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1 The Korean Journal of Hepatology 2009 ; 15 : DOI: /kjhep 만성간질환에서혈청 retinol binding protein 4 의임상적의의 Abstract 가톨릭대학교의과대학내과학교실, 가톨릭대학교의과학연구원 1 권정현 박성태 1 김기대 1 유찬란 김진동 우현영장정원 1 김창욱 배시현 최종영 윤승규 The value of serum retinol-binding protein 4 levels for determining disease severity in patients with chronic liver disease Jung Hyun Kwon, M.D., Seong Tae Park 1, Gi Dae Kim, Ph.D. 1, Chan Ran You, M.D., Jin Dong Kim, M.D., Hyun Young Woo, M.D., Jeong Won Jang, M.D. 1, Chang Wook Kim, M.D., Si Hyun Bae, M.D., Jong Young Choi, M.D., Seung Kew Yoon, M.D. Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea 1 Catholic Research Institutes of Medical Science, Seoul, Korea Backgrounds/Aims: Serum retinol-binding protein 4 (RBP4) is known to be a specific transport protein for retinol, and has recently been reported to be associated with insulin resistance. Hyaluronic acid (HA) is a well-known marker of liver fibrosis. In this study, the degree to which serum RBP4 levels can be used to predict disease severity in patients with chronic liver disease (CLD) was evaluated. Methods: Serum levels of RBP4 and HA were measured in 573 CLD patients [235 with chronic hepatitis (CH), 230 with liver cirrhosis Child-Pugh grade (Child) A, and 108 with liver cirrhosis with Child B and C] and 40 normal controls. Results: The mean age of the whole cohort was 53.1 years and the causes of CLD were hepatitis B virus (61.9%), hepatitis C virus (9.8%), alcohol (9.0%), and nonalcoholic steatohepatitis (3.8%). Serum levels of RBP4 significantly reduced and HA increased with disease condition, from none (normal controls) to advanced cirrhosis (normal control: RBP4 4.3±0.1 mg/dl, HA 25.3±28.1 ng/ml; CH: RBP4 3.6±0.1 mg/dl, HA 75.5±7.8 ng/ml; cirrhosis with Child A: RBP4 2.6±0.1 mg/dl, HA 184.4±14.5 ng/ml; and cirrhosis with Child B and C: RBP4 1.6±0.1 mg/dl, HA 656.5±86.7 ng/ml; P<0.001, respectively). Serum RBP4 level was a distinguishing factor at the early stage of CLD between CH and Child A cirrhosis (post-hoc test; P<0.001) and was correlated with histological fibrosis score (n=80, P<0.05) and several biochemical factors. Antiviral therapy (n=45, median interval 1,205 days) resulted in an improvement in serum RBP4 levels (P=0.001). Conclusions: The results of our study suggest that RBP4 is a serologic marker for disease severity in patients with CLD. It could also be useful as an early marker of CLD and of the relative success of antiviral therapy. (Korean J Hepatol 2008; 15:59-69) Key words: Chronic liver disease; Serologic marker; Retinol-Binding Proteins; Plasma; Hyaluronic Acid Received November 24, 2008; revised February 23, 2009; accepted February 23, 2009 Abbreviations: ALT, alanine aminotransferase; APRI, AST/Platelet ratio index; AST, aspartate aminotransferase; CH, chronic hepatitis; CLD, chronic liver disease; HA, hyaluronic acid; RBP4, retinol binding protein 4; ROC, receiver operating characteristic Corresponding author: Si Hyun Bae, baesh@catholic.ac.kr; Phone: 02) ; Fax: 02) 주소 : 서울시서초구반포동 505, 가톨릭대학교의과대학내과학교실 ( 우 ) This work was supported by a grant from Ministry for Health, Welfare and Family Affairs, Republic of Korea (no. A050021) and the Soungeui Foundation of the Catholic University of Korea for Medical Research

2 The Korean Journal of Hepatology : Vol. 15. No 서론 Retinol binding protein 은혈장과세포내에여러가지형태로존재하는것이알려져있는데, 이중혈청 retinol binding protein 4(RBP4) 는 1968년 Goodman 등 1 에의해처음보고된이후, 간에서주로합성되며비타민 A인레티놀과결합하여이를전달하는운반단백질 (transporter) 로알려져왔다. 2 이외에도혈청 RBP4는만성간질환어린이에서비타민 A의상태를알수있는지표, 3 간절제술후간부전에대한 acute-phase protein, 4 동물모델에서약물유발성간독성을혈청 lactate dehydrogenase 나 aspartate aminotransferase(ast) 보다더잘반영하는표지자 5 등으로보고된바가있으나널리사용되지않았다. 그러나최근지방세포에서분비된혈청 RBP4와인슐린저항성과의연관성이밝혀지면서, 6 그임상적중요성이크게강조되었고, 당뇨병이나비알코올지방간질환환자에서혈청 RBP4 가증가되었다는많은보고가있었다 또한고인슐린혈증과내당장애는대다수의간경변증환자에서도나타나는현상으로, 11 인슐린저항성은간질환의진행과생존율에위험인자라고알려져있다. 12,13 만성간질환은일반적으로원인과상관없이반복적인염증반응과치유과정이장기간진행되면서간섬유화를거쳐간경변증으로진행한다. 간조직검사의제한성으로, 혈청지표를이용하여간섬유화의정도를측정하려는많은연구가있어왔다 지금까지알려진간섬유화의직접적인지표로는세포외기질대사를직접반영하는혈청 hyaluronic acid(ha), type 1과 type 4 collagen, procollagen III peptide, matrix metalloproteinase 와 tissue inhibitor of matrix metalloproteinase 등이있고, 간기능의변화와관련한간접적인지표로는 AST/ alanine aminotransferase(alt) ratio, AST/Platelet ratio index(apri) 등이있으며여러인자들을조합하여만든 Fibrotest, FibroSpect, Hepascore 등이있다. 20 이중혈청 HA는세포외공간에있는다당류로, 간질환으로간내배설이감 소되거나간내생산이증가된경우혈청에서증가하여간섬유화의유용한표지자로알려져있다. 15,18,21,22 본저자들은혈청 HA가간섬유화와간질환의경중을예측하는비침습적인표지자로보고한바있다. 17 지금까지혈청 RBP4는서구에흔한비알코올지방간염환자나만성 C형간염환자에서의인슐린저항성과관련된연구가주를이루었다. 이번연구에서는혈청 RBP4 수치가만성간염, 대상성간경변증, 비대상성간경변증등만성간질환의진행정도를반영할수있는지를알아보고자하였다. 대상및방법 1. 대상 2001년 1월부터 2008년 8월까지강남성모병원소화기내과를방문하여혈청 RBP4, HA를검사한 573명의만성간질환환자와 40명의정상군, 총 613명의자료를후향분석하였다. 만성간질환은만성간염과간경변증으로정의하였고, 간경변증은임상기준에부합되거나간조직생검에서 stage IV의섬유화를보인경우로정의하였다. 간경변증의임상기준은혈소판 150,000/ mm 3, 초음파검사나컴퓨터단층촬영술에서비장비대를동반하는간표면혹은내부의결절성변화와문맥압항진소견, 내시경검사에서확인된식도나위정맥류의존재등 3가지소견중두가지이상을만족할때로정의하였다. 23,24 간경변증으로분류된환자는다시 Child-Pugh 등급에따라구분하였다. 만성간염은만성간질환환자중간경변증의임상적증거가없는환자로정의하였고, 간조직생검을시행한경우에는 stage III 이하의섬유화를보인경우에포함하였다. 정상대조군 40명은동일기간동안소화기내과를방문하여혈청 RBP4와 HA를검사한정상인으로하였고, 간염바이러스보유자는제외하였다. 간질환은원인에따라 B형바이러스성, C형바이러스성, 알코올성, 자가면역성, 비알코올지방간, 기타원인에의한것으로구분하였다. 심각한다른전신질환이있거나, 간농양이나담

3 Jung Hyun Kwon, et al. Serum retinol binding protein 4 in chronic liver disease 관염과같이담도계의문제로비정상간수치를보인경우의환자는제외하였다. 또한급성 A형간염이나약물에의한급성독성간염, 만성바이러스간염환자가급성악화 (acute exacerbation, 정상상한치의 10배이상이고기저치의 2배이상인 ALT 의간헐적상승 ) 25 된경우도제외하였다. 이연구는본기관의윤리위원회의승인을받았다. 2. 조사항목환자의나이와성별, 간질환의원인인자를조사하였고, 혈청 RBP4와 HA와같은시기에검사한혈청 AST와 ALT, 혈청알부민, 혈소판수, 프로트롬빈시간 (prothrombin time), 총빌리루빈, 공복혈당, 트랜스페린 (transferrin) 을조사하였다. 동일시기의영상검사에서복수의유무, 내시경검사에서정맥류의존재와출혈유무, 간성혼수의기왕력을함께조사하였다. 바이러스간염환자의경우혈청 RBP4검사시기를고려하여항바이러스치료유무와치료기간을조사하였고, 간조직생검의경우혈청 RBP4검사시기와 3개월차이이내이면서항바이러스치료등의영향을받지않은경우로제한하여자료를수집하였다. 3. 혈청 RBP4 와 HA의측정혈청 RBP4는면역비탁법 (Nephelometry) 에의한자동분석 (Dade Behring, Marburg, Germany) 으로측정하였다. 혈청 HA는효소결합단백질분석법 (Enzyme-Linked Binding Protein Assay) 을이용한효소면역측정법 (EIA) 키트 (LPIAS-HA, MCM, Japan) 로측정하였다. 4. 통계통계처리프로그램 SPSS(14 th ed. Chicago, USA) 을이용하여분석하였다. 기저자료 (baseline data) 의특성은연속형변수인경우에는평균 ± 표준편차로, 범주형변수인경우에는빈도 ( 백분율 ) 로요약하였다. 각질환의정도에따른연속형변수의비교는분산분석법 (ANOVA) 을이용하였고, 사후검정 (Post-hoc test) 은 Tukey의방법을이용하였 다. 혈청 HA와 RBP4가각질환을진단하는데에대한 ROC(Receiver Operating Characteristic) 곡선을그려, 실제임상에서참고할수있는 cut-off 수치를구했고, 다른검사수치와의상관성은피어슨상관계수 (Pearson s correlation coefficient) 를사용하여검증하였다. 항바이러스치료전후의간기능생화학검사및섬유화지표의비교는 paired t-test를이용하여검증하였다. 각검정의유의수준은 0.05 미만으로정의하였다. 결과 1. 만성간질환환자군과정상군의특성혈청 RBP4 와 HA를검사한 613명의평균나이는 53.1세였고, 남녀성비는 410:203 이었다 ( 표 1). 정상군은 40명이었고, 만성간질환환자군 573명중만성간염은 235명, Child-Pugh A등급간경변증은 230명, Child-Pugh B와 C등급간경변증은 108명이었다. 간질환의원인으로는 B형간염 380명 (61.9%), C형간염 60명 (9.8%), 알코올간염 55명 (9.0%) 순이었다. 혈청검사와동일기간내에시행했던간조직생검환자수는 80명이었으며, 항바이러스치료를시행한 169명중 45명에서치료전후로혈청 RBP4와 HA의호전유무를조사할수있었다. 2. 간질환의진행에따른혈청 RBP4 및기타인자들의변화혈청 RBP4는정상군, 만성간염환자를거쳐 Child-Pugh 등급에따른간경변증으로진행할수록유의하게감소하였고 (P<0.001), 이와반대로혈청 HA는간질환이진행할수록유의하게증가하였다 (P<0.001)( 표 2). 혈청알부민도역시정상군에서만성간염, 간경변증으로진행할수록유의하게감소하였고 (P<0.001), 혈청트랜스페린도간질환의진행에따라감소하였다 (P<0.001). 공복혈당은정상군에서간경변증으로진행할수록의미있게증가하였다 (P=0.004)( 표 2). 혈청 RBP4와 HA, 알부민, 트랜스페린, 공복혈

4 대한간학회지제 15 권제 1 호 2009 Table 1. Basal characteristics of study population Normal control Chronic hepatitis Cirrhosis Cirrhosis Child A Child B & C Total N (%) 40 (6.5) 235 (38.3) 230 (37.5) 108 (17.6) 613 Age (mean±sd) 45.8± ± ± ± ±13.7 Male/female 18/22 173/62 155/75 64/44 410/203 Cause of CLD (%) HBV (61.9) HCV (9.8) Alcohol (9.0) Autoimmune (0.8) Unknown (8.2) Normal (6.5) NAFLD (3.8) Liver biopsy Antiviral therapy NAFLD, Non-alcoholic fatty liver disease. Table 2. Serum retinol binding protein 4 and other markers of liver fibrosis and hepatic function in patients with chronic liver disease Normal control Chronic hepatitis Cirrhosis Child A Cirrhosis Child B & C P-value* RBP4 4.3± ± ± ±1.0 <0.001 HA 25.3± ± ± ±853.9 <0.001 TF 241.8± ± ± ±50.7 <0.001 Albumin 4.5± ± ± ±0.4 <0.001 FBS 93.8± ± ± ± Data are presented as mean±sd. *By ANOVA test. RBP4, retinol binding protein; HA, hyaluronic acid; TF, transferrin; FBS, fasting blood sugar. 당측정치의사후분석을시행하여질환의각단계에따른차이를알아보았다 ( 그림 1). 혈청 RBP4는만성간염환자군에서 Child-Pugh A등급간경변증환자군과 Child-Pugh B와 C등급의간경변증환자군과각각차이를보였고 (P<0.001, P<0.001), Child-Pugh A등급과 B와 C등급간경변증환자군 (P<0.001) 간에도의미있는차이를보였다. 또한, 혈청 RBP4는만성간염환자군에서정상군에비하여감소하는경향을보였다 (P=0.054)( 그림 1A). 반면혈청 HA는만성간염환자군에서는 Child- Pugh A등급과 B와 C등급의간경변증환자군과 각각차이를보였으나 (P=0.025, P<0.001), 정상군에서는 Child-Pugh B와 C등급의진행성간경변증환자군과만차이를보였고 (P<0.001), 정상군과만성간염환자군, 정상군과 Child-Pugh A등급환자군사이에서는의미있는차이를보이지않았다 ( 그림 1B). 간의생합성능표지자로알려진혈청알부민은정상군에서 Child-Pugh 등급에따른간경변증으로진행할수록감소하였고, 사후분석에서도각단계별로진행함에따라모두의미있는감소를보여정상군과만성간염환자군사이에서도차이를보였다 ( 그림 1C). 혈청트랜스페린의경우 Child

5 권정현외 10 인. 만성간질환에서혈청 Retinol binding protein 4 의임상적의의 A B C D E Figure 1. Tukey s post-hoc analysis of retinol-binding protein 4 (RBP4) and other factors as a function of the severity of chronic liver disease. (A) Serum RBP4 exhibited significant reductions between each disease condition from normal control to advanced liver cirrhosis. (B) Serum hyaluronic acid (HA) exhibited significant increases with increased disease severity from chronic hepatitis to advanced liver cirrhosis. This parameter did not differ between normal controls and patients with chronic hepatitis and between normal controls and patients with Child A cirrhosis. (C) Serum albumin exhibited significant reductions between each disease condition from normal control to advanced liver cirrhosis. (D) There were significant differences in serum transferrin levels between patients with Child B and C cirrhosis and those with other degrees of chronic liver disease, including none (normal controls). (E) There was a significant difference in serum fasting blood sugar between normal controls and patients with cirrhosis. P-values were obtained by ANOVA with Tukey s post-hoc analysis. CH, chronic hepatitis; Child A LC, Child-Pugh class A liver cirrhosis; Child B & C LC, Child-Pugh class B and C liver cirrhosis. Pugh B와 C등급의진행성간경변증군에서만이전단계의간질환군과차이를보이면서감소하였고 ( 그림 1D), 공복혈당은정상군에서만간경변증환자군과차이를보였다 ( 그림 1E). Child-Pugh A등급의조기간경변증진단을위 한혈청 RBP4와 HA의 ROC곡선 ( 정상 + 만성간염 vs. Child-Pugh A등급간경변증 ) 에서 area under the curve(auc) 가각각 0.717(P<0.001, 95% confidence interval(ci) 0.669~0.766) 과 0.802(P< 0.001, 95% CI 0.760~0.843) 였다. 한편, Child

6 The Korean Journal of Hepatology : Vol. 15. No A B Figure 2. Receiver operating characteristic (ROC) curve of the markers of liver cirrhosis. (A) The area under the ROC curve for Child-Pugh class A liver cirrhosis is [95% confidence interval (CI), ] for HA, (95% CI, ) for RBP4, and (95% CI, ) for the aspartate aminotransferase/platelet ratio index (APRI). (B) The area under the ROC curve for Child-Pugh class B and C liver cirrhosis is (95% CI, ) for HA, (95% CI, ) for RBP4, and (95% CI, ) for APRI. Table 3. Correlation between serum RBP4 and other markers of liver fibrosis and hepatic function in patients with chronic liver disease (N=613) Pearson s correlation coefficient P-value* Hyaluronic acid <0.001 Transferrin <0.001 Albumin <0.001 Total bilirubin <0.001 Alanine aminotransferase Prothrombin time <0.001 Fasting blood sugar APRI <0.001 APRI, aspartate aminotransferase/platelets ratio index. *By bivariate correlation. Pugh B와 C등급간경변증에대한혈청 RBP4와 HA의 ROC곡선 ( 정상 + 만성간염 +Child-Pugh A등급간경변증 vs. Child-Pugh B와 C등급간경변증 ) 에서 AUC는각각 0.856(P<0.001, 95% CI 0.815~ 0.898) 과 0.919(P<0.001, 95% CI 0.893~0.945) 였다 ( 그림 2). 혈청 RBP4 측정치 ( 정상범위 3.0~6.0 mg/dl) 3.37 mg/dl 를기준으로 Child-Pugh A등급간경변증을진단하고자할때민감도는 80.4%, 특이도는 54.9% 를보였고 ( 그림 2A), 측정치 1.81 mg/dl 를기준으로 Child-Pugh B와 C등급간경변증을예측하고자할때민감도는 82.1%, 특이도는 75.6% 였다 ( 그림 2B). 3. 혈청 RBP4와다른혈청인자및간섬유화정도와의관련성혈청 RBP4가간기능을나타내는여러혈청인자및간섬유화정도와갖는관련성을알아보았다 ( 표 3). 혈청 RBP4 는프로트롬빈시간, 혈청알부민, 혈청트랜스페린, APRI, 혈청 HA, 혈청총빌리루빈순으로의미있는상관관계를보였고, 피어슨상관계수 0.5 이상의관련은프로트롬빈시간에서보였다. 간조직생검을시행한 80명의환자를 Knodell Index에따라섬유화정도를 1/2기, 3기, 4기의세군으로나누었을때, 섬유화정도가진행할수록혈청 RBP4는의미있게감소하였고 (P=0.018), 혈청 HA는증가하였다 (P=0.033). 각단계별로사후분석

7 Jung Hyun Kwon, et al. Serum retinol binding protein 4 in chronic liver disease A B Figure 3. Tukey s post-hoc analysis of RBP4 and HA according to the fibrosis score of liver biopsy tissue (n=80). (A) Serum RBP4 exhibited a significant reduction from stage I/II to stage IV fibrosis and a downward (nonsignificant) trend from stage I/II to stage III fibrosis. (B) Serum HA exhibited a significant increase from stage I/II to stage IV fibrosis. There was no difference between stages I/II and III fibrosis, or between stages III and IV fibrosis. P value was obtained by ANOVA test with Tukey s post-hoc analysis. 1, 2, 3, and 4=stages I, II, III, and IV fibrosis, respectively (from analysis of liver biopsy tissue). Table 4. Changes of fibrosis markers and liver function after antiviral treatment Before treatment After treatment P-value* RBP4 (mg/dl) 2.20± ± HA (ng/ml) ± ±1, TF (mg/dl) ± ± ALT (U/L) ± ± ALB (g/dl) 3.68± ± PLT (10 9 /L) ± ± PT (%) 78.78± ± HBV DNA (IU/mL) ± ± <0.001 Data are presented as mean±sd. *By paired t-test. RBP4, retinol binding protein; HA, hyaluronic acid; TF, transferrin; ALT, alanine aminotransferase; TB, total bilirubin; ALB, albumin; PLT, platelets; PT, prothrombin time. 을시행했을때, 섬유화정도 1, 2기와 3기사이에서혈청 HA는차이를보이지않았으나혈청 RBP4 는 1, 2기보다 3기에서더감소하는경향 (P=0.080) 을보여조기섬유화단계군사이에차이를보였다 ( 그림 3). 4. 항바이러스치료에따른혈청 RBP4와 HA의변화항바이러스치료전후로혈청 RBP4와 HA를측 정한환자 45명에서혈청 RBP4와 HA를포함한여러혈청인자들의변화를비교하였다 ( 표 4). 항바이러스치료전후로의기간은중앙값 1,205일 (113~ 2,787일 ) 이었다. 항바이러스치료후에치료전과비교하여혈청 RBP4와알부민, 트랜스페린은의미있게증가하여호전되었고, 혈청 ALT와 HBV DNA는의미있게감소하였으나, 혈청 HA는차이를보이지않았다

8 대한간학회지제 15 권제 1 호 2009 고찰혈청검사를통하여간질환의중증도를측정하는것은임상에서매우유용하고중요한일이다. 이번연구에서혈청 RBP4 는정상군에서진행성간경변증으로의진행에따라각단계별로유의하게감소함을보여주었고, 만성간질환의조기단계에서부터차이를볼수있는인자인것으로나타났다. 이미비대상성간경변증으로진행한경우는혈청검사외에도임상증후나이학적검사를통해서그진행정도를알수있는경우가많지만실제간염바이러스보유자나만성간염환자군에서조기간경변증으로의진행을구분하는것은현실적으로어려운실정이다. 혈청 RBP4 는만성간질환의초기단계에서부터차이를보였다는점외에도이미알려져있는간기능을대변하는여러생화학적인자들과의높은관련성을보였다. 현재만성간질환의진행정도와혈청 RBP4 의상관관계에대한보고는드물며, 26,27 이전의연구에서도혈청 RBP4 의증가가인슐린저항성과연관되어있고만성간질환환자에서인슐린저항성이증가하기때문에, 간질환이진행함에따라혈청 RBP4가증가할것으로예상되었지만, 결과는본연구와같이오히려감소하였다. 이는혈청 RBP4 가간세포에의해서주로합성되고분비되기때문에, 28 간경변증환자에서는간내생합성능의절대적감소가더큰영향을미치기때문이라고생각할수있다. 동물모델에서의연구결과도이러한결과를뒷받침하는데, 인슐린저항동물모델에서지방조직의 RBP4 발현은증가하였지만간에서의발현은변화를보이지않았으며, 6 반대로간경변증동물모델에서는간에서의 RBP4 발현이정상대조군과비교하여감소한다고보고하였다. 26 혈청 RBP4 가간외에도신장, 고환의세관주위세포와버팀세포 (peritubular and Sertoli cell), 망막색소상피 (retinal pigment epithelium), 뇌맥락막총 (choroid plexus of brain) 등에서도합성되는것으로보고되어있지만, 28 상기동물모델에서의연구를보면간경변증에서의 RBP4 감소는간에서의합성 감소와직접적인연관이있다고할수있다. 또지용성비타민 A는미포용해화 (micellular solubilization) 를위해내강내담즙농도가중요한데, 간질환으로지용성비타민흡수장애에의해비타민 A가감소하면되먹임 (feedback) 기전에의해간세포에서 RBP4 분비가감소되는데이러한기전도혈청 RBP4 감소의원인으로생각할수있다. 3,29 본연구에서혈청 RBP4는 Child-Pugh 등급에포함되는인자들과높은관련성을보여간의단백질합성능과비례함을보였다. 본연구와혈청 RBP4와간질환진행과의관련성을보고한이전두연구와의차이점은혈청 RBP4치가만성간질환의초기단계에서부터정상군과차이를보인점이다. 즉, 혈청 RBP4는정상군보다만성간염환자군에서, 다시 Child A 등급간경변증환자군에서더감소하였다. 또한간경변증진단에대한 ROC곡선에서는간섬유화의지표로잘알려진혈청 HA가혈청 RBP4보다조금씩더높은 AUC를보여주었지만, 혈청 RBP4 는혈청 HA와는달리초기섬유화 1, 2기와 3기간에감소하는경향을보였다. 물론이러한변화는진행성간경변증이나섬유화 4기에서는정상군과더뚜렷한차이를보였다. 이전 Bahr 등의보고에서는혈청 RBP4 가 Child-Pugh A등급간경변증환자와정상군간에차이를보이지않았으나대상환자수가각각 5명과 20명으로적었고만성간염환자군은비교대상에포함되지않았다. 27 또 Yagmur 등의보고에서는 99명의정상대조군과 35명의 Child-Pugh A등급환자에서는차이를보였지만간경변증이없는것으로판명된간질환환자 ( 간세포암종이나유전질환으로인한간이식대상자 ) 18명은정상군과차이를보이지않았다. 26 그러나본연구에포함된만성간염환자는실제임상에서흔하게볼수있는바이러스간염환자가대부분이었으며, 대상환자수도 235명으로정상군이나 Child-Pugh A등급간경변증환자와의차이를보기에충분하였다. 혈청알부민은 Child-Pugh 등급의구성요소로알부민합성속도가 Child-Pugh 등급과비례한다고알려져있으며, 30 이번연구에서도간경변증환자군에

9 권정현외 10 인. 만성간질환에서혈청 Retinol binding protein 4 의임상적의의 서는 Child-Pugh 등급에따라혈청알부민은감소하였다. 뿐만아니라정상군과만성간염환자군사이에서도의미있는차이를보여간기능을반영하는유용한지표임을확인할수있었다. 앞서언급하였듯이비대상성간경변증으로진행한경우보다는간염바이러스보유자나만성간염환자군에서조기간경변증으로의진행을구분하는것이임상적으로의미가있으며, 이러한점에서혈청 RBP4는만성간질환초기단계에서부터간질환의진행정도를보여주는새로운지표로고려할수있겠다. 이번연구에서공복혈당은이전의보고들과마찬가지로간질환이진행할수록증가하였으나, 혈청 RBP4와공복혈당은관련이없는것으로나타났다. 인슐린저항성의여러지표들을측정하지못한것은이번연구의제한점이지만혈청 RBP4 가간경변증환자에서감소되었기때문에, 증가된인슐린저항성과는관련이없음을간접적으로시사한다. 향후에는대사증후군의일환으로여겨지는비알코올지방간환자뿐아니라만성바이러스간질환환자에서도, 증가된인슐린저항성을설명할수있는인자에관한연구가필요하겠다. 또한트랜스페린은혈청철운반체로, 혈색소침착증 (hemochromatosis) 에서나타나는 HFE C282Y 유전자변이가비알코올지방간환자에서있을경우더진행된간섬유화와관련이있다는보고가있었다. 31 국내에서도비알코올지방간환자에서혈중철분과잉이간섬유화의위험인자일가능성이제시되었다. 32 이번연구에서도만성간질환의진행에따라혈청트랜스페린은의미있게감소하였으나간섬유화정도에따른차이는보이지않아추가연구가필요하겠다. 최근항바이러스치료의등장과함께간질환의진행정도와예후를예측할수있는혈청표지자에대한필요가더절실하게되었다. 특히이번연구에서후향적분석이라는제한점은있으나항바이러스치료전후로여러혈청인자들중에서혈청 HA는유의한차이가없었지만혈청 RBP4와알부민이호전된점은주목할만한새로운결과이다. 향후항바이러스치료기간동안혈청 RBP4 를추적관찰하는것이간기능의호전정도를보는데에임상적으로도움이될수있겠다. 이번연구는전체대상환자중간조직생검을시행한환자의비율이적고, 조직검사를시행하지않은경우임상기준으로만성간염환자군과간경변증환자군을구분하였다는제한점이있다. 아직까지단일인자로간섬유화를정확하게대변할수있는지표가없으며, 20 아직도간조직검사는간섬유화의표준검사로남아있다. 따라서간섬유화진단의비침습적표지자로서의혈청 RBP4 유용성에대해서는, 이미간섬유화의표지자로알려진 HA 보다상관계수가낮고, 분석대상이작아향후연구가필요하겠다. 결론적으로혈청 RBP4는정상군에서진행성간경변증으로의진행에따라각단계별로유의하게감소하였고, 간의생합성능을반영하는여러혈청인자들과상관관계를보였다. 또한혈청 RBP4 는만성간질환의초기단계에서부터차이를보였고항바이러스치료후호전되었다. 따라서혈청 RBP4 는만성간질환환자에서질환의진행정도를평가할수있는새로운지표로의미가있겠다. 요약목적 : 혈청 retinol binding protein 4(RBP4) 는레티놀의특이적인운반단백질로알려져있었으나최근인슐린저항성과의연관성이보고되었다. 혈청 hyaluronic acid(ha) 는간섬유화의지표로알려져있다. 이번연구는만성간질환환자에서혈청 RBP4의간질환의진행정도를반영하는혈청표지자로서의역할을알아보고자하였다. 대상과방법 : 강남성모병원소화기내과를방문하여혈청 RBP4와 HA를검사한 573명 ( 만성간염환자 235 명, Child-Pugh A등급간경변증환자 230명, Child-Pugh B와 C등급간경변증환자 108명 ) 의만성간질환환자와정상대조군 40명의결과를분석하였다. 결과 : 대상환자의평균나이는 53.1세였고, 남녀비율은 410:203 이었다. 원인별로는 B형간

10 The Korean Journal of Hepatology : Vol. 15. No 염바이러스에의한간질환이 61.9% 로가장많았고, C형간염바이러스와알코올에의한간질환이각각 9.8% 와 9.0%, 비알코올지방간질환이 3.8% 였다. 혈청 RBP4치는정상대조군에서진행성간경변증으로진행할수록유의하게감소하였고, 반대로혈청 HA치는간질환이진행할수록증가하였다 ( 정상대조군, 만성간염, Child-Pugh A등급간경변증, Child-Pugh B와 C등급에서각각 RBP4는 4.3± 0.1, 3.6±0.1, 2.6±0.1, 1.6±0.1 mg/ dl, HA는 25.3 ±28.1, 75.5±7.8, 184.4±14.5, 656.5±86.7 ng/ml, P<0.001). 사후분석에서혈청 RBP4 는만성간염환자군과 Child-Pugh A등급간경변증환자군간에도차이를보여조기에만성간질환을구분할수있었다. 혈청 RBP4와 HA는간조직검사의섬유화정도와상관관계를보였고 (n=80, P<0.05), 다른혈청간기능지표들과도관련성을보였다. 항바이러스치료전후로혈청 RBP4와 HA를측정하였던 45 명에서 ( 관찰기간의중앙값 1,205일 ), 치료후혈청 RBP4치와혈청알부민치, ALT치, HBV DNA 수치는유의하게호전되었으나 HA 수치는차이를보이지않았다. 결론 : 혈청 RBP4는만성간질환환자에서간질환의진행정도에따라감소하여질환의진행정도를평가할수있는새로운지표로의미가있으며, 항바이러스치료후간질환의호전을관찰할수있는지표로고려할수있겠다. 색인단어 : 만성간질환, 혈청표지자, 레티놀결합단백질, 히알루론산 참고문헌 1. Kanai M, Raz A, Goodman DS. Retinol-binding protein: the transport protein for vitamin A in human plasma. J Clin Invest 1968;47: Blomhoff R, Green MH, Berg T, Norum KR. Transport and storage of vitamin A. Science 1990;250: Feranchak AP, Gralla J, King R, Ramirez RO, Corkill M, Narkewicz MR, et al. Comparison of indices of vitamin A status in children with chronic liver disease. Hepatology 2005;42: Ananian P, Hardwigsen J, Bernard D, Le Treut YP. Serum acute-phase protein level as indicator for liver failure after liver resection. Hepatogastroenterology 2005;52: Isozaki M, Masubuchi Y, Horie T. Retinol binding protein in plasma to evaluate the hepatotoxicity of rats treated with CCl4. Res Commun Mol Pathol Pharmacol 2001;110: Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM, et al. Serum retinol binding protein 4 contributes to insulin resistance in obesity and type 2 diabetes. Nature 2005;436: Wu H, Jia W, Bao Y, Lu J, Zhu J, Wang R, et al. Serum retinol binding protein 4 and nonalcoholic fatty liver disease in patients with type 2 diabetes mellitus. Diabetes Res Clin Pract 2008;79: Graham TE, Yang Q, Bluher M, Hammarstedt A, Ciaraldi TP, Henry RR, et al. Retinol-binding protein 4 and insulin resistance in lean, obese, and diabetic subjects. N Engl J Med 2006;354: Seo JA, Kim NH, Park SY, Kim HY, Ryu OH, Lee KW, et al. Serum retinol-binding protein 4 levels are elevated in non-alcoholic fatty liver disease. Clin Endocrinol (Oxf) 2008;68: Petta S, Camma C, Di Marco V, Alessi N, Barbaria F, Cabibi D, et al. Retinol-binding protein 4: a new marker of virus-induced steatosis in patients infected with hepatitis c virus genotype 1. Hepatology 2008;48: Bugianesi E, McCullough AJ, Marchesini G. Insulin resistance: a metabolic pathway to chronic liver disease. Hepatology 2005;42: Sud A, Hui JM, Farrell GC, Bandara P, Kench JG, Fung C, et al. Improved prediction of fibrosis in chronic hepatitis C using measures of insulin resistance in a probability index. Hepatology 2004;39: Muzzi A, Leandro G, Rubbia-Brandt L, James R, Keiser O, Malinverni R, et al. Insulin resistance is associated with liver fibrosis in non-diabetic chronic hepatitis C patients. J Hepatol 2005;42: Afdhal NH, Nunes D. Evaluation of liver fibrosis: a concise review. Am J Gastroenterol 2004;99: 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: 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: Kim CW, Yoon SK, Jo BS, Shin JY, Jang JW, Choi JY, et al. Prediction of hepatic fibrosis using serum hyaluronic acid in patients with chronic liver disease. Korean J Gastroenterol 2003;42: Fontana RJ, Goodman ZD, Dienstag JL, Bonkovsky HL, Naishadham D, Sterling RK, et al. Relationship of serum fibrosis markers with liver fibrosis stage and collagen content in patients with advanced chronic hepatitis C. Hepatology 2008;47: Poynard T, Imbert-Bismut F, Ratziu V, Chevret S, Jardel C, Moussalli J, et al. Biochemical markers of liver fibrosis in patients infected by hepatitis C virus: longitudinal

11 Jung Hyun Kwon, et al. Serum retinol binding protein 4 in chronic liver disease validation in a randomized trial. J Viral Hepat 2002;9: Manning DS, Afdhal NH. Diagnosis and quantitation of fibrosis. Gastroenterology 2008;134: Kim MY, Baik SK, Jang YO, Suk KT, Kim JW, Kim HS, et al. Serum hyaluronic acid level: correlation with quantitative measurement of hepatic fibrosis in a cirrhotic rat model. Korean J Hepatol 2008;14: Engstrom-Laurent A, Loof L, Nyberg A, Schroder T. Increased serum levels of hyaluronate in liver disease. Hepatology 1985;5: Iloeje UH, Yang HI, Su J, Jen CL, You SL, Chen CJ. Predicting cirrhosis risk based on the level of circulating hepatitis B viral load. Gastroenterology 2006;130: Lee JI, Park HJ, Lee JW, Kim YS, Jeong S, Lee DH, et al. Pretreatment alanine transaminase level may not be the most important predictor of HBeAg loss in the older patient. Liver Int 2009;29: Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007;45: Yagmur E, Weiskirchen R, Gressner AM, Trautwein C, Tacke F. Insulin resistance in liver cirrhosis is not associated with circulating retinol-binding protein 4. Diabetes Care 2007;30: Bahr MJ, Boeker KH, Manns MP, Tietge UJ. Decreased hepatic RBP4 secretion is correlated with reduced hepatic glucose production but not associated with insulin resistance in patients with liver cirrhosis. Clin Endocrinol (Oxf) 2009;70: Newcomer ME, Ong DE. Plasma retinol binding protein: structure and function of the prototypic lipocalin. Biochim Biophys Acta 2000;1482: Harrison EH, Smith JE, Goodman DS. Effects of vitamin A deficiency on the levels and distribution of retinolbinding protein and marker enzymes in homogenates and Golgi-rich fractions of rat liver. Biochim Biophys Acta 1980;628: Ballmer PE, Walshe D, McNurlan MA, Watson H, Brunt PW, Garlick PJ. Albumin synthesis rates in cirrhosis: correlation with Child-Turcotte classification. Hepatology 1993;18: Nelson JE, Bhattacharya R, Lindor KD, Chalasani N, Raaka S, Heathcote EJ, et al. HFE C282Y mutations are associated with advanced hepatic fibrosis in Caucasians with nonalcoholic steatohepatitis. Hepatology 2007;46: Lee D, Jeong SH, Lee M, Cho YA, Kim JW, Park Y, et al. The prevalence of peripheral iron overload and the presence of HFE gene (H63D) mutation among the Korean patients with nonalcoholic fatty liver disease. Korean J Hepatol 2007;13:

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012임수진 Received : 2012. 11. 27 Reviewed : 2012. 12. 10 Accepted : 2012. 12. 12 A Clinical Study on Effect of Electro-acupuncture Treatment for Low Back Pain and Radicular Pain in Patients Diagnosed with Lumbar