Focused Issue J Korean Diabetes 2017;18: Vol.18, No.2, 2017 ISSN 임상및생화학적지표에기반한비알코올성지방간의진단 이

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1 J Korean Diabetes 2017;18: Vol.18, No.2, 2017 ISSN 임상및생화학적지표에기반한비알코올성지방간의진단 이용호연세대학교의과대학내과학교실 Diagnosis of Non-Alcoholic Fatty Liver Disease Based on Clinical and Laboratory Data Yong-ho Lee Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea Abstract Non-alcoholic fatty liver disease (NAFLD) is one of the most common metabolic liver disorders, and its incidence is expected to increase rapidly in the future as the rate of obesity increases and populations age. The gold standard for diagnosing NAFLD is liver biopsy, which involves sample error, high cost, and can be complicated due to its invasive nature. Therefore, many studies have been reported to establish accurate and convenient models to detect NAFLD using clinical and laboratory parameters. Most were derived from relatively small number of subjects and lack external validation, especially in the Korean population. This article summarizes the established and emerging risk factors for NAFLD and reviews non-invasive diagnostic algorithms for NAFLD including hepatic fibrosis. Keywords: Diagnosis, Liver cirrhosis, Non-alcoholic fatty liver disease 서론 비알코올성지방간질환 (non-alcoholic fatty liver disease, NAFLD) 은과량의알코올이나지방간을유발하는약물의복용력이없음에도간내지방이 5% 이상축적되는질환이다 [1]. NAFLD는염증이나섬유화반응이없 Corresponding author: Yong-ho Lee Department of Internal Medicine, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea, Received: May 4, 2017; Accepted: May 16, 2017 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Copyright c 2017 Korean Diabetes Association 102 The Journal of Korean Diabetes

2 이용호 는단순지방간 (simple steatosis), 비알코올지방간염 (nonalcoholic steatohepatitis, NASH), 비알코올지방간연관간경변증으로진행되는간질환을포괄하며, 지방간염및섬유화의진행정도가질환의예후에큰영향을주기때문에이러한병의진행을판단하기위한가장좋은방법 (gold standard) 은간생검이다. 하지만, 간생검은침습적이며, 국소적평가에의한표본오차의한계, 고비용등의단점을가지고있어다양한혈액학적바이오마커및영상학적도구를이용하여비침습적인방법으로진단율을높이려는노력이많아지고있다. 본글에서는 NAFLD에대한위험인자와혈액검사및임상데이터에기반한 NAFLD의진단접근법에대하여정리해보았다. 본론 1. NAFLD의위험인자비만과인슐린저항성이 NAFLD를유발하는기전은많은연구를통해입증되었다 [2]. 2012년미국간학회와 2013 년대한간학회가이드라인에서는입증된 NAFLD 의위험인자로비만, 제2형당뇨병, 이상지질혈증, 대사증후군을, 가능성이있는인자로갑상선기능저하증, 다낭성난소증후군, 수면무호흡증을제시하고있다 [3,4]. 국내연구를통해 NAFLD의유병률은비비만인구집단에서 10~15% 이지만, 비만인구에서는 55~70% 로추정된다고보고하였고 [5], 제2 형당뇨병환자에서는 70% 까지지방간이동반되어있고발표한연구도있다 [6]. 그외뇌하수체기능저하증, 생식선기능저하증등의내분비질환도가능성있는지방간의위험인자로언급하였다. 비만한사람은비만으로인해나타나는여러가지대사적이상 ( 이상지질혈증, 고혈압, 인슐린저항성등 ) 을동반하고있는경우가흔하며, 대사적으로건강한비만한사람 (metabolically healthy obese) 도상당수를차지한다. 대사적으로건강한비만한사람은심혈관계질환의위험성이낮다고알려져있지만, NAFLD에있어서는비만으로인한대사적이상뿐만아니라대사적으 로건강하더라도비만자체가지방간의발생의위험인자임이최근밝혀졌다 [7]. 최근에는사지의근육량이적은근감소증환자에서 NAFLD 또는지방간염의위험성이유의하게높다고여러연구에서보고되고있으며 [5,8,9], 사지의피하지방량이많을수록지방간의위험도는낮다는보고가있어 [10], body mass index (BMI) 자체보다는근육과지방의상대적분포가지방간의발생에더중요할것으로추정된다. B형간염환자에서는 NAFLD가적게발생한다는연구결과도있지만 [11], 더많은연구를통한검증이필요한상황이다. 제2형당뇨병환자에서의 NAFLD에대한대규모전향적연구는홍콩에서 1,918명을대상으로간섬유화스캔 (transient elastrography, fibroscan) 이라는영상장비를이용하여지방간을진단한코호트연구가있다 [12]. 연령이나당뇨병유병기간과지방간유무간의유의한관련성은없었으나, 여성, BMI, 중성지방, 공복혈당, alanine aminotransferase (ALT) 수치와양의통계적유의성을나타내었다. 또한, 간내섬유화의정도와유의한관련성이있었던변수는당뇨병유병기간, BMI, 낮은 high density lipoprotein (HDL), 높은 ALT, 알부민뇨로나타났다. 제2 형당뇨병환자에서 NAFLD의위험인자에대한연구결과는많지않아향후연구가더필요할것으로생각된다. 2. NAFLD 진단모델 : steatosis 현재까지비알코올지방간질환에대한확립된선별검사법은없다. aspartate aminotransferase (AST), ALT와같은간기능검사는 NAFLD 환자에서정상인경우가흔하기때문에선별검사로는민감도가떨어진다. 2016년발표된유럽간학회의가이드라인에서는 NAFLD 가의심되는환자에서당뇨병, 고혈압, 심혈관질환의과거병력및가족력, BMI, 허리둘레, AST, ALT, γ-glutamyl-transferase (GGT), 공복혈당, HbA1c, 공복인슐린, 경구당부하검사 ( 고위험군에서 ), 콜레스테롤 (total HDL), 중성지방, 요산, 전혈구검사 (complete blood count) 등의검사를시행할것을권고하고있다 [1]

3 비알코올성지방간의임상 / 생화학적진단 NAFLD 진단모델로서지금까지가장많이검증되고보 고된비침습적, 비영상학적방법은 fatty liver index (FLI), SteatoTest, NAFLD liver fat score로일반인구에서타연구자들에의해검증이된바있다. 1) Fatty liver index FLI 는지방간진단모델로서쉽게이용할수있다는장 점이있어, 현재까지많은역학연구에서사용되고있다. 이탈리아인을대상으로초음파를이용하여지방간을진단한 496명코호트에서 BMI, 허리둘레, triglycerides, GGT 4 가지변수를이용하여계산되며, 0~100 사이의점수로환산하여 30과 60이라는두개의 cut-off를가지고있다 [13]. 한국인을대상으로한연구에서도 AUROC (area under receiver operating characteristic curve) 0.86으로비교적높은수치를나타내었지만다른연구에서충분한검증이되어있지않으며, 한국인에적용가능한 cut-off는서양인에서제시된 30과 60이아닌수치가조정이되어야한다는한계점이있다 [14]. FLI = 1 / (1 + exp( x)) 100, x = log e (triglycerides) BMI log e (γ-glutamyl-transferase) (Waist circumference) ) NAFLD liver fat score NAFLD liver fat score는 magnetic resonance spectroscopy로지방간을진단한핀란드환자 470명을대상으로확립된모델로, 대사증후군또는제2형당뇨병의유무, 공복인슐린, AST, ALT 수치를이용하였다 [16]. 비교적많은연구에서이용된진단법이며, 한국인을대상으로검증한연구에서 AUROC 0.77~0.82로비교적높은수치를나타내었지만 [14], 다른연구를통한충분한검증이필요하다. NAFLD liver fat score = metabolic syndrome (yes = 1 / no = 0) diabetes (yes = 2 / no = 0) (fasting insulin, mu/l) AST AST/ALT ratio 4) Hepatic steatosis index (HSI) 건강검진을통해초음파로진단된한국인 10,724 명을대 상으로개발된지방간진단법으로 ALT, AST, BMI, 성별, 당뇨병유무라는변수로비교적간단하게구성되어있다 [17]. FLI처럼 30과 36이라는두개의 cut-off를가지고있어 intermediate 구간에대한판단이쉽지않다는제한점이있지만, 다른한국인을대상으로한검증연구에서도 AUROC 0.85로비교적높은수치를보였다 [14]. HSI = 8 ALT / AST ratio + BMI (+2, if diabetes; +2, if female) 2) SteatoTest SteatoTest는 884명이상의프랑스환자코호트에서간생검으로진단된중등증 ~ 중증의지방간에대해 α2-macroglobulin, haptoglobin, apolipoprotein A1, total bilirubin, GGT, 공복혈당, triglycerides, cholesterol, ALT, 나이, 성별, BMI라는열두가지변수를이용한미공개수식으로, 지방간을진단하는모델이다 [15]. NAFLD뿐만아니라, C형간염, 알코올성지방간환자를포함하여모형이구축되었다는특징을가지고있으며, 프랑스코호트에서만검증되었으며, 수식이공개되어있지않아일반적으로사용하기어렵다는제한점이있다. 5) Comprehensive/simple NAFLD score 건강검진에서초음파로진단된한국인 15,676명을대상으로개발되어독립된검진코호트 66,868명에서검증된지방간예측모델이며, 임상변수로구성된 simple score와임상및생화학적변수로구성된 comprehensive score로구분되어있다 [14]. Simple 모델 (SNS) 은나이, BMI, 허리둘레, 당뇨병및이상지혈증의유무, 음주, 운동, 폐경변수로구성되어혈액검사수치없이쉽게적용가능하다는장점이있다 (Table 1). Comprehensive 모델 (CNS) 은나이, BMI, 허리둘레, 당뇨병유무, 음주, 운동, 폐경이외에공복혈당, triglyceride, HDL-cholesterol, uric acid, AST, ALT 수치 104

4 이용호 가추가되었다. 두모델모두 AUROC 0.8~0.9로비교적높은수치를보였지만, 다른연구를통한검증이필요하다. Comprehensive NAFLD score (CNS) NAFLD = 1 / (1 + exp( x)) 100 if male, x = age BMI WC alcohol exercise fasting glucose log e (triglycerides) HDL cholesterol uric acid log e (AST) log e (ALT) if female, x = BMI WC diabetes fasting glucose log e (triglycerides) HDL cholesterol uric acid log e (AST) log e (ALT) menopause ) Framingham Steatosis Index (FSI) 심혈관질환관련유명코호트인 Framingham 대상자 1,181명에서복부 computed tomography를이용하여지방간을진단하였으며, 나이, 성별, BMI, 고혈압, 당뇨병, triglycerides, ALT/AST 변수를포함하는모델을개발하였다 [18]. 독립된미국국민건강영양조사코호트를이용하여검증하였을때 AUROC 0.76으로비교적높은수치를보였지만, 다른연구나한국인을대상으로한검증이필요하다. FSI = age (years) sex (female = 1, male = 0) BMI (kg/m 2 ) triglycerides (mg/dl) hypertension (yes = 1, no = 0) diabetes (yes = 1, no = 0) ALT : AST ratio 1.33 (yes = 1, no = 0). Table 1. A simple NAFLD score (SNS) Variable Score assigned M F Age (y) < Waist circumference (cm) < 80 (M), 75 (F) ~90 (M), 75~85 (F) ~100 (M), 85~95 (F) (M), 95 (F) 4 3 Body mass index (kg/m 2 ) < ~ ~ Diabetes 2 Dyslipidemia 2 Alcohol consumption 1 0 No regular exercise (physically inactive) 1 1 Menopause 0 1 Total score If the score is 8, you are at high risk for NAFLD NAFLD, non-alcoholic fatty liver disease; M, male; F, female. Adapted from the article of Lee et al. (PLoS One 2014;9:e107584) [14]

5 비알코올성지방간의임상 / 생화학적진단 3. NAFLD 진단모델 : steatohepatitis/nash 결론 간생검이아닌임상적, 생화학적, 영상학적방법을이용하 여단순지방간과지방간염을구별하기는매우어렵다 [1]. 현재까지잘알려진마커는세포의자가사멸이나파괴될때생성되는 cytokeratin-18 (CK-18) 분절 (fragment) 이있지만 [19], 정확도에대한논란이있는실정이다. 그외여러가지생화학적지표들을종합하여만들어진, NASH Test R (Biopredictive, Paris, France), NASH diagnostics 등많은진단예측모델이개발되었지만, 아직까지지방간염을진단하는데이러한비침습적검사법이인정되고있지는않다 [1,4]. 4. NAFLD 진단모델 : fibrosis 간섬유화를예측하기위한임상 / 생화학적변수를이용한모델은중등도이하의경미한섬유화에대한정확도는낮지만, 진행된섬유화에대해서는높은정확도를보이고있다. 많은모델중에서 NAFLD fibrosis score (NFS) [20] 과 fibrosis 4 calculator (FIB-4) [21] 는다양한인종의 NAFLD에서검증되었으며비교적정확도가높은방법이다. 이들모델은진행된섬유화에대한검증뿐만아니라, 전체 / 심혈관 / 간관련사망과밀접한연관된다는역학연구결과도다수보고된바있다. NFS 모델은나이, 공복혈당, BMI, platelet, albumin, AST/ALT로구성되어있으며, FIB-4 모델은나이, platelet, AST, ALT로이루어져비교적간단하게계산이가능하다. 그외, enhanced liver fibrosis (ELF), BARD, APRI (AST to Platelet Ratio Index) 등많은점수화된공식이발표되었지만, 충분한검증이더필요한상황이다. NAFLD fibrosis score (NFS) = ( age (years) BMI (kg/m 2 ) IFG / diabetes (yes = 1, no = 0) AST / ALT ratio platelet count ( 10 9 / l) 0.66 albumin [g/dl]) FIB 4 = age (years) AST [U/L] / (platelets [10 9 / l] (ALT [U/L]) 1/2 ) 전세계적으로뿐만아니라국내에서도비만및고령화사회가진행되면서, NAFLD 환자들은점차적으로증가하고있지만, 현재까지지방간진단을위한명확한방법이확립되어있지않은실정이다. 간생검이나영상학적인방법을이용하지않고임상및생화학적지표를기반으로진단하고자하는노력이많이이루어져왔다. 본종설에서다양한지방간진단모델을제시하고있지만, 각모델이개발된환자군의특성에큰차이가있고, 독립된다른환자군이나한국인을대상으로충분한검증이이루어지지않았기때문에적용하는데에있어신중함이요구된다. 유럽간학회가이드라인에서는진행된섬유화를예측하기위한목적으로이러한점수화된모델을이용할수있다언급하고있지만, 그외의경우에사용하기위해서는좀더많은연구가필요할것이다. REFERENCES 1. European Association for the Study of the Liver (EASL); European Association for the Study of Diabetes (EASD); European Association for the Study of Obesity (EASO). EASL-EASD-EASO Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. J Hepatol 2016;64: Yoon HJ, Lee YH, Cha BS. [Causal relationship of nonalcoholic fatty liver disease with obesity and insulin resistance]. J Korean Diabetes 2014;15: Korean. 3. Korean Association for the Study of the Liver (KASL). KASL clinical practice guidelines: management of nonalcoholic fatty liver disease. Clin Mol Hepatol 2013;19: Chalasani N, Younossi Z, Lavine JE, Diehl AM, Brunt EM, Cusi K, Charlton M, Sanyal AJ. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of 106

6 이용호 Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012;55: Lee YH, Jung KS, Kim SU, Yoon HJ, Yun YJ, Lee BW, Kang ES, Han KH, Lee HC, Cha BS. Sarcopaenia is associated with NAFLD independently of obesity and insulin resistance: Nationwide surveys (KNHANES ). J Hepatol 2015;63: Kim SK, Choi YJ, Huh BW, Park SW, Lee EJ, Cho YW, Huh KB. Nonalcoholic fatty liver disease is associated with increased carotid intima-media thickness only in type 2 diabetic subjects with insulin resistance. J Clin Endocrinol Metab 2014;99: Chang Y, Jung HS, Cho J, Zhang Y, Yun KE, Lazo M, Pastor-Barriuso R, Ahn J, Kim CW, Rampal S, Cainzos- Achirica M, Zhao D, Chung EC, Shin H, Guallar E, Ryu S. Metabolically healthy obesity and the development of nonalcoholic fatty liver disease. Am J Gastroenterol 2016;111: Hong HC, Hwang SY, Choi HY, Yoo HJ, Seo JA, Kim SG, Kim NH, Baik SH, Choi DS, Choi KM. Relationship between sarcopenia and nonalcoholic fatty liver disease: the Korean Sarcopenic Obesity Study. Hepatology 2014;59: Lee YH, Kim SU, Song K, Park JY, Kim DY, Ahn SH, Lee BW, Kang ES, Cha BS, Han KH. Sarcopenia is associated with significant liver fibrosis independently of obesity and insulin resistance in nonalcoholic fatty liver disease: nationwide surveys (KNHANES ). Hepatology 2016;63: Subramanian V, Johnston RD, Kaye P, Aithal GP. Regional anthropometric measures associated with the severity of liver injury in patients with non-alcoholic fatty liver disease. Aliment Pharmacol Ther 2013;37: Joo EJ, Chang Y, Yeom JS, Ryu S. Hepatitis B virus infection and decreased risk of nonalcoholic fatty liver disease: a cohort study. Hepatology 2017;65: Kwok R, Choi KC, Wong GL, Zhang Y, Chan HL, Luk AO, Shu SS, Chan AW, Yeung MW, Chan JC, Kong AP, Wong VW. Screening diabetic patients for non-alcoholic fatty liver disease with controlled attenuation parameter and liver stiffness measurements: a prospective cohort study. Gut 2016;65: Bedogni G, Bellentani S, Miglioli L, Masutti F, Passalacqua M, Castiglione A, Tiribelli C. The Fatty Liver Index: a simple and accurate predictor of hepatic steatosis in the general population. BMC Gastroenterol 2006;6: Lee YH, Bang H, Park YM, Bae JC, Lee BW, Kang ES, Cha BS, Lee HC, Balkau B, Lee WY, Kim DJ. Nonlaboratory-based self-assessment screening score for non-alcoholic fatty liver disease: development, validation and comparison with other scores. PLoS One 2014;9:e Poynard T, Ratziu V, Naveau S, Thabut D, Charlotte F, Messous D, Capron D, Abella A, Massard J, Ngo Y, Munteanu M, Mercadier A, Manns M, Albrecht J. The diagnostic value of biomarkers (SteatoTest) for the prediction of liver steatosis. Comp Hepatol 2005;4: Kotronen A, Peltonen M, Hakkarainen A, Sevastianova K, Bergholm R, Johansson LM, Lundbom N, Rissanen A, Ridderstråle M, Groop L, Orho-Melander M, Yki- Järvinen H. Prediction of non-alcoholic fatty liver disease and liver fat using metabolic and genetic factors. Gastroenterology 2009;137: Lee JH, Kim D, Kim HJ, Lee CH, Yang JI, Kim W, Kim YJ, Yoon JH, Cho SH, Sung MW, Lee HS. Hepatic steatosis index: a simple screening tool reflecting nonalcoholic fatty liver disease. Dig Liver Dis 2010;42: Long MT, Pedley A, Colantonio LD, Massaro JM, Hoffmann U, Muntner P, Fox CS. Development and 107

7 비알코올성지방간의임상 / 생화학적진단 validation of the framingham steatosis index to identify persons with hepatic steatosis. Clin Gastroenterol Hepatol 2016;14: e Feldstein AE, Wieckowska A, Lopez AR, Liu YC, Zein NN, McCullough AJ. Cytokeratin-18 fragment levels as noninvasive biomarkers for nonalcoholic steatohepatitis: a multicenter validation study. Hepatology 2009;50: Angulo P, Hui JM, Marchesini G, Bugianesi E, George J, Farrell GC, Enders F, Saksena S, Burt AD, Bida JP, Lindor K, Sanderson SO, Lenzi M, Adams LA, Kench J, Therneau TM, Day CP. The NAFLD fibrosis score: a noninvasive system that identifies liver fibrosis in patients with NAFLD. Hepatology 2007;45: Vallet-Pichard A, Mallet V, Nalpas B, Verkarre V, Nalpas A, Dhalluin-Venier V, Fontaine H, Pol S. FIB-4: an inexpensive and accurate marker of fibrosis in HCV infection. comparison with liver biopsy and fibrotest. Hepatology 2007;46:

05. Roadmap to final diagnosis.hwp

05. Roadmap to final diagnosis.hwp 대한내과학회지 : 제 93 권제 1 호 2018 https://doi.org/10.3904/kjm.2018.93.1.33 Roadmap to diagnosis 비알코올성지방간염의진단 순천향대학교의과대학부천병원내과 유정주 김상균 Diagnostic Approach to Nonalcoholic Steatohepatitis Jeong-Ju Yoo and Sang