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1 PG3 PG Course 2017 Genetic and Autoimmune Disease: Recent Progress in Diagnosis and Management 자가면역간염 : 진단및치료의최신지견 순천향대학교서울병원소화기내과 정승원 Autoimmune Hepatitis: Recent Progress in Diagnosis and Therapeutics Soung Won Jeong Division of Gastroenterology, Department of Internal Medicine, Soonchunhyang University Hospital Autoimmune hepatitis (AIH) is a generally unresolving chronic inflammatory liver disease of unknown cause, and can run a very mild subclinical course or be very acute, rarely leading to fulminant hepatic failure. AIH should be considered in any patient with acute or chronic liver disease, particularly if hypergammaglobulinemia and autoantibodies are present, and if the patient has features of other autoimmune diseases. Molecular pathogenesis of AIH has improved in the last decades, including the identification of autoantigens at the molecular level as well as the function of TH1, TH2, and TH17 cells. In addition, genome-wide association study in recent and upcoming years will help us to understand better disease susceptibility and to identify patients at particular risk. Therapies with corticosteroids alone, or in combination with azathioprine is the standard treatment for AIH. Recently, immunosuppressive drugs including cyclosporin A, tacrolimus or mycophenolate mofetil, offer an alternative for difficult to treat patients, and biological agents, like anti-tnf or anti-b cell antibodies have raised expectations within the AIH scientific community. This review summarized the recent update of pathogenesis, diagnosis, and therapeutics of AIH. 서론 자가면역간염 (autoimmune hepatitis) 은자가항체 (auto-antibody), 고감마글로블린혈증 (hypergammaglobulinemia) 을특징적인소견으로하는만성진행성간질환으로치료받지않으면종종간경변, 간부전으로진행되며, 급성간부전시에는사망할수도있다. 유병률은 100,000명당 명이며, 1-3 매년발생률은유럽에서는 100,000명당 명, 일본에서는 명으로매우낮으며, 4 대부분의연구가코카시언을대상으로한결과로, 바이러스성간염이많은아시아에서의결과는드물다. 자가면역간염은 1951년스웨덴의내과의사인 Jan Waldenstrom이젊은여성에서호발하며, 고감마글로브린혈증과스테로이드치료에잘반응하는만성간염으로처음보고하였고, 년에는항핵항체 (anti-nuclear antibodies, ANA) 와의연관성이발견되어루푸스간염 (lupoid hepatitis) 으로명명되었다 년대에사이에중증자가면역간염환자들을대상으로여러개의전향적연구가진행되었고, 스테로이드단독또는 azathioprine (AZA) 과의병합치료로생존율의향상을보임으로써, 약물치료를통해서생존율을향상시킨첫번째간질환이되었다. 7 Autoimmune hepatitis 라는현재 79

2 Postgraduate Course 2017 의명칭은 1990년대에이르러서 International Autoimmune Hepatitis Group (IAIHG) 에의해서최종명명되었다. 8 진단에있어서는면역형광법 (immunofluorescence), 효소결합면역흡착측정법 (enzyme-linked immunosorbent assay, EIA assay), 그리고분자복제기술 (molecular cloning techniques) 등의발전으로간세포자가항원의진단이가능하게되었고, 치료에있어서는 prednisolone (PD) 과 AZA을대체할수있는새로운약제들에대한연구들이보고되고있다. 그러나아직자가면역간염에대한구체적인병인과최적의관리및치료에대해서는많은연구가필요하다. 여기에서는최근새롭게발표된내용을중심으로병인과진단그리고치료에대해서정리하였다. 발병기전 자가면역간염의원인은명확치않지만유전적요인과환경적요인에의해서간의자가항원을공격하는면역반응이일어나고이를통해서간손상이일어나는만성질환으로여겨지고있다. 가장강한유전적연관성은염색체 6번의단완 (short arm) 에위치한 human leukocyte antigen(hla) 자리의유전자에서발견되는데이유전자는 T세포에항원을전달하는역할을하기때문에후천성면역반응 (acquired immune response) 의개시에영향을미친다. 9 HLA DR3 (DRB1 0301), DR4 (DRB1 0401) 와함께 HLA-DRB1 유전자는유럽과북아메리카의연구에서 1형자가면역간염에강한연관성을보였으며, 10 HLA DR3,DR4는 IAIHG에의해서 1999년에발표된개정진단점수체계 (revised diagnostic scoring system) 에서자가면역간염의중요한진단기준이다. 11 HLA DR7 (DRB1 0701), DR3 (DRB1 0301) 는 2형자가면역간염과연관성이있으며, DRB 양성은좀더공격적이며, 예후가나쁜자가면역간염과관련이있다. 12 HLA-DQB1 0201도자가면역간염 2형의발생과연관이있다. 자가면역간염에대한 genome-wide association study (GWAS) 에서 1형자가면역간염은 major histocompatibility complex (MHC) 뿐만아니라 SH2B3 와 CARD10과도연관성을보였다. 13 유전적민감성이높은경우에자가면역간염으로진행될수있는가능한경로는외부에서들어온인자가구조적으로간의자가항원과유사하여면역반응을일으키는것이다. Herpes simplex virus (HSV) 의 immediate early protein (IE) 은 CYP2D6의 major linear autoepitope와서열상동성 (sequence homology) 을가짐으로서면역반응을일으키며, 14 Hepatitis C virus (HCV) 는 anti-lkm1/anti-cyp2d6 의면역반응을일으킬수있는방아쇠역할을한다. 15 정상에서는자가반응 T세포클론 (autoreactive T cell clones) 의대부분이말초 (periphery) 로가는것을막는자가관용 (self-tolerance) 메커니즘이유지되고있는데이것이깨질때자가면역간염이일어나기쉽다. 그리고정상의자가반응 T세포들 (autoreactive T cells) 은내인성그리고외인성말초관용 (peripheral tolerance) 메커니즘을통해서자가면역에의한조직손상이일어나지않도록조절된다. 이러한기전의핵심역할은 professional regulatory T cells (Tregs) 에의한면역억제이며, 주로말초혈액에서관찰된다. Treg 의활성은활동성질환동안에는매우두드러지지만비정상적으로발생하는자가면역반응을효과적으로억제하기에는부족하다. Tregs 는치료받지않은자가면역간염환자의간에축적되며, 16,17 축적된간내 Tregs 는 PD와 AZA 치료시에선택적으로격감하는것으로보인다. 16 자가면역간염은림프구, 형질세포, 그리고대식세포가밀집되어관찰되는것이특징적인소견인데, 밀집되어있는세포들가운데에서도가장많은비율을차지하는것은 α/β T세포들이다. 이가 80

3 Soung Won Jeong Autoimmune Hepatitis: Recent Progress in Diagnosis and Therapeutics 운데서도대부분이 CD4-positive T-helper cells과 cytotoxic CD8-positive T cells들로간염이조직학적으로심할수록축적이증가된다. 16 면역조직학적으로 T세포를제외한림프구들은상대적으로드물며, 자연살해세포 (natural killer (NK) cells) 와대식세포들이같이관찰된다. 18 자가면역간염의분자적발병기전은먼저항원제시세포 (antigen-presenting cell, APC) 의 HLA class II molecule에위치한자가항원펩티드 (peptide) 가아직활동을하지않은 T helper (Th0) lymphocyte에제시되면, Th0 세포들이활성화가되고주위환경에존재하는사이토카인과항원의특성에따라서 Th1, Th2, 또는 Th17 세포들로분화가되고, 그들이분비한사이토카인에의해서면역반응을시작하게된다 (Fig. 1). Th2 세포는주로 IL-4, IL-10, 그리고 IL-13 을분비해서 B 림프구에서직접자가항체를만들어내도록하고, Th1 세포는 IL-2와 IFN-γ 를분비하며, 이들은 cytotoxic T lymphocytes (CTL) 를자극해서, class I의표현을증가시키고, 간세포표면의 class II HLA molecules 의표현을유도하고대식세포를활성화시킨다. 활성화된대식세포는 IL-1 과 tumour necrosis factor alpha (TNF-a) 를분비한다. Treg 는 transforming growth factor (TGF-β) 의존재시에 Th0 으로부터유도된다. 만약 Tregs 가제지하지않으면, 많은작동세포 (effector cell) 메카니즘이활성화될수있다. 간세포파괴는 CTL의활동에기인한다. 최근에보고된 Th17 세포는 TGF-β와 IL-6가있을때유발되는데, TGF-β 는간에염증이있을때아주잘나타나며, 관해가일어나면줄어든다. 19 Figure 1. Molecular pathogenesis of autoimmune hepatitis 20 Th0, T helper cell0: APC, antigen-presenting cell: CTL, cytotoxic T lymphocytes; MØ, macrophages; TNF-a, tumour necrosis factor alpha; Treg, Regulatory T cells; TNF-β, tumour necrosis factor beta; NK, natural killer; 자가면역간염의대부분은뚜렷한기전이밝혀지지는않았지만, 바이러스감염이나약물이유전적으로민감한사람에게방아쇠인자로작용하는것을고려할수있다

4 Postgraduate Course 2017 바이러스감염으로는 A형간염, 21,22 E형간염, 23 CMV (cytomegalo virus) 감염, 24 그리고 EBV(Epsteine Barr virus) 감염 25 후자가면역간염이발생되었다는보고가있으며, 약물들로는 minocycline, 26,27 interferon α, 28 nitrofurantoin 29,30 그리고 infliximab 31 등이있으며, minocycline 과 nitrofurantoin이대표적이다. 32 그외에도보고된약제들로 ezetimibe, 33 interferon β, 34 diclofenac, 35 methyldopa, 36 ranitidine, 37 atorvastatin, 38 fibrates, 39 adalimubab 40 그리고 A형간염백신 41 등이있으며, 한약복용후발생한예들도있다. 42,43 약인성간염과는달리약물에의해서유발된자가면역간염의경우, 많은환자들이약물을수개월또는수년동안복용해왔고, 진단시간경변이없으며, 면역억제제치료로관해된후약물을중단했을때재발을일으키지않는것이특징적이다. 20 진단 1. Aminotransferase, rgt, IgG 자가면역간염에서는빌리루빈이상승하고 aminotransferases가정상보다수십배이상까지상승할수있으나, 담즙정체성효소는정상이거나약간상승하는것이전형적인소견이다. 8,11,44,45 그러나 aminotransferases의상승정도가조직학적으로심한단계를정확히반영하지는못한다. 최근결과에의하면자가면역간염에서 aminotransferases와함께 alkaline phosphatase (ALP) 보다는 γ-gt가동반상승하며, 이들이치료효과에대한독립적인예측인자로이용될수있다는보고가있다. 46,47 그러나, 자가면역간염의경과가악화와호전을반복하기때문에, aminotransferases와 γ-gt가정상적으로회복 (spontaneous biochemical remission) 되었더라도, 조직학적으로는염증반응이지속되거나, 때때로심한염증을동반할수도있다. 그러한경우임상증상이몇개월이나몇년후에나타나거나또는완전히무증상으로유지될수도있기때문에진단이늦어지거나놓칠수있다. 이런연유로처음자가면역간염을진단받을때약 1/3의환자에서는이미간경변상태이다. 혈청 γ-globulin과 IgG 상승은자가면역간염의약 85% 에서나타나지만, 46,48,49 급성발병시에는 61-75% 로다소낮은결과를보였다. 50,51 IgG의상승은자가면역간염의매우명확한특징으로, IgA는알코올성지방간염에서그리고 IgM은원발성쓸개관경화증 (primary biliary cirrhosis, PBC) 에서상승한다. 주의할점은 γ-globulins과 IgG의정상범위의폭이넓다는점이다. 그래서많은환자들이진단시에정상 IgG 범위에있을수있는데, 이러한환자들의많은수가정상상위값의범위에있다가, 치료후급격한감소를보이며때로는정상범위이하로까지감소한다. 이러한환자들은평소아주낮은 IgG 값에있다가상대적으로상승한경우로여전히통계적으로정상범위에있기때문에처음진단시에배제될수있다. 실제로 IgG 값의변화는치료에대한반응을모니터링하고관해를결정하는데있어서대단히중요하고유용하다. IgG가정상화되는것은때때로경미한염증활성도 (hepatitis activity index (HAI) 5 6) 와같이존재하기도하지만, 52 염증활성도의향상과높은연관성을보인다. 그러므로, transaminase 와 IgG가동시에정상화되는것은완전한생화학적관해를보이는진단소견이다. 53 바이러스성간염유무는자가면역간염의진단기준가운데하나이지만, 바이러스성간염의유병률이높은국가들에서는자가면역간염과바이러스성간염이동시에존재할수있다 이러한경우에자가면역간염진단을위한전제조건으로서바이러스성간염이없는것이포함된다면, 실제로는바이러스성간염과자가면역간염을동시에가지고있으나자가면역간염의진단이간과되어치료를받지못할수도있다. 대개자가면역간염은 B형이나 82

5 Soung Won Jeong Autoimmune Hepatitis: Recent Progress in Diagnosis and Therapeutics C형간염보다좀더심한경과를가지므로자가항체와간조직검사를통한신중한평가를통해서동시감염여부를확인해야한다. C형간염의경우인터페론을더이상사용하지않고경구용항바이러스제를통해서치료할수있게되었기때문에자가면역간염도같이치료할수있는것이쉬워지게되었다. 2. 자가항체 자가항체는자가면역간염의전형적인특징으로진단에있어서매우중요하다 (Table 1). Table 1. Molecular targets and disease associations for autoantibodies in liver diseases.20 ANA, anti-nuclear antibodies; AMA, anti-mitochondrial antibodies; ANCA, antineutrophilic cytoplasmatic antibodies; SMA, smooth muscle antibodies; LKM, liver kidney microsomal antibodies; LM, liver microsomal antibodies; LC1, liver cytosolic antibodies type 1; SLA/LP, soluble liver antigen/liver pancreas antibodies; ASGPR-R, asialoglycoprotein receptor antibodies; UGT1A, UDP glucuronosyltransferase family 1 A; FTCD, formimino-transferase cyclodeaminase; AIH, autoimmune hepatitis; PSC, primary sclerosing cholangitis; PBC, primary biliary cirrhosis; HCV, hepatitis C virus; APECED, autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy. 간접면역형광법 (Indirect immunofluorescence, IFL) 은 soluble liver antigen/liver pancreas antibodies (SLA/LP) 항체를제외하고는모든자가항체진단에서우선적으로선호되는주요한검사법이다. 57 자가항체역가와특이도는질환의진행기간중에매우다양하므로진단시에자가항체가음성이었더라도질환이진행되면서양성으로진단될수있다. 58,59 반복검사를통해서자가항체진단율을높이고정확한진단과분류를시행할수있다. 11,57,60 자가면역간염에서자가항체검출은진단과정에서매우중요하다 (Fig 2). 1) ANA Anti-nuclear antibodies (ANA) 와 smooth muscle antibodies (SMA) 는 1형자가면역성간염의표지자로서, 환자들의 75% 에서발견되지만, 46,62,63 질환특이적이지않고진단역가가넓은범위를갖는다. ANA의형광염색패턴은 Hep2 세포에서균일하지만, 작은반점들이있는 speckled 패턴도가끔볼수있다. 항체는 histones, double-stranded DNA, chromatin 그리고 ribonucleoprotein complexes를포함한다양한항원성과관련이있다. 2) SMA SMA는 F-actin과항 actin 항체를포함한여러개의세포골격요소 (cytoskeletal elements) 에반응한다. 간접면 83

6 Postgraduate Course 2017 역형광법의기질로서콩팥조직이이용될때 SMAvg (vessel/glomeruli) 와 SMAvgt (vessel/glomeruli/tubules) 패턴이확인될수있으며자가면역간염과흔한연관성이있지만, 질환특이적인소견은아니다. ANA와 SMA는같은혈청에서흔히동시에나타나면서재활성화하기때문에진단의강도를높인다. Figure 2. A case based algorithm for patients with a suspicion of autoimmune hepatitis or drug-induced liver injury (DILI) using a response guided approach. 61 *Test also for elevated IgG-levels. **These antibodies are highly specific for the diagnosis of PBC. 3) Anti-LKM1, anti-lc1 Liver kidney microsomal antibodies1 (LKM1) 과 liver microsomal antibodies (LC1) 항체는 2형자가면역간염의혈청표지자로서두항체는종종같이존재하며, 유병률은 LKM1 은 66%, LC1은 53% 이다. 46 ANA와 SMA가항원이질성 (antigen heterogeneity) 이있는반면에, LKM1과 LC1은각각 cytochrome P4502D6 (CYP2D6) 과 formiminotransferase cyclodeaminase (FTCD) 의명확한자가항원표적이있다. 잘밝혀진표적항원에도불구하고, LKM1 과 LC1의어느쪽도질환특이적이지않으며성인의소수 (5-10%) 와만성 C형간염이있는소아환자에서관찰된다. CYP2D6 와 HCV 단백질사이의염기서열상동성 (homology sequences) 에의한분자적유사로인해서자가면역간염에유전적으로민감한 C형간염환자에서 LKM1 항체가주로 DRB1/07 양성으로나타난다. 64 4) Anti-SLA/LP SLA/LP 항체는유일하게질환특이성을가지는자가항체로진단적가치가높으며, 표적항원은 SepSecS 84

7 Soung Won Jeong Autoimmune Hepatitis: Recent Progress in Diagnosis and Therapeutics (synthase (S) converting O-phosphoseryl-tRNA (Sep) to selenocysteinyl-trna (Sec)) 이다. 65,66 SLA/LP 항체는자가면역간염환자의약 30% 에서진단되며, 종종 anti-ro52 항체와연관이있지만, 67,68 때때로유일한자가항체로검출되기도한다. SLA/LP 항체의예후인자로서의의미는아직논란이있지만, 검출시에질환이좀더심하고예후가나쁘다고보고되었다. 69,70 위의다른항체들에서음성일경우에추가로시행하면진단에도움을줄수있다. 5) ANCA Antineutrophil cytoplasmic antibodies (ANCA) 는 1:20으로희석한혈청에에탄올로고정한사람의중성구 (neutrophil) 를이용하여검출할수있다. 원래일차성경화담관염 (primary sclerosing cholangitis) 과염증성장질환 (inflammatory bowel disease) 에특이적인비전형적 panca 항체는 1형자가면역간염에서도빈번하게나타난다. 71,72 최근보고에따르면표적항원이핵막에위치하므로 p-anna (perinuclear anti-neutrophil nuclear antibodies) 라고하기도한다. 73 다른자가항체들이모두음성일때추가로시행하면진단에도움을줄수있다. 11,57 6) AMA AMA는원발성쓸개관경화증의특이혈청학적표지자로서원발성쓸개관경화증소견이없는자가면역간염을가진환자에서때때로진단되기도하는데 (8-12%), 74 이경우에는원발성쓸개관경화증과같이존재할수있다. 그리고이때환자는임상양상에따라서분류되고치료해야한다. 3. 분류 진단된자가항체에따라서자가면역간염은두개또는세개의타입으로분류된다. 초기에는 1형과 2형의 2개로분류되었는데, 1형은 ANA 또는 SMA 항체가존재하고, 2형은 LKM1 또는드물게 LKM-3 또는 LC1이진단된다. 7,46,75,76 초기에는분류에있어서체내를순환하는자가항체만으로하였으나차차다른차이점들도보고되었다 (Table 2). SLA 항체의발견은이전에기술되었던 LP 항체와같은것으로확인이되어서 SLA/LP 항체로 Table 2. Classification of autoimmune hepatitis Type AIH-1 AIH-2 AIH-3 Features The more frequent type (almost 90% of AIH cases) ANA, SMA or anti-sla/lp; HLA DR3, DR4 and DR13 Any age at onset of variable clinical and histopathological severity Rare failure of treatment but variable relapse rates after drug withdrawal and variable need for long-term maintenance therapy 10% of AIH cases Anti-LKM1, anti-lc1 and rarely anti-lkm3; HLA DR3 and DR7 Onset usually in childhood and young adulthood; clinical and histopathological severity commonly acute and advanced Frequent failure of treatment and frequent relapse rates after drug withdrawal; need for long-term maintenance therapy very common SLA/LP positive, otherwise very similar to AIH-1; often Ro52-antibody positive. Possibly more severe AIH, autoimmune hepatitis; ANA, antinuclear antibodies; SMA, smooth muscle antibodies; anti-sla/lp, soluble liver antigen/liver pancreas antibodies; anti-lkm1, liver/kidney microsomal antibody type 1; anti-lkm3, liver/kidney microsomal antibody type 3; anti-lc1, antibodies against liver cytosol type 1 antigen. 85

8 Postgraduate Course 2017 불리게되었고, 3형자가면역간염으로정의되었다. 77 1형과 3형의차이는 1형과 2형의차이와비교했을때잘구분이가지않는다. 일부저자들은 3형의경우에모두그렇지는않지만, 좀더질환의증상이심하고평생동안면역억제치료를받을필요가있다고보고하였다. 65,77,78 그러나 3형의분류에대해서는아직논란이있다. 7 21개기관에서 343명을분석한국내의다기관연구에서는 2형으로진단받은 5명을제외하고는모두 1형으로대부분이 1형으로진단되었다. 또한자가항체에있어서는 ANA, SMA 그리고 LKM1 가각각 94.2%, 23% 그리고 2.9% 로 LKM1 의낮은비율을보였다. 79 Table 3. The Revised international autoimmune hepatitis group modified scoring system

9 Soung Won Jeong Autoimmune Hepatitis: Recent Progress in Diagnosis and Therapeutics 4. 점수체계임상소견, IgG와자가항체등을포함한혈액검사, 조직학적소견, 그리고스테로이드치료반응까지를포함한포괄적점수체계 (Revised original scoring system) 가 1999년 IAIHG에의해서만들어졌다 11 (Table 3). 이점수체계는처음에는임상시험을위한환자코호트를정의하기위해서만들어졌으나현재는진료현장에서자가면역간염의진단을위해서널리이용되고있다. 그러나, 이점수체계의단점은복잡하고담즙정체성간염과의감별이쉽지않다는점이다. 2008년에 IAIHG 에서는 4개의변수 ( 자가항체존재여부와역가, 혈청 IgG 농도, 자가면역간염에상응하는조직소견, 바이러스성간염유무 ) 를근거로하여실제진료현장에서간편하게적용할수있는단순화된점수체계 (Simplified scoring system) 를발표했다 45 (Table 4). Table 4. Simplified diagnostic critieria for autoimmune hepatitis 45 단순화된점수체계는 1999년에만들어진포괄적점수체계와비교시에민감도 (95% vs. 100%) 는낮았으나, 특이도 (90% vs. 73%) 와정확도 (92% vs. 82%) 는높았다 여기에는스테로이드치료후반응은포함되어있지않지만치료시작을위한가이드로서의역할이주된목적이다. 두점수체계를비교한국내다기관연구에서는포괄적점수체계에서 definite AIH 와 probable AIH 의진단은각각 24.8% 와 65.3% 였고, 단순화된점수체계에서는 34.4% 와 35.8% 로진단되었으며, 포괄적점수체계에대한단순화된점수체계의진단적민감도는 69.9%, 양성예측도는 86.4% 로서두진단체계의일치율이다소낮았다. 79 결론적으로단수화된점수체계는사용자가이용하기편리하여, 일선진료현장에서좋은평가도구로이용될수있지만, 진단의 gold standard가아니므로임상의사들은진단에도움을주는진단점수로서만고려해야만하며, 83 진단기준은임상적인판단과함께평가되어져야한다. 이러한맥락에서볼때, 급성또는전격성간염의형태로오는자가면역성간염의경우에도진단기준에서놓칠수있으므로특별한주의를요한다. 이러한경우에증상이갑작스럽게발생하고빈번한급성간부전을보이는것이특징인데, 진단시에자가면역성간염의임상적인특징이부족하고, 점수가진단기준에부족할수있다. 84 실제적으로급성발병하는자가면역 87

10 Postgraduate Course 2017 성간염환자의 25-39% 가정상 IgG 범위에있으며, 50,51 자가항체는 9-17% 에서음성이다. 50,85 이경우에정상 IgG를가진환자들의비율이높은이유는염증기간이짧기때문이다. 조직검사시에자가면역간염의특징적인병변은자주발견되지않고, pericentral necrosis가가장잘나타나는병변이지만, 조직검사는필수적이다. 지금까지발표된점수체계를급성발병한자가면역간염에적용한경우는드물다. 86,87 급성간부전을동반한 70명의환자에서포괄적점수체계 (1999년) 를적용시에 40% 에서자가면역성간염으로진단되었고, 단순화된점수체계 (2008) 를적용시에는 24% 에서만자가면역성간염으로진단되었다. 86 급성및전격성간염을동반한 55명의환자를대상으로한또다른연구에서는포괄적점수체계를적용시에 91% 에서자가면역성간염으로진단하였고, 단순화된점수체계를적용시에는 40% 에서자가면역성간염으로진단되었다. 87 이러한환자들의진단점수체계의효용성에대해서는향후전향적인연구가필요하다. 치료 1. 치료기준 1) 절대적치료기준 3개의무작위대조연구에서 AST가정상의 10배이상이거나또는 5배이상이면서동시에혈청 γ-globulin 이 2배이상인경우는치료받지않을경우에 6개월사망률이 60% 로매우높았다. 뿐만아니라진단시에는조직학적으로 bridging necrosis 나 multilobular necrosis였으나치료받지않았던환자들중에서간경변으로진행된경우는 82% 나되었으며 5년사망률은 45% 에달했다 진단시에이와같은혈액검사결과와조직학적소견은스테로이드치료의절대적기준이며, 49,91 또한간염으로인한피로감이나관절통의정도가일상생활이힘들정도로심한경우도다른지표와관계없이치료기준에해당된다 (Table 5). 나쁜예후인자인증상이있거나진행된섬유화나간경변을동반한환자는항상치료를시작해야하며, 진행된섬유화나간경변의경우에도성공적인치료후상당한섬유화의호전이보고되었다. 자가면역성간염의지속적인진행양상과면역억제치료의효과를고려시에전문가들은활동성질환의경과를보이는모든환자들은치료를받아야한다고권고한다. Table 5. Indications for immunosuppressive treatment 53 88

11 Soung Won Jeong Autoimmune Hepatitis: Recent Progress in Diagnosis and Therapeutics 2) 무증상이나경미한증상의환자조직검사에서경미한염증성괴사를보이는무증상의환자에대한면역억제치료는논란이있어서치료에대한기준이확립되어있지않다. 경미한상태에서치료를받지않았을때 10년생존율은 67-90% 로 96,97 치료받지않은무증상환자들은면역억제치료를받은경우와비슷한생존율을보였다. 98 그러므로치료를하지않는것이정당화될수있으며, 특히스테로이드사용에대한상대적금기가있으며더욱그러하다. 또한자가면역성간염의자연관해가일어날수도있다. 99 그러나, 치료받지않은자가면역성간염이악화와호전의반복과예측할수없는질환의경과로인해서무증상환자의상당수에서경과추적관찰중에증상이있는질환으로진행되며간부전을동반한말기간질환이나간암의발생도가능하다. 97 그러므로경미한질환을가진환자에서치료하지않을경우는일정한간격으로추적검사를하면서만약 transaminase 나 IgG가상승하거나악화호전을반복할경우에는간조직검사등을포함한지속적인추적검사를시행해야한다 (Fig 3). Figure 3. Therapeutic algorithm with case-by-case decisions about commencing steroid therapy, informed by baseline assessments. 61 For example, a patient with active disease (elevated transaminases >3 normal values and hepatitis activity index (HAI) >4/18) requires treatment. Treatment probably no longer indicated in decompensated, burn-out cirrhosis, unless high inflammatory score on liver biopsy. 89

12 Postgraduate Course ) PD나 AZA 치료가적합하지않은환자스테로이드치료는임상증상, 혈액검사결과, 또는조직학적소견상으로활동성간염상태에서만이효과적이다. 비활동성상태나 burned out cirrhosis 상태에서스테로이드치료는이득이되지못하며, 98 약물에의한부작용의위험을높일수있다. 100 또한조절이어려운당뇨, 척추압박골절, 정신병, 또는심한골다공증시에는스테로이드치료전에치료에따른이득에대한철저한평가가이루어져야하며, 심한혈구감소증 ( 백혈구 2.5 x 10 9 /L 또는혈소판 below 50 x 10 9 /L) 이나, thiopurine methyltransferase (TMPT) 활성저하시에는 AZA의사용을피해야한다 101 (Table 5). 2. 관해유도및치료계획자가면역간염의치료목표는 transaminases 와 IgG의정상화와질환의완전관해를유도하고치료종결후에도이를유지하는것이다. 관해유도를위한치료는고용량 PD 단독요법또는 PD와 AZA 병합요법이다 (Table 6). PD 치료후, 증상은빠르게호전되는반면에 transaminases 와 IgG는최대면역억제를얻기까지 6-8주가걸린다. PD의시작용량은단독치료일경우엔 60mg, AZA와병용치료시에 30 mg 이다. 유럽가이드라인에서는치료시작시에 AZA과병합치료를할때도더많은용량의 PD( mg/kg) 를처방한다. 또한유럽에서는 AZA을보통 1 2 mg/kg 로사용하는반면에미국가이드라인에서는 50mg 의정해진용량을사용한다. 53 TMPT 유전자형검사는 AZA 치료후발생할수있는독성을예측할수있다. 그러나치료전검사는일반적으로권고되지않는다. 53 자가면역성간염의진단이불확실하거나 AZA 에대한반응에확실치않다면 PD 단독치료로치료후에 AZA 를 PD 용량을줄일목적으로치료중추가할수있다. 진단이불확실한경우에는 PD 단독치료에대한치료반응이진단에도움이될수있다 11 (Fig. 4). PD 단독또는 PD 와 AZA 병합요법으로치료한국내연구의결과에서는다기관연구에서관해 (remission), 불충분한반응 (incomplete response), 그리고치료실패 (treatment failure) 가각각 85.7%, 10.5%, 3.9% 였으며, 79 또다른단일기관의연구에서는 83.7%, 12.8%, 3.5% 를보여서두연구가비슷하게높은관해를보였다. 102 Table 6. Standard therapy for autoimmune hepatitis 20 90

13 Soung Won Jeong Autoimmune Hepatitis: Recent Progress in Diagnosis and Therapeutics Figure 4. Therapeutic strategy in autoimmune hepatitis. 61 Treatment requires induction of remission and prolonged maintenance therapy. Induction is delivered by steroids and thiopurines are added as steroid sparing strategy. Laboratory endpoints are normalisation of IgG and ALT. MMF, mycophenolate mofetil. 3. 유지치료일단치료후관해에도달하면가능한가장적은용량의면역억제제로유지치료를시행한다. AST/ALT 그리고 IgG가정상으로유지되는완전관해가최소 2-3년동안이루어지고, 조직학적으로도염증의활성화가보이지않는다면면역억제제는중단해볼수있다. 53 그러한완전관해는약 25% 의환자에서만도달할수있다. 46,103,104 그리고최종적으로는약 20% 의환자에서만이완전관해로치료종료후정상 AST/ALT 와 IgG를유지하고조직검사상에서도염증활성도가없는장기간관해를유지할수있다. 완전관해후에는 PD나 AZA 단독요법이나 PD 또는 Budesonide와 AZA 병합요법으로유지치료를시행한다. PD는 5 mg/day까지그리고 Budesonide는 3 mg/day까지감량한다. 53 국내에서도장기간 ( 중간값 33개월, 범위 24-90개월 ) 관해를유지하고치료를중단했던 24명에서, 치료중단후단기간 ( 중간값 4개월, 범위 개월 ) 에 13명 (54.2%) 이나재발을보여서치료중단후높은재발율을보여주었다 불충분한반응의치료일부소수의환자들에서면역억제치료에무반응이나또는경미한반응만보이는경우는항상진단에대해서다시한번평가하고, 면역억제제에대한약제순응도를확인해봐야한다. 치료기간동안반응을보이지않으면서간부전으로계속진행되는경우는신속하게간이식을준비한다. 자 91

14 Postgraduate Course 2017 가면역간염에서진행된간부전에서간이식을시행받지못할경우에사망률이높다 간부전은없지만치료에반응하지않는경우에 PD 용량을정맥주사로 100 mg 까지증량하거나대체약제를사용해야한다.(Fig.4) 대신사용할수있는면역억제제에대한전향적연구는아직부족하여, 전문가집단의의견을따르다. 이때추천되는 2차약제로는 cyclosporin A나 tacrolimus와같은 cyclophilin 저해제들이다. 사용시에는부작용을고려해야한다. 최근에는 AZA 의사용이어려운경우에는 mycophenolate mofetil (MMF) 이 2차약제로서사용된다. 그러나 AZA 의이전치료후효과가없었던경우에는 MMF 의효과역시제한적이다. 45 일차약제로서 MMF 의고무적인결과도보고되었다. 47 최근에는신호전달경로 (signal transduction pathway) 를저해하는생물학적물질들을이용한연구가시행되고있는데, infliximab와같은 TNF 항체 (anti-tnf antibodies) 와 rituximab 와같은 B 세포수용체 CD20 에대한항체이다 108,109 (Table 7). Table 7. Alternative therapies to corticosteroids and azathioprine. 20 Qd, once daily; bid, two times per day. 이러한약물들은환자개인의면역시스템에중대한영향을미치므로치료전개인적인상황을고려하고이익여부를따져본후시행하는것이매우중요하다. Infliximab과 rituximab 의부작용은주로감염이다. 특히 rituximab 치료는잠재성 B형간염 (occult hepatitis B infection) 을재활성화시킬수있다. 그러므로치료시작전에 HBV 상태를반드시확인해서환자가 HBc IgG 항체만양성이라면테노포비어나엔테카비어와같은항바이러스치료를 rituximab 치료와함께예방적으로시행하고, 치료종료후에도 6개월동안투여하여야한다. 또한 Tregs 의입양전달 (adoptive transfer) 도향후치료로서연구가진행되고있다. 5. PD 대체치료피부에바르는스테로이드인 budesonide 가스테로이드에의한부작용을줄이기위해서 PD 에대한대체치료제로서사용될수있다 110 (Table 4). 간경변이없는자가면역성간염환자를대상으로한유럽의다국적연구에서 budesonide는좋은효과를보였다. Budesonide와 AZA의병용치료가스테로이드에의한부작용을줄인대 92

15 Soung Won Jeong Autoimmune Hepatitis: Recent Progress in Diagnosis and Therapeutics 규모전향적연구결과도있다. 103 더욱이 PD를 budenoside로바꾸면스테로이드에의한부작용을줄일수있다. 103 그러나 budenoside 는 PD와같은스테로이드수용체를통해서작용하므로스테로이드치료에효과를보이지못했던환자에게는사용되지않으며, 간경변이없는환자들에게서만사용할수있다. 바르는스테로이드의약리학적효과는간문맥압항진증과문맥대정맥단락 (portocaval shunt) 이있는환자들에게는효과가없다. 111 Budenoside 는어린이와청소년에게도효과적이며, 112 특히 PD 와 AZA 치료후체중증가시에 PD를 budenoside 로바꾸면체중이다시감소한다. PD 단독또는 PD 나 budenoside 와 AZA 와의병용치료중에서어떤치료를선택할것인지는각환자를주의깊게평가후시행한다. 결론 자가면역간염은자가항체 (auto-antibody), 고감마글로블린혈증 (hypergammaglobulinemia) 을특징적인소견으로하는만성진행성간질환으로, 유전적요인과환경적요인에의해서간의자가항원을공격하는면역반응이일어나고이를통해서간손상이발생한다. 이러한기전의핵심역할은 professional regulatory T cells에의한면역억제이며, 자가항체의양성은진단에도움을준다. 점수체계를이용한진단은 IAIHG에의해서 1999년에발표된포괄적점수체계 (Revised original scoring system) 와이를단순화하여실제진료현장에서간편하게적용할수있는단순화된점수체계 (Simplified scoring system) 가 2008년에발표되어이용되고있다. 치료는 PD 단독또는 AZA 와병합치료를시행하며치료후완전관해에도달하면가능한가장적은용량의면역억제제로유지치료를시행한다. 최종적으로는약 20% 의환자에서만이완전관해로치료종료후정상 AST/ALT 와 IgG를유지하고조직검사상에서도염증활성도가없는장기간관해를유지할수있다. 대체약제로는 cyclosporin A 나 tacrolimus와같은 cyclophilin 저해제들이나 MMF가 2차약제로서사용될수있으며, 최근에는 infliximab와같은 TNF 항체와 rituximab 와같은 B세포수용체 CD20 에대한항체도연구되고있다. References 1. Lee YM, Teo EK, Ng TM, Khor C, Fock KM. Autoimmune hepatitis in Singapore: a rare syndrome affecting middle-aged women. J Gastroenterol Hepatol 2001;16: Hurlburt KJ, McMahon BJ, Deubner H, Hsu-Trawinski B, Williams JL, Kowdley KV. Prevalence of autoimmune liver disease in Alaska Natives. Am J Gastroenterol 2002;97: Ngu JH, Bechly K, Chapman BA, Burt MJ, Barclay ML, Gearry RB, et al. Population-based epidemiology study of autoimmune hepatitis: a disease of older women? J Gastroenterol Hepatol 2010;25: Boberg KM, Aadland E, Jahnsen J, Raknerud N, Stiris M, Bell H. Incidence and prevalence of primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis in a Norwegian population. Scand J Gastroenterol 1998;33: Waldenstrom J. [Liver, blood proteins and food proteins]. Dtsch Z Verdau Stoffwechselkr 1952;12: Cowling DC, Mackay IR, Taft LI. Lupoid hepatitis. Lancet 1956;271: Kirk AP, Jain S, Pocock S, Thomas HC, Sherlock S. Late results of the Royal Free Hospital prospective controlled trial of prednisolone therapy in hepatitis B surface antigen negative chronic active hepatitis. Gut 1980;21: Johnson PJ, McFarlane IG. Meeting report: International Autoimmune Hepatitis Group. Hepatology 1993;18:

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18 Postgraduate Course Vergani D, Alvarez F, Bianchi FB, Cancado EL, Mackay IR, Manns MP, et al. Liver autoimmune serology: a consensus statement from the committee for autoimmune serology of the International Autoimmune Hepatitis Group. J Hepatol 2004;41: Gassert DJ, Garcia H, Tanaka K, Reinus JF. Corticosteroid-responsive cryptogenic chronic hepatitis: evidence for seronegative autoimmune hepatitis. Dig Dis Sci 2007;52: Potthoff A, Deterding K, Trautwein C, Flemming P, Strassburg CP, Manns MP, et al. Steroid treatment for severe acute cryptogenic hepatitis. Z Gastroenterol 2007;45: Bogdanos DP, Invernizzi P, Mackay IR, Vergani D. Autoimmune liver serology: current diagnostic and clinical challenges. World J Gastroenterol 2008;14: European Association for the Study of the L. EASL Clinical Practice Guidelines: Autoimmune hepatitis. J Hepatol 2015;63: Werner M, Prytz H, Ohlsson B, Almer S, Bjornsson E, Bergquist A, et al. Epidemiology and the initial presentation of autoimmune hepatitis in Sweden: a nationwide study. Scand J Gastroenterol 2008;43: van Gerven NM, Verwer BJ, Witte BI, van Erpecum KJ, van Buuren HR, Maijers I, et al. Epidemiology and clinical characteristics of autoimmune hepatitis in the Netherlands. Scand J Gastroenterol 2014;49: Kerkar N, Choudhuri K, Ma Y, Mahmoud A, Bogdanos DP, Muratori L, et al. Cytochrome P4502D6( ): a new immunodominant epitope and target of virus/self cross-reactivity in liver kidney microsomal autoantibody type 1-positive liver disease. J Immunol 2003;170: Wies I, Brunner S, Henninger J, Herkel J, Kanzler S, Meyer zum Buschenfelde KH, et al. Identification of target antigen for SLA/LP autoantibodies in autoimmune hepatitis. Lancet 2000;355: Palioura S, Sherrer RL, Steitz TA, Soll D, Simonovic M. The human SepSecS-tRNASec complex reveals the mechanism of selenocysteine formation. Science 2009;325: Zachou K, Gampeta S, Gatselis NK, Oikonomou K, Goulis J, Manoussakis MN, et al. Anti-SLA/LP alone or in combination with anti-ro52 and fine specificity of anti-ro52 antibodies in patients with autoimmune hepatitis. Liver Int 2015;35: Eloranta ML, Barbasso Helmers S, Ulfgren AK, Ronnblom L, Alm GV, Lundberg IE. A possible mechanism for endogenous activation of the type I interferon system in myositis patients with anti-jo-1 or anti-ro 52/anti-Ro 60 autoantibodies. Arthritis Rheum 2007;56: Ma Y, Okamoto M, Thomas MG, Bogdanos DP, Lopes AR, Portmann B, et al. Antibodies to conformational epitopes of soluble liver antigen define a severe form of autoimmune liver disease. Hepatology 2002;35: Czaja AJ, Shums Z, Norman GL. Nonstandard antibodies as prognostic markers in autoimmune hepatitis. Autoimmunity 2004;37: Targan SR, Landers C, Vidrich A, Czaja AJ. High-titer antineutrophil cytoplasmic antibodies in type-1 autoimmune hepatitis. Gastroenterology 1995;108: Zauli D, Ghetti S, Grassi A, Descovich C, Cassani F, Ballardini G, et al. Anti-neutrophil cytoplasmic antibodies in type 1 and 2 autoimmune hepatitis. Hepatology 1997;25: Terjung B, Worman HJ, Herzog V, Sauerbruch T, Spengler U. Differentiation of antineutrophil nuclear antibodies in inflammatory bowel and autoimmune liver diseases from antineutrophil cytoplasmic antibodies (p-anca) using immunofluorescence microscopy. Clin Exp Immunol 2001;126: O'Brien C, Joshi S, Feld JJ, Guindi M, Dienes HP, Heathcote EJ. Long-term follow-up of antimitochondrial antibody-positive autoimmune hepatitis. Hepatology 2008;48: Longhi MS, Ma Y, Bogdanos DP, Cheeseman P, Mieli-Vergani G, Vergani D. Impairment of CD4(+)CD25(+) regulatory T-cells in autoimmune liver disease. J Hepatol 2004;41: Desmet VJ, Gerber M, Hoofnagle JH, Manns M, Scheuer PJ. Classification of chronic hepatitis: diagnosis, grading and staging. Hepatology 1994;19: Baeres M, Herkel J, Czaja AJ, Wies I, Kanzler S, Cancado EL, et al. Establishment of standardised SLA/LP immunoassays: specificity for autoimmune hepatitis, worldwide occurrence, and clinical characteristics. Gut 2002;51: Costa M, Rodriguez-Sanchez JL, Czaja AJ, Gelpi C. Isolation and characterization of cdna encoding the antigenic protein of the human trnp(ser)sec complex recognized by autoantibodies from patients withtype-1 autoimmune hepatitis. Clin Exp Immunol 96

19 Soung Won Jeong Autoimmune Hepatitis: Recent Progress in Diagnosis and Therapeutics 2000;121: Kim BH, Kim YJ, Jeong SH, Tak WY, Ahn SH, Lee YJ, et al. Clinical features of autoimmune hepatitis and comparison of two diagnostic criteria in Korea: a nationwide, multicenter study. J Gastroenterol Hepatol 2013;28: Gatselis NK, Zachou K, Papamichalis P, Koukoulis GK, Gabeta S, Dalekos GN, et al. Comparison of simplified score with the revised original score for the diagnosis of autoimmune hepatitis: a new or a complementary diagnostic score? Dig Liver Dis 2010;42: Czaja AJ. Performance parameters of the diagnostic scoring systems for autoimmune hepatitis. Hepatology 2008;48: Qiu D, Wang Q, Wang H, Xie Q, Zang G, Jiang H, et al. Validation of the simplified criteria for diagnosis of autoimmune hepatitis in Chinese patients. J Hepatol 2011;54: Lohse AW. Recognizing autoimmune hepatitis: scores help, but no more. J Hepatol 2011;54: Yamamoto K, Miyake Y, Ohira H, Suzuki Y, Zeniya M, Onji M, et al. Prognosis of autoimmune hepatitis showing acute presentation. Hepatol Res 2013;43: Ferrari R, Pappas G, Agostinelli D, Muratori P, Muratori L, Lenzi M, et al. Type 1 autoimmune hepatitis: patterns of clinical presentation and differential diagnosis of the 'acute' type. QJM 2004;97: Yeoman AD, Westbrook RH, Al-Chalabi T, Carey I, Heaton ND, Portmann BC, et al. Diagnostic value and utility of the simplified International Autoimmune Hepatitis Group (IAIHG) criteria in acute and chronic liver disease. Hepatology 2009;50: Fujiwara K, Yasui S, Tawada A, Fukuda Y, Nakano M, Yokosuka O. Diagnostic value and utility of the simplified International Autoimmune Hepatitis Group criteria in acute-onset autoimmune hepatitis. Liver Int 2011;31: Schalm SW, Korman MG, Summerskill WH, Czaja AJ, Baggenstoss AH. Severe chronic active liver disease. Prognostic significance of initial morphologic patterns. Am J Dig Dis 1977;22: Baggenstoss AH, Soloway RD, Summerskill WH, Elveback LR, Schoenfield LJ. Chronic active liver disease. The range of histologic lesions, their response to treatment, and evolution. Hum Pathol 1972;3: Cooksley WG, Bradbear RA, Robinson W, Harrison M, Halliday JW, Powell LW, et al. The prognosis of chronic active hepatitis without cirrhosis in relation to bridging necrosis. Hepatology 1986;6: Seo S, Toutounjian R, Conrad A, Blatt L, Tong MJ. Favorable outcomes of autoimmune hepatitis in a community clinic setting. J Gastroenterol Hepatol 2008;23: Czaja AJ. Clinical features, differential diagnosis and treatment of autoimmune hepatitis in the elderly. Drugs Aging 2008;25: Czaja AJ. Autoantibodies in autoimmune liver disease. Adv Clin Chem 2005;40: Czaja AJ, Cookson S, Constantini PK, Clare M, Underhill JA, Donaldson PT. Cytokine polymorphisms associated with clinical features and treatment outcome in type 1 autoimmune hepatitis. Gastroenterology 1999;117: Roberts SK, Therneau TM, Czaja AJ. Prognosis of histological cirrhosis in type 1 autoimmune hepatitis. Gastroenterology 1996;110: De Groote J, Fevery J, Lepoutre L. Long-term follow-up of chronic active hepatitis of moderate severity. Gut 1978;19: Czaja AJ. Features and consequences of untreated type 1 autoimmune hepatitis. Liver Int 2009;29: Feld JJ, Dinh H, Arenovich T, Marcus VA, Wanless IR, Heathcote EJ. Autoimmune hepatitis: effect of symptoms and cirrhosis on natural history and outcome. Hepatology 2005;42: Dufour JF, Zimmermann M, Reichen J. Severe autoimmune hepatitis in patients with previous spontaneous recovery of a flare. J Hepatol 2002;37: Uribe M, Go VL, Kluge D. Prednisone for chronic active hepatitis: pharmacokinetics and serum binding in patients with chronic active hepatitis and steroid major side effects. J Clin Gastroenterol 1984;6: Czaja AJ. Safety issues in the management of autoimmune hepatitis. Expert Opin Drug Saf 2008;7: Kil JS, Lee JH, Han AR, Kang JY, Won HJ, Jung HY, et al. Long-term treatment outcomes for autoimmune hepatitis in Korea. J Korean Med Sci 2010;25: Manns MP, Woynarowski M, Kreisel W, Lurie Y, Rust C, Zuckerman E, et al. Budesonide induces remission more effectively than prednisone in a controlled trial of patients with autoimmune hepatitis. Gastroenterology 2010;139: Muratori L, Muratori P, Lanzoni G, Ferri S, Lenzi M. Application of the 2010 American Association for the study of liver diseases criteria of remission to a cohort of Italian patients with autoimmune hepatitis. Hepatology 2010;52:1857; author reply

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