The Korean Journal of Hepatology 2009 ; 15 : 464-473 DOI: 10.3350/kjhep.2009.15.4.464 논평참조 만성간질환에서간탄성률측정에영향을미치는요인분석 아주대학교의과대학소화기내과학교실, 병리학교실 1, 한림대학교의과대학내과학교실 2, 차의과학대학내과학교실 3, 가톨릭대학교의과대학내과학교실 4 이다미 문은준 황주안 이민석 정재연조성원 김영배 1 김동준 2 황성규 3 양진모 4 Abstract Factors associated with liver stiffness in chronic liver disease Da Mi Lee, M.D., Eun Joon Moon, M.D., Joo An Hwang, M.D., Min Suk Lee, M.D., Jae Youn Cheong, M.D., Sung Won Cho, M.D., Yeong Bae Kim, M.D. 1, Dong Joon Kim, M.D. 2, Seong Gyu Hwang, M.D. 3, Jin Mo Yang, M.D. 4 Department of Gastroenterology and 1 Pathology, Ajou University School of Medicine, Suwon; Department of Internal Medicine, 2 Hallym University College of Medicine, Chuncheon; 3 Pochon CHA University College of Medicine, Seongnam, Korea; 4 St. Vincent Hospital, The Catholic University College of Medicine, Suwon, Korea Background/Aims: Transient elastography is a new noninvasive tool for measuring liver stiffness that accurately predicts significant fibrosis and cirrhosis. However, several studies have indicated that liver stiffness can be significantly influenced by major changes in aminotransferase in patients with chronic viral hepatitis. The aim of this study was to determine the factors influencing liver stiffness in patients with chronic liver disease. Methods: We studied 158 patients with chronic liver disease who underwent transient elastography and liver biopsy sampling. Histologic findings on fibrosis and necroinflammatory activity in the biopsy specimens were evaluated according to the Korean Society of Pathologists Scoring System. Routine biochemical tests were performed according to standard methods. Results: Liver stiffness was strongly correlated with liver fibrosis stage (Spearman coefficient=0.636, P<0.001), lobular activity (Spearman coefficient=0.359, P<0.001), and portoperiportal activity grade (Spearman coefficient=0.448, P<0.001). Liver stiffness was significantly associated with serum levels of total bilirubin (P=0.025), direct bilirubin (P=0.049), gamma-glutamyl transpeptidase (P=0.014), platelet count (P=0.004), albumin (P<0.001), and international normalized ratio (P<0.001). Multivariate analysis showed that fibrosis stage (B 3.50, P=0.009) and lobular activity grade (B 3.25, P=0.047) were independently associated with liver stiffness. Conclusions: Liver stiffness as measured by transient elastography is associated with the grade of necroinflammatory activity and the stage of fibrosis, irrespective of serum ALT levels. (Korean J Hepatol 2009;15:464-473) Key words: Liver stiffness; Fibrosis stage; Necroinflammatory activity; Biochemical test, Viral hepatitis Received July 30, 2009; revised October 25, 2009; accepted October 30, 2009 Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BMI, body mass index; D.bil, direct bilirubin; GGT, gamma glutamyl transpeptidase; INR, international normalized ratio; T.bil, total bilirubin Corresponding author: Sung Won Cho, E-mail: sung_woncho@hotmail.com; Phone: 031) 219-5106; Fax: 031) 219-5999 주소 : 경기도수원시영통구원천동산 5 번지아주대학교병원소화기내과 ( 우 )443-721 * 본연구는보건의료기술연구개발사업의지원에의해이루어진것임 (A050021). - 464 -
Da Mi Lee, et al. Factors associated with liver stiffness 서론간섬유화정도를평가하는것은만성간염에서질환의진행예측과치료의결정에중요하며, 간경변증으로의진행과합병증을예방하는데에도필수적이다. 1 간조직검사는간섬유화단계를평가하는방법의황금률로되어있다. 2,3 그러나간조직검사는통증, 출혈등의합병증이동반될수있고, 환자의거부감이크며간섬유화단계를추적관찰하기위한도구로사용되기어렵다. 4 또한간조직검사는검체채취의오류로인하여 10~20% 의간경변환자에서오진될수있고, 5 생검조직의크기가작을수록진단율이낮은것으로나타났다. 6,7 또한조직생검을통해얻는조직의양이전체간의 5만분의 1 정도라는데서대표성의문제가있으며, 8 병리의사간의해석차이로인하여재현성이낮다는문제점이있다. 5,9 이에따라간생검을대신할수있는비침습적인검사에대한요구가증가하고있으며, 간섬유화를평가하는여러비침습적검사법에대한연구가활발히진행되고있다. 10-13 Transient elastography(fibroscan, EchoSens, Paris, France) 는피부표면에서간접적으로간의탄성률을측정하여간섬유화를진단하는검사법으로비침습적이고재현성이높으며, 비교적정확하고간편하게시행될수있다. 14,15 여러연구에서 transient elastography로측정한간탄성률은만성 B형및 C형간염을포함한다양한만성간질환에서간섬유화정도를정량화하는정확한검사법으로보고되었다. 16-22 Transient elastography 로측정한간탄성률은간섬유화의정도이외에여러요인에의하여영향을받을수있다고보고되고있다. 23-30 최근간탄성률이혈청알라닌아미노전이효소 (ALT) 의상승이있는경우에높게측정되며, 23-25 급성간염의급성기에는실제간섬유화정도보다높게측정되고회복기에감소함이발표되었다. 26-28 따라서간염의활성도가간탄성률에영향을줄것으로생각되고있다. 반면에혈청 ALT치는간탄성률에영향을미치지않는다는보고가있다. 27,30 이를규명하기 위해서는간생검으로확인된염증괴사와간탄성률과의관계에대한연구가필요하나이에대한연구가부족하다. 그외에체질량지수 (BMI), 지방간염, 혈청빌리루빈수치등도간탄성률수치와관련을보인다는보고가있다. 29,30 본연구에서는만성간질환환자에서간탄성률과연관성을갖는혈청및간내인자를알아보고자하였다. 대상및방법 1. 대상 2005년 9월부터 2008년 9월까지만성간질환으로추적관찰중인환자중간조직검사와 transient elastography로간탄성률측정을함께시행한 158 명의환자를대상으로하였다. 간생검은진단또는치료목적으로간생검의적응증이되는경우에시행하였다. 만성 B형간질환환자는혈액검사에서 B 형간염표면항원이 6개월이상양성이었으며, 만성 C형간질환환자는 C형간염바이러스 (HCV) 에대한항체가양성이고혈청 HCV RNA가양성인환자로정의하였다. 연구는모든환자에게연구에대한설명을하였고환자들의참여동의하에진행되었다. 2. 방법 1) 혈액검사혈청생화학검사, 혈액응고검사및말초혈액검사등의혈액검사자료는 transient elastography를시행한시점에시행된검사결과를참조하였다. 2) 간조직검사간생검은초음파영상유도하에경피적으로시행하였다. 조직생검을통해얻은검체는포르말린으로고정시키고파라핀포매하였고, 5 µm 두께로절편한후 hematoxylin-eosin 염색과 Masson-trichrome 염색을하였다. 간섬유화등급및간염활성등급은대한병리학회의만성간염등급체계에따라구분하였다. 간섬유화는간의섬유화가없는 0단계부터간경변증을진단하는 4단계까지구분하였고 (F0, no fibrosis; F1, portal fibrosis; F2 periportal - 465 -
대한간학회지제 15 권제 4 호 2009 fibrosis; F3 septal fibrosis; F4, cirrhosis), 간염활성도는소엽내활성도 (lobular activity) 및문맥역 / 문맥주변부활성도 (porto-periportal activity) 로나누어 0단계에서 4단계까지구분하였다 (G0, no necrosis; G1, minimal; G2, mild; G3, moderate; G4, severe). 지방간단계는육안으로보았을때지방변성이된간실질단면적의비율에따라 4단계로구분하였다 (Grade 0: <5%, Grade 1: 5~33%, Grade 2: 33~66%, Grade 3: >66%), 31 조직판정은 2인의간병리의사가동일조직에대해각각판정한후서로다른판정이있을때는의견을조율하여결정하였다. 3) 간탄성률의측정간탄성률측정은 transient elastography 를이용하여측정하였다. Transient elastography는저주파수탄성파를주사하는피스톤에초음파변환기가더하여진것으로, 조직을통과하는탄성파의속도를초음파영상을통하여측정한후, 측정한속도를이용하여탄성파가통과하는조직의탄성률을계산하는원리이며, 32 탄성률은압력 ( 단위면적에작용하는힘 ) 의단위인 kpa로표현된다. Transient elastography의탐침자 (probe) 를반듯이누운상태에서오른팔을최대한외전시킨환자의우측늑골간에위치시켜간우엽의탄성률을측정하였고, 10회반복하여가장높은값과가장낮은값을제외한값의평균을간의탄성률로하였다. 간탄성률측정과간조직생검의시행은 4개월이내의기간에시행되었다. 4) 통계기저변수들의요약값은연속형변수인경우평균 ± 표준편차로범주형변수인경우는빈도및상대빈도로표현하였다. 간섬유화, 간염활성도단계에따른간탄성률의차이를알아보기위하여비모수적통계방법인 Kruskal-Wallis 검정을이용하였다. 간탄성률과혈액검사수치와의상관관계는 Pearson correlation을이용하였고, 간탄성률과간조직검사상간섬유화단계및간염활성도와의상 Table 1. Baseline characteristics of patients Variables Patients (n=158) Gender (M:F) 113 : 45 (71.5% : 28.5%) Age (years) 43.1±11.7 (range: 19~75) Etiology HBV 126 (79.8%) HCV 30 (19.0%) Autoimmune 2 (1.2%) BMI (kg/m 2 ) 23.8± 3.0 (range 18.0~34.6, n=116) Inflammatory activity grade G0/1/2/3/4 Lobular activity 2/38/41/32/11 (1.6%/24.1%/24.9%/ 20.3%/7.0%) Porto-periportal activity 2/22/38/46/17 (1.3%/13.9%/24.1%/ 29.1%/10.%) Fibrosis stage: F0/1/2/3/4 7/19/54/46/32 (4.4%/12.0%/34.2%/ 29.1%/20.3%) Steatosis: G0/1/2/3 126/13/6/2 (79.7%/8.2%/3.8%/ 1.3%) Liver stiffness (kpa) 13.8±11.1 AST (U/L) 98.4±112.3 ALT (U/L) 146.2±195.0 Bilirubin (mg/dl) 1.3±2.0 ALP (U/L) 186.4±161.9 GGT (U/L) 80.9±75.8 Albumin (g/dl) 4.2±0.6 Platelet count ( 10 3 /mm 3 ) 183.5±75.0 Prothrombin time (INR) 1.1±0.1 Results are given by mean±sd for continuous variables and by frequency for categorical variables. ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; GGT, gamma glutamyl transpeptidase; HBV, hepatitis B virus; HCV, hepatitis C virus; INR, international normalized ratio. 관관계는정규성의가정을만족하지못하여비모수적방법인 Spearman s rank correlation을이용하여분석하였다. 간탄성률과관련된인자를조사하기위하여단변량상관분석에서유의한인자를 - 466 -
이다미외 9 인. 간탄력도측정에영향을미치는요인분석 Table 2. Liver histology and liver stiffness Parameters n Liver stiffness (kpa) P-value Fibrosis stage <0.001 F0 7 4.7±0.2 (4.0~5.4) F1 15 7.4±1.0 (3.96~18.0) F2 38 10.4±1.3 (4.3~48.9) F3 36 14.5±1.3 (4.8~38.5) F4 27 25.9±3.1 (7.8~75) Lobular activity 0.001 G0 2 4.9±0.5 (4.4~5.3) G1 38 11.5±1.5 (3.9~45.0) G2 41 13.6±2.1 (4.3~75.0) G3 31 17.9±2.3 (4.6~57.2) G4 11 18.4±2.7 (6.1~38.5) Porto-periportal activity <0.001 G0 2 4.9±0.5 (4.4~5.3) G1 21 8.9±1.1 (3.9~18.4) G2 37 12.6±2.2 (4.3~75.0) G3 46 16.7±1.9 (4.6~57.2) G4 17 19.3±2.0 (6.1~38.5) Data are expressed by mean±sd (range). P-values were obtained by Kruskal-Wallis test. 모두고려하여다변량회귀분석을실시하였다. P 값이 0.05 미만인경우통계적으로유의하다고정의하였다. 모든통계분석은 SPSS 12.0(SPSS Inc, Chicago, IL, USA) 을이용하였다. 결과 1. 대상환자의임상적특성 ( 표 1) 총대상환자 158명의연령의평균 ± 표준편차는 43.1±11.7 세였으며, 남자가 113명 (71.5%), 여자가 45명 (28.5%) 이었다. 만성간질환의원인은 B형간염이 126명 (79.8%), C형간염이 30명 (19.0%), 자가면역간염이 2명 (1.2%) 이었다. BMI( 총 116명에서측정 ) 는 23.8±3.0( 범위 : 18.0~34.6) 이었다. 혈청생화학검사에서아스파르테이트아미노전이효소 (AST) 와 ALT는각각 98.4±112.3(17~903) IU/L, 146.2 ±195.0(8~1321) IU/L 였고, 총빌리루빈은 1.3± 2.0(0.2~14.6) mg/dl, 알칼리인산분해효소 (ALP) 186.4±161.9(43~1817) U/L, 감마글루타밀트란스펩티다제 (GGT) 는 80.9±75.8(11~550) U/L, 알부민은 4.2±0.6(3.0~8.2) g/dl, 혈소판치는 183.5± 75.0(34~699) 10³/mm 3, 프로트롬빈시간 (PT) 의 INR은 1.1±0.1(0.85~1.93), 총콜레스테롤은 166.4 ±37.2(97~399) mg/dl 였다. 간생검을통한간섬유화단계에따른분포는 F0 7명 (4.4%), F1 19명 (12.0%). F2 54명 (34.2%), F3 46명 (29.1%), F4 32 명 (20.3%) 이었다. 간염의소엽내활성도분포는 G0 2명 (1.3%), G1 38명 (24.1%), G2 41명 (25.9%), G3 32명 (20.3%), G4 11명 (7.0%) 이었고, 문맥역 / 문맥주변부활성도분포는 G0 2명 (1.3%). G1 22명 (13.9%), G2 38명 (24.1%), G3 46명 (29.1%), G4 17 명 (10.8%) 이었다. Transient elastography 로측정한간탄성률은 13.8±11.1(3.5~75) kpa였다. - 467 -
The Korean Journal of Hepatology : Vol. 15. No. 4. 2009 Figure 1. Box plots of liver stiffness relative to fibrosis stage. The extent of the boxes represents the interquartile range where 50% of values occur. The lines in the boxes represent the median values. Liver stiffness values and fibrosis stage were significantly correlated (P<0.001). 2. 간내섬유화및간염활성도와간탄성률간의연관성간섬유화등급에따른간탄성률의평균은 F0, F1, F2, F3, F4에서각각 4.7±0.2 kpa, 7.4±1.0 kpa, 10.4±1.3 kpa, 14.5±1.3 kpa, 25.9±3.1 kpa 였고, 그차이는유의하였다 (P<0.001, 표 2, 그림 1). 단변량상관분석에서간섬유화단계가높아질수록간탄성률이증가하였으며, Spearman 상관계수가 0.636으로유의하였다 (P<0.001, 표 3). 간염의소엽내활성도및문맥역 / 문맥주변부활 성도가높아질수록간탄성률측정치도증가하였으며 ( 표 2, 그림 2) 각단계별평균치의차이는유의하였다 (P<0.001). 단변량상관분석에서도간염의소엽내활성도및문맥역 / 문맥주변부활성도의 Spearman 상관계수가각각 0.359(P<0.001), 0.448 (P<0.001) 로유의하였다 ( 표 3). 3. 혈청생화학적지표와간탄성률과의상관관계 Pearson 분석에서간탄성률은총빌리루빈치, 직접빌리루빈치, GGT치, 프로트롬빈시간 INR과양의상관관계가있었으며, 알부민및혈소판수치와는음의상관관계가있었다 ( 표 3). 그러나혈청 Table 3. The correlation between clinicopathological variables and liver stiffness values Variables Coefficient P-value Inflammatory grade Lobular activity 0.359 <0.001* Porto-periportal activity 0.448 <0.001* Fibrosis stage 0.636 <0.001* Steatosis -0.080 0.338* Age (year) 0.133 0.096 BMI (kg/m 2 ) -0.009 0.925 AST (U/L) 0.084 0.297 ALT (U/L) 0.014 0.859 Total bilirubin (mg/dl) 0.188 0.025 Direct bilirubin (mg/dl) 0.208 0.049 ALP (U/L) 0.091 0.287 GGT (U/L) 0.207 0.014 Albumin (g/dl) 0.305 <0.001 Platelet count (10 3 /µl) -0.236 0.004 Prothrombin time (INR) 0.405 <0.001 P-values were obtained by *Spearman s rank correlation analysis or Pearson correlation analysis. ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase; GGT, gamma glutamyl transpeptidase; HBV, hepatitis B virus; HCV, hepatitis C virus; INR, international normalized ratio. AST, ALT, ALP 수치는유의한상관관계를보이지않았다 ( 표 3). 간섬유화가간탄성률에미치는영향을배제하기위하여간섬유화단계 F0,1,2군과 F3,4군으로나뉘어 Pearson 분석을시행하였으나 ALT, AST는두군모두에서의미있는상관관계를보여주지못하였다 ( 표 4). 4. BMI 및지방간과간탄성률간의연관성 BMI 와간탄성률간에는통계적으로유의한관련성이없었다 (P=0.925, 표 3). 또한지방간단계와간탄성률도유의한상관관계를보이지않았다 ( 표 3). - 468 -
Da Mi Lee, et al. Factors associated with liver stiffness A B Figure 2. Liver stiffness relative to lobular (A) and portoperiportal activity (B). (A) The extent of the boxes represents the interquartile range where 50% of values occur. The lines in the boxes represent the median values. Liver stiffness values and lobular activity were significantly correlated (P<0.001). (B) The extent of the boxes represents the interquartile range where 50% of values occur. The lines in the boxes represent the median values. Liver stiffness values and portoperiportal activity were significantly correlated (P<0.001). Table 4. The correlation between serum aminotransferases levels and liver stiffness values in patients stratified by fibrosis stage Fibrosis stage Variables Coefficient P-value F0,1,2 AST 0.200 0.077 ALT 0.217 0.055 F3,4 AST -0.003 0.981 ALT -0.059 0.607 P-values were obtained by Pearson correlation analysis. ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase. 5. 다변량회귀분석이상의단변량상관분석에서유의한상관관계를보이는요인들을대상으로다변량선형회귀분석을단계진입방식으로시행하였으며, 간탄성률에영향을미치는독립인자는섬유화단계와소엽내간염활성도로나타났다 ( 표 5). 고찰 Transient elastography 는 Sandrin 등 15 에의해소개된이후만성간질환환자에서간섬유화를진 단하는검사로서그유용성에대한여러보고들이있었다. 대부분은만성 C형간염환자들을대상으로한연구들이었으나, 19,20,33 Foucher 등 17 은만성바이러스간염과알코올간염, 지방간염으로대상을넓혀시행한연구에서도간섬유화정도는간탄성률과유의한연관성이있음을보고하였다. 이외의다양한원인의만성간질환에서도간탄성률은간섬유화단계와높은상관관계를가지고있음이보고되었다. 14-18,20-22 본연구에서도만성간질환환자에서간탄성률은조직검사로진단된간섬유화단계별로유의한차이를보였으며, Spearman coef- - 469 -
대한간학회지제 15 권제 4 호 2009 Table 5. Factors associated with liver stiffness values in multivariate analysis Variables Coefficient P-value Inflammatory Grade Lobular activity 3.500 0.047 Fibrosis stage 3.254 0.009 P-values were obtained by stepwise multiple linear regression analysis including the variables with statistical associations at univariate (P<0.05) analysis. Platelet count, prothrombin time (international normalized ratio), and serum levels of albumin, total bilirubin, direct bilirubin, and gamma glutamyl transpeptidase, did not show statistical significance in this analysis. ficient 가 0.636으로높은상관관계를보여 Transient elastography 가간섬유화정도를잘반영함을확인할수있었다. 최근발표된메타분석에서는간경변증의진단에있어서 Transient elastography의평균 AUROC가 0.94~0.96에이르고, 민감도가 87%, 특이도가 91% 에이르는것으로나타났다. 21,22 진행된간질환을의미하는 F2 이상의간섬유화를감별하는데는간경변증의진단에비하여정확도가다소감소하지만 Transient elastography의평균 AUROC 는 0.84(95% CI, 0.82~0.86) 로보고되었다. 21 그러나간탄성률은간섬유화뿐만아니라간염의활성도에의하여도영향을받는것으로보고되어있다. 23-30 본연구에서도 158명의만성간질환환자를대상으로간조직검사와간탄성률측정을같이시행하여비교한결과간섬유화단계뿐만아니라간염활성도도간탄성률과연관을보이는독립인자로나타났다. Fraquelli 등이만성간질환환자 211명에서간조직검사와간탄성률측정을같이시행하여분석한연구와 14 Pinzani 등이시행한연구에서 38 조직검사상의간염활성도는간탄성률과양의상관관계가있고, 간염활성도에따라단계적으로간탄성률이유의하게증가함을보고하였다. Coco 등은만성 B형및 C형간염환자를대상으로시행한코호트연구에서혈청 ALT값이간탄성률에영향을미치는독립인자로보고하였고, 같은간섬유화단계에서도 ALT값이높은군이 ALT가낮은군보다간탄성률이높게측정됨을관찰하여간탄성률을해석하는데있어서 ALT 변화를고려해야함을보고하였다. 23 또한 B형간염바이러스보유 자를대상으로한연구에서조직검사상의간염정도와, ALT가간탄성률에영향을주는인자이며혈청 ALT치의변동이간탄성률과유의한상관관계를보였다. 24 일반적으로 ALT는간염의활성화를반영하는혈청지표이므로 ALT가증가함에따라간탄성률이증가하는것은간염활성도가간탄성률에영향을줌을간접적으로알려준다고하겠다. 또한급성간염환자에서간탄성률변화를관찰함으로써간염활성도가간탄성률에미치는영향을보고한연구들이있다. 급성간염의시기별로간탄성률을순차적으로측정하였을때, 급성간염의초기에는간탄성률이상승된후간염이호전된후에는간탄성률도감소한다고보고되고있다. 27,28 이와같이간탄성률이급성간염과만성간염의급성악화시기에증가하는것은간염이진행하면간문맥주변으로염증세포의침윤이많아지고삼출물이간실질조직으로나오게되며, 간세포괴사, 간세포부종, 혈관충혈등의조직학적변화가발생한다. 이러한변화에의하여간실질의밀도가높아지게되고파동의전달에변화가생기며간탄성률을증가시키게된다. 23,28,35 따라서급성간염또는만성간염의급성악화시기에는간탄성률이실제간섬유화정도보다높게측정될수있음을고려해야할것이다. 본논문에서는간탄성률은간조직상의간염활성도와는상관관계가있었으나간염활성도를반영하는혈청지표인 ALT, AST 수치와는유의한상관관계가관찰되지않았다. 국내의연구에서도 ALT, AST값은간탄성률과유의한상관관계를보여주지못하였다. 27,28,30 이러한차이는우선간탄성 - 470 -
이다미외 9 인. 간탄력도측정에영향을미치는요인분석 률은조직학적간염활성도에따라변화하는것일뿐 ALT와는직접적인관련이없기때문으로생각된다. 서등은급성간염시기별로간탄성률을측정한결과간탄성률은급성간염의증상이시작된지 8~9일에최고치를보이는데비하여 ALT는증상시작 6일에최고치를보이는것을관찰하였으며따라서간탄성률은 ALT와는직접적관련없이급성간염의시기에따라서변화하는것임을보고하였다. 27 서등은 ALT 보다는혈청총빌리루빈수치가간탄성률에영향을미치는독립인자였다고보고하였는데. 27,30 본연구에서도총빌리루빈과직접빌리루빈은간탄성률과양의상관관계를보여주었다. 또한 ALT가간탄성률과유의한상관관계를보이지않은것은 ALT, AST치가간염환자에서조직학적인간염활성도를정확히반영하지못하기때문으로생각된다. 36,37 대부분의논문이간염활성도를간접적으로나타내는 ALT, AST 수치와비교한데비하여본연구는대상환자군에서간조직검사와간탄성률측정을모두시행하여간섬유화및간염활성도단계가간탄성률과연관을보임을확인하였다. 그러나본연구는간조직검사를받은환자들을대상으로시행되어간질환이비교적심한환자들이선택되었는데, 따라서대상환자들의평균 ALT 및 AST 수치가높고간섬유화의단계도 F2 이상이 83.6% 로높아이들변수가정규분포를보이지않는다는점에서선택오류가발생하였을한계점이있다. Poggio 등은지방간이간탄성률과밀접한관련이있으며, 지방간이있는환자에서간탄성률이더높게나타난다고보고하였다. 29 반면지방간이간탄성률과관련이없다는보고도있다. 39,40 본연구에서는지방간단계와간탄성률과는유의한관련성이없는것으로나타났으나 1단계이상의지방간환자수가적어통계적의미를갖지못할것으로생각된다. 지방간이간탄성률에미치는영향에대하여는아직논란이있으며많은수의지방간환자에서의분석이필요할것으로생각된다. 결론적으로만성간질환에서 transient elastography 를이용한간탄성률의측정은간섬유화를 평가하는데비교적정확한검사이나간섬유화정도뿐만아니라간내염증활성도에의해서도영향을받음을확인하였으며. 간탄성률을해석하는데있어서간섬유화및간내염증정도를모두고려해야할것으로생각된다. 요 목적 : 본논문은만성간질환환자를대상으로간탄성률측정에영향을미치는요인을알아보기위해연구를시행하였다. 대상과방법 : Transient elastography와간조직검사를시행한만성간질환환자 158명을대상으로혈액검사및간조직소견을분석하였으며, 간조직검사결과는대한병리학회기준에따라 0~4단계로분류하였다. 결과 : 간탄성률은간조직생검으로확인한간섬유화정도와유의한상관관계를보였다 (P=0.636. P<0.001). 간염의소엽내활성도및문맥역 / 문맥주변부활성도가높아질수록간탄성률측정치도증가하였으며, spearman 상관계수가각각 0.359(P<0.001), 0.448 (P<0.001) 로유의하였다. 또한간탄성률은혈청총빌리루빈치, 직접빌리루빈치, GGT 수치, INR 등과양의상관관계가있었으며, 혈청알부민치및혈소판치와는음의상관관계가있었다. 다변량회귀분석에서는간섬유화 (B 3.50, P=0.009) 및간염의소엽내활성도 (B 3.25, P=0.047) 만이간탄성률과관련이있는것으로나타났다. 결론 : 만성간질환환자에서간탄성률은간섬유화뿐만아니라간내염증활성도에의해서도영향을받음을확인하였으며, 간탄성률의해석에간섬유화뿐만아니라간내염증정도도고려해야할것이다. 색인단어 : 간탄성률, 간섬유화, 간염활성도, 만성간질환 약 참고문헌 1. Lok AS, McMahon BJ. Chronic hepatitis B. Hepatology 2007;45:507-539. - 471 -
The Korean Journal of Hepatology : Vol. 15. No. 4. 2009 2. Bravo AA, Sheth SG, Chopra S. Liver biopsy. N Engl J Med 2001;344:495-500. 3. Dienstag JL. The role of liver biopsy in chronic hepatitis C. Hepatology 2002;36(Suppl 1):S152-S160. 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. Regev A, Berho M, Jeffers LJ, Milikowski C, Molina EG, Pyrsopoulos NT, et al. Sampling error and intraobserver variation in liver biopsy in patients with chronic HCV infection. Am J Gastroenterol 2002;97:2614-2618. 6. Colloredo G, Guido M, Sonzogni A, Leandro G. Impact of liver biopsy size on histological evaluation of chronic viral hepatitis: the smaller the sample, the milder the disease. J Hepatol 2003;39:239-244. 7. Bedossa P, Dargere D, Paradis V. Sampling variability of liver fibrosis in chronic hepatitis C. Hepatology 2003;38: 1449-1457. 8. Maharaj B, Maharaj RJ, Leary WP, Cooppan RM, Naran AD, Pirie D, et al. Sampling variability and its influence on the diagnostic yield of percutaneous needle biopsy of the liver. Lancet 1986;1:523-525. 9. Gronbaek K, Christensen PB, Hamilton-Dutoit S, Federspiel BH, Hage E, Jensen OJ, et al. Interobserver variation in interpretation of serial liver biopsies from patients with chronic hepatitis C. J Viral Hepat 2002;9:443-449. 10. Parkes J, Guha IN, Roderick P, Rosenberg W. Performance of serum marker panels for liver fibrosis in chronic hepatitis C. J Hepatol 2006;44:462-474. 11. 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 2003;38:518-526. 12. Le Calvez S, Thabut D, Messous D, Munteanu M, Ratziu V, Imbert-Bismut F, et al. The predictive value of Fibrotest vs. APRI for the diagnosis of fibrosis in chronic hepatitis C. Hepatology 2004;39:862-863. 13. Imbert-Bismut F, Ratziu V, Pieroni L, Charlotte F, Benhamou Y, Poynard T; MULTIVIRC Group. Biochemical markers of liver fibrosis in patients with hepatitis C virus infection: a prospective study. Lancet 2001;357:1069-1075. 14. Fraquelli M, Rigamonti C, Casazza G, Conte D, Donato MF, Ronchi G, et al. Reproducibility of transient elastography in the evaluation of liver fibrosis in patients with chronic liver disease. Gut 2007;56:968-973. 15. Sandrin L, Fourquet B, Hasquenoph JM, Yon S, Fournier C, Mal F, et al. Transient elastography: a new noninvasive method for assessment of hepatic fibrosis. Ultrasound Med Biol 2003;29:1705-1713. 16. Kazemi F, Kettaneh A, N'kontchou G, Pinto E, Ganne-Carrie N, Trinchet JC, et al. Liver stiffness measurement selects patients with cirrhosis at risk of bearing large oesophageal varices. J Hepatol 2006;45:230-235. 17. Foucher J, Chanteloup E, Vergniol J, Castera L, Le Bail B, Adhoute X, et al. Diagnosis of cirrhosis by transient elastography (FibroScan): a prospective study. Gut 2006; 55:403-408. 18. Ganne-Carrie N, Ziol M, de Ledinghen V, Douvin C, Marcellin P, Castera L, et al. Accuracy of liver stiffness measurement for the diagnosis of cirrhosis in patients with chronic liver diseases. Hepatology 2006;44:1511-1517. 19. Castera L, Vergniol J, Foucher J, Le Bail B, Chanteloup E, Haaser M, et al. Prospective comparison of transient elastography, Fibrotest, APRI, and liver biopsy for the assessment of fibrosis in chronic hepatitis C. Gastroenterology 2005;128:343-350. 20. Colletta C, Smirne C, Fabris C, Toniutto P, Rapetti R, Minisini R, et al. Value of two noninvasive methods to detect progression of fibrosis among HCV carriers with normal aminotransferases. Hepatology 2005;42:838-845. 21. Friedrich-Rust M, Ong MF, Martens S, Sarrazin C, Bojunga J, Zeuzem S, et al. Performance of transient elastography for the staging of liver fibrosis: a metaanalysis. Gastroenterology 2008;134:960-974. 22. Talwalkar JA, Kurtz DM, Schoenleber SJ, West CP, Montori VM. Ultrasound-based transient elastography for the detection of hepatic fibrosis: systematic review and meta-analysis. Clin Gastroenterol Hepatol 2007;5:1214-1220. 23. Coco B, Oliveri F, Maina AM, Ciccorossi P, Sacco R, Colombatto P, et al. Transient elastography: a new surrogate marker of liver fibrosis influenced by major changes of transaminase. J Viral Hepat 2007;14:360-369. 24. Oliveri F, Coco B, Ciccorossi P, Colombatto P, Romagnoli V, Cherubini B, et al. Liver stiffness in the hepatitis B virus carrier: a non-invasive marker of liver disease influenced by the pattern of transaminases. World J Gastroenterol 2008;14:6154-6162. 25. Chan HL, Wong GL, Choi PC, Chan AW, Chim AM, Yiu KK, et al. Alanine aminotransferase-based algorithms of liver stiffness measurement by transient elastography (Fibroscan) for liver fibrosis in chronic hepatitis B. J Viral Hepat 2009;16:36-44. 26. Wong GL, Wong VW, Choi PC, Chan AW, Chim AM, Yiu KK, et al. Increased liver stiffness measurement by transient elastography in severe acute exacerbation of chronic hepatitis B. J Gastroenterol Hepatol 2009;24:1002-1007. 27. Seo YS, Um SH, Suh SJ, Jung ES, Jang JS, Kwon YD, et al. Changes in liver stiffness during the course of acute hepatitis A. Korean J Hepatol 2008;14:465-473. 28. Sagir A, Erhardt A, Schmitt M, Haussinger D. Transient elastography is unreliable for detection of cirrhosis in patients with acute liver damage. Hepatology 2008;47:592-595. 29. Del Poggio P, Colombo S. Is transient elastography a useful tool for screening liver disease- World J Gastroenterol 2009;15:1409-1414. 30. Kim SU, Han KH, Park JY, Ahn SH, Chung MJ, Chon CY, - 472 -
Da Mi Lee, et al. Factors associated with liver stiffness et al. Liver stiffness measurement using FibroScans is influenced by serum total bilirubin in acute hepatitis. Liver Int 2009;29:810-815. 31. Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology 2005;41:1313-1321. 32. Kang JK, Cheong JY, Cho SW, Cho JH, Park JS, Kim YB, et al. Liver stiffness measurement for the diagnosis of hepatic fibrosis in patients with chronic viral hepatitis. Korean J Hepatol 2007;13:521-529. 33. Ziol M, Handra-Luca A, Kettaneh A, Christidis C, Mal F, Kazemi F, et al. Noninvasive assessment of liver fibrosis by measurement of stiffness in patient with chronic hepatitis C. Hepatology 2005;41:48-54. 34. Fung J, Lai CL, Fong DY, Yuen JC, Wong DK, Yuen MF. Correlation of liver biochemistry with liver stiffness in chronic hepatitis B and development of predictive model for liver fibrosis. Liver Int 2008;28:1408-1416. 35. Arena U, Vizzutti F, Corti G, Ambu S, Stasi C, Bresci S, et al. Acute viral hepatitis increases liver stiffness values measured by transient elastography. Hepatology 2008;47: 380-384. 36. Sanai FM, Benmousa A, Al-Hussaini H, Ashraf S, Alhafi O, Abdo AA, et al. Is serum alanine transaminase level a reliable marker of histological disease in chronic hepatitis C infection? Liver Int 2008;28:1011-1018. 37. Luo JC, Hwang SJ, Lai CR, Lu CL, Li CP, Tsay SH, et al. Relationship between serum aminotransferase levels, liver hiotologies and virological status in patients with chronic hepatitis C in Taiwan. J Gastroenterol Hepatol 1998;13: 685-690. 38. Pinzani M, Rombouts K, Colagrande S. Fibrosis in chronic liver diseases: diagnosis and management. J Hepatol 2005;42(Suppl 1):S22-S36. 39. Arena U, Vizzutti F, Abraldes JG, Corti G, Stasi C, Moscarella S, et al. Reliability of transient elastography for the diagnosis of advanced fibrosis in chronic hepatitis C. Gut 2008;57:1288-1293. 40. Kim KM, Choi WB, Park SH, Yu E, Lee SG, Lim YS, et al. Diagnosis of hepatic steatosis and fibrosis by transient elastography in asymptomatic healthy individuals: a prospective study of living related potential liver donors. J Gastroenterol 2007;42:382-388. - 473 -