증례 Lab Med Online Vol. 3, No. 1: 40-44, January 2013 임상화학 초고도로증가된페리틴수치를보이는원인불명열환자 1 예 A Case of Extremely Elevated Ferritin Levels in a Patient with Fever of Unknown Etiology 김혜원 1 장윤하 2 정희정 3 이우창 1 전사일 1 민원기 1 Hyewon Kim, M.D. 1, Yun Ha Jang, M.D. 2, Hee-Jung Chung, M.D. 3, Woochang Lee, M.D. 1, Sail Chun, M.D. 1, Won-Ki Min, M.D. 1 울산대학교의과대학서울아산병원진단검사의학과 1, 검단탑종합병원진단검사의학과 2, 관동대학교의과대학제일병원진단검사의학과 3 Department of Laboratory Medicine 1, University of Ulsan College of Medicine and Asan Medical Center, Seoul; Department of Laboratory Medicine 2, Gumdan Top General Hospital, Incheon; Department of Laboratory Medicine 3, Cheil General Hospital and Women s Healthcare Center, Kwandong University College of Medicine, Seoul, Korea Fever of unknown etiology that occurs along with highly elevated serum ferritin concentrations (>500 ng/ml) is mostly observed in hematologic malignancies and rheumatic diseases such as systemic lupus erythematosus, temporal arteritis, and adult-onset Still s disease (AOSD), among which AOSD is a type of systemic inflammatory disorder with unknown pathophysiology and has very low incidence. AOSD presents with various nonspecific symptoms and signs such as high spiking fever, joint pain, skin rash, and increased leukocytes. Because AOSD is diagnosed after excluding the possibility of other conditions such as neoplasms, infections, and inflammations, diagnosis and treatment are generally delayed. Patients with AOSD often have high serum ferritin levels than those with other conditions, although the underlying mechanism for this is not clearly understood. In addition, decreased proportion of glycosylated ferritin are observed in most patients with AOSD. Therefore a combination of high serum ferritin and a decreased proportion of glycosylated ferritin seems to be important for the differential diagnosis of AOSD that thus may allow early diagnosis of AOSD. Here we report a case of AOSD diagnosed via extremely high serum ferritin levels and decreased glycosylated ferritin proportion. Key Words: Adult onset Still s disease, Ferritin, Glycosylated ferritin 서론 원인불명열로내원한환자의진단을위해서는감염, 종양, 비감 염성염증성질환등을감별해야하는데, 이중전신홍반루푸스 (systemic lupus erythematosus), 측두동맥염 (temporal arteritis), 성 Corresponding author: Won-Ki Min, M.D. Department of Laboratory Medicine, University of Ulsan College of Medicine and Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 138-736, Korea Tel: +82-2-3010-4503, Fax: +82-2-478-0884, E-mail: wkmin@amc.seoul.kr Received: August 2, 2012 Revision received: August 21, 2012 Accepted: August 27, 2012 This article is available from http://www.labmedonline.org 2013, Laboratory Medicine Online This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 인형스틸병 (Adult onset Still s disease, AOSD) 과같은류마티스질환이 15-37% 를차지한다 [1]. 류마티스질환중에서도성인형스틸병은청장년층에서가장빈도가높은불명열의원인인데 [2], 이는전신염증성질환의일종으로발병원인은아직알려지지않았으며매우드문질환이다 [3]. 고열및관절통, 피부발진, 백혈구증가등의비특이적임상소견을보이며악성종양이나, 류마티스질환, 감염등원인불명열의다른원인들을배제하여야한다 [4]. 임상적으로성인형스틸병을진단하기위해서는 Yamaguchi 등이제시한진단기준이가장민감하여널리사용되고있다 (Table 1)[5, 6]. 흔하게관찰되는검사소견으로혈청페리틴의증가가있는데, 페리틴은체내의주된철저장물질로혈색소증 (hemochromatosis) 이나수혈관련헤모시데린침착증 (transfusion hemosiderosis) 등과같은철분과다 (iron overload) 상태, 간질환, 신질환, 감염, 류마티스질환등에서도증가할수있다. 그러나다른질환들에비해성인형스틸병에서는정상참고치의 5배이상 (>1,000 ng/ml) 높게측정되는경우가많으며 [7-9], 당화페리틴 (glycosylated ferritin) 의 40 www.labmedonline.org eissn 2093-6338
비율이대조군에비해낮다는사실에근거하여감별진단에도움 을받을수있다 [10]. 저자들은원인불명열을주소로입원한환자에서매우높은페 리틴수치를보여성인형스틸병으로진단하는데도움을받은 1 예 를보고하는바이다. 증례 현병력, 신체검사및방사선검사소견 : 67 세남자환자가 5 개월 전부터지속된 39 C 이상의간헐적발열을주소로입원하였다. 환 자는현기증과피로감, 식욕감소, 관절통, 인후통을호소하였고신 체검사에서전신의발진과경부림프절비대가있었다. 흉부엑스레 Table 1. Criteria for adult-onset Still s disease [5] At least 5 criteria, including 2 major criteria and no exclusion criteria, are required for diagnosis Major criteria Minor criteria Fever 39 C lasting 1 week* Arthralgia lasting 2 weeks* Typical skin rash: maculopapular, non-pruritic, salmon-pink rash with concomitant fever spikes* Leukocytosis 10,000 cells/mm 3 with neutrophil polymorphonuclear count 80%* Pharyngitis or sore throat* Lymphadenopathy and/or splenomegaly* Abnormalities in liver enzyme levels (aminotransferases)* Negative for rheumatoid factor or antinuclear antibodies* Exclusion criteria Infection, especially sepsis and Epstein-Barr viral infection Malignant diseases, especially lymphomas Inflammatory disease, especially polyarteritis nodosa *Present in the case of our patient; Not observed in the case of our patient. 이촬영및흉부, 복부컴퓨터단층촬영상감염이나종양을의심할만한소견은없었다. 혈액및임상화학검사소견 : 입원당시실시한혈액검사에서백혈구는 17.3 10 3 /μl ( 참고치 4.0-10.0 10 3 /μl) 이었고그중호중구가 92% 였으며, 혈색소는 7.9 g/dl ( 참고치 13.0-17.0 g/dl), 혈소판은 193 10 3 /μl ( 참고치 150-350 10 3 /μl) 였다. 적혈구침강속도 (erythrocyte sedimentation rate, ESR) 는 2 mm/hr ( 참고치 0-9 mm/hr) 였다. C반응단백 (C-reactive protein, CRP) 는 18.0 mg/dl ( 참고치 0-0.6 mg/dl) 로증가하였다. 총단백은 6.0 g/dl ( 참고치 6.0-8.0 g/dl), 알부민은 2.1 g/dl ( 참고치 3.3-5.2 g/dl) 이었고, AST는 164 IU/L ( 참고치 40 IU/L 이하 ), ALT는 26 IU/L ( 참고치 40 IU/L 이하 ), 감마글루타밀전이효소 (γ-glutamyltransferase, GGT) 는 83 IU/L ( 참고치 11-50 U/L), 알칼리인산분해효소 (alkaline phosphatase, ALP) 는 184 IU/L ( 참고치 40-120 IU/L), 젖산탈수소효소 (lactate dehydrogenase, LD) 는 1,396 IU/L ( 참고치 120-250 IU/L) 였다. 총빌리루빈은 0.8 mg/l ( 참고치 0.2-1.2 mg/l), 직접빌리루빈은 0.1 mg/l ( 참고치 0.5 mg/l 이하 ) 였다. 철은 14 μg/dl ( 참고치 50-170 μg/dl), 총철결합능 (total iron binding capacity, TIBC) 는 143 μg/dl ( 참고치 280-400 μg/dl) 이었다. 혈청페리틴이 115,000 ng/ml로크게증가되어있었고 ( 남자참고치 20-320 ng/ml) 2일후시행한검사에서 830,000 ng/ml으로더욱증가하였다. 미생물및면역학검사소견 : 혈액, 소변, 뇌척수액및호흡기검체배양에서는세균및진균이검출되지않았고말라리아검경은음성소견이었다. 호흡기바이러스, 아스페르길루스 (aspergillus), 크립토콕쿠스 (cryptococcus) 항원검사, B형간염바이러스 (hepatitis B virus, HBV) 항원 / 항체검사, C형간염바이러스 (hepatitis C A B Fig. 1. A markedly increased number of granulocytes and hemophagocytes engulfing neutrophils are noted in the bone marrow aspirate (A, Wright stain, 1,000) and biopsy specimens (B, H&E stain, 400). No definite evidence of hemophagocytic lymphohistiocytosis is observed. www.labmedonline.org 41
Body temperature ( C) Ferritin ( 10 4 ng/ml) virus, HCV) 항체검사, HIV 항원 / 항체검사에서음성이었으며, 호 흡기바이러스및거대세포바이러스 (cytomegalovirus, CMV) 배양, 엡스타인 - 바바이러스 (Epstein-Barr virus, EBV), 단순헤르페스바 이러스 (herpes simplex virus, HSV), 결핵 PCR 모두음성이었다. 류마티스인자 (rheumatoid factor, RF), 항 CCP 항체 (anti-cyclic citrullinated peptide, anti-ccp), 항핵항체 (anti-nuclear antibody, ANA), 항호중구세포질항체 (anti-neutrophil cytoplasmic antibody, ANCA), 항 Jo-1 항체 (anti-jo-1), 항 Ro 항체 (anti-ro), 항 La 항체 (anti-la), 항 Scl-70 항체 (anti-scl-70) 등의자가면역질환표지자는 모두음성이었다. 골수흡인및생검, 조직검사소견 : 골수검사에서반응성과립구 증식과경도의혈구포식조직구증소견이있었고악성세포는관찰 되지않았다 (Fig. 1). 경부림프절생검결과는반응성증식소견이 었다. 당화페리틴측정 : Worwood 등 [11] 의방법을이용하여전체페 리틴에대한당화페리틴의비율을구하였다. 입원당일및 2 일후 페리틴검사가의뢰되었던검체를각각 2 개로분주하여한쪽은 콘카나발린 A (concanavalin A, ConA)- 세파로즈 B (sepharose B) 용액을첨가하고다른한쪽은세파로즈 B 만첨가하여실온에서 2 시간동안반응시킨후 3,000 rpm 에서 15 분동안원심분리하였다. 상층액을취하여 Advia Centaur (Siemens Healthcare Diagnostics, Tarrytown, NY, USA) 장비및시약을이용해비당화페리틴과전체 페리틴양을측정하였고, 두값의차이를통해당화페리틴의양을 결정하였다. 입원당일검체의당화페리틴은 1,085.1 ng/ml 였고, 40.0 39.0 38.0 37.0 36.0 35.0 90 80 70 60 50 40 30 20 10 0 methylprednisolone start Days after admissioin -292-114 -14-3 0 3 10 87 94 101 108 193 195 205 286 300 Fig. 2. Changes in body temperature, ferritin and C-reactive protein levels during the patient s clinical course. BT Ferritin CRP 20 18 16 14 12 10 8 6 4 2 0 CRP (mg/dl) 입원 3일째검체의당화페리틴은 740.1 ng/ml였다. 전체페리틴에대한당화페리틴의분율을백분율로환산한결과각각 0.93%, 0.09% 였다. 치료및임상경과 : 환자는입원후경구스테로이드와경험적항생제를투여받고점차증세가호전되어퇴원하였다. 퇴원시혈중페리틴은 1,576.8 ng/ml로감소되었다. 추적관찰기간동안의혈중페리틴의변화는 Fig. 2와같다. 고찰 간헐적인발열의원인이될수있는질환들에는브루셀라증 (brucellosis), 예르시니아감염증 (Yersinia infection), 렙토스피라증 (leptospirosis), Q열 (Q fever), 톡소포자충증 (toxoplasmosis), 열원충감염 (Plasmodium sp. Infection), 헤르페스바이러스감염 (herpes group viral infection) 과같은감염질환, 대장암또는림프종과같은종양성질환, 스틸병 (Still s disease), 베흐체트병 (Behcet s disease), 재발성다발연골염 (relapsing polychondritis) 과같은전신성염증성질환등이있다 [12]. 본증례의환자에서는각종미생물배양검사, PCR, 항원, 항체검사등으로감염성질환을배제할수있었고영상의학적진단및골수검사, 림프절생검소견을통해종양성질환을배제할수있었다. 또한모든자가면역질환표지자가음성이었고스테로이드투여후경과가점차호전된점, 극심한혈청페리틴증가소견을고려하면임상적으로성인형스틸병이가장의심되었다. 성인형스틸병은전신성염증질환의일종으로발병원인은아직알려지지않았으나세균, 바이러스등의외부요인에대한반응으로대식세포 (macrophage) 가활성화되고 IL-6, IL-18과같은염증성사이토카인 (proinflammatory cytokine) 이과생성됨으로써증상이유발되는것으로생각되고있다 [13]. 연간백만명당 1-10 명에서발생하는드문질환으로, 주로 16-35 세에시작되나더늦은나이에도발병할수있다 [3]. 성인형스틸병은발열, 발진및관절통, 백혈구증가등의매우다양한증상과징후를보이지만특이적이지않고다른원인질환을먼저배제해야진단할수있으므로적절한치료시기가지연될때가많다. 성인형스틸병의분류에는 Yamaguchi 등이제안한기준이가장널리사용되는데 [5], 본증례의경우 5개월전부터지속된발열과관절통, 전신적발진, 백혈구증가증이있어대기준 (major criteria) 4항목을모두만족하였고, 인후통, 경부림프절비대, 간효소증가가있으며류마티스인자와항핵항체가음성이어서소기준 (minor criteria) 4항목을모두만족하였다. 또한각종미생물의배양및 PCR 소견이음성이었으며영상의학적검사및림프절과골수검사에서종양성질환을의심할만한소견이없었고임상증상에서기타의염증성질환을의심할 42 www.labmedonline.org
만한소견도없어배제기준 (exclusion criteria) 에해당하는소견이없었다. 성인형스틸병환자에서는다른질환에비해혈청페리틴의증가가두드러지게나타난다 [3, 5, 14, 15]. 페리틴은체내의주된철저장물질이며제1철이온중심부 (ferrous ion core) 를아포페리틴 (apoferritin shell) 이감싸고있는이중구조로이루어져있다. 간과비장의세망내피세포와골수에높은농도로존재하며혈청참고치는성인여성에서 20-200 ng/ml, 성인남성에서 20-300 ng/ml이다. 혈청페리틴양은기저질환이없는상태에서는체내철저장량을반영하여철결핍상태에서감소하고혈색소증 (hemochromatosis) 이나수혈관련헤모시데린침착증 (transfusion hemosiderosis) 과같은철과잉상태에서증가한다. 그러나간질환, 신질환, 악성종양, HIV 또는기타감염증, 겸상적혈구병 (sickle cell disease), 반복적인수혈등과같은상태에서는체내철저장량과관계없이크게증가한다 [14]. 특히, 감염, 종양, 간질환이나저장성질환의경우는페리틴이 3,000 ng/ml 이상으로증가하는경우가드물지만성인형스틸병에서는 10,000 ng/ml 이상으로증가하기도한다 [15, 16]. 성인형스틸병으로진단받은 49명을대상으로한서양의한연구에서는혈청페리틴의평균이 4,753 ng/ml (14-49,267 ng/ml) 로보고된바있으며 [17] 15-32 명을대상으로한국내의성인형스틸병임상상연구들에서는대상군의 79-86% 에서페리틴상승을보였고평균값은 1,200-36,510 ng/ml 인것으로보고되었다 [18-21]. 이처럼병적인상태에서혈청페리틴이증가하는것은급성염증반응을매개하는사이토카인인 IL-Iβ, IL-6, IL-18 및 TNFα 등에의해페리틴의생산이증가하기때문이다 [22]. 또한증가된혈청페리틴수치는증상및징후가완화되면다시정상화되므로질병의활성도를반영하는지표로생각된다 [23]. 페리틴생산이급격히증가하는경우생합성의최종과정인당화과정 (glycosylation) 의속도가페리틴의생산속도를따라가지못해당화페리틴의비율이감소하게되고 [24], 비당화페리틴은당화페리틴에비해혈중제거율이떨어지므로총페리틴의양이증가하게된다. 당화페리틴은페리틴의이소단백질중의하나로정상적으로전체페리틴의 50-80% 를차지하나염증상태에서는 20-50% 정도로, 성인형스틸병에서는 20% 이하로감소한다 [3]. 당화페리틴의감소역시성인형스틸병에특징적인소견은아니지만, 고페리틴혈증 (hyperferritinemia) 과함께성인형스틸병진단에유용한표지자로활용될수있다. Fautrel 등은정상상한치의 5배이상의고페리틴혈증과 20% 이하의당화페리틴으로 AOSD를진단할경우특이도 92.9%, 민감도 43.2% 로성인형스틸병의우수한지표가될수있음을보고하였다 [17]. Worwood 등 [11] 은콘카나발린 Con A에대한당화페리틴과비당화페리틴사이의친화도차이를이용하여당화페리틴의비율을구하는방법을제안하였는데, 이측정법을 이용하여본증례의입원당시와입원 3일째혈청에서당화페리틴비율을측정한결과, 두검체모두에서 1% 미만으로급격히감소된소견을확인할수있었다. 요약 원인불명열의원인질환중류마티스질환이가장흔하며, 그중성인형스틸병은매우드문원인미상의전신염증성질환이다. 발열, 발진및관절염, 백혈구증가등의매우다양한증상및징후를보이지만질병특이적인양상은없다. 종양, 감염, 염증성질환등을배제해야진단이가능하기때문에진단및치료시기가지연될때가많다. 성인형스틸병환자에서혈청페리틴수치의증가가흔하게관찰되므로혈청페리틴검사는성인형스틸병을진단하는데중요한검사이다. 또한당화페리틴비율의감소가성인형스틸병환자에서특징적으로관찰되므로두검사를동시에실시하면성인형스틸병의감별진단에도움을받을수있다. 저자들은높은혈청페리틴수치와당화페리틴비율감소소견을보인 AOSD증례 1례를관찰하였기에이를보고하는바이다. 참고문헌 1. Cunha BA, Durie N, Selbs E, Pherez F. Fever of unknown origin (FUO) due to Rosai-Dorfman disease with mediastinal adenopathy mimicking lymphoma: diagnostic importance of elevated serum ferritin levels and polyclonal gammopathy. Heart Lung 2009;38:83-8. 2. Zenone T. Fever of unknown origin in rheumatic diseases. Infect Dis Clin North Am 2007;21:1115-35, x-xi. 3. Fautrel B. Adult-onset Still disease. Best Pract Res Clin Rheumatol 2008; 22:773-92. 4. Efthimiou P, Paik PK, Bielory L. Diagnosis and management of adult onset Still s disease. Ann Rheum Dis 2006;65:564-72. 5. Yamaguchi M, Ohta A, Tsunematsu T, Kasukawa R, Mizushima Y, Kashiwagi H, et al. Preliminary criteria for classification of adult Still s disease. J Rheumatol 1992;19:424-30. 6. Masson C, Le Loet X, Liote F, Dubost JJ, Boissier MC, Perroux-Goumy L, et al. Comparative study of 6 types of criteria in adult Still s disease. J Rheumatol 1996;23:495-7. 7. Ramirez C, Rubio C, Fernandez de la Puebla RA, Aguilera C, Espejo I, Fuentes F. Clinical significance of increased serum ferritin levels. Medicina Clinica 2004;122:532-4. 8. Akritidis N, Giannakakis Y, Sakkas L. Very high serum ferritin levels in adult-onset Still s disease. Br J Rheumatol 1997;36:608-9. www.labmedonline.org 43
9. Ota T, Higashi S, Suzuki H, Eto S. Increased serum ferritin levels in adult Still s disease. Lancet 1987;1:562-3. 10. Van Reeth C, Le Moel G, Lasne Y, Revenant MC, Agneray J, Kahn MF, et al. Serum ferritin and isoferritins are tools for diagnosis of active adult Still s disease. J Rheumatol 1994;21:890-5. 11. Worwood M, Cragg SJ, Wagstaff M, Jacobs A. Binding of human serum ferritin to concanavalin A. Clin Sci (Lond) 1979;56:83-7. 12. Knockaert DC. Recurrent fevers of unknown origin. Infect Dis Clin North Am 2007;21:1189-211, xi. 13. Chen DY, Lan JL, Lin FJ, Hsieh TY. Proinflammatory cytokine profiles in sera and pathological tissues of patients with active untreated adult onset Still s disease. J Rheumatol 2004;31:2189-98. 14. Lee MH and Means RT Jr. Extremely elevated serum ferritin levels in a university hospital: associated diseases and clinical significance. Am J Med 1995;98:566-71. 15. Meijvis SC, Endeman H, Geers AB, ter Borg EJ. Extremely high serum ferritin levels as diagnostic tool in adult-onset Still s disease. Neth J Med 2007;65:212-4. 16. Hamidou MA, Denis M, Barbarot S, Boutoille D, Belizna C, Le Moel G. Usefulness of glycosylated ferritin in atypical presentations of adult onset Still s disease. Ann Rheum Dis 2004;63:605. 17. Fautrel B, Le Moel G, Saint-Marcoux B, Taupin P, Vignes S, Rozenberg S, et al. Diagnostic value of ferritin and glycosylated ferritin in adult onset Still s disease. J Rheumatol 2001;28:322-9. 18. Hong AR, Song CH, Lee J, Ma KA, Park CS, Lee CH, et al. Clinical Study on Adult Onset Still s Disease: Analysis in 15 Cases. J Korean Rheum Assoc 1997;4:60-9. 19. Lee EB and Song YW. Clinical analysis of adult onset still s disease: 22 cases in Korea. J Korean Rheum Assoc 1995;2:52-9. 20. Cho KS, Yoo DH, Yun HR, Lee MH, Lee JK, Shim SC, et al. Adult onset Still s disease: clinical features and prognostic factors in Korea. J Korean Rheum Assoc 1998;5:64-75. 21. Yang YS, Shin MK, Hong SJ, Lee YA, Lee MH. Clinical study on adult onset Still s disease. Korean Journal of Dermatology 2010;45:388-94. 22. Rogers JT, Bridges KR, Durmowicz GP, Glass J, Auron PE, Munro HN. Translational control during the acute phase response. Ferritin synthesis in response to interleukin-1. J Biol Chem 1990;265:14572-8. 23. Mehta B and Efthimiou P. Ferritin in adult-onset Still s disease: just a useful innocent bystander? International Journal of Inflammation 2012; 2012:298405. 24. Fautrel B. Ferritin levels in adult Still s disease: any sugar? Joint Bone Spine 2002;69:355-7. 44 www.labmedonline.org