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1 Korean J Hematol Vol. 42, No. 1, March, 2007 Case Report 급성 A 형간염과동반된혈구포식증후군 1 예 : 문헌고찰 부산대학교병원내과학교실, 1 진단검사의학교실 이혜정 정주섭 신호진 최영진 박영은 김표준 김일두 이은엽 1 조군제 A Case of Hemophagocytic Lymphohistiocytosis Accompanied by Acute Hepatitis A: Review of the Literature Hye-Jeong Lee, M.D., Joo Seop Chung, M.D., Ho-Jin Shin, M.D., Young Jin Choi, M.D., Young-Eun Park, M.D., Pyo-Jun Kim, M.D., Il-Doo Kim, M.D., Eun-Yup Lee, M.D. 1 and Goon Jae Cho, M.D. Departments of Internal Medicine, 1 Pathology, College of Medicine, Pusan National University Hospital, Busan, Korea A previously healthy 26-year-old female was referred to our hospital because of fever and abnormalities of her blood biochemistry. Her laboratory results displayed leukopenia ( /μl), thrombocytopenia ( /μl), the serum aspartate aminotransferase and alanine aminotransferase levels were elevated to more than 2,000 IU/L, and the serum levels of lactate dehydrogenase and ferritin were markedly increased. Mild hepatosplenomegaly was reported on the abdomen-pelvis computed tomography. The bone marrow smears revealed proliferation of mature histiocytes that were ingesting platelets and erythrocytes, which is consistent with hemophagocytic lymphohistiocytosis. Although the other viral markers were all negative, the anti-hepatitis A IgM was positive and the anti-hepatitis A IgG was negative. Therefore, the patient was diagnosed as hepatitis A-associated hemophagocytic lymphohistiocytosis. Since a fulminant clinical course was suspected, 2 cycles of cyclosporine (3mg/kg iv from day 1 to day 5), dexamethasone (30mg iv qd from day1 to day 4) and immunoglobulin (500mg/kg iv day 1) therapy was started from the seventh day after onset and a favorable clinical outcome resulted. (Korean J Hematol 2007;42:62-66.) Key Words: Hemophagocytic lymphohistiocytosis, Acute hepatitis A, Thrombocytopenia 서 혈구포식증후군은조직구의증식과활성화로인해골수에서혈구포식을보이는질환으로임상양상은고열, 간비종대, 범혈구감소증, 저섬유소원혈증과고중성지방혈증등이며경과가급격히진행하여불량한예후를보이는경우가많다. 1) 기저질환은다양하게보고되는데바이러스감염, 결핵을포함한세균감염, 접수 :2006 년 12 월 1 일, 수정 :2006 년 12 월 19 일승인 :2007 년 1 월 2 일교신저자 : 신호진, 부산시서구아미동 1 가 , 부산대학교병원내과 Tel: , Fax: hojinja@hanmail.net 론 진균감염, 자가면역질환과림프종과같은악성질환등이있다. 2,3) 바이러스와관련된혈구포식증후군의경우일반적으로엡스타인-바바이러스와동반하여발생한증례가많이보고되고있지만기타다른바이러스 - 거대세포바이러스, 뎅기바이러스, 단순포진바이러스, 파르보바이러스 B19, 아데노바이러스 type 11, 홍역, 콕사키바이러스 A9, 풍진, 인플루엔자 A, 수두와사람면역결핍바이러스또한혈구포식증후군을유발함이보고된바있다. 4) 하지만 A형간염바이러스와동반한 Correspondence to:ho-jin Shin, M.D. Department of Internal Medicine, College of Medicine, Pusan National University Hospital 10, Ami-dong 1-ga, Seo-gu, Busan , Korea Tel: , Fax: hojinja@hanmail.net 62

2 이혜정외 : 급성 A 형간염과동반된혈구포식증후군 1 예 : 문헌고찰 63 혈구포식증후군의보고는매우드물어지금까지 9증례가보고되어있다. 1) 이에저자들은 A형간염바이러스에동반된혈구포식증후군 1예를경험하였기에보고하는바이다. 증례환자 : 26세, 여자주소 : 고열, 혈구감소증현병력 : 2005년 12월15일발생한 39 o C의고열과오한을주소로개인병원방문후시행한혈액검사에서호중성백혈구감소증이있어부산대학교병원응급실을방문하였다. 이학적소견 : 내원당시혈압 100/60mmHg, 맥박분당 68회, 호흡수분당 20회, 체온 38 o C였으며, 의식은명료하였고지남력장애는관찰되지않았다. 외견에서 급성병색을보였으나황달은관찰되지않았으며, 경정맥의돌출이나림프절비대는관찰되지않았다. 흉부청진에서심잡음은청진되지않았고, 양폐야에수포음은들리지않았다. 복부진찰에서정상적인장음과함께간과비장은만져지지않았으며경직이나압통도관찰되지않았다. 상하지진찰에서부종이없었고움직임의장애는관찰되지않았다. 검사실소견 : 내원당시백혈구감소증 ( /μ L, 호중성구 12.2%), 혈소판감소증 ( /μl) 과함께 AST/ALT 3,119/2,456IU/L, LDH 3,260IU/L, ferritin 1,209ng/mL으로상승소견, D-dimer 1.01μg/dL, PT (INR) 14.9초 (1.19) 로경미한상승소견을보였으며 fibrinogen 160mg/dL로감소소견, triglyceride 74mg/ dl로정상수치를보였다. 혈청검사에서 A형간염항체 IgM 양성, IgG 음성소견을보였으며 B형간염, C형간염, 엡스타인-바바이 Table 1. Laboratory data Normal ranges and units Hematology Serology WBC 4.0~ /μl 1.79 HBsAg - RBC 3.75~ /μl 4.31 HBsAb + Hb 12.5~15.0g/dL 12.2 HBeAg - PLT 140~ /μl 85 HBeAb - Coagulation HBcAb IgM - PT 11.0~14.1 sec 14.9 HCV Ab - aptt 30~44 sec 38.4 HAV Ab IgM + Fibrinogen 200~400mg/dL 160 HAV Ab IgG - D-dimer 0.06~0.5μg/mL 1.04 EBV DNA - Serum chemistry EBV DNA in BM - Total bilirubin 0.3~1.3mg/dL 2.02 EBV anti-ea-dr IgA - Direct bilirubin 0.05~0.4mg/dL 1.37 EBV anti-ea-dr IgG + AST 10~40IU/L 3,119 EBV anti-ea-dr IgM - ALT 6~40IU/L 2,456 EBV anti-ebna IgG + LDH 218~472IU/L 3,260 EBV anti-ebna IgM - ALP 95~280IU/L 375 EBV anti-vca IgA - GTP 11~73IU/L 167 EBV anti-vca IgG + Total cholesterol 180~210mg/dL 142 EBV anti-vca IgM - TG 37~144mg/dL 74 HSV IgG + HDL 35~72mg/dL 30 HSV IgM - Ferritin 6~282ng/mL 1,209 CMV PCR - CRP 0~0.5mg/dL 0.27 Anti-HIV Ab - Abbreviations: WBC, white blood cell; Hb, hemoglobin; PLT, platelet; PT, prothrombin time; aptt, activated partial thromboplatin time; AST, aspartate aminotransferase; ALT, alanine aminotranferase; LDH, lactate dehydrogenase; ALP, alkaline phosphatase; GTP, glutamyl transpeptidase; TG, triglyceride; HDL, high-density lipoprotein; CRP, C-reactive protein; HCV, hepatitis C virus; HAV, hepatitis A virus; EBV, Ebstein-barr virus; HSV, herpes simplex virus; CMV, cytomegalovirus; HIV, human immunodeficiency virus.

3 64 Korean J Hematol Vol. 42, No. 1, March, 2007 러스, 거대세포바이러스, 단순포진바이러스, 사람면역결핍바이러스에대한검사는모두음성소견을보였다 (Table 1). 과거력 : 특이소견은없었으며백화점직원으로애완견을키우고있었고지속적으로복용하고있는약은없었으며한약복용력도없었다. 방사선학적소견 : 복부전산화단층촬영에서간비장종대가있었고그외다른이상소견은보이지않았다 (Fig. 1). 병리조직학적소견 : 골수조직검사에서경도의세포충실도감소와함께비정형림프구와혈구포식조직구가관찰되었다 (Fig. 2). 경과 : 환자는입원후발열징후를보이지않았으며 Fig. 1. Abdomen-pelvis computed tomography shows splenomegaly, mild hepatomegaly and periportal low density in liver. Collapsed gallbladder with wall thickening and fluid collection in pelvic cavity are also detected. cyclosporine (3mg/kg day 1~5), dexamethasone (30mg intravenously day 1~4), Immunoglobulin (500mg/kg day 1) 시행받았으며 2주후두번째주기치료시행후특별한부작용없이혈구감소증및 LDH의정상화를보이며전반적으로상태가호전되어입원 23일째퇴원하였다. 2006년 1월 17일외래방문당시특별한부작용이발견되지않았으며현재까지혈액검사에서정상혈구수치를보이고있다. 고 본증례는혈구탐식증후군의원인으로 A형간염항체 IgM 양성이증명된경우이다. 바이러스감염과관련된양성반응성조직구증은 1979년 Risdall 등 5) 에의해 virus-associated hemophagocytic syndrome으로처음보고되었다. 이후바이러스감염과연관된혈구탐식증후군의증례들이많이보고되고있는데가장흔하게보고된것은포진바이러스인거대세포바이러스나엡스타인-바바이러스에의한것이다. 5,6) 혈구탐식증후군의진단기준은 1) 7일이상지속되는고열 (>38.5 o C), 2) 말초혈액혈구감소증 ( 혈색소 <9.0g/dL, 혈소판 < /μl, 절대호중구수 < /μl 중 2가지이상 ), 3) 비장비대, 4) 고중성지방증또는저섬유소원증 ( 공복중성지방 >200mg/dL 또는연령보정 3표준편차이상, 또는섬유소원 <1.5g/L 또는연령보정 3표준편차미만 ), 5) 골수, 비장, 림프절에서의혈구포식구증의주진단기준 5가지와 1) natural killer cell 활성도의저하또는부재, 2) 고 ferritin증 (> 500mg/mL), 3) soluble CD25 (soluble interleukin-2 re- 찰 Fig. 2. Bone marrow aspiration showing hemophagocytosis of megakaryocyte (A), and red blood cells (B) (Wright-Giemsa stain, 400).

4 이혜정외 : 급성 A 형간염과동반된혈구포식증후군 1 예 : 문헌고찰 65 Table 2. Case reports of hepatitis A virus associated hemophagocytic lymphohistiocytosis Case Year Age/ Underlying Treatment sil-2r (U/mL) Outcome Sex diseas Watanabe et al (9) /F None Unknown Recovered McPeake et al (10) /F Steroid pulse Unknown Recovered Still s disease Kondo and Date et al (11) /F Steroid pulse, rhg-csf 2,080 Recovered Wu et al (12) /M Steroid pulse Unknown Died HCV carrier Kyoda et al (13) /M None Unknown Recovered Watanabe et al (9) /M HDF, steroid pulse, combination chemotherapy* Unknown Died Onaga et al (8) /F Steoid pulse 1,920 Recovered Watanabe et al (9) /M None 4,870 Recovered /M None 2,590 Recovered HCV carrier Present patient /F Combination chemotherapy Unknown Recovered Abbreviations: rhg-csf, recombinant human granulocyte colony stimulating factor; HDF, hemo-diafiltration; HCV, hepatitis C virus; sil-2r, soluble interleukine-2-receptor. *Combination chemotherapy, cyclophosphamide, vincristine and prednisolone; Combination chemotherapy, cyclophosphamide, prednisolone and immunoglobulin. ceptor) >2,400U/mL의부진단기준 3가지중주진단기준모두만족시진단가능하고 4개의주진단기준과부진단기준중한가지이상동반시진단가능하다. 4) 본환자의경우진단기준중 7일이상지속된고혈, 말초혈액의세포감소증 ( 호중구감소증, 혈소판감소증 ), 비장비대, 저섬유소원증, 골수의혈구포식구증의 5가지주진단기준을모두만족하고고 ferritin증이동반되어있다. 일반적으로혈구포식증후군의경우치명률 20~ 40% 의전격성임상경과를보인다. 특히파종혈관내응고동반시더욱심한경과를보일수있다. 6) 혈구포식증후군에서가장흔한임상양상이간기능장애이고심한경우파종혈관내응고를동반한다발성장기부전이발생할수있지만전격성간부전증에서도파종혈관내응고를포함한다발성장기부전이발생할수있으므로전격성간부전증와간염바이러스관련혈구포식증후군사이의감별은주의깊게이루어져야한다. 바이러스간염에서도혈소판감소증이발생하지만그발생기전은불명확하다. 파종혈관내응고와관련된혈소판소모의증가와골수에서의생성감소, 비장비대, 바이러스-혈소판상호작용에의한혈소판파괴와자가면역기전등과관련이있을것으로생각된다. 7) /μl 이하의혈소판감소증은일반적으로급성간염발생 1~2주사이에약 19% 정도에서발생한다. 4) 본증례의경우혈소판감소증이질병발생 5일째발생하였고응고증가에대한증거보다는섬유용해증가의 증거가우세하였으므로파종혈관내응고보다는혈구포식증자체에의해발생한것으로생각된다. 여러바이러스에의한혈구포식증후군들이보고되고있지만급성 A형간염에의한혈구포식증후군은본증례를포함하여 10증례가보고되고있다 (Table 2). 1,8-13) 10명중 2명의환자 (20%) 는파종혈관내응고또는다발성장기부전으로사망하였고 4명 (40%) 은특별한치료없이회복되었다. 자연회복에서사망에이르기까지다양한예후를보이는것은급성 A형간염과동반한혈구포식증후군에서예후와관련된위험인자를밝히는것이중요하다는것을의미하지만현재까지급성 A형간염과동반된혈구포식증후군의임상적양상자체가잘알려져있지않다. C형간염바이러스감염이동반되었던두증례에서도 C형간염바이러스와의동반감염이증상의악화및예후불량을야기했을것으로추정할수있지만아직까지명확히증명된바는없다. 혈구포식증후군의발생기전은정확하게알려지지않았다. 하지만최근의여러연구에따르면혈구포식증후군은바이러스감염에의해 T세포가활성화되고이에따라정상적인조직구의증식과활성이유발되어발생하는 T세포에의한질환으로생각되고있다. T세포와조직구가활성화되면 interleukine-1 (IL-1), tumor necrosis factor (TNF), IL-6, interferon-γ, soluble interleukine-2-receptor (sil-2r) 등의염증성사이토카인의분비가증가된다. 14) 급성바이러스성간염에서도 IL-1, IL-6, TNF의혈중농도가증가되고혈구포식증후군시

5 66 Korean J Hematol Vol. 42, No. 1, March, 2007 의간독성발생에도주요한역할을하는것으로알려져있다. 여러증례에서도 sil-2r의증가가보고되고있으며 Imashuku 등 15) 은 sil-2r의혈중농도가혈구포식증후군의예후인자라고주장하고있다. 하지만본증례에서사이토카인농도의측정은시행되지않아아쉬운점이있다. 혈구포식증후군의표준치료는아직정립되어있지않다. 제시되고있는발병기전을생각해볼때 T세포억제약물을고려해볼수있으며실제고용량스테로이드요법으로치료에성공한증례가보고되어있다. 8) Carcinostatic agent인 vincristine, etoposide, cyclosporine 또한 steroid와함께투여가능하다. 혈장교환술과혈액투석여과또한사이토카인제거에효과적이다. 하지만특별한치료없이도회복한증례가있어좀더다양한증례에대한연구가필요할것으로생각된다. 요 본증례에서보고된바와같이간기능수치의현저한증가를동반한혈구포식증후군의진단시다른바이러스감염의가능성과함께급성 A형간염바이러스감염의가능성을항상염두에두어초기검사에 A형간염바이러스에대한항목을포함시킴으로써원인바이러스의조기발견과이에대한명확한치료법과예후의정립이필요할것이다. 약 참고문헌 1) Watanabe M, Shibuya A, Okuno J, Maeda T, Tamama S, Saigenji K. Hepatitis A virus infection associated with heamophagocytic syndrome: report of two cases. Intern Med 2002;41: ) Ezdinli EZ, Kucuk O, Chedid A, et al. Hypogammaglobulinemia and hemophagocytic syndrome associated with lymphoproliferative disorders. Cancer 1986;57: ) Shimazaki C, Inaba T, Nakagawa M. B-cell lymphomaassociated hemophagocytic syndrome. Leuk Lymphoma 2000;38: ) Imashuku S. Differential diagnosis of hemophagocytic syndrome: underlying disorders and selection of the most effective treatment. Int J Hematol 1997;66: ) Risdall RJ, McKenna RW, Nesbit ME, et al. Virusassociated hemophagocytic syndrome: a benign histiocytic proliferation distinct from malignant histiocytosis. Cancer 1979;44: ) Mckenna RW, Risdall RJ, Brunning RD. Virus associated hemophagocytic syndrome. Hum Pathol 1981;12: ) Domenech P, Palomeque A, Martinez-Gutierrez A, Vinolas N, Vela E, Jimenez R. Severe aplastic anaemia following hepatitis A. Acta Haematol 1986;76: ) Onaga M, Hayashi K, Nishimagi T, et al. A cause of acute hepatitis A with marked hemophagocytosis in bone marrow. Hepatol Res 2000;17: ) Watanabe M, Shibuya A, Okuno J, Maeda T, Tamama S, Saigenji K. Hepatitis A virus infection associated with hemophagocytic syndrome: report of two cases. Intern Med 2002;41: ) McPeake JR, Hirst WJ, Brind AM, Williams R. Hepatitis A causing a second episode of virusassociated haemophagocytic lymphohistiocytosis in a patient with Still's disease. J Med Virol 1993;39: ) Kondo H, Date Y. Effects of simultaneous rhg-csf and methylprednisolone pulse therapy on hepatitis A virus-associated haemophagocytic syndrome. Eur J Haematol 1995;54: ) Wu CS, Chang KY, Dunn P, Lo TH. Acute hepatitis A with coexistent hepatitis C virus infection presenting as a virus-associated hemophagocytic syndrome: a case report. Am J Gastroenterol 1995;90: ) Kyoda K, Nakamura S, Machi T, Kitagawa S, Ohtake S, Matsuda T. Acute hepatitis A virus infectionassociated hemophagocytic syndrome. Am J Gastroenterol 1998;93: ) Ishii E, Ohga S, Aoki T, et al. Prognosis of children with virus-associated hemophagocytic syndrome and malignant histiocytosis: correlation with levels of serum interleukin-1 and tumor necrosis factor. Acta Haematol 1991;85: ) Imashuku S, Hibi S, Sako M, et al. Soluble interleukin-2 receptor: a useful prognostic factor for patients with hemophagocytic lymphohistiocytosis. Blood 1995;86:

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