fatty liver disease. Hepatology 2010;51: Castéra L, Foucher J, Bernard PH, et al. Pitfalls of liver stiffness measurement: a 5-year prospective study of 13,369 examinations. Hepatology 2010;51: Wong VW, Vergniol J, Wong GL, et al. Liver stiffness measurement using XL probe in patients with nonalcoholic fatty liver disease. Am J Gastroenterol 2012;107: McPherson S, Hardy T, Dufour JF, et al. Age as a confounding factor for the accurate non-invasive diagnosis of advanced NAFLD fibrosis. Am J Gastroenterol 2017;112: Yang JD, Abdelmalek MF, Pang H, et al. Gender and menopause impact severity of fibrosis among patients with nonalcoholic steatohepatitis. Hepatology 2014;59: Williams CD, Stengel J, Asike MI, et al. Prevalence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis among a largely middle-aged population utilizing ultrasound and liver biopsy: a prospective study. Gastroenterology 2011;140: Neuschwander-Tetri BA, Clark JM, Bass NM, et al. Clinical, laboratory and histological associations in adults with nonalcoholic fatty liver disease. Hepatology 2010;52: Ekstedt M, Franzén LE, Mathiesen UL, et al. Long-term follow-up of patients with NAFLD and elevated liver enzymes. Hepatology 2006;44:

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<30382EC0C7C7D0B0ADC1C22E687770> 대한내과학회지: 제 76 권 제 2 호 2009 의학강좌-개원의를 위한 모범처방(Current Clinical Practice) 간기능검사의 이해와 적용 인제대학교 의과대학 일산백병원 내과학교실 김 경 아 Understanding and application of liver function tests Kyung-Ah Kim, M.D. Department of