http://dx.doi.org/10.7180/kmj.2014.29.2.161 K MJ Case Report A Case of Reactivation of Hepatitis B and Fulminant Hepatitis which developed 3 months following Chemotherapy Including Rituximab in a Patient with Lymphoma Tae Won Lim, 1 Hee Taek Oh, 1 Seung Un Song, 1 Hae Won Lee, 1 Ji Yeon Kim, 1 Seon Ja Park 2 1 Department of Gastroenterology, Dae-Dong Hospital, Busan, Korea 2 Department of International Medicine, College of Medicine, Kosin University, Busan, Korea 림프종환자에서 Rituximab 을포함하는항암화학요법종료 3 개월후발생한 B 형간염의재활성화및전격성간부전 1 예 임태원, 1 오희택, 1 송승언, 1 이혜원, 1 김지연, 1 박선자 2 1 대동병원소화기내과 2 고신대학교의과대학내과학교실 Since Wands et al. reported for the first time in 1975 the reactivation of the hepatitis B virus in hematologic disease patients who had been receiving chemotherapy, the efficacy of chemotherapy and immunosuppressants has improved. As a result, the frequency of the reactivation of hepatitis B is increasing. Reported herein is a case of a non-hodgkin lymphoma patient in her 70s who was suspected to have had HBsAg negative/anti-hbs negative occult HBV infection. The patient experienced fulminant hepatitis caused by the reactivation of hepatitis B, and died three months after the R-CHOP regimen was completed. In the HBsAg negative plus HBV DNA-negative case, there were few instances of viral activation of HBV. In this case, antiviral therapy was needed when the patient was confirmed to have become HBV DNA positive through regular monitoring, but its necessity is often overlooked, unlike the preemptive antiviral treatment in the HBsAg positive cases. Key Words: Chemotherapy, Hepatitis B virus, Immunosuppression B형간염바이러스 (hepatitis B virus, HBV) 의재활성화는 1975 년 Wands 등에의해항암화학요법을받는혈액질환환자에서처음으로보고되었으며현재까지여러임상사례들을통해알려져있다. 1,2 B형간염바이러스에감염된후회복기를지나면수개월이내에 B형간염바이러스표면항원 (HBsAg) 이소실되고중화 항체인 B형간염바이러스표면항원에대한항체 (anti-hbs) 및면역글로불린 G형의 Hepatitis B core antigen 에대한항체 (anti-hbc) 가생성된다. 3 그러나 B형간염바이러스감염에서회복되어혈액내에 B형간염바이러스가소실되었더라도간조직내에낮은수준의 B형간염바이러스는여전히존재함이알려져있다. 3,4 이처럼 HBsAg 음성인환자의혈액에서 HBV DNA 유무와상관없이간조직에서 HBV DNA Corresponding Author : Tae Won Lim, Department of Internal Medicine, Dae-Dong Hospital, 187, Chungyeldae-ro, Dongrae-gu, Busan, 607-711, Korea TEL: +82-51-550-9615 FAX: +82-51-553-7575 E-mail: twoni@hanmail.net Received : December 27, 2013 Revised : December 27, 2013 Accepted : February 14, 2014 161
가검출되는경우를 B형간염바이러스의잠재감염 (occult HBV infection) 이라하며, 면역체계가바이러스를제압하고있는상태를의미한다. 5 따라서이러한경우바이러스가증식력이없는상태라할지라도항암화학요법, 장기간의스테로이드사용등환자의면역이약화되는경우에는 B형간염바이러스가증식성을얻어재활성화에따른간염이발생할수있다. 재활성간염은이전에는혈액질환에서강력한세포독성약제를사용하는항암화학요법후발생한사례가대부분이었으나, 최근에는장기이식이활발해지면서면역억제제를장기간투여하는경우가많아지고항암제및면역억제제의효능이보다향상되고강력해지면서혈액질환뿐만아니라유방암, 간암, 폐암및류마티스질환등을치료하는환자군에서도재활성간염의빈도가증가하는추세에있다. 1,2 우리나라는 B형간염바이러스유병률이다른 OECD 국가들과비교했을때높아이러한재활성간염의발생위험도상대적으로크기때문에종양환자를진단하고치료를할때더욱충분한주의를기울일필요가있다. 저자들은 71 세인 HBsAg 음성 /anti-hbs 음성인비호지킨림프종환자에서 R-CHOP regimen 을통한치료종료 3개월후 B형간염재활성화및전격성간염으로인한사망사례를경험하였기에문헌고찰과함께보고하는바이다. 증례보고 환자 : 김OO, 71 세, 여자, 155 cm, 63 kg 주소 : 4일전부터발생한황달, 식욕부진, 전신권태감현병력 : 상기증상으로본원내원하였으며신체진찰소견에서맥박분당 88 회, 호흡분당 17 회, 혈압 114/83 mmhg 로정상이었으며의식은명료하였다. 흉부검진에서이상소견 은없었으며, 복부검진에서도장음은정상이었고, 압통및반발통도없었다. 혈액검사소견에서아스파테이트아미노전이효소 (aspatate aminotransterase, AST), 알라닌아미노전이효소 (alanine aminotransferase, ALT) 를비롯한간기능검사수치들이전반적으로크게상승한것으로확인되어복부전산화단층촬영을시행하였다. 복부전산화단층촬영에서간경변증이나간종양을시사하는소견은관찰되지않았고담관의폐쇄나말초담관의확장소견도관찰되지않았으며담낭의벽은두꺼워져있어간염에의한이차적인변화로추정되었다 (Fig. 1). 환자는 8개월전좌측경부종물을주소로본원이비인후과외래내원하여시행한경부전산화단층촬영에서림프종으로추정 (Fig. 2) 되어상급병원으로전원후경부림프절절제생검상미만성거대 B세포림프종 (Diffuse Large B Cell Lymphoma)(Fig. 3) IIIA 병기로진단받고각주기별로 anti- CD20 단클론항체인 rituximab 900mg 과 Cyclophosphamide 1800mg, Adriamycin 120mg, Vincristine 2mg, Prednisone 100mg 을병합투여하는항암화학요법 (R-CHOP) 을 6주기에걸쳐 3개월전에완료한후완전관해된과거력이있었으며이후 3개월간 R-CHOP 치료를시행한병원에서추적관찰없이집에서지내온상태였다. 40년전만성 B형간염을진단받았다하였으나추적관찰없이지내왔으며, R-CHOP 치료를시행하는동안에도항바이러스제는투여받지않았다. 고혈압, 당뇨병, 결핵및기타호흡기질환등의과거력은없었고수술, 수혈, 침시술을받은병력도없었으며한약재나건강보조식품등의약물복용력또한없었다. 검사실소견 : 일반혈액검사에서백혈구 3,270 /mm 3 ( 호중구 66.9%, 림프구 16.5%, 호산구 2.5%), 혈색소 12.0 g/dl, 헤마토크리트 36.7%, 혈소판 89,000 /mm 3, 프로트롬빈시간 35.6 초 (24%), INR 3.198 였고혈액화학검사에서혈청 AST 2461 IU/L, ALT 2329 IU/L, 알부민 2.9 g/dl, 총빌리루빈 15.0 mg/dl, 직접빌리루빈 9.09 mg/dl, 감마글루타밀전이효소 (gamma glutamyl transpeptidase, gamma GTP) 166 162
A Case of Reactivation of Hepatitis B and Fulminant Hepatitis which developed 3 months following Chemotherapy Including Rituximab in a Patient with Lymphoma Figure 1A Figure 1B Figure 2 Figure 3 IU/L, 알칼리성인산분해효소 (alkaline phosphatase, ALP) 570 IU/L, 혈액요소질소 7.8 mg/dl, 크레아티닌 0.4 mg/dl 였으며그밖에암모니아, 전해질등은정상소견을보였다. 8개월전본원효소면역검사에서 HBsAg 음성 (0.16 IU/mL), anti-hbs 음성 (3.1 IU/mL), Hepatitis C virus 에대한항체 (anti-hcv) 음성이었으며 IgM anti-hbc, IgG anti-hbc 검사는시행하지않았다. 입원후급성간염의원인감별을위하여간염바이러스표지자검사를다시시행하였고그결과 HBsAg 양성 (>1000 IU/mL), anti-hbs 음성 (3.1 IU/mL) IgM anti-hbc 음성, IgG anti-hbc 양성, HBeAg 음성, anti-hbe 음성, anti-hcv 음성, hepatitis A virus 에대한 IgM 형항체음성, HBV DNA 481,000,000 copies/ml 였다 (Table. 1). 치료및임상경과 : IgG anti-hbc 에대한 R-CHOP 치료전검사결과가없기는하나과거감염후잠재감염상태였던 HBV 의 R-CHOP 치료와연관된재활성화에의한간염의가능성이매우높다고판단하여, Ursodeoxycholic acid(600 mg/day) 등보존적치료와함께경구항바이러스제인 Entecavir 0.5mg 1일 1회투여를시작하였다. 다음날환자가 R-CHOP 치료를시행한대학병원에서치료받기원하여전 163
원하였고, 전원후 AST, ALT 는점차호전보였으나황달은점점심해지면서혈청빌리루빈은지속적으로상승하고프로트롬빈시간연장이계속되었고전원 6일째혈청암모니아가 269 로상승하면서간성혼수발생등 (Table. 2) 간부전으로진행하여간이식을준비하던중사망하였다. 최종적으로 R-CHOP 치료를시행한병원에서항암요법전 HBsAg, anti-hbs 는검사하였으나 IgG anti-hbc 에대한선별조사는누락되었던것으로확인되었다. 고찰 만성 B형간염의활성은바이러스와숙주면역능간의상호작용에의해결정되므로항암- 면역치료시숙주의면역능이저하되어 B형간염재활성이발생할수있다. 6-9 HBsAg 양성인종양환자의항암- 면역치료중발생하는 B형간염재활성화비율은약 20-50% 로알려져있으며, 2,7 많은경우무증상이지만이중 5-30% 는황달, 복수및위장관출혈등의간부전증세를보이고심한경우사망까지이르기도하는등다양한경과를보인다. 2,8-10 B형간염재활성은시기별로볼때에는항암화학요법첫번째주기에서발생하는경우보다 2-4 회주기에서발생하는경우가흔하다. 2,10-12 그리고치료전 HBV DNA 수치와무관하게항암- 면역치료종료후 36개월까지도 HBV 재활성화가보고되고있다. 본증례에서는치료종료 3개월후에 B형간염재활성이발생하였다. 혈청학적상태에따라서는 HBsAg 양성인경우가 HBsAg 음성인경우보다재활성간염의빈도가높지만, 전격성간염의빈도는 HBsAg 음성인환자의재활성간염에서더높은경향이있으며, 2,6 본증례도전격성간염의형태로재활성간염이심각한임상경과를보였다. B형간염재활성의진단은 HBsAg 항원양성인경우항암- 면역치료전에비해 B형간염바이러스농도 (HBV DNA) 가 10배이상혹은 10 8 IU/mL 또는 10 5 copies/ml 이상으로상승된경우에진단할수있다. 2,7,10,13,14 HBsAg 음성인경우의재활성은이전에 B형간염을앓고회복된후또는잠재감염의상태로있다가종양치료에의해바이러스재활성이나 164
A Case of Reactivation of Hepatitis B and Fulminant Hepatitis which developed 3 months following Chemotherapy Including Rituximab in a Patient with Lymphoma 타나는경우가많으며, 치료중혈액내 HBsAg 이재출현하거나, 예민한검사법으로 HBV DNA 가재검출되는경우로정의한다. 2,15 바이러스가재활성되었다고해서모든경우에간염이발생하지는않으며항암- 면역치료의종류, 바이러스증식상태에따라다양하지만보통치료의강도가강할수록, 숙주의면역억제정도가심할수록간효소수치가더상승하고간염도심하게나타난다. 재활성간염은 ALT 수치가정상상한치의 3배이상혹은상승폭이 100 IU/L 이상인것으로정의한다. 2,7,12,14,16,17 본증례에서 R-CHOP 치료에포함하여사용된 rituximab 은 B세포에위치한 CD20 항원과특이적으로결합, 세포성면역에직접적으로작용하여 B세포의증식을억제하고거의완전한수준으로결핍시키는강력한약제로최근 B세포림프종, 류마티스질환등에사용되고있는대표적인표적치료제이다. 최근연구에서는 rituximab 의면역억제효과가 6개월에서 12 개월까지지속되며 rituximab 으로치료를 한경우 HBV 잠재감염환자에서치료종료후수년까지재활성화가보고되고있다. 2,5,7,8,13 rituximab 뿐만아니라본증례의 R-CHOP 치료에포함하여사용된 predisone 을비롯한모든약제가 B형간염재활성에영향을미칠수있으나, 18,19 rituximab 의강력한면역억제작용과 B형간염재활성에대해잘알려져있고 B형간염재활성의빈도는 CHOP 치료단독시행군보다 R-CHOP 치료를시행한군에서더욱높은것으로보고된바있어 20 rituximab 에비해스테로이드를비롯한타약제들의 B형간염재활성에대한기여는현저히낮은것으로보인다. HBsAg 양성인경우에비해 HBsAg 음성인경우항암- 면역치료시재활성간염의빈도가낮기는하나본증례와같이 HBsAg 음성환자에서 rituximab 의사용후발생한 B형간염재활성에대해서도학계에보고가되고있다 (Table. 3). 하지만 B형간염재활성이급성간염으로진행하기전에항바이러스제를투여하여임상경과가호전된경우가많으며본증례와같이 B형간염재활성과더불어전격성간염으로사망까지한경우는드물다. 165
일반적으로 HBsAg, Anti-HBs 검사는 B형간염바이러스의선별검사목적으로널리시행되고있으나 B형간염바이러스를진단하는데한계가있으며, B형간염바이러스의유병률이높은국내실정을감안할때혈액내 IgG anti-hbc, 조직내 HBcAg 조직염색및조직내 HBV DNA 등을확인하지않으면 B형간염바이러스의잠재감염까지완전히배제할수없다. 따라서병력청취에소홀하거나환자가이전 B형간염병력을잘기억을못하는경우 HBsAg, Anti-HBs 모두음성인환자는실제로는 B형간염병력이있고잠재감염상태임에도 IgG anti-hbc 과같은추가적인혈청학적검사를하지않은채 B형간염감염이없었던것으로오인할수있다. 대개는이런경우임상적으로별다른문제가없으나항암- 면역치료를하는환자들에게있어서는충분한모니터링이되지않게되면서 B형간염바이러스재활성이라는심각한문제를야기할수있다. 우리나라에서도혈액질환등종양환자의항암- 면역치료시선제적항바이러스치료가널리알려져있으며, 대한간학회가이드라인에서도면역억제혹은항암화학요법을받 을예정인환자에서는치료시작전에 HBsAg, IgG anti-hbc 의선별조사를시행하도록권고하고있다. 8,21 HBsAg 양성인경우항암- 면역치료시작과함께선제적항바이러스제치료를시행하고 HBsAg 음성, IgG anti-hbc 양성인경우 HBV DNA 양성이면선제적항바이러스제치료를시행하고, HBV DNA 가음성이면정확한간격이나기간에대한지침은설정되어있지않아논의가필요할것으로보이나 4주간격으로최소 2년이상주기적인모니터링을통해 HBV DNA 가검출될경우치료를고려하여야한다. 2,5,7,8,13,21 그리고 National Comprehensive Cancer Network 의 2014 년비호지킨림프종에대한가이드라인에서최근에는높은역가의 Anti-HBs 를보이지않으면 anti-hbc 양성인경우 HBV DNA 여부에관계없이항바이러스제치료가선호된다고언급하고있다. 22 본증례는 R-CHOP 치료전 IgG anti-hbc 검사를시행하지않았으나간염발생후 IgM anti-hbc 음성, IgG anti-hbc 양성인점으로미루어볼때 B형간염재활성에따른간염일가능성이매우높다고생각되며치료시작전에충분한사전 166
A Case of Reactivation of Hepatitis B and Fulminant Hepatitis which developed 3 months following Chemotherapy Including Rituximab in a Patient with Lymphoma 선별조사를시행하고적응증이된다면선제적항바이러스제치료시행여부를결정했어야한다. 물론치료전 IgG anti-hbc 검사를시행하여양성이라하더라도대한간학회가이드라인에따라 HBV DNA 가음성이라면당장항바이러스제투여가필요하지않고정기적인추적관찰로서도충분했을것이다. 하지만환자는 HBV DNA 의추적관찰에대한교육이되지않아 3개월간의료기관을방문하지않았다. 따라서 B형간염재활성이급성간염으로급격히진행되고나서야뒤늦게항바이러스제를투여하게되었고 HBsAg 음성인 B형간염바이러스의재활성화는전격성간부전등임상양상도더심하게나타나므로사망까지이르게된것으로보인다. 요컨대우리나라 B형간염바이러스의높은유병률을고려할때항암-면역치료시충분한병력청취및 HBsAg, IgG anti-hbc 과같은사전혈청학적검사를철저히시행하여야하겠고, 항암- 면역치료종료후수개월에서수년후까지도 B형간염재활성이나타날수있으므로유의하여야한다. 특히, HBsAg 음성인경우는 HBsAg 양성인경우에비해임상적으로간과되기쉬운부분이므로각별한주의를필요로하고 HBsAg 음성, Anti-HBs 양성, IgG anti-hbc 양성, HBV DNA 음성이라하더라도 HBV DNA 를반드시주기적으로추적하여야 B형간염재활성의진단과치료가늦어져심각한재활성간염이발생하는것을예방할수있으며, HBsAg 음성, Anti-HBs 음성, IgG anti-hbc 양성인경우최근추세에따라 HBV DNA 에관계없이항바이러스제치료를고려하여야한다. 또한 HBV 가있는항암- 면역치료환자에서 B형간염바이러스의재활성화에대한충분한교육을통해 HBV 에대한항바이러스제치료또는추적관찰을임의중단하거나소홀히하는일이없도록해야할것이다. 참고문헌 1. Wands JR, Chura CM, Roll FJ, Maddrey WC. Serial studies of hepatitis-associated antigen and antibody in patients receiving antitumor chemotherapy for myeloproliferative and lymphoproliferative disorders. Gastroenterology 1975;68:105-12. 2. Jang JW. Management of Patients with Hepatitis B Virus Infection Who Receive Immunosuppressive Treatment or Chemotherapy. Korean J Med 2012;82:149-58. 3. Lim SM, Jang JW, Kim BW, Choi H, Choi KY, Park SJ, et al. Hepatitis B virus reactivation during chlorambucil and prednisolone treatment in an HBsAg-negative and anti-hbspositive patient with B-cell chronic lymphocytic leukemia. Korean J Hepatol 2008;14:213-8. 4. Rehermann B, Ferrari C, Pasquinelli C, Chisari FV. The hepatitis B virus persists for decades after patients' recovery from acute viral hepatitis despite active maintenance of a cytotoxic T-lymphocyte response. Nat Med 1996;2:1104-8. 5. Song SH, Hwang SG. Occult hepatitis B virus infection: transmission and reactivation. Korean J Gastroenterol 2013;62:148-53. 6. Kusumoto S, Tanaka Y, Mizokami M, Ueda R. Reactivation of hepatitis B virus following systemic chemotherapy for malignant lymphoma. Int J Hematol 2009;90:13-23. 7. Lee KS, Kim DJ. Korean Association for the Study of the Liver Guideline Committee. Management of Chronic Hepatitis B. Korean J Hepatol 2007;13:447-88. 8. Chung SM, Sohn JH, Kim TY, Yoo KD, Ahn YW, Bae JH, et al. Fulminant hepatic failure with hepatitis B virus reactivation after rituximab treatment in a patient with resolved hepatitis B. Korean J Gastroenterol 2010;55:266-9. 9. Gupta S, Govindarajan S, Fong TL, Redeker AG. Spontaneous reactivation in chronic hepatitis B: patterns and natural history. J Clin Gastroenterol 1990;12:562-8. 10. Yeo W, Johnson PJ. Diagnosis, prevention and management of hepatitis B virus reactivation during anticancer therapy. Hepatology 2006;43:209-20. 11. Park JW, Park KW, Cho SH, Park HS, Lee WJ, Lee DH, et al. Risk of hepatitis B exacerbation is low after transcatheter arterial chemoembolization therapy for patients with HBVrelated hepatocellular carcinoma: report of a prospective study. Am J Gastroenterol 2005;100:2194-200. 12. Jang JW, Choi JY, Bae SH, Yoon SK, Chang UI, Kim CW, 167
et al. A randomized controlled study of preemptive lamivudine in patients receiving transarterial chemo-lipiodolization. Hepatology 2006;43:233-40. 13. Jung HM, Jun DW, Min JY, Doo EY, Nam KW, Kwon YI, et al. A Case of Acute Hepatitis B by Occult HBV Infection without HbsAg Seroconversion. Korean J Med 2012;83:619-23. 14. Lau GK. Hepatitis B reactivation after chemotherapy: two decades of clinical research. Hepatol In 2008;2:152-62. 15. Kusumoto S, Tanaka Y, Ueda R, Mizokami M. Reactivation of hepatitis B virus following rituximab-plus-steroid combination chemotherapy. J Gastroenterol 2011;46:9-16. 16. Lok AS, Liang RH, Chiu EK, Wong KL, Chan TK, Todd D. Reactivation of hepatitis B virus replication in patients receiving cytotoxic therapy. Report of a prospective study. Gastroenterology 1991;100:182-8. 17. Lau GK, Yiu HH, Fong DY, Cheng HC, Au WY, Lai LS, et al. Early is superior to deferred preemptive lamivudine therapy for hepatitis B patients undergoing chemotherapy. Gastroenterology 2003;125:1742-9. 18. Tur-Kaspa R, Burk RD, Shaul Y, Shafritz DA. Hepatitis B virus DNA contains a glucocorticoid-responsive element. Proc Natl Acad Sci USA 1986;83:1627-31. 19. Kawsar HI, Shahnewaz J, Gopalakrishna KV, Spiro TP, Daw HA. Hepatitis B Reactivation in Cancer Patients; Role of Prechemotherapy Screening and Antiviral Prophylaxis. Clin Adv Hematol Oncol 2012;10:370-8. 20. Yeo W, Chan TC, Leung NW, Lam WY, Mo FK, Chu HL, et al. Hepatitis B virus reactivation in lymphoma patients with prior resolved hepatitis B undergoing anticancer therapy with or without rituximab. J Clin Oncol 2009;27:605-11. 21. The Korean Association for the Study of the Liver. Guidelines for Chronic hepatitis B [Internet]. Seoul: The Korean Association for the Study of the Liver; c2011 [cited 2011 Dec01]. Available from: http://www.kasl.org/html/sub05_03_1.asp 22. Andew D. Zelenetz, Leo I. Gordon, William G. Wierda, Jeremy S. Abramson, Ranjana H. Advani, C. Babis Andreadis, et al. NCCN Clinical Practice Guidelines in Oncology: non- Hodgkin's lymphomas. J Natl Compr Canc Netw. Version 1.2014 23. Dervite I, Hober D, Morel P. Acute hepatitis B in a patient with antibodies to hepatitis B surface antigen who was receiving rituximab. N Engl J Med 2001;344:68-9. 24. Sera T, Hiasa Y, Michitaka K, Konshi I, Masuura K, Tokumoto Y, et al. Anti-HBs-positive liver failure due to hepatitis B virus reactivation induced by rituximab. Intern Med 2006;45:721-4. 25. Kim EB, Kim DS, Park SJ, Park Y, Rho KH, Kim SJ. Hepatitis B virus reactivation in a surface antigen-negative and antibody-positive patient after rituximab plus CHOP chemotherapy. Cancer Res Treat 2008;40:36-8. 168