대한내과학회지 : 제 77 권제 3 호 2009 특집 (Special Review) - 만성간질환치료의최신지견 문맥압항진증치료의최신지견 건국대학교의학전문대학원소화기내과 최원혁 Update on the treatment of portal hypertension Won Hyeok Choe, M.D. Department of Internal Medicine, Konkuk University School of Medicine, Seoul, Korea Portal hypertension is responsible for most of the complications associated with liver cirrhosis, including variceal hemorrhage, ascites, and hepatic encephalopathy. It has become clear that a decrease in portal pressure can prevent or manage these serious complications. Until now, the pharmacotherapy of portal hypertension has focused on agents that reduce splanchnic blood flow, such as non-selective beta blockers and splanchnic vasoconstrictors. However, recent advances in the knowledge of the pathophysiology of portal hypertension have directed future treatment towards modulating the increased intrahepatic vascular resistance, in addition to managing the splanchnic circulation. Consequently, agents that modulate either the hyperdynamic circulation or angiogenesis are new therapeutic targets for managing portal hypertension. Several have been developed or are under investigation. To incorporate these pharmacologic approaches into clinical practice, data on patient-oriented outcomes are needed. (Korean J Med 77:282-289, 2009) Key Words: Portal hypertension; Intrahepatic vascular resistance; Hyperdynamic circulation; Angiogenesis 서론간경변증환자에서간문맥압이비정상적으로상승하는문맥압항진증 (portal hypertension) 이발생할수있고, 이는정맥류출혈, 복수등과같은합병증을유발하여, 궁극적으로환자의주요사망원인이된다 1). 문맥압은간정맥도자술로측정한간정맥쐐기압 (wedged hepatic venous pressure) 에서간정맥자유압 (free hepatic venous pressure) 을뺀값인간정맥압력차 (hepatic venous pressure gradient) 로평가하는데 2), 간정맥압력차가 6 mmhg 이상인경우문맥압항진증이발생하며, 12 mmhg 이상인경우정맥류출혈과복수등이발 생하는것으로보고된다 ( 그림 1) 3). 한편여러임상결과에서약물치료를통해간정맥압력차를효과적으로낮추는경우, 문맥압항진증의합병증발생빈도를줄인다고보고하고있으며 4), 이러한연구결과를바탕으로최근미국간학회에서는문맥압항진증의대표적합병증인정맥류출혈의예방및재발방지목적으로비선택적베타차단제와같은약물치료를시도할것을권고하고있다 4). 하지만실제임상에서문맥압항진증의개선을위해이용가능한치료방법은매우제한적인상황이다. 최근문맥압항진증의병태생리학적기전에대한활발한연구가진행되면서 5), 각각의기전을조절할수있는치료방법에대한연구가시도되고있다 ( 그림 * This work was supported by the Konkuk University Medical Center Research Grant 2008. - 282 -
- Won Hyeok Choe. Update on the treatment of portal hypertension - Figure 1. Measuring portal pressure: the hepatic venous pressure gradient. Figure 3. Mechanical components of the intrahepatic vascular resistance and fibrogenic cascade. Most forms of liver injury result in hepatocyte injury, followed by inflammation, which, in turn, leads to the activation of hepatic stellate cells and extracellular matrix synthesis. 2). 따라서이번글에서는문맥압항진증을개선시킬수있는치료방법및약물에대해주로국내에서진행된연구, 현재임상에서사용가능한치료제및최근임상에적용하기위해주목받고있는치료법등을중심으로, 그병태생리학적작용기전에따라분류하여알아보고자한다. 본 1. 간내혈관저항증가의물리적요인을조절하는치료제 지속적이고만성적인간손상은간섬유화 (hepatic fibrosis) 와간동모양혈관 (hepatic sinusoid) 의구조변화 (architectural change) 를유발하며, 이러한물리적요인 (mechanical component) 의변화는간내혈관저항 (intra-hepatic vascular resistance) 을증가시켜문맥압항진증을발생시키는일차적원인이된다 ( 그림 3). 따라서만성적간손상의원인을제거하거나억제할수있는치료법은물리적변화의진행을억제하거나호전시켜, 문맥압항진증을개선시킬수있다. 많은연구결과에서간경변증의기저질환즉, 만성바이러스성간염, 알코올간질환등을치료하면문맥압항진증을개선시켜, 문맥압항진증으로인한합병증을줄일수있다고보고하였다 6). 하지만이러한문맥압항진증의기저질환치료는치료제사용이불가능하거나반응하지않고, 기저질환치료 론 Figure 2. The pathophysiology of portal hypertension in liver cirrhosis and different approaches to treating it. 에도불구하고문맥압항진증이효과적으로개선되지않는환자군이상당수존재한다는제한점이있다. 기저질환치료이외에도항섬유화제 (anti-fibrotic agents) 가문맥압항진증을개선시킬수있는지에대한연구도활발히진행되고있다 7). 항섬유화제는간섬유화를자극하는간내염증을억제하는방법, 간성상세포 (hepatic stellate cells) 의활성과증식을억제하는방법, 활성화된간성상세포의세포자멸사 (apoptosis) 를유도하는방법및침착된세포외기질 (extracellular matrix) 의퇴화 (degradation) 시키는방법등다양한병태생리학적기전에대한치료제가연구되고있으나, 현재까지임상적으로공인된치료약물은없는실정이다 ( 표 1). 대표적으로임상에서연구된약제는인터페론-감마 (interferon-γ) 로이약제는항섬유화효과뿐아니라항증식, 항바이러스효과까지가지고있어만성 C형간염바이러스에의한간경변증환자에서효과적일것으로기대하였으나, 연구결과는만족할만한치료성적을보여주지는못했다 8). 최근선택적 cyclooxygenase-2 억제제가간성상세포의세포자멸사를유도함으로써간섬유화를호전시킨다는연구결과등이보고되었으나 9), 동물실험단계의연구결과로임상에적용하기위해서는추가적인연구결과가필요하다. 2. 간내혈관저항증가의가역적인요인을조절하는치료제 간경변증에서간내혈관저항의증가원인은간섬유화, 간동모양혈관구조변화와같은물리적요인이외에도역동 - 283 -
- 대한내과학회지 : 제 77 권제 3 호통권제 589 호 2009 - Table 1. Potential therapy for liver fibrosis Mechanistic target Examples Suppress hepatic inflammation TNF-α antagonists (e.g., infliximab, thalidomide), IL-1 antagonists, IL-10, corticosteroids Inhibit HSC activation Anti-oxidants (e.g., vitamin E, phosphatidylcholine), IFN-γ, glitazones, sylimarin, trichostatin A Inhibit HSC proliferation PDGF antagonists, fumigillin analogues Down-regulate HSC fibrogenesis TGF antagonists, ACE inhibitors, AT1 receptor antagonists Enhance matrix degradation MMPs, TIMP antagonists, upa Promote HSC apoptosis Fas ligand, COX2 inhibitor Benzodiazepines, gliotoxin, sulphasalazine Modified from reference 7. Figure 4. Dynamic components of the intrahepatic vascular resistance. Increased intrahepatic vascular resistance in liver cirrhosis as a consequence of hyper responsiveness to vasoconstrictors and hypo-responsiveness to vasodilators. ET, endothelin; NO, nitric oxide. Figure 5. Inhibition of the RhoA/Rho-kinase pathway and activation of the AKT/PI-3K pathway is regulated by statins. 적이고가역적으로 (dynamic and reversible) 조절가능한부분이존재하며 10), 이러한가역적요인이문맥압항진의 30% 정도비중을차지한다는점이밝혀지면서문맥압항진증치료의중요과제로주목받고있다 ( 그림 4). 특히동모양혈관내피세포 (sinusoidal endothelial cell) 를감싸고있는간성상세포의수축과이완을조절하는인자에관한연구가활발히진행중이며, 이중많은연구가간성상세포를이완시키는 nitric oxide (NO) 의간내생체이용효율 (bioavailability) 을높이 는방법에초점이맞춰져있다. 실제로 NO를증가시키는 nitrates 제제는이미임상에서정맥류출혈의예방및치료약물로사용되어왔다. 하지만 nitrates가문맥압항진증을개선시킨다는초기연구결과와달리이후대규모임상결과에서는 nitrates 투여환자에서오히려식도정맥류출혈이더많이발생하였으며 11), 이는 nitrates가간내혈관저항증가를개선시키는순기능효과보다는내장혈관을비롯한전신말초혈관을이완함으로써문맥계유입혈류량 (portal venous - 284 -
- 최원혁. 문맥압항진증치료의최신지견 - Table 2. Theoretical pharmacological strategies for treating portal hypertension 1. Increase intrahepatic NO bioavailability A. Currently used: ISMN, nitroglycerin B. Potential future strategies: - Statins - Gene transfer with enos - Gene transfer of Akt - Selective hepatic NO delivery V-Pyrro-NO NO-ursodeoxycholic acid - Decrease intrahepatic NO degradation anti-oxidant capacity 2. Increase intrahepatic CO 3. Antagonize the effect of intrahepatic vasoconstrictors A. Endothelin-1 antagonism - Bosentan - Newly developed ET-blockers: - Tezosentan B. Angiotensin-II - Selective AT-II-blockers: Losartan, etc. C. Adrenergic antagonists - Prazosin (α-1-blocker) - Carvedilol (α-1 & non-selective β-blocker) D. Somatostatin-receptor-1 analogues Table 3. Drugs used to reduce portal pressure in patients with variceal hemorrhage Drug Administration Action Limitation Vasopressin (VP) + Nitroglycerin (NG) VP : i.v. infusion NG percutaneous vasoconstriction of the splanchnic vascular bed Myocardial infarction, intestinal infarction, limb ischemia Terlipressin i.v. bolus Same as above Unavailable in the USA Somatostatin i.v. bolus, then i.v. infusion Inhibiting the secretion of vasodilatory peptides from the gastrointestinal tract (glucagon etc) Unavailable in the USA Somatostatinanalogues (octreotide) i.v. bolus, then i.v. infusion Same as above Conflicting results flow) 을증가시켜결과적으로문맥압항진증을악화시키는역기능에기인할것으로추정하고있다. 따라서현재미국간학회는정맥류출혈의예방및재발방지목적으로 nitrates 제제를사용하지말것을권고하고있다 4). 이와는달리최근에는내장혈관을비롯한전신혈관에미치는영향은비교적적고, 간내 NO의생체이용효율을높여간내혈관저항을줄일수있는 statin계열약물 (HMG-CoA-reductase inhibitor) 에많은관심을기울이고있다 ( 그림 5). 스페인에서발표한최근임상연구에따르면 statin계열약물중 simvastatin은문맥압항진증을개선시킨다고보고했으며 12), 특히비선택적베타차단제와병합투여가가능하여부가효과를기대할수있을것으로추정하고있다. 하지만콜레스테롤수치가낮은비대상성간경변증환자의예후가더나쁘다는기존임상결과를감안한다면 13), 근본적으로지질강하제인 statin계열약제가환자에게어떤영향을미칠지에대해서는장기적인연구가필요하다. 이외에도간에서만선택적으로 NO를증가시킬수있는약물, NO 생성을증가시키는효소인 nitric oxide synthase (NOS) 를촉진시키는치료, NO 생성을향상시키는조절유전자를주입하는유전자치료, NO 소멸을막기 위한항산화제투여, 간접적으로간성상세포의이완을촉진하는보충제투여등과같이간내 NO 생체이용효율을촉진시키기위한치료방법이연구되고있으나 14), 아직임상에적용하기위해서는많은제한점이있거나뚜렷한임상효과를보이고있지는않다 ( 표 2). 간성상세포의수축을차단하는길항제 (antagonist) 에대한연구도진행되고있으나, 이역시임상에적용하기에는더면밀한연구결과가필요하다. 3. 문맥계혈류량의증가와과역동적혈역학변화를조절하는치료제간경변증에서간내혈관저항증가로문맥압이상승하면측부혈관 (collateral vessel) 의발달을유도하고, 문맥과전신혈관사이의단락 (porto-systemic shunt) 을형성하여심박출량과내장혈류량이증가한다 ( 그림 2). 이는궁극적으로문맥계유입혈류량을증가시켜지속적인문맥압항진상태를유지하게한다. 이와같은과역동적혈역학 (hyperdynamic circulation) 및내장혈관확장 (splanchnic vasodilatation) 변화를억제하거나조절하는약물은현재문맥압항진증을낮추기위한치료제로임상에서가장많이이용되고있다 15). 대표적 - 285 -
- The Korean Journal of Medicine: Vol. 77, No. 3, 2009 - Figure 6. Schematic representation of the hyper-dynamic circulation in portal hypertension and the theoretical and clinical effects of renin-angiotensin-aldosterone-system inhibitors. Figure 7. The novel concept of the stimulation of TNF-α induced by endotoxemia in liver cirrhosis. Intestinal bacterial overgrowth and translocation are a common cause of endotoxemia. 주사약물로는 vasopressin, vasopressin 유사체, somatostatin, somatostatin 유사체등이있다 4). 그중 vasopressin 의경우가장강력한내장혈관수축제이나심근경색, 서맥, 고혈압등의부작용을발생할수있어반드시 nitroglycerin 주사제와병용할것을권장하고있다 ( 표 3). Vasopressin 유사체의대표적약제인 terlipressin 의경우 vasopressin 에비해부작용은적고반감기가길며, 임상결과에서도효과적으로식도정맥류출혈을억제하였다. Somatostatin은 glucacon 등위장관에서분비되는혈관확장호르몬을차단하여내장혈관확장을막고, 궁극적으로내장혈류량과문맥계유입혈류량을줄이는효과를가지고있다. 국내에서는 somatostatin과 terlipressin이식도정맥류출혈의치료제로많이사용되고있으나, 두약제모두미국에서는아직공인되어있지않다. Somatostatin 유사체인 octreotide은정맥류출혈치료제로미 국에서공인되어있으나, 정맥류출혈의지혈효과에대해서는상반된결과를보고하고있어임상적으로사용시주의가필요하다 16). 현재식도정맥류출혈의예방목적으로유일하게공인된경구약물로는 propranolol, nadolol과같은비선택적베타차단제가있으며, 심박출량을줄이고 (β-1 effect 차단 ), 내장혈관을수축 (β-2 effect 차단 ) 하는효과를가지고있다. 최근발표된미국간학회에서는정맥류출혈의예방및재발방지목적으로이약물의사용을적극권고하고있다 4). 하지만약 40% 의환자에서는비선택적베타차단제에반응을보이지않으며 15), 상당수환자에서는현훈, 피로감, 발기부전등으로치료가중단되기도하며, 또한천식, 말초혈관질환, 저혈당병력이있는당뇨환자등에서는이약제의사용이불가능하다. 따라서비선택적베타차단제이외의새로운경구용치료제개발이절실히필요한실정이다. 간경변증 - 286 -
- Won Hyeok Choe. Update on the treatment of portal hypertension - Figure 8. Mechanisms of portosystemic collateral formation. Modified from reference 26. 환자는내장혈류가증가하며이로인해유효혈류량 (effective circulating volume) 은오히려감소하고, 따라서 renninangiotensin-aldosterone system (RAAS) 등이활성화되어수분과염분의저류를초래하며, 이는혈장의증가로인해과역동적혈역학변화를유발하게된다 ( 그림 6). 이러한병태생리학적기전을차단하기위해연구된대표적약물로는안지오텐신변환효소억제제, 안지오텐신-II 수용체길항제등이있다 17). 이들약물들은 RAAS 차단효과이외에도간성상세포가혈관수축물질에과반응하는과정을차단하고, 간섬유화를억제하는부가적인효과도있는것으로알려져있다. 하지만초기의긍정적인임상결과와달리후속연구에서는과역동적혈역학이오히려더조장되는상반된연구결과를보였다 18,19). 이런상반된결과는환자의유전적다형성 (genetic polymorphism) 에기인한약물반응의차이, 간경변증환자에서유지되는항상성의저해, 장기간투여시 RAAS 가원래수치로회복되는반등 (rebound) 현상, 저혈압또는신기능악화와같은부작용등과관련있을것으로추정하고있다 17). 따라서최근에는이들약물을일부제한된환자에서만선택적으로사용하거나 20), RAAS를차단하는효과보다는항섬유화및간내저항증가의감소효과등부가적인기능에초점을두어연구가진행되고있다 21). 이외에도 prazosin과같은 α1-아드레날린성수용체차단제가문맥압항진증치료약물로시도되었으나 22), 이러한약제들이근본적으로혈압강하제라는점을감안하면, 평균동맥압이낮은간경변증환자에서임상효과를보이기위해서는적정한약물용량설정등해결해야할과제가많다. 한편장내세균등에의한내독소 (endotoxin) 는 tumor necrosis factor-alpha (TNFα) 등을분비하여, 내장혈관을확장하고문맥계혈류유입량을증가시키며, 이는궁극적으로문맥압항진증을유발할수있다 23). 따라서이러한기전을차단하기위한방법으로 TNF-α 차단제투여, refaximin 과같은항생제, 또는유산균 Figure 9. Angiogenic signaling pathways between pericytes and endothelial cells. Modified from reference 27. 제 (probiotics) 복용등에대한연구가현재진행되고있다 ( 그림 7). 4. 문맥압항진증의병태생리학적기전에복합적으로작용하는치료제 앞서언급한약물중일부는문맥압항진증의병태생리학적과정중한가지기전에만작용하는것이아니라여러단계에서복합적으로작용하여문맥압항진증을개선할수있다. 하지만이들약제이외에도다양한조절기능을통해문맥압항진증을개선할수있는약물에대한연구가진행중으로, 이중 vascular endothelial growth factor (VEGF) 차단제, platelet-derived growth factor (PDGF) 차단제등과같은종양표적치료제 (cancer targeted therapy) 가최근많은관심을받고있다 24,25). 문맥압이항진되면, 기존에존재하였던작은측부혈관 (collateral vessel) 이수동적으로이완하게될뿐아니라, 신혈관생성 (angiogenesis) 에관여하는 VEGF, PFGF 등이과발현하여내장혈관및측부혈관의신생혈관형성 (neovascularization) 을촉진함으로써 26), 궁극적으로과역동적혈역학변화와문맥계혈류유입량증가를초래한다 ( 그림 8). 또한 VEGF, PFGF 등은동모양혈관내피세포의모세혈관활성화 (capillarization) 와활성화된간성상세포의증식 (proliferation) 에직간접적으로작용하여간섬유화와간내혈관저항증가를초래한다 ( 그림 9) 27,28). VEGF 차단제, PDGF 차단제등은이러한과정을억제하고차단함으로써문맥압상승을막을수있을것으로기대하고있으며, 부가적으로염증유발매개체 (pro-inflammatory mediator) 인 TNF-α, inos 등에의해 - 287 -
- 대한내과학회지 : 제 77 권제 3 호통권제 589 호 2009 - 발생하는내장혈관확장을차단하고문맥계혈류증가를감소시키는효과도기대할수있다. 하지만이러한실험적연구결과와는달리, 항-VEGF 단일항체인 bevacizumab (avastin) 이나 VEGF 차단제인 sorafenib (nexavar) 을간암이동반진행된간경변증환자에게투여한경우상당수환자에서위장관출혈이발생하였던점을감안하면 29,30), 이들약물을문맥압항진증치료제로임상에적용하기에는조심스러운접근이필요하다. 결론간경변증환자에서문맥압항진증은여러병태생리학적기전을통해발생하는것으로알려져있다. 문맥압항진증을치료하기위해현재까지는심박출량을줄이거나내장혈관에작용하여문맥계혈류유입량증가를막는치료제에주로집중되었으나, 앞으로이러한기전뿐아니라간내혈관저항증가의감소, 과역동적혈역학조절및신혈관생성억제등과같은다양한기전을통해문맥압증가를개선할수있는치료제개발에연구가진행되고있다. 하지만이러한치료약물이실제임상에서이용되기위해서는단순히문맥압항진증을개선시키는질환- 중심 (disease-oriented) 의연구결과뿐아니라, 약물투여로발생할수있는부작용, 간경변증환자에서투여가능한적정용량의임상효과, 장기적인생존율향상여부등환자- 중심 (patient-oriented) 의치료결과에초점이맞추어진후속임상연구의뒷받침이반드시필요하다. 그동안간질환의치료는항바이러스치료제, 간암치료제등에주로많은투자가이루어졌으며, 상대적으로문맥압항진증치료에대한연구및투자는미미하였다 31). 현재까지문맥압항진증의치료약물로공인된약제는정맥류출혈의예방및재발방지를위한비선택적베타차단제와정맥류출혈시사용하는내장혈관수축제등으로매우제한적인실정이다. 하지만최근우리나라에서문맥압항진증을치료하기위한다양한연구가활발히진행되고있으며, 이를바탕으로향후좀더개선되고효과적인치료제가개발될것으로기대하고있다. 중심단어 : 문맥압항진증 ; 간내혈관저항 ; 과역동적혈역학 ; 신혈관생성 REFERENCES 1) Garcia-Tsao G. Current management of the complications of cirrhosis and portal hypertension: variceal hemorrhage, ascites, and spontaneous bacterial peritonitis. Gastroenterology 120:726-748, 2001 2) Triantos CK, Nikolopoulou V, Burroughs AK. Review article: the therapeutic and prognostic benefit of portal pressure reduction in cirrhosis. Aliment Pharmacol Ther 28:943-952, 2008 3) Kim MY, Baik SK, Suk KT, Yea CJ, Lee IY, Kim JW, Cha SH, Kim YJ, Um SH, Han KH. Measurement of hepatic venous pressure gradient in liver cirrhosis: relationship with the status of cirrhosis, varices, and ascites in Korea. Korean J Hepatol 14: 150-158, 2008 4) Garcia-Tsao G, Sanyal AJ, Grace ND, Carey W. Prevention and management of gastroesophageal varices and variceal hemorrhage in cirrhosis. Hepatology 46:922-938, 2007 5) Bosch J, Berzigotti A, Garcia-Pagan JC, Abraldes JG. The management of portal hypertension: rational basis, available treatments and future options. J Hepatol 48(Suppl 1):S68-S92, 2008 6) Rincon D, Ripoll C, Lo Iacono O, Salcedo M, Catalina MV, Alvarez E, Nunez O, Matilla AM, Clemente G, Banares R. Antiviral therapy decreases hepatic venous pressure gradient in patients with chronic hepatitis C and advanced fibrosis. Am J Gastroenterol 101:2269-2274, 2006 7) Fallowfield JA, Kendall TJ, Iredale JP. Reversal of fibrosis: no longer a pipe dream? Clin Liver Dis 10:481-497, 2006 8) Pockros PJ, Jeffers L, Afdhal N, Goodman ZD, Nelson D, Gish RG, Reddy KR, Reindollar R, Rodriguez-Torres M, Sullivan S, Blatt LM, Faris-Young S. Final results of a double-blind, placebo-controlled trial of the antifibrotic efficacy of interferon-gamma1b in chronic hepatitis C patients with advanced fibrosis or cirrhosis. Hepatology 45:569-578, 2007 9) Paik YH, Kim JK, Lee JI, Kang SH, Kim DY, Ahn SH, Lee SJ, Lee DK, Han KH, Chon CY, Lee SI, Lee KS, Brenner D. Celecoxib induces hepatic stellate cell apoptosis through inhibition of Akt activation and suppresses hepatic fibrosis in rats. Gut 2009 [Epub ahead of print] 10) Rockey DC. Hepatic fibrosis, stellate cells, and portal hypertension. Clin Liver Dis 10:459-479, 2006 11) Garcia-Pagan JC, Villanueva C, Vila MC, Albillos A, Genesca J, Ruiz-Del-Arbol L, Planas R, Rodriguez M, Calleja JL, Gonzalez A, Sola R, Balanzo J, Bosch J. Isosorbide mononitrate in the prevention of first variceal bleed in patients who cannot receive beta-blockers. Gastroenterology 121:908-914, 2001 12) Abraldes JG, Albillos A, Banares R, Turnes J, Gonzalez R, Garcia-Pagan JC, Bosch J. Simvastatin lowers portal pressure in patients with cirrhosis and portal hypertension: a randomized controlled trial. Gastroenterology 136:1651-1658, 2009-288 -
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