대한간학회 간경변증 간섬유화의비침습적진단 아주대학교의과대학소화기내과학교실 정재연 Non-invasive diagnosis of hepatic fibrosis Cheong Jae Youn Gastroenterology Department, Ajou University School of Medicine Cirrhosis is defined as a diffuse process characterized by hepatic fibrosis and the conversion of normal liver architecture into structurally abnormal nodules. Liver biopsy is the current gold standard for the diagnosis of liver cirrhosis, but it is invasive, and in many instances not favored by patients or physicians. An ideal noninvasive diagnostic test for hepatic fibrosis should be simple, inexpensive, and accurate. Serum markers of liver fibrosis measure indirect markers of liver function or constituents of hepatic matrix and enzymes involved in matrix turnover. Transient elastography is a novel non-invasive method that has been proposed for the assessment of hepatic fibrosis in patients with chronic liver disease, by measuring liver stiffness. Combining transient elastography with serum markers increases diagnostic accuracy and as a result, liver biopsy could be avoided for initial assessment in most patients with chronic hepatitis C. Guidelines are needed for the use of transient elastography and serum markers for diagnosis of liver cirrhosis in clinical practice. Key words: Hepatitis; Liver fibrosis; Diagnosis; Serum marker; Transient elastography 간섬유화에대한치료법에대한연구가진행됨에따라비침습적인간섬유화예측및진단에대한요구가증가되고있다. 1 만성간질환환자의질병진행여부의판단은임상적으로혈액검사및복부초음파검사가주로이용되나, 중증섬유화로의진행이나간경변증의진단에민감도및특이도가낮아정확한예측은어렵다. 2,3 정확한간경변증진단은간생검을통해이루어지지만, 침습적방법으로시술과관련한합병증이발생할수있으며, 검체채취오류 (sampling error), 환자의거부감등으로많은임상의들이간생검을꺼린다. 4 최근에혈액검사만으로간섬유화및간경변증을예측하고자하는시도가활발히이루어지고있으나고가의검사항목이다수포함된경우가많고, 주로 C형간염환자에서의결과가많아국내에서임상에적용하기는어렵다. 5,6 이에대한보완책으로 Transient elastography (Fibroscan) 가개발되어피부를통해간접적으로간탄력도를측정하여간섬유화를비침습적으로진단한결과들이보고되고있다. 따라서간섬유화의혈청표지자와 22
정재연 간섬유화의비침습적진단 Table 1. Serum Markers of Hepatic Fibrosis Indirect Markers AST/ALT GGT Bilirubin Cholesterol Apolipoprotein A1 α2-macroglobulin Haptoglobin Platelet Prothrombin time Direct Markers Collagens Procollagen I (PICP) Procollagen III (PIIINP) Type IV collagen Glycoproteins and polysaccharides Hyaluronic acid (HA) Laminin YKL-40 Collagenase and inhibitors Metalloproteinase (MMP) Tissue inhibitor of MMP (TIMP) Cytokines TGF-β Platelet derived growth factor (PDGF) Fibroscan 등비혈청표지자등을이용하여간생검을대체할수있다면간생검의불편함을줄이고외래에서추적관찰및치료와예후평가에유용할것이다. 간섬유화의비침습적진단표지자로는크게혈청학적검사와간탄력도측정과영상검사같은비혈청학적검사로나눌수있다. 간섬유화의혈청표지자 간경변증의검사실소견으로는알부민저하, 빌리루빈상승, prothrombin time 연장등이며 AST/ALT 비는약간증가할수있고, 백혈구및혈소판감소가흔하다. 그러나이런결과는진행된간경변증환자에서는잘보이지만대상간경변증에서는뚜렷치않은경우가많고, 특히간섬유화의단계를구분할수는없다. 간섬유화의혈청표지자는직접표지자와간접표지자로구분할수있다 ( 표 1). 직접표지자는세포외기질의교체를측정하는것들이대부분이며, 간접표지자는간섬유화자체보다는간기능변화를반영하며, AST/ALT 비, 혈소판등이포함된다. 1. 간접표지자 (1) 기본혈액검사를통한간섬유화예측 1) AST/ALT 비만성간염환자에서간섬유화가심해질수록 AST/ALT 비는증가하며, 간경변증에서 Child 등급이높을수록 AST/ALT 비가증가한다. 7 2) AST/ 혈소판비 (AST to Platelet Ratio Index, APRI) APRI= [AST(/ 정상상한치 ) 100] [ 혈소판수 (10 9 /L)] 만성 C형간염환자에서중증섬유화와간경변증을예측하는데에우수하였다. 8 간섬유화가진행되고문맥압이 23
대한간학회 간경변증 상승함에따라동모양혈관내피세포에서 AST 제거는감소하고, 진행된간경변에서미토콘드리아의손상으로인한혈액내유출로인해 AST 는증가한다. 9,10 혈소판이감소하는원인은 thrombopoietin 생성이감소되며비장에서혈소판의격리가증가하기때문이다. 11 APRI 의가장큰장점은간편하여기억하기쉽고, 다른검사가필요없다는것이다. 본교실에서는만성 B형간염환자들에서 AST/ALT 비, APRI 와간생검결과를비교하여간섬유화정도를가장정확히반영하는표지자는 APRI 임을보고하였다. 12 3) Forns index 나이, γ-glutamyl transpeptidase (GGT), 콜레스테롤, 혈소판을조합한것으로만성 C형간염환자에서 METAVIR F2~F4 섬유화의진단에 94% 의민감도를보였으나, 지방대사이상에의해영향을받을수있는단점이있다. 13 4) 기타혈소판, ALT/AST 비, INR 로구성된 CDS (cirrhosis discriminant score), 14 AP index (age-platelet index), 15 AST/ALT 비와혈소판으로구성된 Pohl score 16 등이보고되었다. Lackner 등은 C형간염에서기본혈액검사를조합한 AAR, CDS, AP index, Pohl score, APRI 의진단정확도를조사한결과소수에서만간생검의필요성을감소시켜보다정확한혈청표지자가필요하다고보고하였다. 17 (2) 간접표지자를이용한간섬유화예측 α2-macroglobulin 은간세포및간성상세포에서생성되는염증성단백질로서간섬유화가증가함에따라증가하며, haptoglobin 은섬유생성과염증반응시간세포성장인자와 TGF-β1 의반대작용을하며섬유화가진행되면감소한다. Apolipoprotein A1은콜레스테롤을운반하는역할을하며간세포에서합성되고, 교원질에의해간세포에서분비가줄어드므로간섬유화가진행하면감소한다. 1) PGAA index Prothrombin time, GGT, apolipoprotein A1, α2-macroglobulin 으로구성되며, 알코올성간질환에서보고되었다. 18 2) Fibrotest / Fibrosure FibroTest (Biopredictive, Paris, France) 와 Fibrosure (LabCorp, Burlington, NC) 는동일한검사로유럽과미국에서다른이름으로시판되고있다. Fibrotest 는 α2-macroglobulin, haptoglobin, apolipoprotein A1, 빌리루빈, GGT 5가지항목을이용한검사로간섬유화표지자로서많은보고가있다. 6,19-21 제한점으로는경증섬유화를진단하는데어려움이있으며 22 길버트증후군이나담즙정체의경우처럼빌리루빈이증가하는경우나 C형간염환자를 ribavirin 으로치료하는경우간혹관찰되는용혈에의한 haptoglobin 의감소시위양성결과를보일수있으며, 급성염증반응에서 α2-macroglobulin 과 haptoglobin 이증가하여결과에영향을줄수있다. 현재국내에서 α2-macroglobulin 을제외한검사들은쉽고저렴하게측정가능하다. 이상에소개한혈액검사들은간전체를대변한다는점에서간생검에비해우수하다. 그러나간섬유화의간접표지자는심한섬유화를감별하는데는유용하나 F2 혹은 F3의중등도섬유화를감별하기는어렵다. 2. 직접표지자 간섬유화는역동적인과정으로섬유생성과용해가모두증가하여혈액내세포외기질구성성분이증가한다. 24
정재연 간섬유화의비침습적진단 세포외기질은교원질, 당단백질, proteoglycan 등으로구성된다. 간섬유화의직접표지자들은세포외기질의생성및제거에직접적으로관여하는것들이다. Hyaluronic acid (HA) 는비분지성다당체로세포외기질의중요구성성분이며, 직접표지자중가장예민한검사중하나로심한간섬유화및간경변증의진단에유용하다. 23 관절강내의활막세포에서합성되고, 간내동모양혈관내피세포를통해흡수되어라이소좀에서제거된다. 24 따라서류마티스관절염이나골관절염등의관절내염증으로생성이증가하거나간섬유화로내피세포의수와기능이감소하여 HA 의제거가감소할때혈청농도가증가한다. 25 Oberti 등은간섬유화의직접적인표지자들의진단정확도를조사한결과 HA (86%) 가 procollagen III N-terminal peptide (PIIINP) (74%), laminin (81%), TGF-β1 (67%) 에비해우수하다고보고하였다. 26 486 명의 C형간염환자연구에서 HA 값이 60 μg/l 이하이면음성예측도 93% 와 99% 로진행된섬유화나간경변을배제할수있었다. 23 교원질은간성상세포에서전교원질 (procollagen) 로분비되고, propeptidase 에의해 amino-terminal propeptides 와 carboxy terminal propeptides 로분해되어혈류로유입되어세포외기질합성이나분해를반영한다. Procollagen III N-terminal peptide (PIIINP) 는섬유소합성 (Col 1-3) 과섬유소용해 (Col 1) 를모두반영하며, 급성간염과진행된간섬유화에서모두측정될수있어염증도같이반영하는표지자로생각된다. 27 Matrix metalloproteinase (MMP) 는세포외기질을분해시키고, tissue inhibitor of metalloproteinase (TIMP) 는이를억제하는것으로알려져있으나실제서로어떻게균형을이루며, 혈중 MMP/TIMP 의농도가간섬유화의단계에따라보이는양상은확실치않다. Boeker 등은만성 C형간염환자에서 pro-mmp-2 와 TIMP-1 의진단정확도를조사한결과간경변증진단에 HA 와유사하였다. 28 그러나다른보고에서는 MMP- 1,2,9 및 TIMP-1, TIMP-2 를조사하여 PIIINP 와 HA 와비교하였을때 PIIINP 와 MMP-1 을조합한경우정확도가가장높았다. 29 최근 194 명의 C형간염환자를대상으로한연구에서 TIMP-1 과 PIIINP를함께측정하여진행된섬유화를좀더정확하게진단하였다. 29 YKL-40 는 lectin 계에속한당단백으로연골이나간에다량분포하며, 세포외기질분해및내피세포나섬유아세포의성장인자로작용할것으로추측된다. 30 알코올간질환환자를대상으로한연구에서간섬유화진단에 HA나 PIIINP와비슷한정확도를나타냈고, 활동적인섬유생성이일어나는곳에서뚜렷하였다. 31 그러나 YKL- 40은다양한조직에분포하며, 악성종양및염증성질환, 대사질환에서높게측정될수있다. 32-34 3. 직접표지자와간접표지자의조합 Fibrospect II는 HA, TIMP-1, α2-macroglobulin 을조합한 panel 로 AUROC 가 0.831 로 METAVIR stage F2~F4 를진단하였으나 ( 양성예측도 74.3%, 음성예측도 75.8%) 특정한섬유화단계를구분하지는못했다. 35 European Liver Fibrosis (ELF) index 는이전의연구들이주로만성 C형간염을대상으로한것과는달리다양한간질환을포함한 1,021 명의환자를대상으로한대규모다기관연구로여러세포외기질관련단백질을분석한결과나이, HA, PIIINP, TIMP-1 이간섬유화의진단에가장정확하였다. 36 Hepascore 는만성 C형간염환자에서 10개의혈청표지자를검사하여다변량분석및 AUROC 분석을통해 6가지 (bilirubin, GGT, HA, α2-macroglobulin, 나이, 성별 ) 인자를조합한것으로 Fibrotest 와비슷한결과를보였다. 37 Cales 등은 51개의혈청생화학검사와 Fibrotest, Fibrospect, ELF index, APRI, Forns index 를비교분석하여 Fibrometer ( 혈소판, prothrombin index, AST, α2-macroglobulin, HA, urea, 나이 ) 라명명한새로운 25
대한간학회 간경변증 조합패널을제시하였고, AUROC 값이 0.883 으로기존의패널보다다소우수하였다. 38 영상진단 간경변증의영상진단은간의형태학적변화및혈역학적변화를확인하는것으로나뉜다. 비용-효과면을고려하여임상에서가장유용한검사는복부초음파검사이며, 간표면규칙성, 간실질에코조대, 간우엽및미상엽크기, 간문맥직경, 평균문맥혈류속도, 비장크기및복수유무등을조사한다. 복부초음파를이용한다양한간경변증진단법이보고되었지만아직까지국내에서초음파를이용한간경변증을진단하기위한기준은제시되지못하고있다. 1. 간경변증의형태학적변화 (1) 간표면결절성및간실질에코조대간표면결절성은간경변증진단에매우민감한소견으로재생결절, 섬유화반흔및간엽의비균일적위축과비대때문이다. 39,40 재생결절은직경이 2 mm~2 cm 정도로초음파에서고에코의섬유조직이나지방성결합조직에의하여둘러싸인저에코결절로보인다. 알코올간경변증, 담즙성간경변증에서는재생결절이대개 3 mm 이하인미세결절형이고 B형간염관련간경변증에서는대결절형이다. (2) 간엽의형태변화간경변증환자에서는우엽과좌엽내측구역이위축되고미상엽과좌엽외측구역이커진다. 미상엽 / 우엽비는초음파및 CT 에서간경변증진단에유용한지표이다. 41 초음파검사에서미상엽 / 우엽비가 0.65 이상이면 B형간염에의한간경변증은 66%, 다른원인에의한간경변증은 34% 의민감도로진단한다. 41 2. 간경변증의혈역동학적변화 (1) 간문맥확장및문맥혈류속도감소문맥압항진증이발생하면문맥혈류속도는감소하고, 문맥은확장되는데, 이는간경변증의진단에유용하다. 2,42 간섬유화가진행됨에따라문맥혈류속도는감소하므로간경변증환자에서문맥혈류속도는정상인보다감소하며비장은커진다. 43,44 정상인의문맥직경은 0.64~1.21 cm, 간경변증이있는환자에서는평균 1.2 cm으로알려져있으며문맥직경과비장크기는밀접한관련이있다. 2 (2) 간정맥파형의변화정상인의간정맥도플러초음파소견은삼상파형 (tri-phasic waveform) 이다. 45 이는간정맥이심장주기에영향을받아대정맥혈류방향이역전되는시기에같이역전되기때문이다. 그러나간경변증에서는간실질의탄력성이떨어지면서심장주기의영향을덜받게되어초기에는파형의역전없이진폭만낮아지고진행하면완전히편평파형 (flat waveform) 으로변한다. 46 이러한결과는한국인을대상으로한연구에서도확인되었다. 47 간정맥의도플러파형과간섬유화의관계를분석한보고에서는약한상관관계를보였다. 42,48 26
정재연 간섬유화의비침습적진단 Transient elastography (Fibroscan ) 을이용한간탄력도측정 Fibroscan (EchoSens, Paris, France) 은간내탄력파동의속도를측정하여간탄력도를평가하는장비이며비침습적으로간섬유화를정량적으로측정한다. 49 진동자와초음파변환기로이루어진탐촉자를환자의늑간에수직으로위치시킨후버튼을누르면, 진동으로유발된탄력파동이조직으로전달되고초음파변환기가포착하여탄력파동의속도를측정하게된다. 조직이딱딱할수록전파되는속도가빠른것을이용해간실질의탄력도를측정하는것이며, 단위는 kilopascal (kpa) 이고, 10회측정한중간값을결과로취한다. 측정되는간탄력도수치는 2.5~75 kpa 이다. 장점은통증이없고 100 회정도훈련후쉽게시행할수있으며, 약 5분만에빠른결과를얻을수있고, 재현성이높으며, 타장기의영향이없이직접간실질탄력도를측정하고, 간실질을 1 2 cm 부피로측정하여간생검보다 100 배이상검체용적이크므로전체간을더잘대변하는것이다. 하지만비만인경우 (BMI 28.0 kg/m 2 이상 ) 탄력도를측정할수없는경우가흔하며, 50 복수가있거나늑간공간이좁은경우는측정이불가능하다. 간탄력도측정은간경변진단에유용한방법으로보고되어있다. 51-54 간탄력도측정에대한연구는대부분이 C형간염바이러스에의한간경변증환자를대상으로하였으며간탄력도가 12.5~17.6 kpa 이상이면간경변증으로예측하였다. 51-54 간경변증의진단에서간탄력도측정의예민도는 73~87%, 특이도는 91~97%, 양성예측률은 77~95%, 음성예측률은 70~97% 였다. 만성 C형간염환자를대상으로한다기관연구에서간경변증의 AUROC 는 0.97 인반면 F2 이상의의미있는섬유화의 AUROC 는 0.79 로간탄력도측정의정확도는간경변에비하여의미있는섬유화의진단에서감소하였다. 51 그러나간탄력도측정으로중간정도의섬유화 (F2~F3) 를구분할수없고, 섬유화의조기진단에어려움이있으므로임상에서보편적으로이용하는데한계가있다. 55 간경변증의진단정확도는임상과혈액소견만으로진단하는것에비하여간탄력도수치를추가로제공할때더욱향상되었다. 56 저자등은 108 명의만성바이러스간염환자를대상으로간탄력도를측정하였고, 간섬유화와비교하였다. AUROC 곡선은 F2 이상에서 0.925 로정확도가높았으며, F3이상에서 0.718, F4는 0.796 이었다. 57 최근간탄력도는 ALT 상승에의해영향을받음이보고되고있다. 만성간염에서급성악화기에탄력도가 1.3~3 배증가하며, ALT 치가안정된경우에는탄력도에변화가없음이관찰되어급성악화가있는경우에탄력도측정을한차례만시행할경우실제보다높은섬유화단계로오진할수있다. 58 이러한경우악화된간염이호전됨에따라간탄력도는점차감소하였다. 간탄력도는 B형간염바이러스에의한간경변증에서는 AUROC 가 0.80 으로간경변진단의정확도가다소낮았다. 57 또한간경변환자에서대결절이있는경우, 조직학적활성도가없는비활동성간경변인경우에는간탄력도측정에위음성을보일수있다. 54 간탄력도는문맥압과연관이있으며식도정맥류의유무를예측할수있는가능성이제시되었다. 59,60 간탄력도측정의재현성은일반적으로양호한것으로알려져있으나지방간, BMI 의증가, F2 이하인경우에는재현성이감소하였다. 61 혈청표지자와 Transient elastography 의조합 혈청표지자들을조합한여러가지패널검사가나오고, 간탄력도측정의유용성이보고됨에따라만성 C형간염의경우에는간조직검사를시행하기전에정해진알고리듬에따라단계적으로비침습적혈청표지자들을분석함으로써진단율을향상시키고, 간조직생검의대상자를줄여보고자하는시도들이계속되고있다 ( 그림 1). 62 183 명의 C형간염환자를대상으로한연구에서간탄력도와혈청표지자인 Fibrotest 를조합하여 F2 이상섬유화와 27
대한간학회 간경변증 Figure 1. Proposed algorithm for clinical practice combining FibroScan and Fibrotest as first line assessment of hepatic fibrosis in patients with chronic hepatitis C F3 이상섬유화를진단하는데우수함을보였다. 52 간탄력도와 Fibroscan 의결과가일치하는 70~80% 의경우에 F2 이상을진단하는데 84%, F3 이상을 95%, F4의 94% 에서간생검결과와일치하였다. Castera 등은이러한결과를이용한진단알고리듬을제안하였고, 77% 의환자에서간생검을피할수있음을보였다. 52 동일저자들은 Fibroscan 은간섬유화를과소평가하며, Fibrotest 는반대로과대평가하는경향이있음을발표하였다. 다른연구에서 Fibroscan 과 fibrostest 의조합을이용한간섬유화의진단은정상 ALT 를가진 C형간염환자에서도유용하였다. 63,64 간섬유화진단을위한새로운시도 1. Proteomics 기법혈액을통한간섬유화예측은 proteome 분석기술을도입하는단계에까지이르렀다. Poon 등은 46명의만성 B형간염환자의혈청을 SELDI protein chip 을이용하여분석한결과중증섬유화와간경변증예측하는 30개의특징적양상을보고하였고, 이분석에서중증섬유화의예측에는 AUROC 값이 0.906, 간경변증의예측에는 0.921 로높은정확도를보였다. 65 다른연구에서는 HCV 와 schistosomiasis 동시감염환자에대한 10년간의전향적연구에서 hepatic mrna 와 YKL-40 및 TGF-β 의관련성을밝혔으며, 동시감염군에서빠르게섬유화가진행되는것과관련되었다. 66 Proteome 분석은한번의혈청검사로수백개이상의단백을분석할수있는장점은있으나, 기술적인한계가있으며, 비용문제등이있어현재는유용한혈청표지자를발견하는스크리닝방법으로이용되고있다. 간섬유 28
정재연 간섬유화의비침습적진단 화가진행됨에따라변화하는단백들을찾아간질환환자에서혈청농도를조사하고기존표지자들과정확도를비교하여최종적으로간섬유화및간경변증의진단에최적의간섬유화진단패널을개발할수있을것으로기대되나이를임상에적용시킬수있을지에대한연구가필요하다. 2. Glycomics 기법대부분의혈청당단백은간세포나형질세포에서합성되고, 간세포에서 asialoglycoprotein 및 mannose/nacetyl glucosamine 수용체는당단백의제거에중요한역할을한다. 따라서혈청 N-glycome profile 은간세포의변화및 B림프구의생리적기능에영향받는다. 최근 DNA sequencer/fragment 분석기술에기반하여간질환환자의혈액에서측정한혈청단백중 N-glycan 의 profile 은대상성간경변증과만성간염을구분하는데에 79% 의민감도, 86% 의특이도를보였고, 비대상성간경변증과의감별은 100% 의민감도및특이도를보였다. 67 또한보고된 GlycoCirrhotest 와 Fibrotest marker 를조합하면거의 100% 의특이도를보여간조직생검을대체할수있을지관심을모으고있다. 맺음말 만성간질환환자치료의궁극적인목표는간염의진행을막고, 간섬유화를호전시켜간질환으로인한사망률을감소시키는것이다. 국내간질환의대다수를차지하는 B형간염의경우지속적으로항바이러스제가개발되고있으며, 현재까지는주로 ALT, 혈청 HBV DNA, HBeAg/antiHBe 등의혈액검사소견으로치료반응을판정하고있다. 향후이상적인간섬유화표지자의조건을만족하는혈청표지자가개발되고, 여기에 Fibroscan 및영상진단방법이발전하여이들을조합한비침습적간경변증진단법이확립된다면간섬유화및간경변증의진단뿐아니라치료반응판정에도쉽게이용할수있으면서도신뢰할만한진단법으로자리매김할것이다. 참고문헌 1. Afdhal NH, Nunes D. Evaluation of liver fibrosis: a concise review. Am J Gastroenterol 2004;99:1160-1174. 2. Aube C, Oberti F, Korali N, Namour MA, Loisel D, Tanguy JY, et al. Ultrasonographic diagnosis of hepatic fibrosis or cirrhosis. J Hepatol 1999;30:472-478. 3. Needleman L, Kurtz AB, Rifkin MD, Cooper HS, Pasto ME, Goldberg BB. Sonography of diffuse benign liver disease: accuracy of pattern recognition and grading. AJR Am J Roentgenol 1986;146:1011-1015. 4. Piccinino F, Sagnelli E, Pasquale G, Giusti G. Complications following percutaneous liver biopsy. A multicentre retrospective study on 68,276 biopsies. J Hepatol 1986;2:165-173. 5. Wong VS, Hughes V, Trull A, Wight DG, Petrik J, Alexander GJ. Serum hyaluronic acid is a useful marker of liver fibrosis in chronic hepatitis C virus infection. J Viral Hepat 1998;5:187-192. 6. Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Lancet 2001;357:1069-1075. 7. Williams AL, Hoofnagle JH. Ratio of serum aspartate to alanine aminotransferase in chronic hepatitis. Relationship to cirrhosis. Gastroenterology 1988;95:734-739. 8. Wai CT, Greenson JK, Fontana RJ, Kalbfleisch JD, Marrero JA, Conjeevaram HS, et al. A simple noninvasive index can predict both significant fibrosis and cirrhosis in patients with chronic hepatitis C. Hepatology 29
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