Symposium: 비알콜성지방간및지방간염 비알코올성지방간질환및지방간염의진단 순천향대학교의과대학내과학교실 김영석 Invasive/noninvasive diagnosis in nonalcoholic fatty liver disease/nonalcoholic steatohepatitis Young Seok Kim, M.D. Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon, Korea Abstract Nonalcoholic fatty liver disease (NAFLD) is a burgeoning cause of chronic liver disease. NAFLD ranges from simple liver steatosis to nonalcoholic steatohepatitis (NASH), which can progress to cryptogenic cirrhosis. Liver biopsy traditionally has been the gold standard for evaluating the degree of hepatic necroinflammation and fibrosis. But, this is invasive procedure and carries substantial interpretation errors. Several noninvasive tests for assessing inflammation and fibrosis have become available in clinical practice. Further validation for these invasive and noninvasive tests is necessary to refine their clinical significance. Keyword: Nonalcoholic fatty liver disease, Nonalcoholic steatohepatitis, Diagnosis 서 론 알코올성간질환의특징적인병리소견을보이지만음주와관계없이간에중성지방 (triglyceride, 이하 TG) 이과도하게축적되는비알코올성지방간질환 (nonalcoholic fatty liver disease, 이하 NAFLD) 은비만, 인슐린저항성, 2 형당뇨병, 고혈압, 고지혈증등대사증후군 (metabolic syndrome) 과관련 1 이있다. 2 Corresponding Author: Young Seok Kim, M.D., Department of Internal Medicine, Soon Chun Hyang University College of Medicine, Bucheon Hospital, 1174 Jung-dong, Wonmi-gu, Bucheon-si, Gyeonggi-do 420-767, Korea Tel: 032-621-5085; E-mail: liverkys@schmc.ac.kr - S55 -
2010 년대한간학회추계학술대회 NAFLD에서비알코올성지방간염 (nonalcoholic steatohepatitis, 이하 NASH) 과초기간섬유화를판정하는방법은아직간조직검사가표준검사로간경변증등으로진행할수있는환자를조기에찾아낼수있는다양한비침습적검사가개발되었다. 권고수준을정할만한연구가아직부족하여임상지침의제정이어려운상황에서외국에서도전문가의견을종합한정도의백서만이발표된실정으로 3 본고에서는 NAFLD의조직학적진단법과현재연구되고있는다양한혈액검사및기타영상진단에대해요약하여소개하고자한다. 비알코올성지방간질환의정의 NAFLD는단순지방간 (simple steatosis) 과 NASH로구분할수있으며단순지방간은과도하게지방이침착된상태로임상적으로예후가양호한양성질환으로여겨지나 NASH는지방침착과함께간세포손상과염증이동반된상태로간섬유화, 간경변증, 간세포암종을초래할수있으므로 NASH가발생하면 5년생존율이 67%, 10년생존율이 59% 로낮아진다. 4 NAFLD의진단을위해서는 2차적으로지방간질환을초래하는바이러스감염, 자가면역질환, 유전적소인을배제하여야하며특히음주력을확인하여야한다. 대사증후군의진단은 National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) 기준을근간으로 American Diabetes Association (ADA) 의수정안을따르는것이일반적이며 2005년 International Diabetes Foundation (IDF) 의수정안도이용된다. 대사증후군위험인자가없는정상체중인의 16% 에서도 NAFLD가발견되지만 5 일반적으로대사증후군과의관련성이높고 NAFLD가만성 C형바이러스간염, 혈색소증, 알코올성간질환등과동반되어간손상을더욱악화시킬수도있으므로 6 최근에는 NAFLD 보다대사성지방간질환 (metabolic fatty liver disease) 이나대사성지방간염 (metabolic steatohepatitis) 으로질환명을개정해야한다는주장도있다. 비알코올성지방간질환의역학 미국의 NAFLD 유병율은전인구의 10-30% 로매우흔하며새로진단된만성간질환의 39% 도 7 NAFLD가원인이고 5년간의료비지출의 26% 가직간접적으로이질환과관련이있다. 8,9 유럽과극동에서의이환율이높아초음파검사로 NAFLD를판정시각각 20-30%, 10 15% 가이에해당한다. 11 NASH 역시흔히볼수있어아미노트랜스퍼라제가상승한환자의 43-55%, 12 심각한비만자의 49%, 13 만성간질환자의 67% 가 8 NASH로진단되어미국전인구의 3-6% 가 NASH로추정된다. 미국의경우심지어건강한생체부분간이식간공여자에서조차도 27-38% 에서 NAFLD가조직학적으로진단되었으며 6-15% 는 NASH라는 14 보고가있으며개발도상국에서도 NAFLD가 8.7% 에이르며이들환자의 75% 의체질량지수는 25 kg/m 2 미만이라는점은 15 주목할만하다. - S56 -
김영석 비알코올성지방간질환및지방간염의진단 진단법 표준진단법이간조직검사이기는하지만질환에이환될가능성이높은환자나치료를고려하는환자를 선별하기위해서는비침습적진단법개발이필요하다. Aminotransferase 혈청아미노트랜스퍼라제는간질환의확인을위해통상적으로측정하지만 NASH의선별검사로 ALT를이용하였을때 16 기준점을여성 19 IU/L, 남성 30 IU/L로하면민감도와특이도가 99% 와 8% 이고, 40 IU/L를기준으로하면 86% 와 32% 에불과하며시간경과에따라변화가심하고검사실간의차이가있다. 17,18 하지만원인미상의 ALT 상승이있는환자에서섬유화와간경변증의가장흔한원인은 NASH이다. 19 NAFLD에서대개 ALT/AST가 1을넘지만역전되면섬유화가심하거나간경변증으로진행하였음을시사한다. AST, ALT는일반적으로정상상한치의 4배를넘지않으며지방증이나섬유화정도와비례하지는않는다. 20 NAFLD에서 ALT가상승되어있으면 74% 가 NASH로 AST, ALT, AST/ALT 비가 NASH에서더높은경향을보이지만 ALT가정상이어도 62% 에서 NASH로진단된 21 연구결과를볼때 ALT를기준으로 NASH와그밖의 NAFLD를구분할수는없다. 혈청표지자 인슐린저항성으로대표되는대사증후군과관련이높아인슐린저항성검사가필요하다. NAFLD에서이용되는혈청검사법은 22-24 ( 표 1) 지방증판정, 괴사염증반응이있는지방간염의진단, 섬유화예측으로구분할수있으며이중 NAFLD 진행에중심역할을하는염증반응표지자가가장중요하다. 1) 지방증 (steatosis) 에대한혈액검사인 Fatty liver index (FLI) test는 25 지방증을예측하여초음파를대체하는대규모선별검사로유용하며 SteatoTest와 26 NAFLD score도 27 초음파검사에비해민감도가높고지방증의정도를정량측정할수있다. 2) 지방간염의진단은섬유화진행위험성이높은환자를색출하여집중적인식습관및생활습관의상담치료와함께약물치료를시행할수있어유용하다. 28 저비중지단백 (low-density lipoprotein, LDL) 과같은산화스트레스를반영하는물질, 또는 leptin 이나 adiponectin (ADP) 와같은물질의측정이도움이된다고하나아직논란이많다. Homeostasis Model Assessment for Insulin Resistance (HOMA-IR) 과혈청 adiponectin/leptin 비를종합하면단순지방간과 NASH를감별할수있다. 29 C-reactive protein (CRP) 와 high sensitivity CRP (hs CRP) 가이용되며 30 혈청 ferritin과 31 혈장 pentraxin 3 (PTX3) 도 32 NASH환자감별에유용하며섬유화의정도를반영하지만비알코올성지방간이외의질환에서도상승할수있다. interleukin-6 (IL-6) 는 NAFLD에서상승하며 33 TNF-α는 NASH로의진행에관여한다. 34 Caspase-3 경로에서유도된 cytokeratin-18 (CK-18) fragment는간세포의세포자멸 (apoptosis) 의마지막단계를반영하는것으로 NASH - S57 -
2010 년대한간학회추계학술대회 Table 1. Serological markers for nonalcoholic steatosis and fibrosis 23,24 Serological markers Advantage Disadvantage C reactive protein (hs-crp) Independent risk factor for progression of NAFLD Marker of systemic inflammation Lack of specificity for NASH Conflicting results : some increased hs-crp with NASH compared with NAFLD ROS Maker of oxidative stress Conflicting results : some correlation between NASH and increased level of ROS Leptin Marker of insulin resistance Conflicting results : higher levels in some studies Adiponectin (ADP) Marker of insulin sensitivity Lower in NASH patients Plasma pentraxin 3 Can differentiate between NASH and non progressive NAFLD Fibrosis marker in NAFLD Lack of specificity for NASH Hyaluronic acid Identify fibrosis at a cut-off value of 45 ng/ml Cannot differentiate NASH from simple steatosis Tissue inhibitor of metalloproteinases Cytokeratin 18 Polypeptide specific antigen Endothelin 1 Fibrosis marker Marker of hepatocyte apoptosis Significant higher in NASH Marker in differentiating NASH from pure fatty liver Can differentiate NASH from simple steatosis Cannot differentiate NASH from simple steatosis Limited utility in clinical practice Marker for various cancers Lack of specificity for NASH 에서는 380.2 U/L 이상으로현저하게나타나나지방증에서는발현되지않아매우유망한혈청표지자로여겨진다. 35,36 그러나단독으로는진단적가치가떨어지며 37 섬유화정도에따라혼란을줄수있다. 35 Tissue polypeptide specific antigen은세포자멸중분비되는단백질로섬유화의표지자이며 ALT 보다정확하며 38 체중감량시현저히감소되므로 NASH가동반된비만환자에서추적검사에유용하다. 23 Palekar 39 등은 50세이상, 여성, AST가 45 IU/L 이상, AST/ALT 비가 0.8 이상, hyaluronic acid가 55이상의인자중 3가지이상을만족하면 NAFLD에서 NASH를감별하는민감도가 73.7%, 특이도가 65.7% 라하였다. NASH를감별하기위해개발된 NASH Test는 40 SteatoTest가양성인경우에만시행한다. 3) 섬유화를판정하는검사로는주로유럽쪽에서개발되었으며미국에서는간조직검사를선호하는편이다. 고식적방법으로는 AST/ALT 비와 APRI (AST to Platelet Ratio Index) test 가있으며체질량지수 (BMI), 조직검사시연령 (age), ALT, 중성지방 (triglyceride) 4가지인자로간섬유화를예측하는점수체계인 BAAT가 41 있다. 현재유럽에서는 FibroTest가 42,43 미국에서는 FibroSpect와 FibroSure가가장많이사용되며이외 44 Enhanced liver fibrosis (ELF) panel, 43 FibroMeter fatty liver 45 NAFLD fibrosis score, 46 BARD score 47 등이있다. 또한, 최근 1,000명이상의 NASH CRN 등록환자를대상으로한연구에서 16 이들이제안한공식을이용하였을때지방간염과풍선변성, 진행된섬유화에대한예측도는중등도정도이었다. 이와 - S58 -
김영석 비알코올성지방간질환및지방간염의진단 같이다양한검사법이있으나대부분은진행된섬유화만을판정할수있어조기에경도또는중등도섬유화를찾아내어질환의진행을막는역할을하기에는부족하다. 영상검사 간에지방침착이 20-30% 이상인경우에초음파검사, 전산화단층촬영, 자기공명영상으로도지방증을판별할수있으나지방증과지방간염을감별하고섬유화의정도를판정하기에는불충분하다. 2 초음파검사는지방증을진단하는민감도가 60-94% 로 20 NAFLD의 1차선별검사로이용된다. 그러나섬유화정도를알수는없이오직지방침착만확인할수있고간내지방침착이 30% 미만이면민감도도매우떨어진다. 48 일부의연구에서초음파점수체계가내장비만과간조직소견을반영한다고하나 49 초음파검사를이용한지방증의정량측정은재현성이떨어지고시술자에따라차이가있어신뢰할수없다. 50 초음파로비장의장축의길이를측정하여 116 mm 이상이며 NASH를예측할수있으며 51 도플러초음파로간정맥의도플러파형을측정하여 52 NAFLD를진단하기도한다. 조영제주입후초음파로관찰시시간경과에따라신호강도가 NASH에서는의미있게감소하였으나소규모연구라는단점이있다. 53 CT를이용하면피하지방의두께와내장지방을측정할수있으며간내지방침착도알수있지만간내지방이 30% 미만에서는정확도가떨어진다. 또한 54 간-비장감쇠비 (attenuation ratio) 를측정하여지방침착정도를특이도 100%, 민감도 82% 로파악할수있다. 54 하지만중등도의섬유화를인지하기곤란하고방사선노출위험성때문에추적검사도어렵다. 자기공명영상은정확하고신속하게 3% 이상의간내지방증을측정할수있으며 T1 강조영상에서신호강도가감소하면국소지방침착을인지할수있다. 55 양성자자기공명분광기 (MR spectroscopy) 는예민하게간내중성지방을측정할수있어 56 이검사법을이용하면미국성인의 34% 가 NAFLD로진단하게된다. 57 또한 NASH의정도도파악할수있으나아직더많은연구와기관에따른표준화가필요하고고비용이므로사용용이성에제한이있다. 58 이외에섬유화정도를측정하는방법으로 diffusion weighted imaging과 MR elastography가있으며 MR elastography는체질량에상관없이섬유화정도를정확히판정할수있다. 59 섬유화스캔 (fibroscan) 선별된 NAFLD 환자에서 transient elastography를이용한간경도측정 (liver stiffness measurement, LSM) 은섬유화의진단에이용되어 60,61 섬유화병기가 IV기이면민감도와특이도가 87%, 91% 이며 II-IV기이면 70% 와 84% 이지만 62 섬유화단계를구분하는기준수치 (cut-offs) 가확정되지않은문제가있다. 염증정도에따른간경도가차이를보일수있으며 63 마찬가지로지방증도간경도를약간증가시킨다. 64 하지만지방증으로인해간경도가오히려상쇄되어지방간질환에서는실제섬유화정도에비해간경도가낮게측정될수있다. 65 간단하고즉시결과를알수있으며 sampling error를줄일수있다는장점이있으나체질량지수 (body mass index, BMI) 가 30 이상이면 25%, 35 이상이면 41% 에서측정실패가발생하는 66 검사상의 - S59 -
2010 년대한간학회추계학술대회 한계도있으며기타다른질환이나상태도간경도를증가시킬수있다. 67-69 Acoustic radiation force impulse (ARFI) sonoelastography는기존의초음파장치를이용하여장기의탄력도를측정하는방법으로일반적인초음파검사를하면서바로시행할수있다는장점이있으나아직 NAFLD의진단에대한연구는부족하다. 70 간조직검사 성인 NASH는거대수포성지방증 (macrovesicular steatosis), 간세포손상 (hepatocellular injury) 과혼합염증반응 (mixed inflammatory-cell infiltration) 이라는 3가지병변이주로 3구역 (zone 3), 중심소엽 (centrilobular) 에분포하는것을특징으로한다. 특히지방증은이미지방이사라진간경변증을제외하고는 NAFLD 진단의전제조건으로최소 5% 이상의간세포가지방소포 (fat droplets) 를함유하고있어야한다. 간세포손상을반영하는소견은간세포의풍선변성 (ballooning degeneration) 이가장중요하며호산체 (acidophilic body) 나초점괴사 (spotty necrosis) 가동반될수도있다. 71 간소엽의염증세포침윤 (lobular inflammation) 이특징으로 NASH가심하게진행되면문맥주위염증 (portal chronic inflammation) 이나타난다. 72 섬유화증은 NASH의정의에포함되지않으나동주위섬유화 (perisinusoidal fibrosis) 는 NASH의특징적인조직소견중하나이고동주위섬유화와문맥섬유화 (portal fibrosis) 에따라병기를분류한다. 73 다형핵백혈구와말로리소체 (Mallory-Denk body) 침윤이 NASH에서보일수있으나진단에필수적인사항은아니다. Matteoni 등은 74 질병의예후와비례하는조직학적분류로 NASH를 4군으로분류하였고이중 3과 4형이 NASH에해당한다고하였으며 Brunt 등이 75 제안한분류체계는 NASH의진단에대해서는자세히분류하고있지만전체적인 NAFLD에적용하기는곤란하고성인을대상으로한분류이므로소아 NASH를포함하지못한단점이있다. 이를극복하기위해 2002년부터 National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) 에의해 The Nonalcoholic Steatohepatitis Clinical Research Network (NASH CRN) 이구성되어 NASH의원인, 기여인자, 자연경과, 합병증및치료에대한다기관공동연구가진행되었고 2005년 NAFLD Activity Score (NAS) 가제안되었다 ( 표 2). 73 NAS는 HE 염색과 Masson s trichrome 염색등으로판독이가능한장점이있으며지방증, 풍선변성, 소엽염증정도의점수를합산하여 5점이상이면 NASH로, 2점이하이면 NASH가아닌것으로판정하였다. NAS 점수 3-4점환자는확실한진단을내리기곤란한상태로 (uncertain) 판정하지만과거의분류기준에의하면 NASH로진단할수있었으므로이들환자가향후어떤경과를보일지추적관찰이요구된다. 그러나 NAS가 5점이상임에도 16% 정도의환자는 NASH 에합당하지않으므로 16 NAS는 NASH의진단을위한검사라기보다는치료에따른조직소견의변화를확인하는데주로이용된다는점은명심해야한다. 조직학적으로특별한양상을보이는 NASH도있다. 소아의 NASH는문맥염증, 섬유화, 지역편중이없는 (azonal) 지방증이특징이며풍선변성과동주위섬유화는드물다. 76,77 비만수술 (bariatric surgery) 후발생한 NASH는고립문맥섬유화 (isolated portal fibrosis) 와지역편중이없는지방증이특징이다. 71 NASH 환자의 25-33% 는진단시에가교섬유화 (bridging fibrosis) 가동반되어있으며간경변증이동반된경우도 10-15% 이다. 78 또한원인불명의간경변증환자에서대사증후군의위험인자가존재하면이들중 30-75% 는소진된 (burned-out) NASH가원인으로알려져있다. 79 - S60 -
김영석 비알코올성지방간질환및지방간염의진단 연령과최초조직검사시의괴사염증 (necroinflammation) 은섬유화진행의가장강력한예측인자로알려져있으나드물게는단순지방간소견만있어도섬유화가진행된다. 80 이는지방간염으로진단하기에는불충분한비특이적염증소견만있었거나 81,78 조직검사시에지방간염부위를피해조직이채취되었을가능성으로해석된다. 이와같이간조직검사를이용한 NAFLD의진단은표본획득오류 (sampling error) 가가장큰제한점이다. 특히염증병변과풍선변성으로인해진단을놓치거나병기를낮추어진단하기도한다. 82,83 따라서다른만성간질환과마찬가지로최소 15 mm 이상, 되도록 25 mm 이상의조직을획득하도록권고하고있다. 83 비알코올성지방간염의진단전략 NAFLD의위험성이높은환자나의심이되는환자를대상으로각각의상황에맞는전략에따라간조직검사를비롯한적극적검사를시행하여야하며이를통해가교섬유화나간경변증과같은진행된간질환을진단하고선별된환자에서식이조절과생활방식의변화, 약물투여를결정한다. 2009년 EASL에서는다음과같은진단전략을제안하였다. 3 1) 전인구중 NASH의이환율, 이로인한사망률에대한자료가부족하고전인구를대상으로하는선별검사의비용대비효과에잘알려져있지않으므로전인구를대상으로한선별검사는권고하지않는다. 2) 인슐린저항성이의심되는상황 ( 비만, 2형당뇨, 지질이상등 ) 에서는 NASH의위험성이높다. 따라서대사증후군이나인슐린저항성이있는환자에서는 NAFLD에대한선별검사를권장한다. Table 2. NASH Clinical Research Network Scoring System for NAFLD 73 NAFLD score (0-8) Correlation between total NAS * and an overall histological diagnosis of steatohepatitis Sum of 1+2+3 NAS * Histological diagnosis of steatohepatitis 1. Steatosis (0-3) 0= <5% hepatocyte involved 1=5-33% hepatocyte involved 2=33-66% hepatocyte involved 3= >66% hepatocyte involved 5 3-4 2 Probable or definite-nash Uncertain Not NASH 2. Lobular inflammation (0-3) 0=none 1= <2 foci per x 200 field 2=2-4 foci per x 200 field 3= >4 foci per x 200 field 3. Hepatocellular ballooning (0-2) 0=none 1=few ballooned cells 2=many cells/prominent ballooning Fibrosis stage 1 Perisinusoidal or periportal 1A Mild, zone 3, perisinusoidal 1B Moderate, zone 3, perisinusoidal 1C Portal/periportal fibrosis only 2 Perisinusoidal and portal/periportal fibrosis 3 Bridging fibrosis 4 Cirrhosis * NAS: NAFLD activity score. - S61 -
2010 년대한간학회추계학술대회 3) 아미노트랜스퍼라제는 NAFLD의예민한검사법이아니지만 ALT가상승된인슐린저항성환자에서전체비만또는당뇨인구에비해 NASH와간섬유화로의이환율이높다는점을고려하여 8ALT가상승되거나초음파검사에서지방간이있으면 1차검사로혈청또는영상을이용한비침습적검사를우선고려한다. 이때비침습적검사에서진행된섬유화소견이의심되거나, 검사소견이진행된섬유화를배제하기에불충분한경우에만간조직검사를시행한다. ALT의상승과초음파검사에서지방간소견이동반되어있으면 1차검사로간조직검사를선택한다. 4) NAFLD는만성 C형간염, 알코올성간질환, 혈색소증과같은다른만성간질환에동반되어섬유화를악화시킬수있다. 그러므로만성간질환환자에서대사증후군위험인자, 인슐린저항성을검사하고초음파검사로지방간여부를확인한다. 만약이들모두가있으면 NAFLD가동반되어있는지확인하기위해간조직검사를시행한다. 비만수술은 NASH의고위험군이며담석과 NAFLD는위험인자를공유하므로비만수술이나담낭절제술을하는경우에는간조직검사를하도록제안하고있다. 위의내용을종합하여다음과같은실제적전략을제시하였다. NAFLD가의심되어간전문의에게의뢰되면각각의상황에따라간조직검사를시행하는것이좋다. 진단뿐만아니라예후에대한정보를제공할수있기때문이다. 최근갑자기체중변화가발생한사람에서는간조직검사를피하는것이좋으며체중변화가없으면서생활습관이안정된경우에는 4-6개월간관찰기간동안식이조절과생활습관개선을하도록한다. 이기간동안체중감량과 ALT의정상화, 인슐린저항성개선이있으면간조직검사를연기하고 ALT와섬유화를반영하는비침습적표지자로모니터링한다. 이런사항이개선되지않으면간조직검사를고려하지만비침습적으로섬유화정도를판정할수있는혈청과영상검사모두에서의미있는섬유화가없다고판단되면되도록간조직검사를피하도록한다. 결 론 아직 NAFLD에서괴사염증과섬유화정도, 침착된지방량측정에있어표준은전통적으로간조직검사이지만침습적인방법이며조직검사를하여도치료방침의변화를주는경우는거의없으므로점차로비침습적진단법이각광받고있으나아직표준화되어있지않으며임상적용까지는더많은연구가필요하다. 참고문헌 1. Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc 1980;55:434-438. 2. Angulo P. Nonalcoholic fatty liver disease. N Engl J Med 2002;346:1221-1231. 3. Ratziu V, Bellentani S, Cortez-Pinto H, Day C, Marchesini G. A position statement on NAFLD/NASH based on the EASL 2009 special conference. J Hepatol 2010;53:372-384. 4. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. - S62 -
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