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1 전남의대학술지제 44 권제 2 호 Chonnam Medical Journal Vol. 44, No. 2, pp 복수가동반된간경변증환자에서폴리에틸렌글리콜을이용한장투과성평가 서남대학교의과대학내과학교실, 1 가정의학과교실 한문종ㆍ이숭 * ㆍ임재규ㆍ이현민ㆍ한민석ㆍ김우진ㆍ박인형ㆍ손승철 1 Assessment of Intestinal Permeability Using Polyethylene Glycol in Liver Cirrhosis with Ascites Moon-jong Han, Soong Lee*, Jae-kyu Lim, Hyun-min Lee, Min-seok Han, Woo-jin Kim, In-hyung Park and Seung-cheol Son 1 Departments of Internal Medicine, 1 Family Medicine, College of Medicine, Seonam University Hospital, Gwangju, Korea Increased intestinal permeability and endotoxemia have been implicated in pathogenesis, progression and development of complications of liver cirrhosis (LC). No study has thus far been reported in Korea on the assessment of intestinal permeability using polyethylene glycol (PEG). The aim of this study was to determine whether intestinal permeability is altered in LC and correlated with clinical characteristics. 65 patients with LC and 26 healthy control subjects were studied. The intestinal permeability value is expressed as the percentage of retrieved PEG 400 and 3350 that had been orally administered in 8-hr urine samples as determined by high performance liquid chromatography. The causes of liver cirrhosis were alcohol (n=38), virus (HBV 17, HCV 9) (n= 26) and alcohol combined with HBV (n=1). Mean values for PEG 400 and 3350 retrieval were 46.5±3.22 and 0.24±0.03 in controls, 44.1±5.17 and 0.21±0.02 in LC without ascites, and 37.4±3.55 and 0.29±0.04 in LC with ascites, respectively. Intestinal permeability index (IPI) was significantly higher in LC with ascites than in healthy controls or LC without ascites (0.84±0.21 vs. 0.52±0.05 or 0.54±0.04, p<0.05). A sub-analysis relating intestinal permeability to the Child-Pugh class of LC showed significant differences between class A, B and C for PEG 3350 and IPI (p<0.05). According to sub-analysis relating IPI to the presence of encephalopathy, hypoalbuminemia of LC, there were significant differences (p<0.05), but not for patients as indicated by prolonged prothrombin time, esophageal varix or hyperbilirubinemia. The present study suggests that increased intestinal permeability is probably of importance in the pathophysiology and progression of liver cirrhosis with ascites. Keywords: Permeability; Polyethylene glycol; Liver cirrhosis 게재결정 : 2008 년 7 월 8 일 * 교신저자 : 이숭, , 서남대학교의과대학내과학교실, Phone: , FAX: , lsmed@hanmail.net 87

2 88 전남의대학술지제 44 권제 2 호 2008 서론인체장관은장내세균의저장소로서화상, 출혈성쇼크등과같은심각한임상상황에서중요한역할을하는것으로알려져있고, 1 정상에서점막장벽기능, 면역글로불린분비, 대식세포계등과같은일련의방어체계들이독소나장내세균전위를억제하나문맥압항진증이동반된간경변증에서는장관의점막이상이존재하고, 간손상과장관의기능적활성도와서로연관있음이보고되고있다. 2,3 장투과성증가에따른장내세균의전위, 내독소유입증가는만성간손상의병인과간경변증에서간성뇌증과세균감염같은심각한합병증발생의기여인자로서연관되어있음이보고되었으나, 4 일부에서는장투과성증가가간경변증환자의세균감염병태생리에중요하지않음이보고되었다. 5,6 이처럼간경변증에서장투과성은정상혹은증가하는것으로다양하게보고되고있다 전신적인내독소혈증은싸이토카인의분비를통해장투과성을증가시키고, 숙주의면역손상과장내세균전위를촉진시켜간경변증에서감염성합병증즉, 자발성세균성복막염과균혈증을초래하는것으로알려져있으나, 13,14 이런비정상적장투과성증가의기전은아직정확히알려져있지않으며추가적인연구가필요하다. 8 복수가동반된간경변증환자의폴리에틸렌글리콜 (polyethylene glycol, PEG) 을이용한장투과성변화에대한연구는거의없으며국내에서는아직보고가없는실정이다. 이에저자들은복수를동반한간경변증환자에서 PEG를이용하여장투과성변화를살펴보고임상양상과의연관성을비교분석하여장투과성의역할을규명하고자하였다. 대상및방법 1. 연구대상 32명의복수가있는간경변증환자, 33명의복수가없는간경변증환자, 그리고 26명의건강대조군을대상으로했고대조군은알코올성, 바이러스성간염의기왕력이없고신체검사및혈액검사상정상이며장투과성이증가할만한질환이없는경우로하였다. 본연구에서는위장관질환, 신장질환및당뇨환자는제외되었고, 장투과성검사에영향을줄수있는락툴로오스, 비스테로이드성항염증제, 알코올을 2주전에복용한환자도제외시켰다. 본연구는서남 대학교건강과학연구소의임상시험위원회에서승인받았으며본연구에포함된모든대상자들의동의서를받았다. 간경변증환자는초음파및상부소화관내시경상비종대, 식도정맥류, 복수등전형적인소견과연장된프로트롬빈시간, 저알부민혈증등의검사실결과를보인환자로하였다. 간질환의중증도는 Child-Pugh 분류에따랐다. 자발성세균성복막염의진단은뚜렷한감염의원인이없으면서복수에서다형핵세포수가 250 cells/mm 3 이상일때, 요로감염은소변에서다형핵세포수가 10 5 /ml보다많거나소변배양검사상양성일때로정의하였다. 전신감염은혈액배양검사상 2번에서양성일때진단하였고폐렴은객담배양검사상양성이거나전형적인흉부방사선소견, 폐결핵은객담항산균염색검사상양성과전형적인흉부방사선소견에근거하여진단하였다. 2. 장투과성의측정혈액검사는장투과성검사 1주이내에실시하였으며장투과성검사는 PEG 400, 3350을이용하였다. 시험대상군모두검사전날저녁 8시이후금식시키고시험당일아침에소변을보게한후아침식전 1시간전에 PEG g, PEG g을물 100 ml와혼합하여복용시켰다. 이후 8시간소변을모아복용한 PEG 중회수된양을백분율로표시하였다. 소변에서저분자량표지자인 PEG 400과고분자량표지자인 PEG 3350를증발광산란효과를이용한고성능액체크로마토그래피 (high performance liquid chromatography, HPLC) 방법을이용하여동시에검출하였다. 모인소변에서 2 ml를채취하여 0.45μm syringe filter (Nylon membrane) 로여과하여 4 o C에서보관하였다. 채취된소변 1 ml는곧바로냉각장치가달린 Waters 717+autosampler에놓여졌다. 소변에서미세불순물을제거하기위해일회용 Security Guard kit (Phenomenex, Torrance, CA USA) 를거친후 polystylene divinyl benzene (PS/DVB) 중합체염주로채워진 5μm PLRP-S 100Å ( mm, Polymer Laboratories, Amherst, MA USA) 를통과시켰다. 그후친수성과소수성물질을분리하기위해 gradient mobile phase (acetonitrile/h 2O) 가 40~60분동안이용되었다. HPLC 전기용매는불순물이먼저추출되고후에원하는표지자인 PEG 400과 3350가최대치중복없이분리되도록고안된 gradient controller program에의해분리되었다. 분리된혼합물은증발산란광검출기 (PL-ELSD 2100 under con-

3 한문종외 7 인 : 복수가동반된간경변증환자에서폴리에틸렌글리콜을이용한장투과성평가 89 ditions of evaporation-85 o C, nebulizer 85 o C and gas flow 1.0; Polymer Laboratories) 를이용하여분석하였다 (Fig. 1). 측정곡선은 200~1,500 mg/l (PEG 400) 과 10~200 mg/l (PEG 3350) 의범위에서얻었으며장투과성은 PEG 농도와총소변량을통해, 장투과성지수 (IPI, in %) 는 PEG 400에비례한 PEG 3350의장투과성을나타낸 PEG 회수율로다음과같이계산하였다. Total excretion of PEG (ppm)=urinary concentration volume of urine Permeability (%)=(Total excretion of PEG)/(Ingestion of PEG) 100 Intestinal permeability index (%)=(Permeability of PEG 3350)/(Permeability of PEG 400) 통계적분석 자료는변수들에따라평균값, 표준오차, 백분율로작성되었다. 정상대조군, 복수를동반한간경변증, 복수가없는간경변증환자의세그룹간차이는 ANOVA test에의해분석하였고의미가있을때평균치간의차이를조사하기위해 Scheffe post hoc comparisons를이용하였다. Independent samples t-test, Mann-Whitney test, Fisher s exact test로 p value가 0.05 미만인경우통계적유의성이있는것으로단정하였다. 두변수들간의관련성에대해서는 Pearson s correlation coefficient 또는 Kendall s tub를이용했고통계적분석을위해 SPSS 11.0 프로그램을이용하였다. Fig. 1. HPLC chromatogram of urine of cirrhotic patient with ascites. 1. 환자의특징 결 간경변증환자와건강대조군간의나이, 성별간차이는없었고간경변증의원인은알코올 (38예), 간염바이러스감염 (HBV 17, HCV 9; 26예 ) 과알코올과 B형간염바이러스동반이 1예였다. 요소와크레아티닌으로평가된신장기능은모든대상군에서정상이었다. 복수가있는간경변증환자중 2명, 복수가없는간경변증환자중 7명에서동시감염이있었다. 나이, 성별, 원인, 중증도, 간경변증의합병증유무, 동시감염에대한자세한사항은 Table 1에기술하였다. Table 1. Demographics and characteristics of the subjects Cirrhotics Cirrhotics Healthy with ascites without ascites controls (n=32) (n=33) (n=26) Age (yr±se) 55.3± ± ±9.2 Sex (M/F) 28/4 26/7 17/9 Etiology Alcohol 20 (62.5%) 18 (55.5%) Viral* 11 (34.3%) 15 (44.5%) Alcohol/viral 1 (3.2%) 0 (0%) Child class 1/20/11 27/6/0 (A/B/C) (3.2%/62.5%/34.3%) (81.8%/18.2%/0%) Child-Pugh score 8.8± ±0.34 Serum albumin (g/dl±se) 2.8± ±0.12 Serum bilirubin (mg/dl±se) 5.1± ±0.43 Prothrombin time (s±se) 15.7± ±0.40 AST (IU/L) 78.3± ±11.4 ALT (IU/L) 34.1± ±=8.9 Encephalopathy 11 (34.6%) 2 (7.4%) Esophageal varix 14 (42.3%) 11 (33.3%) Concurrent infection Total patients 2 7 SBP 2 0 Bacteremia 0 1 UTI 0 4 Others 0 2 *viral etiology-cirrhosis with ascites (HBV-7, HCV-4), cirrhosis without ascites (HBV-10, HCV-5); viral etiology-hbv-1; Others: pneumonia, one; pulmonary tuberculosis, one; Different letters denote significant difference by post hoc of Scheffe (p<.05); significantly different at p<.01; significantly different at p<.001. SBP, spontaneous bacterial peritonitis; UTI, urinary tract infection. 과 2. 건강대조군및간경변증환자에서장투과성변화 PEG 400 과 3350 회수율의평균값은건강대조군에서

4 90 전남의대학술지제 44 권제 2 호 ±3.22와 0.24±0.03, 복수가없는간경변증환자군에서 44.1±5.17와 0.21±0.02, 복수가동반된간경변증환자군에서 37.4±3.55와 0.29±0.04로복수를동반한간경변증환자군에서두군에비해 PEG 3350 회수율이높았으나통계적유의성은없었다. IPI의평균값은건강대조군과간경변증환자군간에차이가있었고, 건강대조군과복수가없는간경변증환자군에비해복수가있는간경변증환자군에서유의하게높았다 (0.52±0.05 and 0.54±0.04 vs. 0.84± 0.21, p<0.05). 그러나건강대조군과복수가없는간경변증환자군간에는유의한차이가없었다 (Table 2). Table 2. Intestinal permeability in the healthy control subjects and cirrhotic patients Cirrhotics Cirrhotics Healthy with ascites without ascites controls (n=32) (n=33) (n=26) PEG ± ± ±3.22 PEG ± ± ±0.03 IPI 0.84±0.21* 0.54± ±0.05 *Different letters denote significant difference by post hoc of Scheffe (p<0.05). PEG, polyethylene glycol; IPI, intestinal permeability index. 3. 간경변증환자에서장투과성과임상양상및검사실소견과의유의성장투과성과간경변증의중증도를나타내는 Child-Pugh 분류의비교에서분류 C에서 A나 B에비해 PEG 3350 회수율 (0.43±0.02 vs. 0.21±0.02, 0.24±0.11, p<0.05) 과 IPI (1.10±0.19 vs. 0.50±0.22, 0.69±0.13, p<0.05) 가유의하게높았다. 또한 PEG 3350 회수율은저알부민혈증이있는경우없는군에비해유의하게높았으며 (0.26±0.22 vs. 0.22±0.31, p<0.05) IPI는간성뇌증과저알부민혈증이있는군에서없는군에비해유의하게높았고 (0.81±0.28 vs. 0.57±0.01, 0.83±0.03 vs. 0.66±0.05, p<0.05) 프로트롬빈시간연장, 식도정맥류, 고빌리루빈혈증유무등에서는유의한차이가없었다 (Table 3). 감염이동반된간경변증환자군과동반되지않은군, 그리고알코올과비알코올성간경변증환자간장투과성 (PEG 400, 3350 회수율및 IPI) 에있어서유의한차이는없었으나간경변증환자에서 Child-Pugh 점수와장투과성증가간에는양의상관관계가있었다 (r=0.494, p< for PEG 3350 and r=0.447, p<0.01 for IPI). Table 3. Analysis relating intestinal permeability to the clinical and laboratory findings in the cirrhotic patients No. PEG400 PEG3350 IPI (%) Child-Pugh classification A ± ± ±0.22 B ± ± ±0.13 C ± ±0.02* 1.10±0.19* Serum albumin (g/dl±se) > ± ± ±0.01 < ± ±0.22* 0.81±0.28* Serum bilirubin (mg/dl±se) > ± ± ±0.12 < ± ± ±0.21 Prothrombin time (s±se) > ± ± ±0.3 < ± ± ±0.4 Encephalopathy No ± ± ±0.05 Yes ± ± ±0.03* Esophageal varix No ± ± ±0.12 Yes ± ± ±0.11 *Different letters denote significant difference by post hoc of Scheffe (p<0.05); significantly different at p<0.01; significantly different at p< PEG, polyethylene glycol; IPI, intestinal permeability index.

5 한문종외 7 인 : 복수가동반된간경변증환자에서폴리에틸렌글리콜을이용한장투과성평가 91 고찰장투과성은여러병적인상황에서증가하는것으로알려져있고알코올성간질환, 간경변증등에서연관성이보고되고있으며, 5,15 중증질환에서는내독소와장내세균의전위가증가하며이는간의손상정도를증가시키고, 높은빈도로감염과패혈증을초래한다고알려져있다. 16 장투과성에대한다양한연구가시도되고있으며그중알코올성간질환에서 51 Cr-EDTA를이용한장투과성증가가보고된후여러간질환에서당류및 PEG 등을이용한장투과성연구가이루어지고있으나간경변증환자에서 PEG를이용한연구는국내에서는아직없는실정이다. 투과성측정물질로 PEG를이용하는장점은첫째이중합체는항원과같은거대분자를포함하는넓은범위의분자크기를포함한다는것이고, 둘째크로마토그래프측정은음식과소변안에있는당의존재에영향을받지않고, 식이조절도필요치않다는것이다. 하지만투과성측정물질의모든필요조건이충족되어도장투과성을평가하기위한 PEG 혼합물의전신적사용은작은크기의분자와큰크기의분자를결정할때다른분석방법을사용해야하는본질적인기술적복잡성의문제가있었으나본연구에서는증발광산란검출기를이용한 HPLC 기술로소변에서 PEG 400과 3350 의분석을할수있는적출법개발에의해이런시간과복잡성문제를해결하였다. PEG 회수율에의한장투과성측정에관한연구에서알코올성간질환과중증의급성췌장염환자들의 PEG 회수율증가와혈중내독소농도사이에유의한연관성이있다고보고되어 PEG가이전장투과성측정물질들 ( 분자량 300 Da-1200 Da) 보다내독소의간문맥과소화관림프계로의이동평가에더신뢰할수있는물질이라는것이증명되었다. 7 분자량 200 Da와 1,200 Da 사이의분자크기를갖는 PEG (PEG 400) 는장투과성변화와관련된다고생각되는만성염증성질환, 류마티스성관절염, 셀리악병, 음식알레르기등의질환에대한연구에서장투과성측정물질로사용되었다. 17,18 그러나 Lipid A는장내세균의주를차지하는그램음성세균의 Lipopolysaccharide (LPS) 의내독소주성분으로, 변화되지않은형태에서만염증반응을유발하며분자량은 1,900 Da이다. 19 그러므로 51 Cr-EDTA, PEG 400과같은분자량 1,200 Da 아래의분자량을가진화합물의연구결과는내독소전위결과에대한신뢰성이낮다. 최근연구에서는서로다른분자량을갖는 PEG (PEG 400, 3350) 가화학적구조의독특한특성과연관하여장투과성연구에이용되는데이는독성이없고, 수용성이며숙주나장내세균에의해대사되지않는특징이있으며혈액내로이동후극성 PEG 분자는소변으로배설된다. 20 균일한화학적성질, 적절한분자크기, 내독소와유사한선형, 체인과같은모양때문에 PEG는장관을통한 LPS 이동평가에가장적절한측정물질로생각되고있다. 21 단당류또는이당류, 당알코올, 방사성핵종복합체 ( 51 Cr-EDTA, 99m Tc- DTPA), 단백질과이들의복합체등이전에이용된장투과성측정물질들은이런조건들을충족시키지못한다. 22 분자량이다른두 PEG 측정물질을동시에사용하는것은쉽게확산되는 PEG 400에비해적게투과되는 PEG 3350의이동값을반영하는지표로서광범위한장투과성을측정가능하게한다. 또한측정물질의흡수전실험결과에영향을미칠수있는위배출과소화액분비에의한희석, 흡수후영향을미칠수있는전신적인분포와신장청소율과같은요인들이두분자에똑같이작용하므로서로다른개인간직접적으로비교될수있는장점이있다. 23 측정물질들은분자량이작은경우세포를통한 (transcellular) 경로로, 분자량이큰경우세포옆공간을통한 (paracellular pathway) 경로로통과한다고알려져있으나, 7 본연구에서모든대상자들의 PEG 400과 3350 회수율의유의한차이가없는것으로보아내독소와세균성독소의장관에서간문맥계로의이동이어느경로를통과하는지명확히언급하기는어렵다. 이에관하여 PEG를이용한검사동안간경변증환자에서장점막의형태적또는분자적변화에대한연구가더필요하다고생각한다. 복수내로 PEG 가유출되어낮은소변배설률을초래하고그에따라장투과성검사결과가저평가될가능성이있으나 51 Cr-EDTA를이용한 9명의간경변증환자의장투과성검사에서 51 Cr-EDTA의복수내로의유출은거의없으며, 24 복수천자가소변 51 Cr-EDTA 배설에중요한영향이없는것으로보아복수자체가결과에영향을미치지는않는것으로보고한결과와같이, 5,6 본연구에서도 6명의간경변증환자의복수에서 PEG가검출되지않아복수내로의 PEG 유출에의한낮은소변배설률의가능성은배제할수있었다. 장투과성증가가자발성세균염이나균혈증같은감염성합병증과연관이있다고보고되고있으나, 25,26 본연구에서는감염증이있는군과없는군사이에차이가관찰되지않았다. 이는감염이동반된환자수가적고각감염질환마다차이가있어단순비교보다는질환의발병시기와호전시

6 92 전남의대학술지제 44 권제 2 호 2008 기에각각측정비교하는것이합리적이라고생각하였다. 장투과성증가와간경변증의중증도사이의관련성은다양하게보고되고있으나, 7,10,11 본연구에서는 Child-Pugh 분류 A와 B환자에비해 C환자에서 PEG 3350 회수율과 IPI가유의하게높은것이관찰되었다. 이는아마타보고와검사방법의차이, 대상환자군의차이때문일것이다. 기존연구들과본연구결과의단순비교는검사에이용된측정물질의구성과사용된분석기술이다를수있고환자집단의차이, 간경변증의중증도를포함한평가방법의차이가있을수있어다소무리가따른다고볼수있다. 이상의결과를토대로 PEG를이용한장투과성연구는임상적유용성이있을것으로사료되고장투과성증가는복수를동반한간경변증의병태생리와진행에아마도중요한역할을할것으로생각하며저알부민혈증과간성뇌증발생에일부기여할것으로생각되었으나추후내독소, 싸이토카인, 산화체매개등과연관된연구가추가되어야할것이다. References 1. Wilmore DW, Smith RJ, O'Dwyer ST, Jacobs DO, Ziegler TR, Wang XD. The gut: a central organ after stress. Surgery 1988;104: Berg RD. Translocation and indigenous gut flora. In: Fuller (ed). Probiotics. London:Champman Hall, 1992; Manevska B. Enzymatic changes in the mucous membrane of the small intestine in tetrachlormethane-induced experimental liver cirrhosis. Eksp Med Morfol 1976;15: Kalaitzakis E, Johansson JE, Bjarnason I, Bjärnsson E. Intestinal permeability in cirrhotic with and without ascites. Scand J Gastroenterol 2006;41: Ramachandran A, Balasubramanian KA. Intestinal dysfunction in liver cirrhosis: its role in spontaneous bacterial peritonitis. J Gastroenterol Hepatol 2001;16: Zuckerman MJ, Menzies IS, Ho H, Gregory GG, Casner NA, Crane RS, et al. Assessment of intestinal permeability and absorption in cirrhotic patients with ascites using combined sugar probes. Dig Dis Sci 2004;49: Rahman SH, Ammori BJ, Larvin M, McMahon MJ. Increased nitric oxide excretion in patients with severe acute pancreatitis: evidence of an endotoxin mediated inflammatory response? Gut 2003;52: DeMeo MT, Mutlu EA, Keshavarzian A, Tobin MC. Intestinal permeation and gastrointestinal disease. J Clin Gastroenterol 2002;34: Loret S, Nollevaux G, Remacle R, Klimek M, Barakat I, Deloyer P, et al. Analysis of PEG 400 and 4000 in urine for gut permeability assessment using solid phase extraction and gel permeation chromatography with refractometric detection. 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경락경혈학회지 Vol.27, No.1, pp.87 106, 2010 Journal of Meridian & Acupoint Dept. of 1 Meridian & Acupoint, 3 Acupuncture & Moxibustion, College of Oriental Medicine, Daejeon University 2 Division of Clinical