원발담즙간경변증 울산대학교의과대학서울아산병원소화기내과 김강모 Primary Biliary Cirrhosis Kang Mo Kim, M.D. Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Primary biliary cirrhosis (PBC) is a slowly progressive chronic cholestatic liver disease of autoimmune etiology, characterized histologically by portal inflammation and necrosis of the interlobular and septal bile ducts. Patients affected by PBC are often asymptomatic middle-aged women who are commonly diagnosed after evaluation for abnormal serum liver function tests. Fatigue, pruritus, and/or unexplained hyperlipidemia may also be found at initial presentation. Anti-mitochondrial antibody (AMA) positivity is nearly diagnostic of PBC when present. The identification of PBC is important, as effective medical therapy with ursodeoxycholic acid (UDCA) has been demonstrated to slow disease progression and improve survival independent of liver transplantation. However, therapeutic options for the medical complications of PBC, such as fatigue and metabolic bone disease, are currently limited. Mathematical models have been developed which accurately characterize and predict the natural history of PBC. Key words: Primary biliary cirrhosis; Anti-mitochondrial antibody; Alkaline phosphatase; Pruritus; Ursodeoxycholic acid 서론 원발담즙간경변증은천천히진행하는자가면역질환의하나로문맥역의염증과간내담도손상을특징으로한다. 문맥역의염증과담도손상이진행하면섬유화가발생하고결국간경변으로진행하여간이식이필요한상황이생기기도한다. 이전에는피로감이나소양감, 고지혈증등의증상이발생한이후나원인모를간경변증등으로해서원발담즙간경변증을진단하는경우가많았으나요즈음은정기검진이활발해지면서증상이없이알칼리성포스파타제가증가해있는환자에서 anti-mitochondrial antibody(ama) 양성을발견하여진단하게되는경우도적지않다. 또한병의초기에진단하여 ursodeoxycholic acid(udca) 를사용하는경우병의진행경과를늦출수있다는것이알려져있으므로원인모를간기능이상을보이는환자에서원발담즙간경변증의가능성을의심하는것이더욱중요해지고있다. 아직우리나라전체를대상으로하는원발담즙간경변증의실태나치료경 21
과, 예후등에대한자료는없는실정이나이러한연구에앞서서이글에서는최근까지알려진병의병태생리, 자연경과, 진단, 치료등에대해알아보고자한다. 본론 1. 병태생리 역학및병인원발담즙간경변증은모든인종과지역에서발생하지만지역에따른발생률은차이가많이나서북유럽에서가장많이호발하는것으로알려져있으며그유병률은백만명당 40~400 명에달한다. 1,2 평균발병연령은 50세지만 20세에서 90세에걸쳐발병하며, 여성에서남성보다 9배더호발하지만여성에서의병의경과가남성과다르지않은것으로알려져있다. 환자의 first-degree relative 에서호발하여 mother-daughter, sister-sister 조합이흔하게나타난다. 3 원발담즙간경변증에서간내담도가특이적으로손상되는기전이 cellular or humoral autoimmunity 에의한다는여러증거가나오고있으나정확한기전은아직밝혀지지않고있다. 4 Cellular autoimmunity 에서 CD4+ 와 CD8+ T-세포에의해간내담도손상이일어나고 B-세포나 natural killer 세포도여기에기여한다는여러연구발표가있었다. 5,6 Humoral autoimmunity 에대해서는 AMA 가주로연구되었는데이항체는미토콘드리아의 inner matrix 에존재하는 pyruvate dehydrogenase E2 complex(pdc-e2), branched chain 2-oxo-acid dehydrogenase E2 complex(bckd-e2), ketoglutaric acid dehydrogenase E2 complex(ogdc-e2), dihydrolipoamide dehydrogenase binding protein(e3-bp) 에반응하는항체로서이들단백에공통으로존재하는 lipoylated lysine residue 와반응하는것으로알려져있다. 4 또한 AMA 에의한 direct cytotoxicity 를반대하는의견도있는데 AMA 음성원발담즙간경변증의존재, AMA titer 와간손상의정도가연관이없는점, 간이식후 AMA 양성인상황에서원발담즙간경변증의재발이없는점등이그이유이다. 모든세포의미토콘드리아에공통으로존재하는이단백에모두자가면역반응이일어나지않고, 원발담즙간경변증환자에서간내담도세포에특이적으로자가면역반응이일어나는이유에대한연구도활발히진행되고있는데간내담도세포의자멸사과정에서 glutathione 결합유무에의해 lipoyl domain 의항원성이변화한다는보고가있다. 7 원발담즙간경변증의유전적소인을가진환자에서자가면역반응을촉발시키는원인으로외부요인에의한 molecular mimicry 가제시되고있는데 Escherichia coli 나 Novosphingobium aromaticiv 등의세균이나 8,9 halogenated hydrocarbon 과같은화학물질이 10 미토콘드리아내 lipoyl domain 과유사하여자가면역반응을촉발한다는보고들이있다. 2. 병리소견및병기 원발담즙간경변증에서간조직검사는진단당시병기를알기위해서나 AMA 음성환자에서진단을위해필요하며, 병리소견에의한원발담즙간경변증병기는아래와같다. 11 Stage Ⅰ: portal tract inflammation due to predominantly lymphoplasmacytic infiltrates resulting in the destruction of septal and interlobular bile ducts up to 100 μm in diameter. Focal duct obliteration with granuloma formation is considered almost pathognomonic for PBC when 22
김강모 원발담즙간경변증 present. Hepatic lobular involvement is uncommon, but rare microgranulomas are seen in some cases. Stage Ⅱ: periportal hepatitis or ductular proliferation. Extension of the portal infiltrates to periportal areas is most commonly observed with associated interface hepatitis (piecemeal necrosis). Histologic findings of cholangitis, granulomas, and ductular proliferation are most commonly observed. Lobular involvement is similar to stage I. Stage Ⅲ: septal or bridging fibrosis Stage Ⅳ: biliary cirrhosis 3. 원발담즙간경변증의자연경과및예후예측모델 UDCA 가사용되기이전에증상이발생한후진단되었던원발담즙간경변증환자 (stage III~IV) 의자연경과및예후는나빠서결국간경변증과사망에이른다고보고하여진단으로부터중앙생존기간이 8년밖에되지않았으며, 혈청 bilirubin 이 8~10 mg/dl 이상인경우중앙생존기간은 2년에불과하였다. 12,13 이러한환자의예후를예측하기위한수학적예후예측모델이이미개발되어널리사용되고있다 (http://www.mayoclinic.org/gi-rst/ mayomodel1.html). 14 이모델에서는환자의나이, bilirubin, albumin, prothrombin time, 말초부종여부, 이뇨제사용여부를이용하여환자의시기별 estimated probability of survival 을나타내주어서유용하게사용될수있을것이며 UDCA 를사용하는환자의예후예측에도유용하다는최근의보고도있다. 14 요즈음진단되는원발담즙간경변증환자의특징은건강검진의확대에따라증상이없는상태에서진단되는환자가점점늘어나는것과대부분의환자가초기 (stage I~II) 에 UDCA 치료를받는다는점이다. 진단당시무증상이었던원발담즙간경변증환자도 5년에 50%, 20년에 95% 에서결국증상을발현하는것으로알려져있으며나이와성별을맞춘건강대조군에비해중앙생존기간은낮은것으로보고되고있다. 15 하지만이러한무증상환자에서 UDCA 를사용하는경우 25~30% 에서간기능의완전한호전이보고되어있고, 16 일부환자에서는 10년이상간조직소견의진행이없었으며, 17 최근 stage I~II 원발담즙간경변증환자에게 8년이상 UDCA 를사용하는경우건강대조군과비교하여생존기간의차이가없다는보고도있다. 18 따라서원발담즙간경변증의진행은사람에따라다양해서초기에치료하는경우병의진행이양성경과를가지는환자가약 20~30% 에서는존재한다고볼수있으며, 병이진행한상태에서진단된환자는결국간경변, 간부전등으로진행하는경과를밟는다고볼수있겠다. 4. 임상증상전술한바와같이요즈음은 50~60% 의원발담즙간경변증환자가증상이없을때발견된다. 19,20 증상이없는환자의약 30% 에서는수년간증상이없을수도있지만많은수의무증상환자도 2~4 년내에증상을발현한다고보고된다. 20,21 이때증상으로가장흔한것이피로감과소양감이다. 22 피로감은많게는 78% 의원발담즙간경변증환자에서나타난다고보고되는데병의심한정도와상관관계가없으며특별한치료법도없는것으로알려져있다. 23,24 소양감은 20~70% 의환자에서보고되고밤에심해지는국소적혹은전신적소양감이황달이생기기수개월에서수년전에나타난다고보고된다. 25 소양감의기전은잘알려져있지않으나담즙산의축적이나 endogeneous opioid 의상승과연관이있을것으로추정되며 antihistamine, cholestyramine, rifampin, nalox- 23
one, naltrexone 등이치료에사용된다. 이외에원발담즙간경변증에동반되는증상으로고지혈증, 갑상선기능저하증, osteopenia, Sjӧgren 증후군, scleroderma 등이있으며, 26 간경변증으로진행하는경우간문맥고혈압에의한정맥류출혈, 복수같은증상이생길수있고간세포암종의위험이증가할수있다. 5. 진단 원발담즙간경변증의진단은다음 3가지의진단기준을모두만족하는경우내릴수있으며 (definite diagnosis) 3가지기준중두가지를만족하는경우 probable diagnosis 를내릴수있다. 27 1) 혈청내 anti-mitochondrial antibody (AMA) (titer 1:40) 2) 담즙정체를나타내는간기능이상이 6개월이상존재 ( 주로알칼리성포스파타제상승 ) 3) 간조직검사에서합당한소견 이러한진단기준에서원발담즙간경변증의병기를알기위해서는반드시간조직검사를시행하여야하지만 1), 2) 의기준을동시에만족하는경우진단을위해간조직검사를반드시하여야하는지는논란의여지가있다. 또한간기능이상을동반하지않고혈청 AMA 만양성인경우에도간조직검사를시행하여야하는지도알려져있지않다. 그리고잘알려져있는것처럼원발담즙간경변증의 5~10% 에서는혈청 AMA 가음성이며, 이러한환자의경과가 AMA 양성환자의경우와다르지않다는것을알고있어야한다. 혈청 AMA 가양성인환자에서그 titer 는병의경과와연관이없는것으로알려져있으며, 원발담즙간경변증의 36~66% 에서 anti-nuclear Ab나 anti-smooth muscle Ab가발견되기도한다. 원발담즙간경변증에서보일수있는생화학적검사이상에서가장특징적인것은알칼리성포스파타제의상승이다 (>3~4 ULN). Aspartate aminotransferase(ast) 와 alanine aminotransferase(alt) 의상승을동반하는경우는흔하지만 ALT 가 200 IU/L 이상상승하는경우바이러스간염이나독성간염의동반여부를확인해야한다. 병이진행하면혈청 bilirubin 상승, albumin 감소, prothrombin time 연장을동반하는데이러한경우는나쁜예후를나타낸다. 이외에고콜레스테롤혈증이원발담즙간경변증환자의진단당시 85% 에서발견되며혈청 IgM level 이상승되어있는경우도보고된다. 28 원발담즙간경변증의감별진단은표 1과같다. Table 1. 원발담즙간경변증의감별진단 Extrahepatic biliary tract obstruction: Choledocholithiasis, Strictures, Malignancy Primary sclerosing cholangitis Drug-induced cholestasis (e.g. estrogens, phenothiazines) Granulomatous hepatitis Autoimmune hepatitis Chronic hepatitis C Alcoholic hepatitis Sarcoidosis Celiac disease 24
김강모 원발담즙간경변증 6. 치료 1) 대증치료원발담즙간경변증환자의소양감의치료에는 antihistamine, cholestyramine, rifampin, naloxone, naltrexone 등을사용한다. 증상이있는환자에서우선 antihistamine 과 cholestyramine 을사용해보고증상의호전이없으면 rifampin 을시도하며이에도반응이없을경우 naloxone 이나 naltrexone 을사용할수있다. 이러한치료에실패한경우간이식을대기하는환자에서 plasmapheresis 가도움이되었다는보고도있다 ( 표 2). 29 원발담즙간경변증환자에서고지혈증이있더라도심혈관계질환의위험이더증가한다는보고는없으며일부고지혈증은 UDCA 의치료로호전되는경우가있다. Statin 제제의사용이고지혈증을호전시킨다는보고는있으나아직경험이부족하다. 원발담즙간경변증환자에서동반되는 osteopenia 나 osteoporosis 는골절의위험을증가시키는것으로알려져있는데, 우선모든환자에서칼슘섭취가충분하도록 (1,000~1,200 mg/d) 교육하여야하고 vitamin D의부족이확인되는경우이의보충이필요하다. 경구 alendronate 가골밀도를증가시킨다는보고가있으나장기연구결과는아니며, 30 폐경기여성환자에서의 hormone replace therapy 는비교적안전하게시행할수있다는보고가있다. 31 2) Ursodeoxycholic acid Ursodeoxycholic acid(udca) 는원발담즙간경변증에사용하도록미국 FDA 에서허가된유일한약이다. UDCA 의기전은여러가지인것으로연구되어있는데, 담즙산분비촉진작용이외에도세포막안정화, 간세포에서 HLA I형항원발현감소, 사이토카인생성감소, 세포자멸사억제등의작용을일으키는것으로알려져있다. 원발담즙간경변증에서 UDCA 를사용한여러연구에의하면 UDCA 12~15 mg/kg/d 를사용할경우증상의호전과간기능검사이상의정상화를가져오고초기일경우간조직검사이상의안정화도나타나는것으로보고되어있다. 32-35 따라서초기에사용할경우원발담즙간경변증의진행을늦추고간이식없이환자의생존기간을증가시키는것으로보인다. UDCA 는부작용이거의없고비교적안전한데드물게체중증가, 탈모, 설사등이보고되기는한다. 일부최근보고에서 UDCA 의효과에대해의문시하는몇몇보고가있으나, 36,37 앞에서전술한여러효과를 Table 2. 원발담즙간경변증환자의소양감치료에사용되는약제 Drug Cholestyramine, colestipol Rifampin Naloxone, naltrexone Antihistamines Comment Nonabsorbed quaternary ammonium resins; dose, 8~24 g daily; effective in >90% of patients who can tolerate these drugs; 2~4 day delay between administration of drug and Sx relief; bound by many drugs, other medications to be taken at least 2 hr before or after these resins Relieves Sx in most patients who do not respond to or cannot tolerate resins; starting dose, 150 mg twice daily; preferred to resins by many patients; may be used as initial drug to treat pruritus Opioid antagonists; effective in some patients who do not respond to resins or rifampin Useful in patients with mild pruritus if given at bedtime to help sleep 25
Figure 1. 원발담즙간경변증병기분류모식도 (Ludwig 분류 ). Zakim and Boyer s Hepatology - A Textbook of Liver Disease 5th Ed. 뒤집기에는아직증거가약하다. 하지만일단진행한원발담즙간경변에서의효과는증명되지않았다. 3) Colchicine, methotrexate Colchicine 0.6 mg bid 를원발담즙간경변증에사용하여간기능의개선을보고하기도하였지만 UDCA 단독치료에비해효과가떨어진다. UDCA 와 colchicine 의병합치료가 UDCA 단독치료보다우월하다는보고도있으나장기간의연구결과가필요하다. Methotrexate 의면역조절작용을이용하여원발담즙간경변증에사용함으로써 (0.25 mg/kg/week po) 간기능개선과간조직소견의개선을이루었다는보고가있으나아직더많은결과가필요하며, UDCA 와 methotrexate 의병합치료는 UDCA 단독치료보다나은점이없다고알려져있다. 또한 methotrexate 를사용한경우 15% 에서 interstitial pneumonitis 의보고가있다는사실을염두에두어야한다. 4) 기타약제 Budesonide 를 UDCA 와같이사용하였을때간조직소견의개선이있었다는보고가있으나 osteopenia 를악화시킬수있어서장기간사용이어렵다. Prednisone 도짧은기간사용하여간기능호전을보고한것은있으나장기간사용시 osteoporosis 의위험이증가한다. Autoimmune hepatitis-primary biliary cirrhosis overlap syndrome 에서 corticosteroid and/or UDCA 치료가효과적일수는있으나여기에서는언급하지않겠다. 이외에 bezafibrate, tamoxifen, sulindac 이일부효과적이라는보고가있으나흔히추천되지는않는다. Silymarin, chlorambucil, penicillamine, azathioprine, cyclosporine, malotilate, thalidomide, mycophenolate mofetil 등도연구되었으나효과가없는것으로밝혀졌다. 5) 간이식말기간질환으로진행한원발담즙간경변증환자의경우간이식이유일한치료법이다. 간이식을시행한경우생존율은다른원인에의한간이식과비교해서나쁘지않아서 92%, 85% 의 1년, 5년생존율을보인다. 다만이식후원발담즙간경변증의재발도보고되었는데이식후 3년, 10년에각각 15%, 30% 에이르는것으로알려져 26
김강모 원발담즙간경변증 있다. 38,39 6) 원발담즙간경변증치료약제사용의실제현재원발담즙간경변증의치료에대해정해진가이드라인등은없는실정이다. 다만 UDCA 등의치료에대한반응에있어개인마다차이가많이난다는것이알려져있다. 우선소양감등의증상이있는원발담즙간경변증환자에게는대증치료를시행하고모든원발담즙간경변증환자에게 UDCA 단독치료를시작할수있을것이다. 약 1년간의 UDCA 단독치료에도간기능이정상화되지않고소양감등의증상이지속되는경우 colchicine 을추가하여 UDCA 와병합치료할수있다. 1년간의추가병합치료에도반응이없을때에는 methotrexate 를추가할수있으나 methotrexate 를사용하는경우는 interstitial pneumonitis 가가능하므로 1년이상사용하는것에주의가필요하다. 27 결론 과거에는드물다고생각되었으나최근진단방법이발전하여증상이없는원발담즙간경변증환자도많이진단되고있는실정이다. 또한병의초기에적절한용량의 UDCA 를사용할경우병의진행을늦추고환자의생존기간을늘릴수있으므로원인모를간기능이상, 특히담즙정체를주소로내원한환자의경우원발담즙간경변증의가능성을항상염두에두고 AMA 검사를시행하여야한다. 또한원발담즙간경변증환자의 5~10% 에서는 AMA 음성이므로임상적으로의심이되는경우에는조기에간조직검사도고려하여야한다. 장기적으로는우리나라에서원발담즙간경변증에대한관심을더기울여서우리나라환자에게고유한병의경과를조사하고한국인에게적합한치료방침이나예후예측모델등의개발을위해힘을모아야할것이다. 참고문헌 1. Howel D, Fischbacher CM, Bhopal RS, Gray J, Metcalf JV, James OF. An exploratory population-based case-control study of primary biliary cirrhosis. Hepatology 2000;31:1055-1060. 2. Sood S, Gow PJ, Christie JM, Angus PW. Epidemiology of primary biliary cirrhosis in Victoria, Australia: high prevalence in migrant populations. Gastroenterology 2004;127:470-475. 3. Bittencourt PL, Farias AQ, Abrantes-Lemos CP, Goncalves LL, Goncalves PL, Magalhães EP, et al. Prevalence of immune disturbances and chronic liver disease in family members of patients with primary biliary cirrhosis. J Gastroenterol Hepatol 2004;19:873-878. 4. Gershwin ME, Ansari AA, Mackay IR, Nakanuma Y, Nishio A, Rowley MJ, et al. Primary biliary cirrhosis: an orchestrated immune response against epithelial cells. Immunol Rev 2000;174:210-225. 5. Kita H, Matsumura S, He XS, Ansari AA, Lian ZX, Van de Water J, et al. Quantitative and functional analysis of PDC-E2 specific autoreactive cytotoxic T lymphocytes in primary biliary cirrhosis. J Clin Invest 2002; 109:1231-1240. 6. Kita H, Naidenko OV, Kronenberg M, Ansari AA, Rogers P, He XS, et al. Quantitation and phenotypic analysis of natural killer T cells in primary biliary cirrhosis using a human CD1d tetramer. Gastroenterology 2002; 123:1031-1043. 7. Odin JA, Huebert RC, Casciola-Rosen L, LaRusso NF, Rosen A. Bcl-2-dependent oxidation of pyruvate 27
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