15_2_06_( )_저자교정.indd

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1 Focused Issue - 비알코올성지방간 (Non-alcoholic fatty liver disease, NAFLD) 비알코올성지방간의진단 성균관대학교의과대학삼성서울병원소화기내과곽금연 Diagnosis of Non-alcoholic Fatty Liver Disease Geum-Youn Gwak Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea Abstract 82 Although the classical gold standard for diagnosing and staging non-alcoholic fatty liver disease (NAFLD) and assessing fibrosis is liver biopsy, the procedure has several drawbacks, such as sample error, subjectivity in interpretation, high cost, and a small but real risk of complications.in an attempt to replace liver biopsy and to subcategorize patients with NAFLD into different prognoses, many non-invasive methods using various biomarkers, scoring systems, and imaging methods, such as elastography, have been attempted in the last decade. This article summarizes non-invasive diagnostic tests for the diagnosis of NAFLD/Nonalcoholic steatohepatitis, as well as the limitations and merits of liver biopsy. (J Korean Diabetes 2013;15:82-92) Keywords: Non-alcoholic fatty liver disease, Nonalcoholic steatohepatitis, Diagnosis, Liver biopsy 서론 비알코올성지방간 (Non-alcoholic fatty liver disease, NAFLD) 은지방간염및섬유화정도에따라예후에큰차이를보이기때문에이들환자에서지방간염과섬유화동반여부를확인하는것은임상적으로매우중요하며현재까지이를위한가장좋은방법 (gold standard) 은간생검이다. 그러나간생검은침습적성격으로인한합병증발생의위험성, 표본오류 (sampling error), 고비용등의이유로모든 NAFLD 환자에서시행하기는현실적으로어려우며또한불필요하기도하다. 따라서그간간생검을대체하여비침습적인생화학적, 영상학적방법으로 NAFLD 의조직학적중증도를예측하려는노력이꾸준히경주되어왔다. 비침습적진단법 1. 간지방증 (steatosis) 의진단 생화학적방법 1) Steatotest Steatotest 는 α2-macroglobulin, haptoglobin, apolipoprotein A1, total bilirubin, GGT, fasting glucose, triglycerides, cholesterol, ALT, age, gender, BMI 의열두가지변수를포함한미공개수식으로, 700 명이상의프랑스환자코호트에서중등증 ~ 중증의지방간의진단에대해 AUROC 0.79 라는비교적높은정확도를보였다 [1]. 그러나 93% 라는좋은음성예측도 (negative predictive value, NPV) 에비해양성예측도 (positive predictive value, PPV) 는 63% 에불과하였다. Steatotest 는이후에병적비만환자 288 명을대상으로하는다른프랑스코호트및메타분석에서도유사한결과를보였다 [2,3]. 하지만이방법은 AUROC 가썩만족스럽지못하고, 프랑스코호트에서만검증되었으며, 수식이공개되지않아일반적으로 교신저자 : 곽금연, 서울시강남구일원로 81 성균관대학교의과대학삼성서울병원소화기내과, gy.gwak@samsung.com

2 비알코올성지방간의진단 사용하기어렵다는단점을안고있다. 2) Fatty liver index (FLI) FLI 는 Dionysos Nutrition & Liver Study 에서파생된알고리듬으로 [4] 초음파를표준진단법으로이용하고있다. 이지수는 BMI, 허리둘레, triglycerides, GGT 를이용하여아래와같은방법으로계산되며 0~100 사이의점수로표시된다. 그러나 FLI 는초음파를표준진단법으로이용하였다는단점이있으며주로는값비싼초음파검사를대체하여역학연구에이용되고있다. 최근 2,075 명의중년백인을대상으로 15 년간추적관찰한연구에서 FLI 는전체사망률및심혈관질환과암관련사망과독립적인연관성을보였다 [5]. FLI = (e (triglycerides) BMI (GGT) Log e Log e (waist circumference) ) / (1 + e (triglycerides) Log e BMI (GGT) (waist circumference) Log e ) 100 3) Lipid accumulation product (LAP) LAP 는 FLI 를고안한같은연구자들에의해제안된방법으로성별, 허리둘레와 triglycerides 를이용한방법이다. 이를 log 변환하게되면단위 log 증가시마다간지방증의위험도가 4.28 배씩증가하게된다 [6]. 이방법은매우간단하다는장점이있으나아직다른연구자들에의한검증작업이이루어지지않았다. LAP = (waist circumference - 65) triglycerides if men, (waist circumference - 58) triglycerides if women 4) NAFLD liver fat score NAFLD liver fat score 는 magnetic resonance spectroscopy (MRS) 를표준진단법으로하여만들어진방법으로, 대사증후군의유무, 제 2 형당뇨병의유무, 공복시혈청인슐린, AST, AST/ALT 비를이용하며, 95% 의예민도와특이도를보인다 [7]. NAFLD Liver Fat Score = (metabolic syndrome - yes = 1 / no = 0) (type 2 DM - yes = 1 / no = 0) (fasting serum insulin, mu/l) (AST, IU/L) (AST/ALT) 영상학적방법 1) 초음파 (Ultrasonography, US) US 는간지방증진단을위해임상현장에서사용되기시작한첫영상장비로, 가격이저렴하고장비가널리보급되어있다는장점이있고, 간지방증진단에대한예민도와특이도는각각 60~94% 와 66~97% 이다 [8-10]. 그러나경증의지방증진단에대한정확도는매우낮다. 100 명의생체간이식공여자를대상으로한연구에서조직학적으로간세포내지방함량이 10% 미만인경우 US 는이를감지해낼수없었으며, 간세포내지방함량이 10~19%, 20~29% 인경우각각 55% 와 72% 의환자들을진단해낼수있었다 [11]. US 결과는다분히검사자의주관적판단에의존하기때문에이를보다객관적으로평가하기위한노력이기울여져왔다. 이가운데 hepato-renal index contrast 는 7.0 db 이상일때간지방증의진단에대해각각 91% 와 84% 의예민도와특이도를보였다 [12]. 또다른방법인 ultrasonographic fatty liver indicator (US-FLI) 는다음과같은기준으로산출된다 [13]. a) brighter liver than kidney, whose intensity in contrast can be graded as mild/moderate (2 points) or severe (3 points). b) one extra point for each of the following: i. posterior attenuation of ultrasound beam, ii. vessel blurring, iii. difficult visualization of the gallbladder wall, iv. difficult visualization of the diaphragm, v. areas of focal sparing. 이방법으로 2 점이상이면간지방증의존재를시사하고, 4 점이상이면 NASH 의존재를시사한다. 그러나 US 는간지방증의진단에있어여러한계가있다. 경증의지방증에대해서는 PPV 가 67% 에불과하며 [14], 검사자간에그리고동일한검사자의경우에도지방증의존재와중증도의판정에불일치를보인다 [15]. 그리고병적비만자의경우지방증진단의예민도와특이도는급격히떨어져서각각 50% 와 75% 에미치지못한다 [16]. 또한, 간섬유증, 괴사, 부종, 그리고간외지방조직에의해측정상의오차가발생할수있다. 2) 전산화단층촬영 (Computed tomography, CT) CT 는간지방증진단에있어서 US 와비슷한정확성을보인다 [17]. 간지방증은조영증강을하지않은 CT 에서간실질감쇠현상으로진단된다 [18]. CT 에서간지방증을진단하는방법은간실질의감쇠, 간 - 비장감쇠차이및비율이며이들모두특이도는 100% 에달하지만예민도는낮다 [19]. 하지만간지방증의진단에있어서 CT 는방사능노출의부담, 다른미만성간질환의 83

3 Focussed Issue - 비알코올성지방간 (Non-alcoholic fatty liver disease, NAFLD) 84 존재가간지방증으로오인될가능성, 간내철함유량에의한간실질의감쇠효과변화, 감쇠치가스캐너의존적이며기계제조업체간에표준화가되어있지않다는등의한계점으로인해임상적이용이매우제한적이다. 3) 자기공명영상 (Magnetic resonance imaging, MRI) MRI 는경도의간지방증진단에있어 US 보다우수하며 3% 의간지방증까지감지할수있다 [20]. MRI 는물과지방의양성자신호의공진주파수차이를이용하여지방의비율을정량화한다 [14]. 최근에는간세포의중성지방에존재하는 acyl- 기로부터의양성자신호를직접측정하는 MRS 가간지방증을놀랍도록정확하게진단하고정량화한다. 간생검을통한지방증과의상관관계를보면, AUROC , 예민도 92~100%, 특이도 92~97% 이다 [21]. 하지만이두방법간의진단적불일치는오히려간생검의한계때문일수있다. MRS 는생검조직보다훨씬더큰부피의간을평가하기때문에표본오차가적다. 그리고 MRS 는간실질내의중성지방을감지하는데비해간생검은지방소포을함유하고있는간세포의수를정량화하는것이기때문에두방법은측정대상이다르다. 아울러 MRS 는조직학적으로확인가능한거대소포를만들기에는부족한소량의중성지방도민감하게진단해내기때문에오히려생검결과보다더정밀하다 [17]. 하지만 MRS 가향후간지방증의진단에있어서간생검을대체하는표준진단법으로자리잡기에는염증괴사반응과섬유화를진단할수없으며, 비용이막대하고장비의보급성이낮다는단점이있다. 4) 제어감쇠매개변수 (Controlled attenuation parameter, CAP) CAP 는지방이초음파의전파에영향을끼치는원리를이용하여 transient elastography probe (Fibroscan R ) 에서얻어지는신호를간지방증의진단에접목한방법이다. 그결과는 100~400 db/m 로표현된다. Sasso 등은 CAP 를이용하여 115 명의환자들을후향적으로분석한결과 10% 와 33% 이상의간지방증의진단에대해 AUROC 를각각 0.91 과 0.95 로우수하게보고하였다 [22]. 또한 CAP 치는간섬유화에의해영향을받지않았다. CAP 검사는방사선노출이없고, 시행이간편하며, 주관적해석이아니기때문에검사자의존적이지않다는장점이있으며간생검에비해 100 배이상의조직을평가하기때문에표본오차가적다. 하지만비만한사람에서는측정에실패할수있다. 2. 비알코올성지방간염 (Non-alcoholic steatohepatitis, NASH) 의진단 Aminotransferase 치는 AUROC 0.6~0.7 정도로 NASH 진단에정확도가매우낮다 [23-25]. 기준치를 19 IU/L 로낮추면예민도는 70% 까지올릴수있으나특이도가현격히떨어진다 [26,27]. 따라서간지방증이있고 aminotransferase 치가상승되어있는경우 NASH 의위험도가높아지기는하나 aminotransferase 치가정상이라고하여 NASH 를배제할수있는것은아니다 [28]. Alkhouri 등은호중구 : 림프구비율이 NASH 의예측에도움이된다고하였는데단위 unit 증가시 NASH 의확률이 70% 씩상승하였다 [29]. US 를이용하여 NASH 를진단하는방법들은대부분 AUROC 0.8 이하의정확도를보여주었다. US-FLI 점수는 94% 의 NPV 로 NASH 를배제할수있었다 [13]. 비장의장경 116 mm 를기준으로하였을때 NASH 진단에대한 AUROC 는 0.920, 예민도 88%, 특이도 95% 로보고되었다 [30]. 이외에도 CT 상체표면적으로보정한비장직경 [31], 조영제증강초음파 [32] 등이 NASH 진단에시도되어왔으나아직까지영상진단법은 NASH 의진단에는정확도가떨어진다. 여러혈청표지자들을이용한시도들도활발하게이루어지고있다. Adiponectin[33-36], tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6)[34,35,37-40], CC-chemokine ligand-2 (CCL2)[41,42] 와같은사이토카인에대한연구결과들이보고되었으나아직임상에서의가치는입증되지못하였다. 급성기단백질중 highly sensitive C-reactive protein (CRP)[42-45] 과 pentraxin-3[46] 역시만족스러운결과를얻지못하였다. 산화스트레스는 NASH 의병인에관여하고있으며간내지질과산화가증명되기는하였으나 [47] 혈장산화스트레스표지자농도는간내농도와상관관계가없었다. Keratin 18 (CK18) 분획은간세포사멸의표지자로유일하게 10 개이상의연구와 1,000 명이상의지방간환자에서검증된표지자로단일표지자로서는간지방증과 NASH 를구분하는가장좋은표지자이다 [23,48]. 한메타분석은 AUROC 0.82, 예민도 78%, 특이도 86% 로보고하였다 [48]. 세포괴사의표지자인총 CK18 또한 NASH 진단에있어서 CK18 분획만큼의높은정확도를보였다. 이외에도 homocysteine[49], serum prolidase enzyme activity (SPEA)[26], soluble receptor for advanced glycation end products (SRAGE)[50] 등도연구중이다.

4 비알코올성지방간의진단 NASH 의진단을위해다소복잡한모델이고안되기도하였다. Dixon 등은 HAIR score (hypertension, ALT 증가, insulin resistance) 를제안하였으며이는 NASH 의진단에정확도가높았으나병적비만자들을대상으로하였고아직외부검증절차가이루어지지않았다 [51]. Palekar 등은나이, 성별, 비만, hyaluronic acid, AST 및 AST/ALT 비의조합을이용한 Palekar s score 를제안한바있다 [52]. SteatoTest 를만든 Poynard 등은 13 개의매개변수를이용하여공개되지않은수식인 NashTest 를발표하였으며이는특이도가 94% 에이르렀으나예민도는 33% 에불과하였다 [53]. 이외에도 NASH Diagnostics (Undisclosed formula: cleaved/total CK18 (M30 and M65 antigens), adiponectin, resistin)[54], Apoptosis Panel (CK18 fragments, soluble Fas, Fas ligand)[55], Nice 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)])[56] 등이소개되었다. 이외에카페인이경구생체이용률이높고거의독점적으로시토크롬 P4501A2 에의해대사가이루어진다는점을이용하여 C- 카페인호기검사를간기능평가의비침습적도구로이용하기도하였는데이검사법은 NASH 와섬유화진단에대한정확도가우수하였다 [57,58]. 마지막으로, 99m Tc-phytate 와 99m Tc-HIBI 를이용한간신티그래피도 NASH 의진단에시도된바있는데, 전자는간 / 비장섭취비율로간내쿠퍼세포에의한식균작용을 [59], 후자는간 / 심장섭취비율로미토콘드리아기능장애를평가하였다 [60]. 3. 간섬유화의진단 1) 혈청검사 Aminotransferases 치는간섬유화가진행하더라도간지방증이나염증이호전되면그수치가감소하기때문에간섬유화의진단에그다지도움이되지못한다 [61]. 또한간경변증을포함하여지방간의어떤단계에서라도정상 aminotransferases 치를나타낼수있다 [62]. 이보다는오히려 AST/ALT 비율이더가치가있어서몇몇연구는 AST/ALT 비가 1 이상이면진행된간섬유화의예측인자임을밝히기도하였다 [63,64]. GGT 를이용한소규모연구에서도 96.6 IU/L 의기준치를적용하였을때각각예민도 83%, 특이도 69% 의진단력을보였다 [65]. 또한세포외기질성분이간섬유화의평가를위한좋은예비지표들이다. Hyaluronic acid (HA) 는콜라겐합성이촉진될때생산이증가하며진행된간질환에서동모양혈관의내피기능장애가발생하면그제거능력이감소된다. 몇몇소규모연구들은 HA 의진행된간섬유화진단에대한 AUROC 를 로보고하였다 [52,66-68]. IV 형콜라겐 7S domain 도 HA 와유사한결과를보고하였으며 [67,69], pentraxin-3 를이용한결과도보고되었다 [46]. 2) 점수화모델간섬유화를예측하기위한몇몇모델은진행된섬유화에대해서는좋은정확도를보였지만경미하거나중등증의섬유화에대해서는그렇지못하였다. Ratziu 등이고안한 BAAT 점수는연령, BMI, 중성지방및 ALT 를통합한방법으로예민도는높지않지만 100% 의특이도를보였다 [70]. 유럽간섬유화연구그룹이제안한 ELF 점수는연령, HA, amino-terminal propeptide of type III collagen, tissue inhibitor of metalloproteinases (TIMP-1) 를병합한방법으로 NASH 에서진행된간섬유화에대해 AUROC 0.87 의좋은정확도를보여주었다. 그러나, 초기및중간단계의섬유화에대해서는진단적정확도가낮았다 [71]. FibroTest 는나이, α2-macroglobulin, bilirubin, GGT, apolipoprotein A1 을통합한미공개수식이다 [72]. 처음에는바이러스성간염을위해개발되었지만이후지방간으로확대되었고, 유의한섬유화의진단에대해 AUROC 및우수한특이도를보였다. 하지만경증과중등증의섬유화는구분하지못하였다. NAFLD fibrosis score 는가장연구가많이된모델로 13 개의연구에서 3,000 명이상의환자들에서검증되었다 [48]. 이것은연령, glycemia, BMI, 혈소판치, 알부민및 AST/ALT 비율로부터산출되며진행된섬유화에대해훌륭한진단적정확도를보인다. 이외에도 BARD (BMI, AST/ALT 비, DM 의존재 )[73], FIB-4 ( 연령, aminotransferases, 혈소판치 )[74,75], Fibrometer ( 포도당, 혈소판치, aminotransferases, ferritin, 체중, 연령 )[76], NAFLD Diagnostic Panel (DM, 중성지방, TIMP-1, AST)[77] 등이간섬유화의진단을위해고안된모델들이다. 3) 간경도측정 Transient elastography (Fibroscan R ) 는 pulseecho 초음파를이용해간의경도를측정하는방법이다. 이는만성 C 형간염에서섬유화를평가하는데에우수 85

5 Focussed Issue - 비알코올성지방간 (Non-alcoholic fatty liver disease, NAFLD) 86 한정확성을보여주었으며 NAFLD 에대해서는비록그보다는정확도가떨어지지만역시유용할것으로여겨진다 [78]. Transient elastography 를이용한첫 NAFLD 에서의보고를살펴보면 67 명의일본인환자에서간경도는간섬유화가진행할수록증가하였으며유의한섬유화, 진행된섬유화, 간경변증에서 AUROC 는각각 0.876, 0.914, 이었다 [79]. 간경변증을배제하기위한 NPV 는 100% 였다. Fibroscan R 을이용한첫대규모연구는프랑스와중국에서시행되었는데앞서연구와유사한진단적정확성을보였으며최적의 cut-off 값은유의한섬유화, 진행된섬유화, 간경변증에서각각 7.0 kpa, 8.7 kpa, 10.3 kpa 이었다 [80]. 이후루마니아, 일본, 인도등여러다른인종그룹에서검증된결과도유사하였다 [81-83]. 하지만 Fibroscan R 은비만한경우, 복수, 늑간사이간격이좁을때측정에실패할수있으며, 급성간염, 담즙정체및간울혈상태에서경도가실제보다높게측정되어질수있다. Acoustic radiation force impulse (ARFI) sonoelastography 는 short duration acoustic pulse 로조직을물리적으로자극하는기전을이용하며기존의 US 시스템에통합하여사용할수있다 [84]. NAFLD 를포함한만성간질환환자들에게적용하였을때간섬유화에대하여 Fibroscan R 과유사한정도의정확도를보였다 [85]. Real-time elastography 는 elastography 를기존의 US 스캐너에접목한방법으로 B- 모드 US 기계를사용하여조직의상대적경도를실시간으로색으로표현해낸다. 181 명의 NAFLD 환자들에게적용하였을때섬유화에대한진단적정확도는모든단계에서 % 였다 [86]. MR elastography 는간전체를평가할수있다는장점이있다. NAFLD 를포함한만성간질환환자들을대상으로하였을때 2.93 kpa 의 cut-off 값은섬유화진단에대해 98% 의예민도와 99% 의특이도를보였다 [87]. 이방법은경증, 중등증, 중증의섬유화진단을구분하는데에도좋은정확도를보였다. Fibroscan R 과의비교연구에서측정성공률및진단적정확도도더우수하였다. 하지만이방법의주요제한점은고비용과장비의보급성이낮다는점이다 [48]. 1. 간생검의장, 단점 간생검 간생검은 NAFLD 환자들에서 NASH 의정확한진단과다른질병과의감별진단, 예후예측, 치료효과평 가를위한가장좋은방법이다. 그러나 NAFLD 환자들의대부분을차지하는단순지방증환자들에서는간생검이필요치않으며, 간생검에수반될수있는합병증, 표본오차, 고비용, 검사자간의해석차이, 그리고 NASH 로진단된다하더라도생활습관교정이외에는정립된표준치료법이없다는점이제한점으로지적되고있다. 그리하여일반적으로간생검은진행된간섬유화가의심되는경우에시행하도록권고하고있다 [88]. 2. 간생검의제한점 1) 표본오차간생검시채취되는간조직은불과전체간부피의 1/50,000 가량으로표본오차가발생할수있다. 표본오차를방지하기위해서는충분한양의조직을채취하는것이필수적이며, 가능한한굵은생검침을사용하여 [89] 최소한 15~16 mm 이상의길이로두군데이상에서조직을채취하는것이바람직하다 [90,91]. Ratziu 등의보고에의하면 51 명의 NAFLD 환자에서두개의경피적간생검조직을비교하였을때지방성비교적일관성있는결과를보였지만섬유화단계는 41% 에서차이를보였다 [92]. 한생검조직에서 bridging fibrosis 가관찰된환자의 35% 에서는다른채취조직에서오직경미한섬유화만관찰되거나혹은아예섬유화가관찰되지않았다. NASH 의진단에필수항목인 ballooning degeneration 의경우도환자들의 18% 에서두조직간에불일치를보여만약생검조직이한군데에서만얻어졌다면진단이간과되었을가능성을시사하였다. 한보고에서는생검이간양엽에서시행되었을때환자의약 30% 에서한등급이상의조직학적차이를보였으며 [93], 지방변화나섬유화보다염증정도에대한판정이불일치하는경우가빈번하였다 [94]. 2) 검사자간, 그리고같은검사자에서의진단불일치검사자사이, 그리고같은검사자에서도진단이불일치한다는사실또한 NAFLD 의조직학적진단의심각한문제이다. Younossi 등의보고에지방변화 (κ = 0.64) 및섬유화 (κ = 0.60) 진단은검사자들간에비교적일치율이높았으나염증반응평가는일치율이낮았다 (κ = 0.33)[95]. 3) 합병증간생검시술의합병증으로통증의빈도가 20% 정도로보고되었으며경미한불쾌감을포함한다면그빈도가 84% 까지도증가한다. 심각한합병증과사망발생

6 비알코올성지방간의진단 빈도는 0.3~0.57% 와 0.01% 로보고되었다 [96-98]. 합병증발생률을줄이기위해서는경험많은검사자가초음파유도하에서시행할것을권한다 [99,100]. 3. 조직학적진단 NASH 의전형적인조직학적특징은 fat deposition in hepatocytes, inflammatory cell (neutrophil and lymphocyte) infiltration in lobules, ballooning degeneration of hepatocytes, Mallory-Denk bodies, pericellular fibrosis, sinusoidal fibrosis, giant mitochondria, eosinophilic necrosis, iron deposition 등이다 (Fig. 1). 그러나한환자에서이현상들이모두관찰되는것은드물며 NASH 진단을위한통합된진단기준도아직까지는마련되어있지않다. 이중대표적인진단법을소개하자면, Matteoni 등은다음과같이 4 가지유형으로 NAFLD 를분류하였다 [101]. Type 1, fat deposition alone; type 2, fat deposition and inflammatory cell infiltration in the parenchyma; type 3, fat deposition and ballooning degeneration of hepatocytes; and type 4, type 3 criteria plus Mallory-Denk bodies or fibrosis. 이들은약 8 년의추적관찰기간동안간질환관련사망률이 type 1 과 2 에서는 1.7% 에불과한반면, type 3, 4 에서는 11% 로증가하는것을관찰하였다. 그리하여이들은예후측면에서 type 3, 4 를 NASH 로간주할것을제안하였다. Nonalcoholic Steatohepatitis Clinical Research Network (NASH-CRN) 이제안한 NAS scoring system 은지방변화 (0-3 점 ), 염증 (0-3 점 ), 간세포의풍선변성 (0-2 점 ) 을기준으로하여 5 점이상인경우 NASH 로, 2 점이하인경우 non-nash 로, 그사이값은경계치로진단하였다 [102]. NASH-CRN 산하기관에서수행된 NAS 유효성연구에서일부연구자들은 5 점이예민도가떨어진다고하여 4 점이적당하다고주장하기도하였다 [103]. NAS 는재현성이뛰어나고특수염색이필요치않으며소아에서도적용이가능하고, 임상연구에서치료효과를평가하는데유용하다. 그러나 NAS 는지방변화및염증은호전되고섬유화만남아있는소위 burned out NASH 의경우는진단이불가능하다. 그리고최근에는 Matteoni 의분류체계가 NAS 보다 NASH 의진단및예후를더잘반영한다는연구결과가보고되기도하여 [104] NAS 는 NASH 의진단도구로서보다는치료효과를판정하는도구로더가치를인정받고있다. Younossi 등에의해제안된 NASH 의새로운정의는 (1) any degree of steatosis along with centrilobular ballooning and/or Mallory-Denk bodies, 혹은 (2) any degree of steatosis along with centrilobular pericellular/perisinusoidal fibrosis or bridging fibrosis 이다 [105]. 이는 Matteoni 의분류법에잘부합하며간질환관련사망률예측에무게를둔다. 그리고이분류법은섬유화의존재에중요성을더부과함으로써 burned out NASH 의진단을가능하게하였다. 87 결론 Fig. 1. Microscopic finding of nonalcoholic steatohepatitis. There are macrovesicular fatty change, ballooning degeneration of hepatocytes, and focal hepatocyte necrosis with inflammatory cell infiltration (H&E, x400). 요약하자면아직까지 NAFLD 진단의표준검사법은간생검이다. 하지만 NAFLD 와같이흔하고대부분환자들의임상경과가양호하며치료법이제한적인질환에서간생검과같은침습적인진단법은일반적으로추천되지않으며임상경과에유의한영향을끼칠수있는진행된섬유화가예상되는환자에서선별적으로시행할것이추천된다. 본장에서언급된비침습적인 NAFLD 진단법들은그종류와정확도가너무나도다양하여오히려임상의들이선택하기에혼란만가중시킨다. 하지만이중 NAFLD fibrosis score 는많은수의환자에서그유용성이비교적잘입증되어있어간생검이필요한환자들을선별하는데에도움이될수있을것으로여겨진다. 그리고최근에큰진보를보이고있는 elastography 를이용한간경도측정법은앞으로도발전가능성이많은부분으

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9 Focussed Issue - 비알코올성지방간 (Non-alcoholic fatty liver disease, NAFLD) ;45: Zimmermann E, Anty R, Tordjman J, Verrijken A, Gual P, Tran A, Iannelli A, Gugenheim J, Bedossa P, Francque S, Le Marchand-Brustel Y, Clement K, Van Gaal L, Sorensen TI, Jess T. C-reactive protein levels in relation to various features of non-alcoholic fatty liver disease among obese patients. J Hepatol 2011;55: Yoneda M, Uchiyama T, Kato S, Endo H, Fujita K, Yoneda K, Mawatari H, Iida H, Takahashi H, Kirikoshi H, Inamori M, Nozaki Y, Kobayashi N, Kubota K, Saito S, Maeyama S, Sagara M, Aburatani H, Kodama T, Nakajima A. Plasma Pentraxin3 is a novel marker for nonalcoholic steatohepatitis (NASH). BMC Gastroenterol 2008;8: Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, Luketic VA, Shiffman ML, Clore JN. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology 2001;120: Musso G, Gambino R, Cassader M, Pagano G. 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10 비알코올성지방간의진단 disease. Liver Int 2005;25: Yoneda M, Mawatari H, Fujita K, Yonemitsu K, Kato S, Takahashi H, Kirikoshi H, Inamori M, Nozaki Y, Abe Y, Kubota K, Saito S, Iwasaki T, Terauchi Y, Togo S, Maeyama S, Nakajima A. Type IV collagen 7s domain is an independent clinical marker of the severity of fibrosis in patients with nonalcoholic steatohepatitis before the cirrhotic stage. J Gastroenterol 2007;42: Lesmana CR, Hasan I, Budihusodo U, Gani RA, Krisnuhoni E, Akbar N, Lesmana LA. Diagnostic value of a group of biochemical markers of liver fibrosis in patients with non-alcoholic steatohepatitis. J Dig Dis 2009;10: Sakugawa H, Nakayoshi T, Kobashigawa K, Yamashiro T, Maeshiro T, Miyagi S, Shiroma J, Toyama A, Nakayoshi T, Kinjo F, Saito A. Clinical usefulness of biochemical markers of liver fibrosis in patients with nonalcoholic fatty liver disease. 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11 Focussed Issue - 비알코올성지방간 (Non-alcoholic fatty liver disease, NAFLD) 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 Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012;55: Goldstein NS, Hastah F, Galan MV, Gordon SC. Fibrosis heterogeneity in nonalcoholic steatohepatitis and hepatitis C virus needle core biopsy specimens. Am J Clin Pathol 2005;123: Vuppalanchi R, Unalp A, Van Natta ML, Cummings OW, Sandrasegaran KE, Hameed T, Tonascia J, Chalasani N. Effects of liver biopsy sample length and number of readings on sampling variability in nonalcoholic Fatty liver disease. Clin Gastroenterol Hepatol 2009;7: Larson SP, Bowers SP, Palekar NA, Ward JA, Pulcini JP, Harrison SA. Histopathologic variability between the right and left lobes of the liver in morbidly obese patients undergoing Roux-en-Y bypass. Clin Gastroenterol Hepatol 2007;5: Ratziu V, Charlotte F, Heurtier A, Gombert S, Giral P, Bruckert E, Grimaldi A, Capron F, Poynard T. Sampling variability of liver biopsy in nonalcoholic fatty liver disease. Gastroenterology 2005;128: Janiec DJ, Jacobson ER, Freeth A, Spaulding L, Blaszyk H. Histologic variation of grade and stage of nonalcoholic fatty liver disease in liver biopsies. Obes Surg 2005;15: Merriman RB, Ferrell LD, Patti MG, Weston SR, Pabst MS, Aouizerat BE, Bass NM. Correlation of paired liver biopsies in morbidly obese patients with suspected nonalcoholic fatty liver disease. Hepatology 2006;44: Younossi ZM, Gramlich T, Liu YC, Matteoni C, Petrelli M, Goldblum J, Rybicki L, McCullough AJ. Nonalcoholic fatty liver disease: assessment of variability in pathologic interpretations. Mod Pathol 1998;11: Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med 2001;344: van der Poorten D, Kwok A, Lam T, Ridley L, Jones DB, Ngu MC, Lee AU. Twenty-year audit of percutaneous liver biopsy in a major Australian teaching hospital. Intern Med J 2006;36: Cadranel JF, Rufat P, Degos F. Practices of liver biopsy in France: results of a prospective nationwide survey. For the Group of Epidemiology of the French Association for the Study of the Liver (AFEF). Hepatology 2000;32: Rockey DC, Caldwell SH, Goodman ZD, Nelson RC, Smith AD. Liver biopsy. Hepatology 2009;49: Friedman LS. Controversies in liver biopsy: who, where, when, how, why? Curr Gastroenterol Rep 2004;6: Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC, McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 1999;116: Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, Ferrell LD, Liu YC, Torbenson MS, Unalp-Arida A, Yeh M, McCullough AJ, Sanyal AJ. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41: Hjelkrem M, Stauch C, Shaw J, Harrison SA. Validation of the non-alcoholic fatty liver disease activity score. Aliment Pharmacol Ther 2011;34: Brunt EM, Kleiner DE, Wilson LA, Belt P, Neuschwander-Tetri BA. Nonalcoholic fatty liver disease (NAFLD) activity score and the histopathologic diagnosis in NAFLD: distinct clinicopathologic meanings. Hepatology 2011;53: Younossi ZM, Stepanova M, Rafiq N, Makhlouf H, Younoszai Z, Agrawal R, Goodman Z. Pathologic criteria for nonalcoholic steatohepatitis: interprotocol agreement and ability to predict liver-related mortality. Hepatology 2011;53: