추계 Single Topic Symposium-편집.hwp

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1 Etiologic treatment and lifestyle modification 이태희건양대학교의과대학소화기내과 Tae Hee Lee Department of Internal Medicine, Konyang University College of Medicine, Daejeon, Korea Liver cirrhosis had been considered an irreversible end-state of disease. However many experimental and clinical evidence are supporting that liver cirrhosis is dynamic. Discontinuing the causative factors and permitting enough time can reverse liver fibrosis/ cirrhosis. Anti-viral therapy for the patients with chronic hepatitis B or C has a role in improving fibrosis/ cirrhosis and clinical outcomes. Clinical evidence of reversal of cirrhosis in the alcohol-induced cirrhotic is still lacking. Histological improvements differ according to the degree of weight loss in the case of nonalcoholic fatty liver disease. However, the study of reversal of non-alcoholic fatty liver-related cirrhosis is sparse. Immunosuppressants including corticosteroid could reverse fibrosis in the patients with autoimmune hepatitis. Fibrosis in the patients with primary biliary cirrhosis could be improved by ursodeoxycholic acid. We need more concrete evidences for the reversal of cirrhosis in the patients with various end-stage liver diseases. And we should find where the point of no return is in liver cirrhosis. Keywords: Cirrhosis, Fibrosis, Reversal, Regression 서론 간경화는만성적인간손상에대한상처회복의결과로나타난다. 간세포의수가감소하고세포외기질이 증가하여섬유화를유발하여조직학적으로섬유화반흔에의해둘러싸인재생결절이나타나며이에따라 다양한합병증들이나타나는질환이다. 1 예전에는간경화는만성바이러스간염, 알코올성간질환, 비알코 올성지방간질환, 자가면역성간질환등의최종단계로인식되어비가역적인것으로알려져왔다. 2 그러나 1970 년대이후연구가진행되어간내에서콜라겐분해효소가발견되고, 3 동물실험에서유발요인 을중단하고충분한시간을준다면간경화가가역적일수있음을보고하였다. 4 동물실험의명확한증거 는사염화탄소를이용한연구와담관결찰모델에서확인되었다. 5-6 임상적인관찰로는 20 년간 100 명의간 경화환자들을추적하여 20 명에서식도정맥류가자연소실되었다고보고하였다. 이들은 C 형간염환자

2 2017 대한간학회추계 Single Topic Symposium 명, 알코올성간경화 6명, 혈색소증환자 5명이었다. 7 이후간경화의기전들이밝혀지면서항섬유화치료에대한기대도높아졌고여러가능한기전으로시도되고있다. 이글에서는원인질환의치료와생활습관의개선에따른간섬유화와간경화의호전과이에따른문맥고혈압의개선에대해알아보고자한다. 본론 1. 만성 B형간염항바이러스제치료에의한간섬유화 / 간경화의호전에대해서는여러보고가있으며아래표에일부를정리하였다 (Table 1). 라미부딘으로 1년간치료한 47명환자의간생검조직의면역조직화학염색에서위약군에비해유의하게 Table 1. Several studies for the regression of fibrosis/cirrhosis (biopsy-proven) in the patients with hepatitis B virus Drugs Author, Year N/Treatment duration Main Results LAM Kweon, et al. 8 (2001) 47 / 52 weeks A significant decrease in α-sma and PIIICP expression (P<0.05) Dienstag, et al. 9 (2003) 63 / 3 years HAI: 35/63 (56%) improvement, 21/63 (33%) no change, 7/63 (11%) worsening Reversal of cirrhosis in 8/11 patients (73%) Xu, et al. 10 (2015) 28 / 10 years Ishak fibrosis: 4/19 complete regression; 9/19 improved ; 6/19 no improvement About 75% patients: inflammatory/fibrotic improvement ETV Chang, et al. 11 (2010) TDF Marcellin, et al. 12 (2013) IFN Papatheodoridis, et al. 14 (2005) van Zonneveld, et al. 13 (2006) 57 / 6 years (3~7 years) 96%: histological improvement 10/57: advanced fibrosis or cirrhosis (Ishak score 4~6) at baseline All 10 patients achieved at least a 1-point reduction in the fibrosis score 348 / 5 years 74% (72/96) of cirrhosis no longer cirrhotic 147 HBe Ag(-) / 6~12months 110 HBe Ag(+) / 52 weeks Fibrosis improved in 17.5% of treated (sustained responders: 40%, relapsers: 9%, nonresponders: 12%) and 4% of untreated patients Fibrosis worsened in 34% (sustained responders: 7%, relapsers: 40%, nonresponders: 48%) and 70% of untreated cases, respectively (P=0.002). The fibrosis score improved (decrease of at least 1 point) in 17 patients (33%) of the combo therapy group vs. 13 patients (22%) of the PEG-IFN mono group (P=0.23). Fibrosis score in the PEG-IFN mono group improved more often in responders (39%) than in non-responders (15%, P=0.04) LAM, lamivudine; ETV, entecavir; TDF, tenofovir dipivoxil fumarate; IFN, interferon; N, number 34 대한간학회 The Korean Association for study of the Liver

3 이태희 Etiologic treatment and lifestyle modification α-smooth muscle actin (αsma) 과 C-terminal procollagen a1 (III) propeptide (PIIICP) 가호전되었고, ALT가호전된군에서더유의하였다. 8 3년간치료하여간생검조직을비교하였을때 11명의간경화환자중 8명에서간경화가반전되었다. 9 한편 Ishak score 4점이상인환자 28명을 10년간치료하여 19명의간생검조직을비교한연구에서는 4명은완전히호전되었고 (F0) 9명은개선된섬유화점수를보였으며 6명은호전을보이지않았다. 10 엔테카비어를 3~7년간 ( 중앙값 6년 ) 치료하면 96% 에서조직학적인개선이나타났고치료전에진행된섬유화 (Ishak score 4~6) 를보인환자 10명은추적검사에서모두가최소 1점이상의섬유화점수의개선을보였다. 11 테노포비어를 5년간치료하여간생검조직을비교하였을때 96명의간경화환자가 5년후 72 명 (74%) 이더이상간경화가아니었다. 12 e항원양성만성 B형간염환자를대상으로페그인터페론과라미부딘을병용한군 (52명) 과페그인터페론단독군 (58명) 에서의간생검조직의비교에서는병용치료군에서 33% 환자에서섬유화점수가 1점이상개선되었고단독치료군에서는 22% 에서개선되었으며단독치료군의경우반응군에서더많은환자들에서개선을보였다 (39% vs. 15%, P=0.04). 13 e항원음성만성 B형간염환자를대상으로페그인터페론치료로섬유화점수개선이 17.5% ( 지속반응군 40%, 재발군 9%, 비반응군 12%) 에서나타났고치료하지않은군은 4% 에서만나타났다. 섬유화의악화는각각 34% 와 70% 로유의한차이가있었다. 14 한후향적연구에서 12명의식도정맥류를가진간경화환자를라미부딘으로치료하면절반의환자에서식도정맥류의개선이나소실이나타났고 25% 에서는변화가없고나머지 25% 에서는악화되었다 년간 370명의만성 B형간염환자를엔테카비어로치료하여 MELD score ( ), 차일드등급 ( ), APRI, FIB-4 index, Fibrosis index 등이유의하게개선되었다고보고하였다. 16 간조직생검이외에간탄력도를측정하여섬유화의변화를알아보았는데정상상한치의 2배이하의 ALT값을가진 120명의만성 B형간염환자들을 5년치료하면기저치가 14.5kPa에서 5년후 8.4kPa로호전되었고기저치가 12kPa 이하인환자들이더잘 7.2kPa 미만 (<F3) 으로호전되었다. 처음 2/3환자가간경화 (>11.0kPa) 에해당하였으나 5년후 17.5% 만이해당되었다 만성 C형간염 C형간염을가진간경화환자에서인터페론기반치료를하고지속바이러스반응 (SVR) 여부에따른간경화의반전을조직생검으로확인한 443명의환자 6개연구를포함한메타분석에서하였고 SVR을획득한 137명중 73명 (53%) 에서간경화의반전을확인하였다. 18 이들은조직검사간의기간이 36개월이상인경우가 36개월미만인경우보다비교위험이더높게나타났다 (4.33 vs. 1.79). Shiratori 등의연구에서 SVR군에서는시간이경과하면할수록섬유화단계가더호전되는것을확인하였다. 19 페그인터페론과리바비린을병용치료를포함한만성 C형간염의치료군 3,010명에서도 20% 에서간섬유화가호전되었고지속반응 35

4 2017 대한간학회추계 Single Topic Symposium Table 2. Several studies of hepatitis C virus-related liver fibrosis/cirrhosis (biopsy proven) and clinical outcomes Author, year N, Study design 1 endpoint Main Results Mallet, et al. 24 (2008) Veldt, et al. 25 (2007) Morgan, et al. 26 (2010) Bruno, 27 et al. (2010) D Ambrosio, et al. 28 (2011) Rincon, et al. 29 (2006) Roberts, et al. 30 (2007) van der Meer, et al. 31 (2016) 96, retrospective cohort, Median f/u 118 months 479, retrospective cohort, Median f/u 2.1 years 140 SVR, 309 NR, 77 BT/R 7.5 years 218, Sub from prospective, Median 11.4 years 127, prospective, f/u 18~108 months after Tx Liver-related events and death Death, liver failure, and HCC Death, LT, decompensation, and HCC EV development Regression of cirrhosis 18. The transplantation-free survival rate at 10 years: 100% in patients with regression of cirrhosis and 74.2% in patients without regression of cirrhosis (P=0.025). Four patients with and 83 without SVR: at least 1 event SVR: significant reduction in the hazard of events (adjusted HR, 0.21, P=0.003). The adjusted HR for time to death/lt (HR=0.17) or development of liver-related morbidity / mortality (HR=0.15) or HCC (HR=0.19) was significant for SVR compared to NR None of the SVR patients developed EV 22/69 (31.8%) of the untreated (P<0.0001) 45/115 (39.1%) of the non-svr patients (P<0.0001). EV course De novo EV developed in 10 (9.1%) patients (2/57 SVR and 8/53 non-svr, 3.5% vs 15.1%; P=0.047), whereas EV progressed in size in 3 patients (1/5 SVR and 2/12 non-svr, P=0.87). Two non-svr patients bled EV and one died 20, prospective HVPG The percentage of HVPG decrease: significantly greater in patients with a ETR [26.2 (12.5)% vs (8.5)%, P=0.05] 47, prospective HVPG HVPG (SVR vs NR = -2.1 vs +0.6 mmhg; P=0.05) 464, retrospective cohort Platelet count Median platelet count: SVR (+) à increased by /L (P<0.001), SVR (-) à decline of /L (P<0.001) f/u, follow-up; SVR, sustained virologic response; HCC, hepatocellular carcinoma; NR, nonresponse; BT/R, breakthrough/relapse; LT, liver transplantation; EV, esophageal varices; HVPG, hepatic venous pressure gradient; ETR, end-of-treatment response 군에서 25% 로더높았다. 치료전기저간경화가있었던 153 명중 75 명 (49%) 에서간경화가소실되었다. 관 련인자로는기저섬유화단계 (odds ratio [OR]=0.12; P<0.0001), 지속바이러스반응 (OR=0.36; P<0.0001), 40 세미만나이 (OR=0.51; P<0.001), 체질량지수 <27 kg/m 2 (OR=0.65; P<0.001), no or minimal baseline activity (OR=0.70; P=0.02), 바이러스정량 <3.5 millions copies/ml (OR=0.79; P=0.03) 이었다 명을 치료한보고에서도간섬유화는 56% 에서호전되었고간경화가있던 14명중 9명에서호전을보였다. 21 5년간 150명을추적한연구에서 49명에서간조직생검을두번시행하였고 40명에서섬유화의호전이있었고 10명에서는정상또는거의정상으로회복하였다. 22 SVR을보인 38명을 61개월간추적한연구에서간경화의호전은 61% 에서, 콜라겐양의감소는 89% 에서나타났다. 23 C형간염에의한간경화환자에서치료후반응에따른임상결과와문맥고혈압의변화를연구한문헌 36 대한간학회 The Korean Association for study of the Liver

5 이태희 Etiologic treatment and lifestyle modification 은다음표에정리하였다 (Table 2). 한후향적연구에서는 96명의간경화환자중 18명에서간경화가소실되었고이들은 10년간간이식없이생존하였다 명의진행된간섬유화또는간경화환자를대상으로치료후반응에따른임상결과를알아본연구에서 30% 가량의환자가 SVR을보였고주로간부전을감소시켜여러임상결과들을호전시키는역할을하였다. 25 C형간염관련대규모연구를다시분석한바에따르면조직학적으로진행된간섬유화 (Ishak score 3) 를보인환자들을약 7.5년간추적하여사망, 이식, 비대상성, 간세포암등으로의진행이 SVR군에서확연히감소함을보여주었다. 26 이탈리아에서 218명의대상성간경화환자를약 12년간 3년간격으로내시경검사를추적하여 SVR군에서는한명도정맥류가발생하지않았지만치료를하지않았거나 SVR을보이지않은환자에서는 32~39% 에서정맥류가발생하여 SVR 이새로운식도정맥류의발생을줄인다고보고하였다. 27 다른연구에서도 127명을 5년이상추적하여 SVR 을보인환자들이새로운정맥류의발생 (3.5% vs. 15.1%, P=0.047) 이적었으나정맥류의악화 (1/5 vs 1/12, P=0.87) 는유의한차이가없었다. 28 진행된섬유화나간경화를가진환자에서치료전후간정맥압력차 (HVPG) 를비교한연구에서 20명환자중단한명을제외한 19명에서문맥고혈압이호전 (13.8 mmhg 10.2 mmhg) 되었고치료종료반응 (ETR) 이있는군에서유의하게더감소하였다 명의간경화환자에서 SVR이문맥고혈압에미치는영향을조사한연구에서는 21% 에서 SVR을보였고 HVPG가 20% 이상감소한환자가 SVR군에서는 71%, 비반응군에서는 20% 로유의한차이가있었다. 30 진행된간섬유화나간경화를가진 464명의환자에서치료후 24주에확인한혈소판수가 SVR후증가하였고해가지날수록더확연하게 SVR(-) 군과구별되었다. 또한혈소판수의변화와는음의상관관계로비장의크기는감소하였다. 31 인터페론기반의 C형간염의치료후섬유화나간경화의호전이확인되었고일부에서는정맥류의발생, HVPG 등에도좋은영향을미치는것을확인할수있었고임상결과도호전되는것을확인하였다. 현재강력한직접작용항바이러스제 (DAA) 가사용중이므로향후간경화의호전이나소실에미치는영향과임상결과에미치는영향도주의깊게확인하여야할것이다. 3. 알코올성간질환금주에의해알코올성간경화가호전된다는임상증거는부족하다. 1960~1990년대의연구들은대부분무작위시험이아니고후향적연구가많지만금주의역할을지지하는데, 대상성알코올간경화환자에서 5년생존율은금주시 63~90%, 지속적인음주시에는 41~70% 로보고하고있다 명의조직학적으로증명된알코올성간경화환자를 5년이상추적하여 5년생존율이전체적으로 43% (66%, 50% and 25% in Child-Pugh class A, B and C) 였고, 다변량분석에서나이 (P=0.01), Child-Pugh score (P=0.0001), 소화관출혈 (P=0.01), HBs Ag 또는 anti-hcv 양성 (P=0.03), 흡연 (P=0.01), 조직에서알코올성간염의부재 (P=0.05), 지속적인음주 (P=0.002) 등이사망의위험비증가와유의한관계가있었다

6 2017 대한간학회추계 Single Topic Symposium 조직학적으로증명된 100명의알코올성간경화환자를약 7년간추적하였을때간경화의정도보다는진단후 1개월째의금주가 7년생존율에가장큰영향을미치는것으로알려졌다 (72% vs 44%) 비알코올성지방간질환비알코올성지방간질환은체중을감량하면그정도에따라지방증의호전 ( 체중 3% 이상감량 ), 풍선양변화와염증의호전 (5% 이상감량 ), 지방간염의호전 (7% 이상감량 ), 섬유화의호전 (10% 이상감량 ) 등을이룰수있는것으로알려져있다. 39 전향적으로 293명의비알코올성지방간염환자들을 52주간생활양식변경을통해체중감소에따른조직학적인변화를관찰한연구에서간섬유화의개선을위해서는 10% 이상의체중감소가필요하고특히처음부터섬유화가있을때더욱그러하였다. 40 비만수술의효과는잘정리되어있는데지방을 50.2% 개선하고섬유화는 11.9%, 간세포풍선양변화는 67.7%, 간소엽염증은 50.7% 에서개선하였다. 이들은대사비만수술이가지는담즙흐름의변화, 위크기의감소, 영양소흐름의변화, 미주신경의조작및장내호르몬의변화에의해지방대사, 인슐린내성등이개선되고염증이감소하여효과를나타나는것으로설명하고있다. 41 그러나실제간경화환자에서비만수술은 3개월치사율이 1.9~6% 까지보고되고있고 42 원내사망률은간경화가없을때 0.3%, 대상성간경화 0.9%, 비대상성간경화 16.3% 로유의한차이를보이고, 다른변수를교정하여도오즈비가각각 2.17과 21.2로나타났다. 43 또한간경화의소실까지의장기결과에대한보고가거의없는상태이다. 5. 자가면역성간질환자가면역성간염에의한간경화환자에게면역억제제를사용하여섬유화가호전된증례들은 1990년대부터여러보고가있었다 명을대상으로 corticosteroid치료후간생검조직을비교한연구에서 53% 환자에서간섬유화가호전되었고 14명의간경화환자중 3명에서는간경화가소실되었다. 49 치료후섬유화가악화되는환자 18명을대상으로한연구에서는 HLA DR3/DR4가연관이있다는보고도있다. 50 진행된간섬유화를가진 19명의환자를대상으로 prednisolone 또는 cyclosporin으로유도요법을하고 azathioprine으로유지요법을하면 3년이상의간격으로간조직생검을하여섬유화점수가 4.53에서 2.16으로유의하게호전되었고 AST-Platelet-Ratio Index (APRI) 가좋은예측인자라고보고하였다. 51 현재사용되는여러약제들뿐만아니라섬유화의진행을억제하는다양한방법들이연구되고있다 조직검사와 anti-mitochondrial Ab(+) 로원발성담즙성간경화 (PBC) 환자로확진된 145명에서 Ursodiol과위약으로 4년간투약하였다. 첫 2년지나서임상반응의현저한차이를보였고 4년까지치료하여간이식과사망의위험을유의하게감소시켰다. 54 한편 102명의환자를대상으로 4년간치료하며간조직생검을한연구에서는연간간경화로의진행률이 UDCA군에서는 7%, 위약군에서는 34% 로확연한차이를보였고 4년째간경화로진행하지않을확률이 UDCA군에서는 76%, 위약군에서는 29% 였다 대한간학회 The Korean Association for study of the Liver

7 이태희 Etiologic treatment and lifestyle modification 결론 원인질환의치료로간섬유화와간경화는호전될수있으며일부에서는간경화의합병증도호전될수 있음을알수있다. 하지만조직에직접작용하여섬유화를억제하거나섬유화의해소를촉진시키는등의 방법과표적수용체와그에결합하는물질에대한상호작용을이용하는치료도시도되고있어향후새로 운항섬유화치료로기대되고있다. 56 또한섬유화와염증의개선이결국간기능, 문맥고혈압의개선으로 나타나는전향적인연구들은아직도부족한상태이다. C형간염의경우최근의 DAA들의효과가매우우수하여 SVR뿐만아니라간경화의소실, 문맥고혈압의개선, 합병증의소실이나개선등의임상결과가기대된다. 하지만아직도과연어떤것이결정적으로간의별세포를원래상태로복귀시키는지또는사망에이르게하는지모르는상태이다. 또한실제로어떤상태의간경화까지가회복이가능한지는알려져있지않아추가연구가더필요하다. 57 REFERENCES 1. Bacon BR. Cirrhosis and its complications. In: Longo DL, ed. Harrison's Principles of Internal Medicine, 18ed. USA: The McGraw-Hill Companies, Inc, 2012: Mallory FB. The Principles of Pathologic Histology. 1st ed. Philadelphia, PA:WB Saunders, 1914: Okazaki I, Maruyama K. Collagenase activity in experimental hepatic fibrosis. Nature 1974;252: Pérez-Tamayo R. Cirrhosis of the liver: a reversible disease? Pathol Annu 1979;14: Iredale JP, Benyon RC, Pickering J, McCullen M, Northrop M, Pawley S, et al. Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors. J Clin Invest 1998;102: Issa R, Williams E, Trim N, Kendall T, Arthur MJ, Reichen J, et al. Apoptosis of hepatic stellate cells: involvement in resolution of biliary fibrosis and regulation by soluble growth factors. Gut 2001;48: Müting D, Kalk JF, Fischer R, Wiewel D. Spontaneous regression of oesophageal varices after long-term conservative treatment.retrospective study in 20 patients with alcoholic liver cirrhosis, posthepatitic cirrhosis and haemochromatosis with cirrhosis. J Hepatol 1990;10: Kweon YO, Goodman ZD, Dienstag JL, Schiff ER, Brown NA, Burchardt E, et al. Decreasing fibrogenesis: an immunohistochemical study of paired liver biopsies following lamivudine therapy for chronic hepatitis B. J Hepatol 2001;35: Dienstag JL, Goldin RD, Heathcote EJ, Hann HW, Woessner M, Stephenson SL, et al. Histological outcome during long-term lamivudine therapy. Gastroenterology 2003;124: Xu B, Lin L, Xu G, Zhuang Y, Guo Q, Liu Y, et al. Long-term lamivudine treatment achieves regression of advanced liver fibrosis/cirrhosis in patients with chronic hepatitis B. J Gastroenterol Hepatol 2015;30: Chang TT, Liaw YF, Wu SS, Schiff E, Han KH, Lai CL, et al. Long-term entecavir therapy results in the reversal of fibrosis/cirrhosis and continued histological improvement in patients with chronic hepatitis B. Hepatology 2010;52: Marcellin P, Gane E, Buti M, Afdhal N, Sievert W, Jacobson IM, et al. Regression of cirrhosis during treatment with tenofovir 39

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김범수

김범수 Analysis of Outcomes after Resection of Sarcomatous Hepatocellular Carcinoma Purpose: Sarcomatous hepatocellular carcinoma (HCC) is rare. Therefore, the clinicopathologic characteristics and prognosis