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1 대한내과학회지 : 제 75 권제 6 호 2008 특집 (Special Review) - 담석증의진단과관리 담석의병태생리 경희대학교의과대학내과학교실 주광로 Pathophysiology of gallstone Kwang Ro Joo, M.D. Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul, Korea Gallstones form as the culmination of a complex series of events that results in precipitation of insoluble substances including cholesterol or bilirubin in the gallbladder. Bile formation is essential for lipid digestion and the removal of excess cholesterol from the body either by direct excretion or after conversion to bile acids. Gallstones occur when insoluble lipids and inorganic salts secreted by the liver cannot be solubilized as they normally are in bile by the detergent properties of bile salts. For this to occur, metabolic events must take place to produce bile that contains excess amounts of either cholesterol or bilirubin (supersaturation), both of which are relatively insoluble in aqueous solution. Additionally, physical factors must allow rapid nucleation within the residence time of bile in the biliary tree. (Korean J Med 75: , 2008) Key Words: Gallstone; Bile; Pathophysiology 서 론 요인에대해기술하고자한다. 담석은불용성물질 (insoluble substances) 들이담낭내에서응결또는부착되어침전되는복잡한일련의과정의결과로형성된다. 담즙 (bile) 은지방을녹일수있는생리적세제 (detergents) 인담즙산 (bile acid) 을포함하고있다. 담즙산은간에서불용성분자를담즙으로배설시키고장에서는음식물에포함된지방을흡수하는기능을갖는다. 담석은간에서분비되는불용성지질과무기성염 (inorganic salts) 이정상적으로담즙산에의해용해되지않을때발생된다. 따라서담석발생에있어대사성이벤트는콜레스테롤또는빌리루빈이담즙내에서과포화상태 (supersaturation) 로존재하는것이며, 물리적요소는이러한담즙이담낭을포함한담도계에머무르는동안핵화 (nucleation) 과정을거쳐담석결정체를형성하는것이다. 본원고에서는담석의병태생리와관련하여담즙의구성과기능, 그리고담석발생기전중주로물리및대사적인 담즙의구성담즙은지질소화에필수적이며체내에서과다하게생성되는콜레스테롤을직접또는담즙산으로변환시켜담도로배설시키는기능을가지고있다. 담즙구성은 90% 가물이며나머지가주로세가지종류의지질로구성되어있다. 지질의성분및분포는무게기준으로콜레스테롤이 4%, 인지질 (phospholipid) 이 24%, 그리고담즙산이 67% 를차지한다. 이러한각각의성분들의이동은간세포세관막 (canalicular membrane) 에발현되어있는 ATP 전달체 (transports) 에의해조절된다. ABCB4는인간에서 multi-drug resistant p-glycoprotein MDR3 로잘알려져있는유전자로인지질을세포막밖으로이동시키는기능을가지고있다 1). MDR3 유전자의돌연변이는 progressive familial intrahepatic cholestasis (PFIC) type 3에서관찰된다. ABCB11은 bile salt export pump (BSEP) 로잘알려진주된담즙산전달체 2) 로 PFIC type 2와

2 - The Korean Journal of Medicine: Vol. 75, No. 6, benign recurrent intrahepatic cholestasis (BRIC) type 2에서변이가관찰된다. 콜레스테롤은 ABCG5와 ABCG8에의해이동된다. 이유전자의변이의대표적인질환은 sitosterolemia 이다. ABCB4, ABCB11, ABCG5/8 유전자발현은최소한 2 개의핵수용체에의해조절을받는다 3, 4). Farnesoid/bile acid receptor (FXR/BAR) 는 ABCB4와 ABCB11의전사 (transcription) 를조절하며 ABCG5/8는 FXR에의해매개되는 oxysterol 또는 liver X receptors (LXRα/β) 에조절을받는다. 1. 콜레스테롤간내콜레스테롤은대부분은음식섭취로부터얻어진다. 주로 scavenger receptor B1 (SR-B1) 를통해혈청으로부터 high-density lipoprotein (HDL) 의유입으로이루어지며일부는 apolipoprotein (Apo) B/E receptor를통한 low-density lipoprotein (LDL) 이동으로구성된다 5). 음식물소화흡수로장점막에서생성된콜레스테롤이풍부한지질단백인 chylomicron remnants 는 LDL-receptor-related protein (LRP) 에의해간으로이동된다 6). 한편내인성콜레스테롤은 3-hydroxy- 3-methylglutaryl coenzyme A (HMG CoA) reductase 에의해간자체에서합성된다. 담즙으로배설되는콜레스테롤양은간내유리콜레스테롤양과세관막을통한담즙산의유입에의해결정된다. 2. 인지질담즙을구성하는주된인지질은 phosphatidylcholine (lecithin) 이다. 이는 glycerol로에스터화된두개의지방산사슬을포함하고이지방산은 phosphorylcholine과공유결합을이룬다. 세균에서분비되는 phospholipase A는 phosphatidylcholine을 lysolecithin과지방산으로분해한다. Phosphatidylcholine 분해산물이많이증가할경우칼슘과반응하여 fatty acid soaps 를형성하고이는갈색색소성담석형성기전과관련이있다. 3. 담즙산담즙산은콜레스테롤로만들어진세제 (detergents) 분자로스테로이드핵과 1~3개의 hydroxyl 군과 glycine 또는 taurine 과결합된 carboxylic acid side chain으로구성된다. 일정한농도이상으로농축되면단량체담즙산 (bile acid monomers) 은융합하여단순미셀 (simple micelles) 을형성한다. 일차담즙산은간세포에서직접만들어진것으로 trihydroxy bile salt 인 cholate (taurocholate, glycocholate) 와 dihydroxy bile salt인 chenodeoxycholate (taurochenodeoxycholate, glycochenodeoxycholate) 가여기에포함되며, 이차담즙산은일차담즙산이장내세균에의해변화된것으로 deoxycholates, ursodeoxycholates, lithocholates 등이있다. 담즙산의세제능력은이들담즙산의상대적인비율에따라결정된다 7). 담즙산합성에는여러효소가관여하지만주로고전적경로인간내 cholesterol 7-α-hydroxylase에의한담즙산합성과정 8) 과대체경로인 sterol 27-hydroxylase에의해말초조직에서콜레스테롤분해과정을거쳐담즙산을형성하는과정이있다 9). 고전적경로는간에서이루어지며소수성담즙산 (hydrophobic bile acids), thyroxin, glucocorticoids 등에의해조절된다. 대체경로는고전적경로와달리혈관내피세포, 대식세포등다양한조직에서일어나는데말초조직에서 sterol 27-hydroxylase에의해 27-hydroxycholesterol (oxysterol) 이형성되고이는간으로이동하여 oxysterol 7-α-hydroxylase에의해담즙산으로변환된다 9, 10). 혈관내피 (endothelium) 에존재하는 sterol 27-hydroxlase는세포내콜레스테롤침착을예방한다 11). 콜레스테롤항상성 (Cholesterol homeostasis) 간세포는콜레스테롤항상성을조절하고담즙형성에중추적인역할을한다. 간세포에서유리콜레스테롤풀 (free cholesterol pool) 은 HMG CoA reductase 에의해생성되는내인성합성과혈청지질단백으로부터이동되는콜레스테롤유입으로구성된다. 지질단백에서콜레스테롤의유입은앞에서기술한 SR-B1, Apo B/E receptor, LRP 을통해일어난다. 담즙산의합성은 cholesterol 7-α-hydroxylase에의해콜레스테롤로부터생성되고일부는말초조직에서이동된 27-hydroxycholesterol이간에서 oxysterol 7-α-hydroxylase에의해형성된다. 유리콜레스테롤은 acyl cholesterol acyl transferase (ACAT) 에의해에스터화형태로저장될수있고에스터화된콜레스테롤은지질단백으로이동되거나다시가수분해되어콜레스테롤풀로이동된다. 궁극적으로콜레스테롤배설은담즙산형태또는직접적으로담즙을통해서만이루어진다 ( 그림 1). 담즙결정체담석형성은담즙내과포화된불용성물질이결정체를이루어형성된다. 콜레스테롤결정체와비결합빌리루빈결정체가대표적인담즙결정체이다

3 - Kwang Ro Joo. Pathophysiology of gallstone - Oxysterol 7αhydroxylase Figure 1. Metabolic pathways in cholesterol and bile salt synthesis. The free cholesterol pool in the hepatocyte derives from endogenous synthesis via the rate limiting enzyme HMG-CoA reductase and uptake of cholesterol from serum lipoproteins. Bile salt synthesis occurs after hydroxylation of cholesterol by the rate limiting enzyme cholesterol 7-α -hydroxylase (classic pathway). Peripheral conversion of cholesterol to 27-hydroxycholesterol and subsequent transport to the hepatocyte appears to be the initial step in a substantial fraction of bile salt synthesis (alternative pathway). Cholesterol may be stored in the esterified form after esterification by ACAT. Cholesterol esters may be exported in lipoproteins or hydrolyzed to augment the free cholesterol pool. Ultimately, net cholesterol excretion occurs only via cholesterol and bile salt secretion into bile with incomplete enterohepatic circulation (From Donovan JM. Physical and metabolic factors in gallstone pathogenesis. Gastroenterol Clin North Am 28:75-97, 1999). Figure 2. Biliary lipid aggregates. The relative and total concentrations of bile salts, phosphatidylcholine and cholesterol determine the type and proportion of biliary lipid aggregates. In cholesterol unsaturated bile, bile salts form simple micelles by apposition of their hydrophobic surfaces. Simple micelles can also solubilize small amounts of cholesterol. Mixed micelles (40-80Å) contain bile salts, phosphatidylcholine, and cholesterol. When the micellar solubility of cholesterol is exceeded, vesicles are formed. Excess cholesterol is carried both in supersaturated mixed micelles and vesicles. Unilamellar vesicles range from 500 to- 1000Å in size, and can fuse and aggregate to form multilamellar vesicles up to 10,000Å. The thermodynamic instability of cholesterol-rich vesicles allows formation of cholesterol crystals (From Donovan JM. Physical and metabolic factors in gallstone pathogenesis. Gastroenterol Clin North Am 28:75-97, 1999). 1. 콜레스테롤결정체담즙내지질구성원인담즙산, 인지질, 콜레스테롤은모두양쪽친매성물질 (amphiphilic molecules) 로물을싫어하는소수성부분 (hydrophobic portion) 과물을좋아하는친수성부분 (hydrophilic portion) 으로나누어져있다. 따라서담즙산의경우물-지질계면 (lipid-water interface) 에서친수성부분인히드록실기나펩티드결합또는 taurine 및 glycine side chain은수상 (aqueous phase) 에위치하여용해되며소수성인스테로이드핵은지질상 (lipid phase) 에용해된다. 마찬가지로레시틴및콜레스테롤도친수성인히드록실기는수상에서용해되며소수성인나머지부분은지질상에용해된다 12). 담즙산, phosphatidylcholine, 콜레스테롤은각각의농도비율에따라다양한담도내지질결정체를형성한다. 담즙산 /phosphatidylcholine의비율이높을경우열역동학적으로안정된혼합미셀 (stable mixed micelles) 이만들어진다 13). 지질농도가높을경우혼합미셀은작은공모양의형태를이루 고지질농도가낮은경우큰막대형대를보인다. 그러나 phosphatidylecholine과콜레스테롤이상대적으로높을경우이들층으로이루어진단층판소포 (unilamellar vesicles) 가형성된다. 콜레스테롤이풍부한단층판소포는콜레스테롤을이동시키기는하나용해시키지는못하다 14). 단층판소포는콜레스테롤농도가높기때문에열역동적으로매우불안정한상태로서로뭉쳐다층판소포 (multilamelllar vesicles) 를만들고시간경과에따라콜레스테롤결정체를형성한다 15) ( 그림 2). 2. 비결합빌리루빈결정체비결합빌리루빈은헴의분해산물로 hydrocarbon side chains과두개의 hydrophilic propionic acid side chains을갖는 4개의 hydrophobic pyrrole rings으로구성된다. 정상적으로생체내에서불용성인비결합빌리루빈은 glucuronides 또는다른친수성물질과결합하여용해력을얻어결합빌리루빈형태로담즙으로배설되며적은양 (2% 이하 ) 만이비결합

4 - 대한내과학회지 : 제 75 권제 6 호통권제 580 호 형태로담즙에존재한다. 담즙산과 phosphatidylcholine은비결합빌리루빈을어느정도용해시킬수있다 16). 빌리루빈결정체는색소성담석의주된구성성분이다. 담즙에세균이오염된경우세균에서생성되는 β-glucuronidase는담즙내결합빌리루빈을가수분해하여비결합빌리루빈으로변환시킨다. 세균감염이없는경우에는간담도상피에서생산되는내인성 β-glucuronidase 및비효소성가수분해 (nonenzymatic hydrolysis) 에의해비결합빌리루빈이형성된다. 이러한비결합빌리루빈이담즙내과다하게존재하게되면결정체가형성되고이는색소성담석발생기전의근간이된다 17, 18). 담석의병태생리 (pathophysiology) 담석은구성성분과형성기전에따라콜레스테롤담석 (cholesterol stone), 흑색색소성담석 (black pigment stone), 그리고갈색색소성담석 (brown pigment stone) 으로나눈다. 콜레스테롤담석은콜레스테롤이 90% 이상을차지하는순수콜레스테롤또는점액소당단백기질 (mucin glycoprotein matrix) 과뭉쳐진 cholesterol monohydrate crystals로주로구성되며미세성분으로비결합빌리루빈과칼슘인산염 (calcium phosphate) 이있다. 흑색색소성담석은비결합빌리루빈의칼슘염이주된구성성분이며부가적으로점액소기질내칼슘인산염이혼합되어있다. 칼슘인산염으로인해흑색색소성담석은방사선비투과 (radio-opaque) 로관찰된다. 갈색색소성담석은담도감염과담즙정체의이차적결과로발생한다. 구성은주로담도내지질또는지방산및비결합빌리루빈의칼슘염이장내세균에의해분해된산물로이루어지며일부에서콜레스테롤침착이있다. 흑색색소성담석에비해 calcium phosphates와 calcium carbonates는아주적은양으로존재한다 19, 20). 1. 콜레스테롤담석콜레스테롤담석형성의일차적원인은콜레스테롤과분비에의한담즙내콜레스테롤과포화이다. 콜레스테롤과분비는담낭운동저하를일으키고담낭상피세포에서점액소의분비를증가시킨다. 담당저장기능의감소는장내세균에의한담즙산의분해기회를증가시켜담즙구성성분에변화를일으킨다. 그결과로이차담즙산인 deoxycholate가담즙내상대적으로증가되고이는담즙으로콜레스테롤과분비를증가시킨다 21). 콜레스테롤과분비에의한과포화, 점액소생산의증가, deoxycholate 양의증가는콜레스테롤결 Figure 3. Ternary phase diagram of major gallbladder lipids. Mixed micelles are found in Phase 1 mixtures of cholesterol, phospholipids and bile salts. Higher amounts of cholesterol or lower amounts of phospholipids and/or bile salts yield metastable (Phase 2 and 3) compositions, characterized by unilamellar and multilamellar vesicles that may give rise to cholesterol crystal (From Marschall HU. Gallstone disease. J Intern Med 261: , 2007). 정체형성을빠르게증가시켜담석형성에기여한다. 1) 콜레스테롤과포화수용성배지에서불용성인콜레스테롤은담즙산및 phosphatidylcholine (lecithin) 과함께미셀을형성하여담즙에서용해된다. 그러나콜레스테롤이과다하게있을경우즉, 콜레스테롤포화지수가 1 이상인경우콜레스테롤크리스탈이형성되는데이는인지질 : 콜레스테롤비율이낮은경우, 상대적으로인지질이낮고담즙산이높은농도로존재할경우에발생된다 ( 그림 3) 22). 콜레스테롤과포화의주된원인은콜레스테롤의과분비이다. 콜레스테롤의과분비는간으로콜레스테롤유입의증가및간내콜레스테롤대사에이상이있는경우에발생한다. 간내콜레스테롤대사와관련된주된효소로는콜레스테롤 de novo 합성과관련된 HMG CoA reductase, 담즙산생산과관련된 cholesterol 7α-hydroxylase (CYP7A1), 그리고콜레스테롤에스터형성과관련된 acyl cholesterol acyl transferase (ACAT) 등이있다. 이러한효소에이상이발생할경우간내콜레스테롤합성의증가, 콜레스테롤의담즙산또는콜레스테롤에스터로변환감소등으로유리콜레스테

5 - 주광로. 담석의병태생리 - Figure 4. Enterohepatic circulation of bile salts and bilirubin. (A) Apart from a small spill-over into the colon with bile salt loss in faeces, there is highly efficient portal venous return to the liver for re-uptake and resecretion into bile. The diagram also shows, in the case of bilirubin following its uptake, conjugation and secretion into bile, its route through the gastrointestinal tract is towards quantitative excretion in faeces without any substantial enterohepatic cycling. (B) A leading cause of an induced enterohepatic circulation (EHC) of bilirubin is bile salt malabsorption. Bypass, injury or disease of the ileum effectively interrupts the EHC of bile salts, leading to increased spillage of bile salts into the large intestine. Excess colonic bile salts aid in solubilization of unconjugated bilirubin, prevent or delay urobilinoid formation and interfere with calcium bilirubinate formation and precipitation, thereby promoting passive colonic absorption of the bile pigment (From Vítek L. Enterohepatic cycling of bilirubin as a cause of black pigment gallstones in adult life. Eur J Clin Invest 33: , 2003). 롤이증가되고이는담즙내콜레스테롤과분비를발생시킨다. 그러나담석과관련된연구에서담도계콜레스테롤과분비와이들효소와의관계는아직명확하게규명하지못했다. 간자체콜레스테롤합성 (de novo synthesis) 은담도계콜레스테롤양의 10% 밖에차지하지않는다. 대부분의콜레스테롤은음식물섭취에서얻어진다 23, 24). 담도계로콜레스테롤분비정도가담석의발생과관련이있다. 즉혈중콜레스테롤이높아담석이발생되는것이아니라담즙으로분비되는콜레스테롤이많은경우담석이발생한다 23). 담즙에서콜레스테롤과포화와관련된다른기전으로담즙산내 deoxycholic acid의증가가있다. 담석환자에서이차담즙산인 deoxycholate는정상인에비해높은비율로존재한다 25). 장통과시간 (intestinal transit time) 이연장되어장내세균에담즙노출이증가되거나또는세균성 7α-dehydroxylation activity의증가로인해과다하게생성된 deoxycholate 는장간순환 (enterohepatic circulation) 을통해간으로이동되어콜레스테롤의담즙내방출을증가시켜담즙내콜레스테롤과포화를조장시킨다 21, 26, 27). 더욱이 deoxycholate는부적절한비율로인지질을용해시킴으로직접적으로콜레스테롤결정화를가속화시킨다 28). 2) 담낭운동저하 (hypomotility) 과포화담즙은종종건강한사람에서도발생된다. 그러나 문제가되지않는것은담낭내형성된크리스탈이음식섭취시담낭수축 (postprandial gallbladder emptying) 으로의해효과적으로배출되기때문이다. 식간담낭배출 (interdigestive gallbladder emptying) 도담석형성에중요한역할을한다. 식간담낭배출의저하는담낭에서담즙농축시간을증가시키고농축된담즙은불안정소포 (unstable vesicles) 를거쳐콜레스테롤크리스탈의형성과침전을일으킨다 29, 30). 담낭운동저하는당뇨병환자, 완전비경구영양 (total parenteral nutrition) 을받거나, 급격한체중감량을하는환자등에서관찰된다 31). 따라서담낭운동저하로발생되는담석의예방을위해완전비경구영양을받고있는환자나체중감량을위해적은지방양을섭취하는사람에서 cholecystokinin 투여가권고되기도한다 32, 33). 한편담석이일단형성되면증상발생위험성은담낭운동저하가있는환자보다담낭배출이높은사람 (>70% emptying) 에서더발생할가능성이높다 34). 담즙내콜레스테롤과포화가직접적으로담낭수축력을저하시킨다는연구가있다 35, 36). 담낭수축력의저하는담즙정체와관련이있고담즙정체는담석형성의필수조건인핵화 (nucleation) 를조장하기에충분하다. 또한담낭수축력저하에따른장내담즙노출시간의증가는앞에서언급한장내세균에의한담즙성분변화에영향을주어담즙내콜레스테롤과포화로악순환된다

6 - The Korean Journal of Medicine: Vol. 75, No. 6, Table 1. Putative pathogenetic conditions facilitating enterohepatic circulation of unconjugated bilirubin Mechanism Cause Clinical conditions Higher rates of bilirubin deconjugation in the small intestine Deficiency of bacteria capable of reducing UCB in the large intestine Augmented solubilization of UCB in the large intestine Prolonged intestinal transit time Colonization with β-glucuronidase producing bacteria Extraintestinal supply of β-glucuronidase Postnatal period Acquired in gut sterilization Bile salt malabsorption with higher bile salt concentrations in the proximal large intestine; prevention of bilirubin from complexing with intraluminal Ca2+ Fasting Total parenteral nutrition Delayed feeding of newborns Small bowel obstruction Breast-milk jaundice Neonatal jaundice Antibiotic treatment Ileal disease, injury, resection or bypass Bile acid therapy to effect gallstone dissolution High cholesterol or carbohydrate diets Alcohol abuse Immaturity of ileal apical sodium-coupled bile salt transporter-asbt (neonatal jaundice) Dysfunctional mutations of ASBT causing mild to moderate spillage of bile salts Therapy with bile acid resorption inhibitors 3) 핵화촉진단백질과포화담즙에서미세결정 (microcrystals) 형성은핵화과정을통해일어난다. 담석증환자에서의핵화형성시간은정상인에비해짧다. 생체외연구를통해다양한억제또는촉진단백질이보고된바있다. 이중담도상피세포에서분비되는당단백질혼합물인점액소 (mucin) 가대표적인담낭슬러지의결정화촉진단백질 (crystallization promoting protein) 이다 37, 38). Lithogenic bile에서점액소증가의기전은명확하지않으나인지질의일종인 eicosanoid precursors 흡수로인한담낭점막내 prostaglandin 합성의증가, 점막으로흡수된콜레스테롤분자의활성화및점막세포독성등이관련된것으로생각한다 39). 그러나담낭담석환자에서콜레스테롤결정체형성에점액소를포함한단백질이관련이없다는연구도있다 40). 2. 흑색색소성담석 (Black pigmented gallstones) 흑색색소성담석은주로 calcium bilirubinate로구성되고 calcium phosphate, 그리고 calcium carbonate와함께점액소당단백기질이혼합되어있다. 콜레스테롤은 20% 이하에서포함된다. 흑색색소성담석은형성은담즙내비결합빌리루빈의과포화가근본원인이다. 정상적으로간에서담즙으로배설된빌리루빈은결합형태이다. 약 2% 미만에서비결합빌리루빈이담즙에존재할수있는데이는내인성간담도 β-glucuronidase에의한가수분해결과이다 41). 그러나용혈성빈혈및부적절한조혈 (ineffective hematopoiesis) 등에의해빌리루빈이과다하게생성되어담즙으로배설되는경우내인성간담도 β-glucuronidase에의해 1~2% 만불용성비결합빌리루빈으로전환되어도그양은빌리루빈결정체를형성하기에충분하다. 또한길벗증후군과같이 hepatic bilirubin UDP-glucuronosyltransferase 감소로담즙으로배설되는빌리루빈이 bilirubin diglucuronides (BDG) 에비해내인성 β- glucuronidase에잘분해되는 bilirubin monoglucuronides (BMG) 가상대적으로많은경우역시담즙내비결합빌리루빈은증가하게된다. 한편담즙산의재사용에매우중요한역할을하는장간순환이흑색색소성담석의형성과정에기여를한다. 정상적으로결합빌리루빈의경우는장간순환은거의발생하지않는다 ( 그림 4A). 그러나다양한원인에의해장내빌리루빈이비결합형으로변환되고이것이담즙산에용해될경우빌리루빈의장간순환이가능하다 42-44). 빌리루빈의장간순환의주된기전은담즙산염의흡수장애이다 ( 표 1). 회장기능부전 (ileal dysfunction) 을가진크론씨병또는회장절제환자에서담즙내빌리루빈이증가되어있다 45, 46). 회장에문제가있는경우담즙산염의장간순환에장애가발생하고그결과로장으로흡수되지못한담즙산염은대장으로이동하게된다. 대장에서담즙산염은장내세균에의해탈

7 - Kwang Ro Joo. Pathophysiology of gallstone - Table 2. Clinical conditions associated with black pigment gallstones putatively caused by enterohepatic recycling of unconjugated bilirubin Clinical condition Crohn s disease Ileal resection or bypass Therapy with unconjugated bile acids High cholesterol intake Carbohydrate-rich diets Total parenteral nutrition Alcohol abuse Cystic fibrosis Pathophysiologic mechanism (s) Impaired ileal bile salt resorption as a result of chronic inflammation of the ileum Removal or bypass of active bile salt resorption sites in the distal ileum Excess free and conjugated bile salts in the proximal large intestine secondary to oral administration of bile acids Excess bile salts in the large intestine as a result of down-regulation of active bile salt resorption transporters in the distal ileum Excess bile salts in the proximal large intestine due to starch-induced bile salt sequestration or osmotically induced diarrhea Decreased intestinal motility with increased bilirubin conjugate hydrolysis and resorption of unconjugated bilirubin from the small intestine Defects in intestinal motility and bile salt resorption because of ethyl alcohol-induced damage to ileal mucosa, and bile salt malabsorption as a result Cause of bile salt malabsorption not determined. Possibly resulting from bile salt binding to undigested carbohydrates and proteins, as well as precipitation of glycine conjugates from hyperacidity of the upper small intestine. However, in vivo functional down-regulation of the ileal apical sodium-dependent bile salt transporter is possible 결합된비용해성비결합빌리루빈을용해시켜비결합빌리루빈이 urobilirubin 으로변환되거나칼슘과함께결정체형성을못하게하여장흡수를통한장간순환을증가시킨다 ( 그림 4B) 43, 46). 빌리루빈의장간순환은비결합빌리루빈의담즙내과분비를초래하고담즙산의분비저하에따른이온화칼슘농도의증가는 calcium bilirubinate 과포화를더욱가속화시켜담석형성을일으킨다 43). 또한콜레스테롤담석과마찬가지로촉매인자인담낭점액소가담석형성에중요한역할을한다. 흑색색소성담석동물모델에서담낭내비결합빌리루빈의증가또는담낭점막에비결합빌리루빈의침전이점막세포를손상시켜점액소과분비가일어난다는연구가있다. 장간순환증가에의한흑색색소성담석형성과관련된질환의병태생리는표 2의요약과같다. 3. 갈색색소성담석갈색색소성담석은세균또는기생충에의한담도계감염의결과로인한 bilirubin glucuronides 의탈결합과관련이있다. 갈색색소성담석이형성되기위해선유기적또는기능적담관내정체가있어야하고이와함께만성적혐기성세균감염이있어야한다. 갈색색소성담석은콜레스테롤및흑색색소성담석과달리담석중앙에세균세포뼈대 (bacterial cytoskeletons) 의존재가확인되었고, 담즙및담석 배양에서세균양성소견을보인다 47). 세균감염은담즙의용해화에미묘한변화를일으키고담도지질의침전을일으킨다. 세균에서분비되는 β-glucuronidase는결합빌리루빈을비용해성인비결합형태로전환시키고이는칼슘염으로침전된다. Bacterial phospholipase는 phosphatidylcholine을가수분해하여 lysolecithin과 fatty acid 로변화시키고이역시칼슘염으로침전된다. 또한담즙산염의경우는담즙산으로탈결합되고칼슘염으로침전된다. 담즙의용해화의감소, 인지질및담즙산염의감소는콜레스테롤역시침전시킨다. 갈색색소성담석이흑색색소성담석또는콜레스테롤담석을핵으로하여발생되는경우가있다. 이는흑색색소성담석또는콜레스테롤담석이총담관에서담즙흐름의장애를초래하고이로인한만성적세균감염은갈색색소성담석을발생시킨다. 파터팽대부주위게실의경우도갈색색소성담석의형성을조장시키는데이역시게실에의한유두괄약근기능부전으로인해총담관내세균집락형성의결과로생각된다 48). 결론담석의발생기전에있어담즙내불용성물질인콜레스테롤및빌리루빈의과포화가각각콜레스테롤담석및색소

8 - 대한내과학회지 : 제 75 권제 6 호통권제 580 호 성담석형성에있어가장근간이되는기전이다. 콜레스테롤담석형성에있어일차적손상은담즙내로콜레스테롤과분비이다. 콜레스테롤과분비는콜레스테롤과포화와직접또는간접적으로담낭운동저하, 점액소과분비등담낭의기능장애를일으킨다. 담낭기능장애는담낭에저류되는담즙을더농축시켜핵화를촉진시키고, 식간소장으로담즙의이동을증가시켜담즙의세균노출시간을증가시킨다. 그결과불용성담즙산의증가, 장간순환의증가, 담즙산염풀의감소는결국담석형성을촉진시킨다. 흑색색소성담석은빌리루빈이과도하게생산되는여러상황에서담즙내불용성비결합빌리루빈과포화의결과로발생되며또한담즙산의장간순환의감소를일으키는회장기능부전의경우담즙산이대장으로이동하여비결합빌리루빈의장간순환을증가시켜결국담즙내비결합빌리루빈의과포화를일으킨다. 흑색색소성담석은담즙의정체와세균감염으로인한담도지질과빌리루빈분해물이칼슘이온과결합한불용성칼슘염의침전으로발생한다. 중심단어 : 담석 ; 담즙 ; 병태생리 REFERENCES 1) Smit JJ, Schinkel AH, Oude Elferink RP, Groen AK, Wagenaar E, van Deemter L, Mol CA, Ottenhoff R, van der Lugt NM, van Roon MA, van der Valk MA, Offerhaus GJA, Berns AJM, Borst P. Homozygous disruption of the murine mdr2 P-glycoprotein gene leads to a complete absence of phospholipid from bile and to liver disease. Cell 75: , ) Gerloff T, Stieger B, Hagenbuch B, Madon J, Landmann L, Roth J, Hofmann AF, Meier PJ. The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver. J Biol Chem 273: , ) Lu TT, Repa JJ, Mangelsdorf DJ. Orphan nuclear receptors as elixirs and FiXeRs of sterol metabolism. J Biol Chem 276: , ) Zollner G, Marschall HU, Wagner M, Trauner M. Role of nuclear receptors in the adaptive response to bile acids and cholestasis: pathogenetic and therapeutic considerations. Mol Pharm 3: ) Acton S, Rigotti A, Landschulz KT, Xu S, Hobbs HH, Krieger M. Identification of scavenger receptor SR-BI as a high density lipoprotein receptor. Science 271: , ) Beisiegel U, Weber W, Ihrke G, Herz J, Stanley KK. The LDL-receptor-related protein, LRP, is an apolipoprotein E- binding protein. Nature 341: , ) Heuman DM. Quantitative estimate of the hydrophilichydrophobic balance of mixed bile salt solutions. J Lipid Res 30: , ) Stravitz RT, Hylemon PB, Heuman DM, Hagey LR, Schteingart CD, Ton-Nu HT, Hofmann AF, Vlahcevic ZR. Transcriptional regulation of cholesterol 7-alpha-hydroxylase mrna by conjugated bile acids in primary cultures of rat hepatocytes. J Biol Chem 268: , ) Cali JJ, Russell DW. Characterization of human sterol 27-hydroxylase. A mitochondrial cytochrome P-450 that catalyzes multiple oxidation reaction in bile acid biosynthesis. J Biol Chem 266: , ) Björkhem I, Andersson O, Diczfalusy U, Sevastik B, Xiu RJ, Duan C, Lund E. Atherosclerosis and sterol 27-hydroxylase: Evidence for a role of this enzyme in elimination of cholesterol from human macrophages. Proc Natl Acad Sci USA 91: , ) Reiss AB, Martin KO, Javitt NB, Martin DW, Grossi EA, Galloway AC. Sterol 27-hydroxylase: High levels of activity in vascular endothelium. J Lipid Res 35: , ) Carey MC, Small DM. The physical chemistry of cholesterol solubility in bile: Relationship to gallstone formation and dissolution in man. J Clin Invest 61: , ) Donovan JM, Carey MC. Separation and quantitation of cholesterol "carriers" in bile. Hepatology 12:94S-104S, ) Sömjen GJ, Gilat T. Contribution of vesicular and micellar carriers to cholesterol transport in human bile. J Lipid Res 26: , ) Halpern Z, Dudley MA, Kibe A, Lynn MP, Breuer AC, Holzbach RT. Rapid vesicle formation and aggregation in abnormal human biles: A time-lapse video-enhanced contrast microscopy study. Gastroenterology 90: , ) Ostrow JD, Celic L, Mukerjee P. Molecular and micellar associations in the ph dependent stable and metastable dissolution of unconjugated bilirubin by bile salts. J Lipid Res 29: , ) Spivak W, DiVenuto D, Yuey W. Non-enzymic hydrolysis of bilirubin mono- and diglucuronide to unconjugated bilirubin in model and native bile systems: Potential role in the formation of gallstones. Biochem J 242: , ) Ho KJ, Hsu SC, Chen JS, Ho LH. Human biliary P- glucuronidase: Correlation of its activity with deconjugation of bilirubin in the bile. Eur J Clin Invest 16: , ) Malet PF, Takabayashi A, Trotman BW, Soloway RD, Weston NE. Black and brown pigment gallstones differ in microstructure and microcomposition. Hepatology , ) Cetta FM. Bile infection documented as initial event in the pathogenesis of brown pigment biliary stones. Hepatology 6: , ) Berr F, Pratschke E, Fischer S, Paumgartner G. Disorders of

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