Postgraduate Course 2011: The Liver and Other Organs 류마티스질환과간 한양대학교류마티스병원 김태환 Connective tissue diseases and the liver Tae-Hwan Kim Hanyang University Hospital for Rheumatic Diseases Connective tissue diseases including systemic lupus erythematosus (SLE), rheumatoid arthritis, Sjögren s syndrome, and scleroderma are systemic disorders. The systemic manifestations vary, and there is frequent overlap among the syndromes. Liver involvement in patients with connective tissue diseases has been well documented but is generally known to be rare. Because connective tissue diseases show chronic nature and need a lot of medication, hepatic evaluation is needed for long term follow up. I briefly describe connective diseases which can show hepatic involvement and special situation which liver can be affected in rheumatic diseases. 류마티스관절염 (Rheumatoid arthritis, RA), 전신홍반성루푸스 ( 루푸스 ) 등결체조직 ( 류마티스 ) 질환은머리부터발까지전신질환으로자가면역질환에속한다. 대부분의질환이발병의원인을모르고임상양상은환자마다다르기때문에많은경험을필요로한다. 류마티스질환에서간증상이나타나는경우는환자마다매우다양하지만간이흔하게침범되는장기는아니다. 류마티스질환중 RA, 루푸스, 쇼그렌증후군과전신경화증에서흔하지는않지만간침범이보고되고있다. RA는통증을동반한관절변형을특징으로소염진통제, 스테로이드및항류마티스제제 (DMARDs) 로치료한다. 이들약제는효과적이기는하지만위, 장, 간등에많은부작용을일으킨다. 루푸스의치료는증상을나타내는장기마다다르지만고용량의스테로이드로부터면역억제제까지치료범위가다양하고이들약제또한간을포함한장기에부작용을일으키는경우가흔하다. 또한만성간염이있는환자에서위에서언급한약제뿐아니라최근개발되고있는생물학적제제또한많은문제점을일으킬수있다. 이에간침범이비교적흔한류마티스질환의특징을간략하게소개하고, 류마티스질환에서사용되는약제중간에문제를일으킬수있는약제, B/C형및불현성간염환자에서사용할때문제가될수있는약제를중심으로간략하게기술하기로한다. 22
김태환 류마티스질환과간 간침범이흔한류마티스질환 1. 루푸스루푸스는다양한자가항체를특징으로머리부터발끝까지전신에증상을나타낼수있는만성질환이다. 진단은 1997년에개정된루푸스진단기준을사용하지만전신또는일부장기만증상을나타내는환자등진료및치료에다양한경험이필요한질환이다. 진단기준은 Table 1에서보듯이 11가지중에서 4가지가합당하면진단내릴수있다. Table 1. 루푸스진단기준분류기준 정 의 뺨의발진 (Malar rash) 뺨위로편평하거나융기된고정홍반 원판상발진 (Discoid rash) 각화된인설의부착과모낭충전을동반한융기된홍반성반점으로위축성반흔이 생길수있음 광과민성 (Photosensitivity) 자외선에노출되면발생하는발진 구강궤양 의사에의해관찰된구강및비인두의궤양 관절염 두개이상의말초관절에압통, 종창, 삼출액등이동반된비미란성관절염 장막염 (Serositis) 심전도나마찰음에의해입증된흉막염이나심막염이있을때또는심낭액의증거가 있을때 신질환 하루에 0.5 g 이상이거나 3+ 이상초과된단백뇨또는세포성원주 신경학적질환 다른원인을규명할수없는간질발작혹은정신병 혈액학적질환 유발할수있는약제없이용혈성빈혈또는백혈구감소증 (4,000/mm 3 이하 ) 또는 림프구감소증 (1,500/mm 3 이하 ) 또는혈소판감소증 (100,000/mm 3 이하 ) 면역학적질환항핵항체 항 dsdna항체, 항 sm항체와 / 또는항인지질항체항핵항체를유발할수있는약제없이어떤시점에서면역형광법또는동등한측정법으로측정된비정상적항체역가 루푸스에서간의이상은진단기준에포함되지않을정도로간은주요기관이아니고심각한이상의발생도드물다. 보고마다다르지만, 간기능이상은 25-50% 로보고되기도하고간비대가 35% 에이른다는보고도있지만임상적으로심각한경우는드물다. 간조직검사소견으로는지방침입과간세포위축이흔하다. 1959년 Mackay등은 119명의루푸스환자에서간증상이심한 14명을 hepatic lupus라고불렀는데모두만성활동성간염소견을보였고염증세포들의많은침윤이있었다고보고하였다. hepatic lupus는현재자가면역간염으로알려져있고이자가면역간염은루푸스의임상양상과비슷한점도있지만간침범정도, 혈액검사로확실히구별되는간질환으로루푸스의간침범과반드시구별되어야한다. Table 2는루푸스의간침범증상과자가면역감염을비교하였다. 루푸스환자의 30% 에서는항인지질항체증후군이동반된다. 항인지질항체증후군은동맥, 정맥혈관의혈전, 자연유산을특징으로하고전신증상을나타낼수있다. 특히 Budd-chiari 증후군이나타나는경우반드시루푸스나항인지질항체증후군을고려해야한다. 23
Postgraduate Course 2011 Table 2. 루푸스의간침범과자가면역감염비교 Lupus Hepatitis AIH type I (Lupoid hepatitis) AIH type II AIH type III ACR criteria fulfillment 100% 20% Symptoms Asymptomatic or mild Asymptomatic or symptoms of acute/chronic hepatitis (25% acute) Diagnosis 1999 revised ACR criteria 1999 revised IAHG criteria Age Young Any age, >10 years old Rare in adults 30-50 y Occurrence Mild increased AST/ALT activity 8-50%, jaundice 25%, hepatomegaly 20-39% 0.1-1.9/100,000, 11-23% of chronic liver Dz Less common Women (%) >90% 78% 89% 90% Associations with lupus activity Close correlation No correlation Complement level Commonly low in active disease Normal, occasionally low C4 Auto-antibodies ANA, anti-dsdna, anti-sm ASMA, ANA, LKM1, anti-lc1 Anti-SLA/LP ASGPR ANA >99%, Strong positive 80% (homogeneous and speckled) negative negative ACA 25% 25% Anti-smooth muscle Ab 30% 60-80% Anti-dsDNA 80-90% 14-58% (temporal)~negative upto 98% (34-64% in ELISA, rarely in IF) Anti-ribosomal P 90% (10-16% in SLE) 0% Anti-TPO 5.9% 8-12% Roles of auto-antibodies Correlations with lupus activities No correlation with necro-inflammatory activity, organ involvements Association with other autoimmune disease (%) 41% 34% 58% Associated autoimmune diseases rare Thyroid, UC, ITP, type 1 DM, RA, erythema nodosum, vitiligo Gamma globulin + +++ + ++ HLA association DR2, DR3, DQB1, but not studies in B8, DR3, DR4 B14, Dr3, Uncertain lupus hepatitis C4AQO Response to steroid /immunosuppressive ++ (commonly response to typical SLE therapies) +++ ++ +++ Progress to LC (%) No (0.8-1.1% at autopsy) 45% 82% 75% Pathophysiology Secondary changes to SLE, including Fatty liver, hepatic congestion Autoimmune destruction by liver membrane autoantibodies Histopathology Chronic active hepatitis in biopsy Risk factors of progression to CAH Inflammation in mainly lobular, occasionally periportal with paucity of lymphoid infiltration 2.4% (Recent Japanese study by autopsy, LC and CAH 2% in SLE) High anti-dsdna, anti-ribosomal P+, LE cell Periportal piecemeal necrosis associated with lobular activity, lymphoid infiltration and bridging necrosis as well as rosette formation 24
김태환 류마티스질환과간 2. 류마티스관절염 RA는가장흔한염증성관절염의하나로서다수의관절을동시에침범하고류마티스인자와같은자가항체를동반하는자가면역질환이며관절이외에도다양한종류의장기침범증상을가져오는전신질환이다. RA의정확한발생원인은아직확실하게밝혀져있지않지만주로유전적인요인과환경적인요인, 그리고이두요인들간의복합적인작용에의한것으로알려져있다. 유병률은인구의약 0.7-1% 정도이며주로중년여성에서많이발생되며여자가남자보다약 2-4배더많다. RA의직접적인원인은아직규명되어있지않으나대부분의학자들은약 30-40% 의유전적인소인과 60-70% 의환경적인요인들이복합적으로작용하여관절염이발생될것으로추정하고있다. RA도당뇨병, 고혈압등의다른만성적인내과질환과마찬가지로지금까지개발된다양한치료법을잘이용하면일부소수의환자를제외하고는대부분의 RA 환자들에게큰도움을줄수있다. 특히최근 5년간, 의학의발전에따른다양한약물의개발로과거에비해대단히향상된치료성적을보이고있다. RA는수개월에걸쳐점진적으로여러관절을침범하는만성관절염의소견이며약 2/3 환자에서는피로감, 식욕부진, 전신쇠약감등의전신증상이선행한다. 일부환자에서는증상이처음에한개내지두세개의관절에만증상이나타나기도하지만대부분질병이경과하면서대칭적인다발성관절염을보인다. 손가락이나발가락같은작은관절이초기부터잘침범되며병이진행함에따라팔꿈치관절, 어깨, 발목, 무릎등비교적큰관절에도증상이나타난다. 신체어느부위에도증상이발생할수있지만가장특징적인관절소견은손가락, 발가락의작은관절에증상이대칭적으로나타나는것이다. 척추증상이있는경우경추증상이흔하지만경추이외의증상이있는경우에는 RA 이외의질환을반드시생각해야한다. 조조강직은가장일반적인증상으로대개 1시간이상지속된다. 조조강직은 RA면나타나는증상이고얼마나오래지속되느냐로얼마나심한지를간접적으로측정할수있다. 관절외증상이나타나는경우류마티스인자 (rheumatoid factor) 가양성인경우가많고, 예후가나쁘다. 류마티스피하결절, 폐, 심장증상도나타날수있고입, 눈이건조한증상도흔하게나타난다. 관절증상이심하지않은데도관절외증상이흔한경우도있다. 류마티스관절염의진단은 1987년에개정된미국류마티스학회기준에의해이루어지나, 어느정도진행이된후에야진단할수있는기준이다. 현재는 RA의조기발견이중시되어 2010년에류마티스인자, 항 CCP 항체등이포함된조기에진단이가능한새로운분류기준이제시되어사용되고있다. RA 환자에서간침범은 18-50% 까지보고마다다양하다. 관절염의유병기간과는큰상관없고간조직검사에서는정상, 비특이적염증소견, 지방침입등이나타난다. Felty 증후군은 RA, 백혈구감소및간비장비대를특징으로하는경우를일컫는데이경우에는관절염도심한양상을보이고간이상을보이는경우도많다. ALT, AST가정상이지만 alkaline phosphatase가올라가는경우가흔한데이경우 alkaline phosphatase가 RA와같이동반되는골다공증에기인한것인지는반드시구별해야한다. RA 자체보다도같이사용하고있는약제에의한이차적인간독성이더흔하고심한경과를보인다. Methotrexate (MTX), Leflunomide 등은간독성이증명되었고최근많이사용되는생물학적제제인 anti TNF (etanercept, infliximab, adalimumab) 와 anti CD20 등은간염이있는특수한상황에서는주의를요한다. 25
Postgraduate Course 2011 3. 전신경화증전신경화증은피부, 관절등결체조직, 폐, 심장, 소화기, 간등을침범하는만성류마티스질환으로전신적으로나타나는전신형과신체의일부분만경화되는제한형으로구분할수있다. 모든환자에서레이노현상이보이고피부경화와특수한자가항체를지닌다. 제한형인 CREST증후군에서간침범은드물고, 727명의전신경화증환자에서 8명정도간침범이보고될만큼흔하지는않다. 전신경화증환자의 6명에서일차성담도경화증이발견된보고도있고역으로일차성담도경화증환자 83명중 14명에서전신경화증이발견된보고도있다. 4. 쇼그렌증후군 (Sjogren's syndrome) 쇼그렌증후군은외분비샘의임파구침윤을특징으로하는만성자가면역질환으로, 외분비샘의분비저하에의한구강건조증과안구건조증등의건조증세가나타난다. 1933년덴마크의안과의사였던 Sjogren이류마티스관절염이의심되는환자중안구건조증과구강건조증을가진 32명의환자의임상적, 조직적소견을발표하면서이러한질환을 keratoconjunctivitis sicca 라고명명하였다. 다른질환없이쇼그렌증후군단독으로발생하는경우를일차성쇼그렌증후군이라하고, 다른질환과함께병발하는경우를이차성쇼그렌증후군이라한다. 이차성쇼그렌증후군의경우류마티스관절염, 전신홍반루푸스, 전신성경화증, 혼합결합조직질환, 일차성담도경화증, 혈관염, 만성활동성간염등과동반될수있다. 쇼그렌증후군의가장특징적인안구증상은건조각결막염 (keratoconjunctivitis sicca) 이다. 환자는눈이따가운느낌, 모래가끼거나긁힌듯한통증, 가려움증, 충혈, 광과민성등을호소한다. 마른음식을넘기기가힘들어지고, 말을계속이어서하기가불가능해지며, 미각이변하고, 입이타들어가는느낌을호소한다. 충치가증가되거나의치를사용하는데문제가생긴다. 약 1/3의환자에서샘외증상을보이는데이는면역복합체나혈관염에의해발생한다. 대표적으로관절통이나관절염 (60%), 레이노현상 (37%), 임파절종대 (14%), 폐질환 (14%), 혈관염 (11%), 신장침범 (9%) 등이있다. 쇼그렌증후군에서간침범은 alkaline phosphatase, AST, ALT이상이흔하다. 일차성쇼그렌증후군의 10%, 이차성쇼그렌증후군의 42% 에서 antimitochondrial antibody (AMA) 가발견되며이경우간증상이나타난다는보고가있다. 300명의쇼그렌증후군환자를분석한결과약 7% 에서간기능이상이있고이환자들에서 AMA가발견된다는보고도있다. 결론적으로쇼그렌증후군에서간침범은흔하지않으며, 증상이심하지는않지만일차성담도경화증과유사한간병변을일으킬수있고, AMA는간침범정도를알수있는가장유용한검사라고결론내릴수있다. C형간염은쇼그렌증후군환자의약 13% 에서관계가있다는보고가있는만큼쇼그렌증후군환자에서간이상이발견되는경우 C형간염도고려해야한다. 류마티스질환에서흔히사용되는약제에의한간독성 류마티스관절염, 루푸스등류마티스질환은만성경과를보이고통증, 관절변형, 장기침범에따른다양한증상으로인해장기적인투약이필요하다. 류마티스관절염환자들은통증을조절하는 acetaminophen, tramadol, 비스테로이드성소염진통제 (NSAIDs), 스테로이드와관절변형을예방하는 MTX, leflunomide 등다양한 DMARDs를 26
김태환 류마티스질환과간 Table 3. 류마티스관절염에서많이사용되는약제및부작용 Drugs Time to benefit (months) Usual maintenance dose Toxicity M ethotrexate 1-2 7.5-15 m g/week GI symptoms, stomatitis, rash, alopecia, hepatotoxicity, pulmonary toxicity, myelosuppression, Sulfasalazine 1-2 1 g twice or 3 times daily Rash, GI intolerance infrequent myelosuppression, fever Hydroxychloroquine 2-4 300-400 mg/day Infrequent rash, diarrhea, pigmentation rare retinal toxicity Leflunomide 1-2 10-20 mg daily diarrhea, rash, hepatoxicity, marrow suppression, interstitial pneumonitis Cyclosporin 1-3 100-150 mg daily GI symptoms, Hair, Myelosuppression, infrequent hepatotoxicity, Azathioprine 2-3 50-150mg daily Myelosuppression, infrequent hepatotoxicity, flu-like illness with fever, GI symptoms, elevated LFTS Tacrolimus 1-2 1-3mg.daily Sickness, diarrhea, heartburn, myalgia, headache. Infection, Early signs of high blood sugar or DM, renal toxicity 꾸준히복용하게된다. 루푸스는침범되는장기에따라선택되는약제가다르지만스테로이드및면역억제제를사용하게된다. 이들약제는통증완화, 관절변형예방, 루푸스에서장기침범완화등의좋은효과가있지만소화기계, 간, 신장등의부작용은반드시점검해야한다. 류마티스질환에서흔하게사용되는약제및부작용은 Table 3, 4와같다. 류마티스관절염관절변형치료제의대표적인약제는 MTX이다. MTX는가장효과적이고, 복용방법이간편하다는특징이있다. 최근에각광받는생물학적제제도 MTX와같이사용하는경우효과가있고대부분신약의효과를 MTX와비교한다. Leflunomide는효과가탁월하지만폐, 간섬유화를일으킬수있고 MTX와같이사용하는경우간독성에더욱관심을기울여야한다. B, C, 불현성간염등특수한경우 B/C형간염이인구의 3-4% 이고류마티스관절염의유병율은인구의약 1% 이다. 간염은류마티스관절염치료시항상고려해야할질환이다. 특히 MTX, leflunomide등간독성이있는약제뿐아니라고용량의스테로이드, 항 TNF 제제, anti CD20등최근사용되는생물학적제제를사용할때도반드시 B/C형간염및불현성감염검사후처방되어야한다. TNF가 B형간염의증식을억제하기때문에항TNF를사용하면 B형간염활성화를반드시고려해야한다. 항 TNF사용전항바이러스제제를사용하거나간전문의와함께추적관찰을요한다. 항TNF제제중특히 inflximab 은특히간염활성이더많이알려져주의를요한다. HBsAg은음성이고 anti HBc는양성인불현성간염환자에서의항TNF제제사용도관심을끌지만간독성은심하지않다. 본교실에서는 258명을분석했는데이중 anti HBcAb양성인 88명을추척관찰중 14명에서간이상이보였다고보고하였다. 대부분의 C형간염환자는항 TNF제제에큰문제없는경우가많다. 27
Postgraduate Course 2011 Table 4. 류마티스질환에서많이사용되는생물학적제제 Drug Structure Half life Dosage Infliximab Etanercept Adalimumab Rituximab Abatacept Chimeric anti-tnf α antibody Soluble TNF-α fusion protein Human anti- TNF α antibody Anti-CD20 antibody T cell costimulamodu 9days IV 3 mg/kg (10 mg/kg 까지증량가능 ) 0,2,6,8주 8주간격 4days SC 25 mg twice/wk or 50 mg once a wk Common side effect Infusion reactions (itching, hives, rash, nausea, headache), URI (colds, sinusitis, bronchitis, etc) Injection site reactions, URI (colds,sinusitis, bronchitis,etc) 2wks SC 40 mg/2 wks Injection site reactions, URI (colds,sinusitis, bronchitis,etc) 40hr- 16days IV 1,000 mg (2 주간격 2 회 ) 13.1days IV <60 kg: 500 mg (0,2,4주 4주 간격 ) Swelling, Hives Blurred vision Dizziness, Chills Drowsiness, Headache, cough, Wheezing or trouble breathing, headache, upper respiratory tract infection, nasopharyngitis, and nausea Serious S/Ex Anaphylaxis (severe allergic reactions with swelling of lips, difficulty breathing, low blood pressure), Bacterial infection (e.g., pneumonia or joint infection), unusual infections (Tb or fungal infections), optic neuritis or multiple sclerosis, nerve disorders, worsening of heart failure Bacterial infection (pneumonia or joint infection), unusual infections (Tb or fungal infections), optic neuritis, multiple sclerosis, nerve disorders, worsening of heart failure Bacterial infection (pneumonia or joint infection), unusual infections (Tb or fungal infections), optic neuritis, multiple sclerosis, nerve disorders, worsening of heart failure bacterial and/or viral infections (ex)re-activate a hepatitis B infection progressive multifocal leukoencephalopathy(pml) High blood pressure Heart attack, cardiac arrhythmias and angina, Allergic reactions Hypersensitivity, infection, malignancy Table 5. 류마티스질환과 B/C 형간염 Rituximab은항CD20제제로 B 임파종및만성림프구성백혈병치료에사용되고항TNF 제제에효과가없는 RA와루프스치료에사용된다. B/C형간염및불현성간염환자에서항CD20을사용한경우간이상및간증식이발생하였다는보고가있다. 또한 B/C형간염이있는경우류마티스질환이동반되는경우가흔하다 (Table 5). B형간염은혈관염과 C형간염은 cryoglobulinemia의병인에관여한다고알려져있어이경우정확한검사및추적관찰을요한다. 28
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