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 Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea Nonalcoholic fatty liver disease (NAFLD) is composed of nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH) and NASH related cirrhosis and these are defined by histological findings. These diseases have absolutely typical and different clinical findings and natural courses respectively. NAFL generally has benign process however; NASH and NASH related cirrhosis have an increased risk for liver-related morbidity and mortality. So, the accurate diagnosis and differentiation of steatohepatitis or advanced fibrosis are essential in the management of patient and the prediction of prognosis. The gold-standard of diagnosis of NAFLD is liver biopsy however; it has some limitations in clinical practice. So many studies have been done to find out noninvasive diagnostic methods. These methods can be divided into 2 groups: those that predict the presence of NASH and that predict the presence of advanced fibrosis. This paper provides an overview of various noninvasive methods for detecting NAFLD and their clinical meanings in clinical practice. (Korean J Med 2014;86:405-415) Keywords: Nonalcoholic fatty liver disease; Nonalcoholic steatohepatitis; hepatic fibrosis; Liver biopsy; Noninvasive diagnosis 서론비알코올지방간질환은유의한알코올섭취, 지방간을초래하는약물의복용, 동반된다른원인에의한간질환등이없으면서영상의학검사나조직검사에서간내지방침착의소견을보이는질환이다. 비알코올지방간질환의유병률에대한연구는아직까지제한적이며 [1-6] 국내의경우도전향적코호트연구자료가부족하지만, 건강검진수진자를대상으로초음파검사를이용하여진단한비알코올지방간질환의유병률은 16-33% 로보고되고있다 [7-9]. 비알코올지방간질환은비알코올지방간, 비알코올지방간염과비알코올지방간연관간경변증을포괄하는진단명이며, 이는병리학적인소견을기초로한분류로써상기각질환은임상적특성과의미또한매우다르다. 비알코올지방간염은비알코올지방간에비해서간경변증발생률이높고 (3% vs. 21-28%), 간경변증에따른합병증, 간부전, 간암등으로진행위험또한높다 [10-12]. 특히, 최근메타분석에따르면비알코올지방간염은비알코올지방간에비해서간관련사망발생의위험도가 5.7배높으며, F3 이상의진행된간섬유화가동반되어있는경우사망발생위험도는 10배 Correspondence to Moon Young Kim, M.D., Ph.D. Department of Internal Medicine, Yonsei University Wonju College of Medicine, 20 Ilsan-ro, Wonju 220-701, Korea Tel: +82-33-741-1229, Fax: +82-33-745-1228, E-mail: drkimmy@yonsei.ac.kr Copyright c 2014 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution - 405 - Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
- The Korean Journal of Medicine: Vol. 86, No. 4, 2014 - 정도높은것으로알려져있다 [13]. 따라서비알코올지방간질환내에서상기질환들을감별해내는것은환자의치료계획수립과예후예측에있어서매우중요하다할수있다. 상기질환의분류가병리학적소견을기준으로한만큼이들질환의진단및감별또한간조직검사가가장유용하다. 그러나비알코올지방간질환이빠르게증가하고있는현실에서간조직검사를실제임상에서광범위하게적용하기에는한계가있다. 특히, 간조직검사는간전체의 1/50,000의조직만으로진단하는것이기에이작은조직이간전체를대변할수있는가하는문제가있고, 침습적이어서합병증및그로인한사망발생 (1/10,000) 의위험이있다 [14,15]. 더욱이질환에대한치료가진행됨에따라그반응평가를위해서현실적으로조직검사를반복적으로쉽게진행할수없다는제한점이있다 [15-17]. 따라서임상현장에서간조직검사를대신하여비침습적이고쉽게이용할수있는진단방법이필요하며이들의개발을위해많은연구가진행되어왔다. 본문에서는비알코올지방간질환의선별과비알코올지방간염과 F3 이상의진행된간섬유화의진단을중심으로현재까지제시되어온검사법과이들의임상적의미에대해서살펴보고자한다. 본론비알코올지방간질환의비침습적진단및선별검사병력청취시에비알코올지방간질환과알코올지방간질환을구별하는유의한알코올섭취량의상한선은일일 10-40 g ( 순수알코올량 ) 으로연구마다다양하게정의되어사용되었기때문에명확한기준을제시하기어렵다. 하지만최근미국, 이탈리아및우리나라권고안에따르면 [18-20] 유의한알코올섭취량을최근 2년간남자의경우주당 210 g, 여자의경우주당 140 g을초과하는경우로정의하고있다. 비알코올지방간질환의진단은일반적으로다른원인의간질환을배제하는과정이라고할수있다. 지방침착과더불어임상적으로만성간질환이의심되는경우나간기능검사에서이상소견이발견되는경우, 우리나라에서는만성간질환의중요원인인만성 B형및 C형간염, 알코올간질환은물론, 약물유발간질환, 자가면역간질환, 윌슨병등을배제하기위한병력청취및혈청학적검사를시행해야하며다른원인에의한질환발생가능성을배제해야한다. 간기능검사에서이상소견이발견된경우가아닌경우, 어떤환자들을대상으로비알코올지방간질환유무에대한선별검사를해야할지에대한명확한지침은아직까지없다. 이는나라와인종, 성별및연령에따라다양한위험인자와임상양상을보이기때문으로, 일반적으로비알코올지방간질환발생의중요위험인자로잘알려져있는인슐린저항성과그에따른대사증후군환자들에대한접근에있어서도유럽과미국이서로다른입장을보이고있다. 2009년유럽간학회의에서는인슐린저항성과연관된질환으로내원하는환자는상대적으로비알코올지방간염의동반가능성이높으므로비알코올지방간질환에대한혈액검사및복부초음파검사를권고하였으나 [21] 2012년미국간학회진료가이드라인에서는아직비알코올지방간질환의진단과치료방법이명확히확립되어있지않고선별검사의장기적이익과비용대비효과가밝혀지지않았기때문에권고하지않고있다 [19]. 비알코올지방간질환에대한선별검사로는여러가지방법이시도되고있으나현재까지는확립된선별검사법은없다. 일반적으로 AST, ALT와같은간기능검사와복부초음파검사가많이사용되고있으나간기능검사는비알코올지방간혹은지방간염환자에서정상일수있어민감도가떨어지며, 복부초음파검사는간편하고, 지방의침착을보기위해가장일반적으로이용되고있으나간내지방이간전체의최소 30% 이상의침착을보일때만감별해낼수있는한계가있다. 또한복부초음파만으로는지방간염이나간섬유화를감별해낼수없는제한이있다. 그외혈청 ferritin, 요산검사등이선별검사로연구되고있지만그효용성을평가하기위해서는추가연구가필요하다 [22,23]. 한편, 다른질환에대한검사또는건강검진으로시행한복부영상검사에서우연히지방간질환이발견되는경우, 어떤접근을해야하는가에대해서도아직명확한기준이없다. 간기능검사에서이상소견을보이는경우라면간질환의정확한진단을위하여음주력과약물복용력등을확인하고다른간질환을배제하기위한검사들을시행해야한다. 간기능검사가정상인경우다른동반질환유무를파악하기위한선별검사가필요한지에대해서도명확하지않다. 그러나최근비알코올지방간질환이대사증후군, 제2형당뇨, 관상동맥질환의발생과관련이있다는연구보고들이많고, 이들대사질환들에서는비알코올지방간질환과는달리질 - 406 -
- Moon Young Kim. The diagnosis of nonalcoholic fatty liver disease - 병의진행이나합병증의발생을막는효과적인치료법이존재한다는점등을고려할때영상학적으로우연히간의지방변화가발견된경우대사증후군, 제2형당뇨병및관상동맥질환등에대한검사를고려할수있다 [20,24-26]. 비알코올지방간염및진행된섬유화에대한비침습적검사법비알코올지방간염의비침습적검사 Biomarkers of apoptosis 비알코올지방간염의발생에있어서간세포의세포자살 (apoptosis) 은중요한기전이며 [27], 이과정에서활성화된 caspase 3 등에의한세포내구조물의분해과정에서만들어진혈장 cytokeratin-18 (CK-18) 분절은비알코올지방간염을나타내는대표적인표지자이다 [13,28]. 정상또는비알코올지방간환자와비교했을때혈장 CK-18 분절은지방간염환자에서유의하게증가되어있으며 [29,30], 메타분석에서도유의한결과 ( 민감도 78%, 특이도 87%, Area Under ROC curve (AUROC) 0.82) 를보여 [13] 비알코올지방간염에대한선별검사로서의가능성을보여주었다. 그러나본표지자는아직까지임상현장에서일반적으로이용할수없고진단에대한기준값도보고된개별연구마다달라향후에그기준값에의견일치및그를통한검증연구가필요하다. Markers of oxidative stress 산화스트레스또한간세포의손상과지방간염으로의진행에있어서중요한역할을하는것으로알려져있으나그정확한기전은아직까지알려져있지않다 [31-33]. 여러연구에서산화스트레스에의해생성되는산화산물의측정을통해서비알코올지방간과지방간염의감별에도움이되는표지자를개발하고자하는노력이있어왔으나아직까지진단적으로도움이될만한표지자는제시되지못하고있다 [34]. Markers of inflammation 만성적인염증의동반은비알코올지방간에서지방간염으로의진행에매우중요하며, 이과정에서필연적으로발생하는 tumor necrosis factor-α (TNF-α) 나 interleukin (IL)-6와같은 proinflammatory 싸이토카인들은비알코올지방간에비해서지방간염에서유의하게높다. 그러나이들싸이토카인들을이용해서비알코올지방간염과지방간을감별하기에는그차이가확연하지않아진단에이용하기는어렵다 [35,36]. 그 밖에다른싸이토카인들 (IL-1B, macrophage inflammatory proteins) 과 adipokines (resistin, visfatin, retinol-binding protein 4) 등도비침습적감별진단방법으로연구가되어왔으나연구마다일관된결과를보여주고있지는못하다. 또다른염증관련표지자로혈청 ferritin은소위 acute-phase reactant로서만성적인염증상태에서증가가관찰되며특히비만과관련된당뇨병이나대사증후군등에서증가되어있는것을볼수있다. 최근진행된 Nonalcoholic steatohepatitis clinical research network (NASH CRN) 코호트연구에서정상상한치의 1.5배이상으로증간된 ferritin치는비알코올지방간염과진행된간섬유화를감별함에있어서유의함을보여주었으며향후이와관련된추가적연구가기대된다 [37]. Predictive models 이와같은다양한 biomarker들이발견됨에따라이들과 AST, ALT 를포함한혈액검사결과와신체계측지수 (anthropometric data) 등의조합에의해비알코올지방간염의진행을하는모델의개발연구가많이이루어졌다. 그대표적인것으로최근에 NASH CRN 그룹에서개발한예측모델로 AST, ALT, AST/ALT 비, 나이, 인종, 성별, 민족과고혈압, 제2형당뇨병, 체중질량지수, 허리둘레, 허리 / 엉덩이비율, acanthosis nigricans 등의동반질환을조합으로비알코올지방간염을진단함에 AUROC of 0.79 (95% CI, 0.76-0.83) 의예측력을보여주었고지방간염의대표적인병리학적소견인 ballooning degeneration을예측함에도유사한 AUROC 값을보여주었다. 그러나본예측모델은 AUROC의절대값이상대적으로낮고많은인자들을복잡한식에넣고구해야하기에실제임상적활용가능성은낮아보인다 [38]. 이외에도 10여개에가까운예측모델들이보고되었고이들의상당수는매우높은진단력 (AUROC > 0.80-0.9) 을보여주었지만대부분이다른연구자들에의한전향적인검증결과가없어아직까지널리이용되지는못하고있다 (Table 1) [38-45]. 비알코올지방간연관간섬유화의비침습적검사간섬유화의동반여부와중증도는간경변증및연관된합병증의발생을예측함에있어서가장중요한요소이며특히, 임상적으로의미있는간섬유화 ( F2) 또는진행된간섬유화 ( F3) 를감별해내는것이중요하다 [46]. 이를위해중요한임상적관련인자들인제2형당뇨병, 비만, 45세이상의나이, 증가된 AST/ALT 비, 고혈압및고지혈증등을조합하여 - 407 -
- 대한내과학회지 : 제 86 권제 4 호통권제 644 호 2014 - Table 1. Models for predicting nonalcoholic steatohepatitis Author, [Ref.] Score s name Population Composition Results Palekar NA et al. [44] Poynard T et al. [40] Younossi ZM et al. [42] Tamimi TI et al. [45] Palekar s score 80 NAFLD patients Score calculated by the sum of 6 risk factors: 1. Age 50 yr 2. Female sex 3. Elevated AST ( 45 IU/L), 4. BMI 30 kg/m 2 NASH Test NASH Diagnostic Panel Apoptosis Panel Anty R et al. [41] Nice model 160-training group 97-validation group 383-controls 5. AST/ALT ratio 0.8 6. Plasma levels of hyaluronic acid 55 μg/l Undisclosed formula incorporating: α2-mg, haptoglobin, apolipoprotein A1, total bilirubin, GGT, ALT, AST, triglycerides, cholesterol, age, gender, height, weight 79 patients Undisclosed formula incorporating: diabetes mellitus, sex, BMI, triglycerides, M30 and M53 antigens 95-training group 82-validation group (morbid obese) 464 morbid obese patients Includes: CK18 fragments, soluble Fas and Fas ligand Model = -5.654 + 3.780e-02 ALT (IU/L) + 2.215e-03 CK 18 fragments (IU/L) + 1.825 (metabolic syndrome: yes = 1, no = 0) Logarithmic transformation = 1/[1 + Exp (-Nice Model)] 3 factors: AUROC of 0.763 Se 74%, Sp 66%, PPV 68%, NPV 71% AUROC 0.79 Se 33%, Sp 94%, PPV 66%, NPV 81% AUROC 0.81 2 cut-offs, 0.221 and 0.6183-Se 91%, Sp 92%, PPV 83%, NPV 86% AUROC 0.93 Cut-off-0.5509-Se 88%, Sp 89%, PPV 86%, NPV 91% AUROC 0.83-0.88 Cut-off 0.14-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. 진단모델을개발하고자하는노력 [39,47,48] 과영상의학적기술을이용해서간섬유화를진단해내고자하는노력이진행되어왔다 (Table 2). 생화학적모델혈청학적검사에의한요소들과신체계측상 (anthropometric) 의요소들의조합에의한진단모델은매우다양하게개발, 제시되어왔으나대부분에서진단능력이충분히검증되지않아비교적여러연구를통해서검증이이루어진대표적인진단모델들만을소개한다. AST/ALT ratio AST, ALT 및 AST/ALT 비는가장흔히이루어지는검사로일반적으로비알코올지방간질환에서는 ALT가 AST에비 해높으나 AST/ALT 비가 1을넘는경우에는진행된간섬유화와관련이있고높은음성예측률 (negative predictive value) 을가지고있어진행된간섬유화의배제에유용한것으로알려져있다 [49]. 그러나 AST/ALT 비의높고낮음으로비알코올지방간과지방간염을감별할수는없고치료에따른효과도반영하지못하는한계가있다. 따라서 AST/ALT 비는체질량지수 (body mass index, BMI) 등과함께 BARD score 나 NAFLD fibrosis score (NFS) 와같은더진전된예측모델의한요소로서주로이용되고있다 [50-52]. BARD score 827명의비알코올지방간질환환자를대상으로개발된 BARD score 는체질량지수, AST/ALT 비, 당뇨병동반여부 - 408 -
- 김문영. 비알코올지방간질환의진단 - Table 2. Models for predicting fibrosis in noalcoholic fatty liver disease Author, [Ref.] Model name Population Composition Results Guha IN et al. [59] Ratziu V et al. [56] Angulo P et al. [61] Harrison SA et al. [53] Cales P et al. [62] McPherson S et al. [49] Simplified ELF FibroTest NAFLD Fibrosis Score 196 NAFLD patients ELF = -7.412 - [Ln (hyaluronic acid) 0.681] - [Ln(amino-terminal pro-peptide of type III collagen) 0.755] - [Ln (TIMP-1) 0.494] 170-training group 97-validation group 480-training group 253-validation group Undisclosed formula incorporating: age, α2-macroglobulin, total bilirubin, GGT and apolipoprotein A1-1.675 + 0.037 age (yr) + 0.094 BMI (kg/m 2 ) + 1.13 IFG/diabetes mellitus (yes = 1, no = 0) + 0.99 AST/ALT ratio - 0.013 platelet ( 10 9 /L) - 0.66 albumin (g/dl) BARD 827 NAFLD patients Includes 3 variables: 1. BMI 28 kg/m 2 (1 point), 2. AST/ALT ratio 0.8 (2 points), 3. Diabetes mellitus (1 point) Fibrometer 235 NAFLD patients 0.4184 glucose (mmol/l) + 0.0701 AST (IU/L) + 0.0008 ferritin (mg/l) - 0.0102 platelet (G/L) - 0.0260 ALT (IU/L) + 0.0459 body weight (kg) + 0.0842 age (yr) + 11.6226 FIB-4 145 NAFLD patients age (yr) AST (IU/L)/platelet count (10 9 /L) ALT1/2 (IU/L) AUROC 0.87 for advanced fibrosis, in NASH cut-off -2.3824-Se 91%, Sp 59%, PPV 42%, NPV 95% AUROC 0.75-0.86 for significant fibrosis 2 cut-off: 0.3 and 0.7-Se 77%, Sp 98%, PPV 90%, NPV 73% AUROC 0.84 for advanced fibrosis 2 cut-off: -1.455 and 0.676-Se 82%, Sp 98%, PPV 90%, NPV 93% AUROC 0.81 for advanced fibrosis Score 2-4-PPV 43%, NPV 96% AUROC 0.943 for significant fibrosis 2 cut-off: 0.611 and 0.715-Se 79%, Sp 96%, PPV 88%, NPV 92% AUROC 0.86 for advanced fibrosis cut-off: 1.3-Se 85%, Sp 65%, NPV 95% 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. 의세개의요소로구성되어있으며각항목에점수를부과하여 (BMI 28 = 1점 ; AST/ALT ratio 0.8 = 2점 ; 당뇨병동반 1점 ), 총점수가 2점이넘는경우에는진행된간섬유화의예측에있어서 odds ratio 가 17 (95% CI, 9.2-31.9), AUROC 0.81 로비교적우수한결과를보여주었다 [53]. 그러나이후의다른연구에서 AUROC가 0.70 to 0.77로비교적낮게보고되었고 [49,54] 6개의연구를대상으로분석한최근의메타분석에서도진행된간섬유화에대해 AUROC가 0.78 (0.72-0.84) 로기대보다는낮은예측력을보였다 [13]. FIB4 index FIB4 index는원래만성 C형간염에의한간섬유화를평가하기위해개발된것으로나이, 혈소판수치, ALT 와 AST치로구성되어있다 [55]. 비알코올지방간질환환자에서는기준 값을 1.3으로하였을때, 그이하에서는진행된섬유화를배제할수있는음성예측률이 90-95% 로비교적높게나타났다 [49,54]. Nonalcoholic steatohepatitis clinical research network model NASH CRN 연구는비알코올지방간염에대한다기관연구를목적으로결성된것으로간조직검사결과가함께확인이가능한 1,101명의환자를대상으로한대규모의연구이다. 이연구에서간섬유화및지방간염의예측을위해개발한 NASH CRN 모델은기본적으로 AST, ALT, AST/ALT 비에나이, 인종, 성별, 민족의요소와동반질환 ( 고혈압, 제2형당뇨병, 체질량지수 (BMI), 허리둘레, 허리 / 엉덩이비율, acanthosis nigricans, 그리고기타혈청학적검사치 (alkaline phosphatase, rgt, globulin, albumin, total and direct bilirubin, interna- - 409 -
- The Korean Journal of Medicine: Vol. 86, No. 4, 2014 - tional normalized ratio, hematocrit, white blood cells, platelet count, total cholesterol, triglyercides, HDL cholesterol, LDL cholesterol, HbA1c, HOMA-IR, fasting serum glucose, fasting serum insulin, autoimmune markers [ANA, AMA, ASMA]) 를함께수식에포함하여만들어졌다 [38]. 이모델에따르면진행된간섬유화 ( F3) 를예측함에 AUROC가 0.85 (95% CI, 0.82-0.89), 간경변증 (F4) 에대한예측능력은 AUROC가 0.96 (95% CI, 0.93-0.98) 으로여타의예측모델에비해좋은결과를보고하였고이코호트데이터를이용해서다른예측모델을검증했을때 NASH CRN 모델이가장우수하였다. 그러나본모델은지방간염의예측에있어서는상대적으로기대할만한결과를보여주지못했고그수식이매우복잡하고많은요소를대입해야하는불편으로인해서실제임상에서활용되기에는한계가있다. FibroTest FibroTest는 haptoglobin, α2-macroglobulin, apolipoprotein A1, total bilirubin과 rgt의다섯가지요소로구성되어있다. 본모델은다양한원인질환에따른간섬유화를진단하고평가하는연구들이많이진행되었는데, 비알코올지방간질환중진행된간섬유화를예측함에있어서는 AUROC 0.88 (95% CI, 0.82-0.92) 로비교적좋은결과를보고하였다 [56]. 그러나최근의메타분석에서두개의연구를대상으로분석했을때, F2 이상의유의한간섬유화를예측함에있어서 AUROC가 0.78 (0.72-0.85) 로상대적으로낮게보고되었고 [13] 특히, 본모델은특허가등록되어있어그값을구하는데별도의비용을지불해야하기에실제임상에서이용하기에는제약이있다. NAFLD fibrosis score NFS는생화학적표지자모델중가장많은연구와검증이이루어졌다. 임상적또는생화학적으로쉽게측정되는 6 개의요소 ( 연령, 체질량지수, 당뇨병 / 내당능이상의유무, 혈소판수, 알부민, AST/ALT 비 ) 로구성되어있고웹사이트 (http://nafldscore.com) 를통해서쉽게무료로계산할수있다. NFS는간섬유화의평가에있어두개의기준치 [cut-off value, < -1.455 (low probability) 와 > +0.676 (high probability)] 를갖는다. 13개연구 3,064명의환자를대상으로한메타분석에따르면 [13], NFS 는 F3 이상의진행된간섬유화를진단함에있어서 AUROC 0.85 (95% CI, 0.81-0.90) 의높은값을 보여주었고, < -1.455를기준으로하였을때진행된간섬유화를배제하는데 90% 의민감도와 60% 의특이도를 > +0.676 을기준으로하였을때진행된간섬유화의진단하는데 67% 의민감도와 97% 의특이도를나타냈다. 또한 NFS는비교적쉽고저렴하며여러가지임상조건 ( 인종, BMI 및당뇨여부등 ) 에서검증이이루어졌다는장점이있다. 특히, 서구의환자들에비해체질량지수가상대적으로낮은국내환자를대상으로한연구에서도외국의결과와유사한진단능력을나타냈다 [57]. 그러나약 20-58% 의환자에서는두기준치사이값을보여진행된간섬유화에대한 high 또는 low probability 어느쪽으로도분류되지못하는경우가발생하고 (indeterminate probability) 이러한경우에는간조직검사가필요하다 [13]. 최근에처음 NFS를제안한 Angulo 등이조직검사를통해서진단된비알코올지방간질환 320명을대상으로중간값 104.8개월 (3-317 months) 동안추적한결과에따르면, NFS상 intermediate군과 high probability군으로분류된환자들은 low probability군으로분류된환자군에비해서간질환관련합병증발생위험 (hazard ratio [HR] 7.7 [1.4-42.7], 34.2 [6.5-180.1]) 과사망발생위험 (HR 4.2 [1.3-13.8], 9.8 [2.7-35.3]) 을예측함에있어서 AST/platelet ratio index, FIB-4 score, and BARD score 보다우수한결과를보여주어 [58], 이제까지개발된모델중에서는가장임상적유용성이높아보인다. Enhanced liver fibrosis Enhanced liver fibrosis (ELF) 모델은최근에유럽을중심으로간섬유화평가방법으로연구가진행되고있는것으로, 간섬유화와관련된 3개의기질단백 (hyaluronic acid, tissue inhibitor of metalloproteinase 1, aminoterminal peptide of procollagen III) 으로구성되어있다. 진행된간섬유화에대해서 ELF모델은 AUROC 0.90 (95% CI, 0.84-0.96), 민감도 80%, 특이도 90% 의좋은결과를보였고, ELF 모델과 NFS 모델을결합시켜평가할때, 진행된간섬유화를진단함에있어 AUROC가 0.98로진단의정확도가매우높아짐을보였다 [59]. ELF 모델은비알코올지방간질환외에도여타의다른원인에의한간섬유화의평가에도활발히적용, 연구되고있으며특히, 비알코올지방간질환환자 44명을포함한만성간질환환자의예후예측연구에서간질환관련질병발생및사망을예측함에있어서우수한결과를보여 [60] 향후에후속연구결과가기대되는모델이다. - 410 -
- Moon Young Kim. The diagnosis of nonalcoholic fatty liver disease - 영상의학검사복부초음파검사는간기능검사에서이상을보이는무증상환자들의선별검사에서많이이용되고있으나, 검사가주관적이며간내지방이 30% 미만인경우에는진단의민감도가 70% 미만으로낮고특히비알코올지방간과비알코올지방간염을감별할수없다는한계가있다 [63,64]. 전산화단층촬영 (computed tomography) 은간내지방의양을평가함에있어서특이도는높으나민감도가낮으며 magnetic resonance image (MRI) 는적은양의지방침착을평가함에있어서초음파보다좋은것으로알려졌다 [65-67]. 또한 magnetic resonance spectroscopy (MRS) 의경우에는매우정확하게간내중성지방 (triglyceride) 의양을측정할수있다. 그러나이러한고가의검사들역시비알코올지방간과비알코올지방간염및간섬유화의감별에는크게도움이되지않으며따라서이러한목적으로임상현장에서이용되고있지는않다 [65,68]. Liver stiffness measurement Transient elastography 초음파를이용한간의탄성도측정을통해간섬유화를평가하는간탄성도검사 (transient elastography, TE, Fibroscan ) 의경우비알코올지방간질환환자를대상으로한연구가비교적많이진행되었다 [69-74]. 최근의메타분석에따르면비알코올지방간질환의 F3 이상의진행된간섬유화의예측에있어서 AUROC 0.94 (0.86-0.99), 기준치를 8.7 kpa 로했을때각각 94% 와 95% 의높은민감도와특이도를보여주어이질환의적절한선별검사로서의가능성을보여주고있다. 그러나간탄성도검사는비알코올지방간질환환자에서흔히나타나는비만 ( 체질량지수 30 kg/m 2 ) 이동반된경우에는검사정확성이떨어지고검사자체를할수없는경우도비교적많은한계가있다 (5-13%) [13]. 최근에소개된 Controlled attenuation parameter (CAP) 은지방침착의정도를비교적정확히평가할수있는것으로알려졌으며향후많은임상연구결과가보고될것으로기대된다 [75-77]. Magnetic resonance elastography 최근에개발되어일부에서시도되고있는 magnetic resonance elastography (MRE) 는비알코올지방간의지방량의평가뿐만아니라비알코올지방간염및섬유화감별에도유용하며 [78] 간탄성도검사와달리간전체에대한측정이가능하고, 검사자의존도가없으며비만여부에제한받지않는다는장점 이있어 [79] 미래에가장유용한검사법이될가능성이있다. 그러나이검사법은고비용의문제와모든의료기관에서보편적으로이용할수없다는한계가있다. 간조직검사앞서알아본비침습적검사들이진행된섬유화나지방간염의존재를의심하는데도움은될수있다. 그러나간조직검사는여전히비알코올지방간질환을진단하는데가장확실하고기준이되는진단검사이다. 조직검사는비알코올지방간과지방간염을감별하는것외에도간섬유화의정도를평가할수있고예후예측에도움이되며이를통해향후환자의치료및관리계획을세우는데있어중요한정보를제공하고 [80,81] 만성간염을유발하는다른질환의감별에도도움이될수있다 [82]. 누구를대상으로언제간조직검사를해야하는가에대해서는연구자료가부족하고일치된결론이아직까지없어임상의가주관적으로판단해야하는경우가많다. 간조직검사를통해서질환의진단, 치료방향및예후예측에도움이될대상자만을선정하여시행할필요가있다. 기존의보고에따르면연령, 체질량지수, 당뇨병 / 내당능이상의유무, AST/ALT 비, 혈소판수, 알부민, 인슐린저항성등이지방간염이나진행된섬유화를예견하는인자라고알려져있어 [21,39,47,61] 이러한소견들을보이면서기존의진단적접근으로정확한평가가어려운경우에는간조직검사를고려해볼수있겠다. 특히, 앞서살펴본여러검사법중에서비교적여러연구를통해서그유용성이입증된 NFS, 간탄성도검사등을이용한체계적인접근과그에따른간조직검사필요여부판단이여러전문가들에의해권고되고있다 (Fig. 1). 결론비알코올지방간질환은아직까지질환자체의발생기전과장기적자연경과에대한자료가매우부족하며치료약물도개발되지못한상태이다. 그러나이미서구의만성간질환의주요원인으로자리를잡았고, 국내에서도체계적인연구는아직부족하나매우높은유병률을가질것으로판단되는질환이다. 따라서이에대한명확한진단기준과진단법을갖는것이매우시급하다. 비알코올지방간질환의진단에있어서현재로서는간조직검사를대체할만큼검 - 411 -
- 대한내과학회지 : 제 86 권제 4 호통권제 644 호 2014 - Figure 1. Algorithm for diagnostic process for decision of liver biopsy. To minimize the unnecessary liver biopsy, this algorithm use the most validated methods, NAFLD Fibrosis Score (NFS) and transient elastography (FibroScan ) for the evaluation of fibrosis and CK-18 fragments for the evaluation of NASH. The most significant prognostic factor is the fibrosis severity, hence is the first one to be screened. If NFS suggests advanced fibrosis, it is essential to exclude cirrhosis, which needs special management, and a liver biopsy is recommended. If the NFS suggests low probability for advanced fibrosis, this can be excluded for fibrosis. However, the exclusion of NASH is still important and if CK18 is available we can try it for the next steps. If it suggests NASH, it should be confirmed by liver biopsy, since it will be a false positive in 14% of the patients. In the patients unclassified for NFS, FibroScan can be useful, with the need to confirm cirrhosis with liver biopsy if it suggests advanced fibrosis (modified with Reference 13). 사의신뢰도가입증되고만족할만한결과를보여주는진단방법은없다. 이제까지살펴본비침습적검사법들의일부는좋은결과들을보여주고는있으나대부분이단면연구를통한결과로질환의진행이나치료에따른반응평가에서의유용성은아직까지연구가부족하다. 가능한대안이있다면 NFS나간탄성도검사와같이간단한검사를먼저적용해보고, 여기서진행된간섬유화가강력히의심되거나명확히판단하기어려운경우에간조직검사를하는것이현실적일것이다. 간섬유화가없더라도지방간염의존재는별개의것으로향후에간섬유화로진행될가능성이높기에이에대한예측모델의적용도고려해봐야한다. 그러나무엇보다중요한것은임상현장에서비알코올지방간질환을과거와같이단순한지방간으로간과하지않고본질환이가지고있는의미를다시금생각하고조금더진 지한진단적접근을모색하는것이가장중요한것일것이다. 중심단어 : 비알코올지방간질환 ; 비알코올지방간염 ; 간섬유화 ; 간조직검사 ; 비침습적검사 REFERENCES 1. Hamaguchi M, Kojima T, Takeda N, et al. The metabolic syndrome as a predictor of nonalcoholic fatty liver disease. Ann Intern Med 2005;143:722-728. 2. Suzuki A, Angulo P, Lymp J, et al. Chronological development of elevated aminotransferases in a nonalcoholic population. Hepatology 2005;41:64-71. 3. Lee JY, Kim KM, Lee SG, et al. Prevalence and risk factors of non-alcoholic fatty liver disease in potential living liver donors in Korea: a review of 589 consecutive liver biopsies in a single center. J Hepatol 2007;47:239-244. - 412 -
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