HELLP (hemolysis, elevated liver enzymes, and low platelets ) syndrome 에합병된미만성폐포출혈 1 예 울산대학교의과대학서울아산병원내과학교실, 산부인과학교실 1 정우진, 허진원, 유미현, 최영준, 전민혁, 심재윤 1, 홍상범 A Case of Diffuse Alveolar Hemorrhage Complicated by HELLP (Hemolysis, Elevated Liver Enzymes, and Low Platelets ) Syndrome Woo Jin Jeong, M.D., Jin Won Huh, M.D., Mi Hyun Yu, M.D., Young Jun Choi, M.D., Min Hyok Jeon, M.D., Jae Yun Sim, M.D. 1, Sang-Bum Hong, M.D. Department of Internal Medicine, Division of Pulmonary & Critical Care Medicine, Department of Obstetrics and Gynecology 1, Asan Medical Center, Ulsan University College of Medicine, Seoul, Korea A diffuse alveolar hemorrhage (DAH) is a distinct form of pulmonary hemorrhage that originates from the pulmonary microcirculation. Disseminated intravascular coagulation (DIC) is one cause of DAH. Although HELLP syndrome associated with DIC can cause DAH, there are no published case reports that the authors are aware of. We report the case of a pregnant woman with HELLP syndrome who developed DAH. Because pregnant women with HELLP syndrome can develop DAH as a form of ARDS, a bronchoalveolar lavage may be used to make a differential diagnosis of this lung manifestation. (Tuberc Respir Dis 2005; 59: 418-422) Key words : Diffuse alveolar hemorrhage, HELLP syndrome, Disseminated intravascular coagulation. 서 1982년에 Weinstein 등은 1 용혈 (hemolysis), 간효소수치의상승 (elevated liver enzymes), 및혈소판감소 (low platelets) 가있는전자간증임산부를 HELLP syndrome이라명명했다. HELLP syndrome은높은모성사망및주산기사망을일으키고합병증으로는급성신부전, 폐부종, 흉수, 복수, 파종성혈관내응고 (Disseminated intravascular coagulation), 간피막하혈종, 뇌출혈, 급성호흡곤란증후군등이알려져있다 2,3. 특히 HELLP syndrome의합병증으로파종성혈관내응고가있는임산부에서단순흉부촬영상양측성폐침윤이발생할때원인으로폐부종과급성호흡곤란증후군이보고되어있다. 미만성폐포출혈은폐미세순환에서발생하는폐출 론 Address for correspondence : Sang-Bum Hong, M.D. Division of Pulmonary & Critical Care Medicine, University of Ulsan College of Medicine, Asan Medical center, 388-1 Pungnap-Dong, Songpa-Ku, Seoul, 138-736, South Korea Phone : 02-3010-3893 Fax : 02-3010-4709 E-mail : sbhong@amc.seoul.kr Received : May. 26. 2005 Accepted : Aug. 26. 2005 혈의한형태로서, 여러원인질환중파종성혈관내응고도보고되어있다 4,5. 파종성혈관내응고는 HELLP syndrome 환자의 15% 에서 3 보고되나아직까지미만성폐포출혈이 HELLP syndrome의합병증으로보고된예는없었다. 최근저자들은 HELLP syndrome 이합병된임신 36주임산부에서미만성폐포출혈의한예를경험하였기에문헌고찰과함께보고하는바이다. 증례환자 : 탁, 31세여자주소 : 내원 1일전부터발생한상복부통증현병력 : 임신 36주로상복부통증과두통으로일차병원진료상고혈압및간효소수치상승소견있어본원산부인과로전원되었다. 과거력 : 특이사항없음가족력 : 특이사항없음사회력 : 흡연력이나음주력없음이학적소견 : 내원당시급성병색이었으며혈압 190/ 120 mm Hg, 호흡수분당 20회, 맥박수분당 76회, 체온은 36.5도였다. 의식은명료하였고이학적검사상특이소견없었다. 418
Tuberculosis and Respiratory Diseases Vol. 59. No. 4, Oct. 2005 검사실소견 : 말초혈액검사상백혈구 17,800/mm 3, 혈색소 13.1 mg/dl, 혈소판 50,000/mm 3 였고혈액응고검사상 Prothrombin time(pt) 66.1% (INR 1.43), Act ivated partial thromboplastin time(aptt) 36.1초였다. 혈청생화학검사상 Blood urea nitrogen(bun) 12.2 mg/dl, Creatinine(Cr) 1.0 mg/dl, Aspartate ami notransferase(ast) 1,381 IU/L, Alanine aminotran sferase(alt) 458 IU/L, Alkaline phosphatase(alp) 94 IU/L, Total bilirubin 3.4 mg/dl, Lactic dehydro genase(ldh) 2,121 IU/L 이었다. 혈액도말검사상정상 색소정상적혈구빈혈, 분열적혈구 (fragmented RBC), 중등도의혈소판감소가보였다. A형, B형, C형간염바이러스검사는모두음성이었다. 임상경과및치료 : 태아심박동검사상다양성태아심박동감소 (variable deceleration) 소견보여본원산부인과에서 HELLP syndrome 및태아곤란증 (fetal distress) 으로진단하에응급제왕절개수술로분만을하였다. 입원다음날환자는호흡곤란과기침을호소하였다. 말초혈액검사상백혈구 15,900/mm 3, 혈색소 8.6 mg/dl, 혈소판 94,000/mm 3, 혈액응고검사상 PT 45.0% A B C Figure 1. Initial chest PA shows no active lung lesion (A). At second day, chest PA shows diffuse bilateral alveolar infiltration (B). At sixth day, bilateral alveolar infiltration is more aggravated (C). 419
WJ Jeong et al. : A case of diffuse alveolar hemorrhage complicated by HELLP ( hemolysis, elevated liver enzymes, and low platelets ) syndrome (INR 1.84), aptt 47.2초, Fibrinogen 149 mg/dl, Fibrin degradation products 320 ug/ml 이상, D-dimer 24.7 ug/ml, Antithrombin Ⅲ 48% 이었다. 혈청생화학검사는 BUN 28 mg/dl, Cr 2.8 mg/dl 로상승하였다. 입원직후촬영한흉부방사선사진상정상흉부소견이었으나 (Fig. 1-A), 다음날기침과호흡곤란이발생한후촬영한흉부방사선사진에서는양측성미만성침윤을보였다 (Fig. 1-B). 당시응급제왕절개수술시와다음날까지총 5units의농축적혈구와 20units 의혈소판수혈을하였고소변량은시간당 20-30밀리리터로유지되었다. 본저자들은 HELLP syndrome 의합병증으로급성신부전, 폐부종및파종성혈관내응고로진단하고이뇨제에반응이없어혈액투석을시행하였으나저산소증이계속진행하여입원 3일째기계환기를시작하였다. 입원 6일째적절한혈액투석, 기계환기와응고장애교정을위해신선동결결장과혈소판수혈을하였으나흉부방사선사진은점차악화소견을보였고 (Fig. 1-C), 기관지내관을통하여객담흡인시혈담이나와기관지내시경을시행하였고반복적인기관지폐포세척술상폐포세척액이점차적으로붉어지는혈성으로관찰되었다. 폐포세척액의세균배양, 바이러스배양, 결핵균배양검사는모두음성이었다. 혈청 antinucle ar cytoplasmic antibody(anca), antiglomerular ba sement membrane antibody, antinuclear antibody (ANA) 및 antiphospholipid antibody 등면역관련항체도모두음성이었다. 본저자들은미만성폐포출혈로진단하고신선동결혈장과혈소판수혈로응고장애를계속치료하였고, 이후점차적으로소변량은증가하여내원 10일째혈액투석을중단할수있었다. 이후인공호흡기를이탈하고간기능검사, 크레아티닌, 혈액응고검사모두호전되어퇴원하였다. 고찰 HELLP syndrome 환자의 70~80% 는분만전에증상이발생한다. 그러나일부환자는분만후에발생하고, 이때중요모성합병증과더연관이있다 3. 그래서분만후에도지속적감시가필요한질환이다. HELLP syndrome 이병발한임신의모성사망률은 1% 이고폐부종 (8%), 급성신부전 (3%), 파종성혈관내응고 (15%), 태반조기박리 (9%), 간출혈또는간부전 (1%), 급성호흡곤란증후군, 패혈증, 뇌졸증 (<1%) 등의합병증이발생할수있다 3. 또한주산기사망률 (7.4% - 20.4%) 이증가되는것으로보고되고있다. Van Dam 등 6 은 HELLP syndrome에서파종성혈관내응고발생시혈관벽손상및혈관투과성증가, 관류변화, 대식세포활성화, 동맥및정맥미소혈전으로조직저산소증, 허혈성괴사를일으켜신장및호홉기합병증이더증가한다고보고하였다. 여러중요장기출혈에대해서는보고가있지만미만성폐출혈에대해서는아직보고된바가없다. 파종성혈관내응고가있는환자에서폐포출혈이발생하는경우에대한보고는많지는않으나 Robboy 등 7 과 Saka등 8 은전립선암과급성전골수세포성백혈병환자에서파종성혈관내응고에의해미만성폐포출혈이발생한예를보고하였으며, Katsumura등 9 이 87명의파종성혈관내응고환자부검시 14명 (16.1%) 에서폐출혈이보였다고보고하였다. 그러므로파종성혈관내응고가동반된 HELLP syndrome 에서도미만성폐포출혈이발생할수있을것이다. 미만성폐포출혈의진단은객혈, 흉부방사선소견상양측성폐침윤, 폐미세혈관에서폐포내출혈로인한혈색소감소로추정할수있다 4,5. 흉부방사선소견은폐부종, 급성호흡곤란증후군, 미만성침윤을보이는폐렴과감별이필요하다 10. 기관지폐포세척시연속된기관지폐포액이점차적으로혈성으로진해지는것이특징이고세척액에서혈철소 (hemosiderin) 을가진대식세포의관찰이진단에도움이된다. 즉기관지폐포세척술없이는임상적으로확진하기는어려운질환이다. 그래서 HELLP syndrome에서미만성폐포출혈진단이보고되지않았을가능성이있다. 치료는원인질환에따라다르며고용량스테로이드투여나세포독성약제 (cytotoxic agent; cyclophosphamide, azathioprine 등 ), 혈장분리반출술 (plasmapheresis) 등이고려될수도있다. 보존적치료로는혈소판수혈, 산소공급, 주의깊은수액요법등이있다. 이번증례에서는혈액응고장애의교정등보조적치료만으로 420
Tuberculosis and Respiratory Diseases Vol. 59. No. 4, Oct. 2005 호전되었다. HELLP syndrome 의폐합병증의임상양상은주로기침과호흡곤란, 흉부 X-선촬영상양측성폐침윤을보이는경우이다. 원인으로흉수, 폐부종및급성호흡곤란증후군등이보고되어있지만미만성폐포출혈에대해서는아직보고된바가없다. 폐부종, 급성호흡곤란증후군과미만성폐포출혈의감별이중요한이유는원인에따라치료가다르기때문이다. 폐부종은조기에이뇨제와투석등의적극적인치료로기계환기를피할수도있고 11 과투과성부종이주된원인인급성호흡곤란증후군은적절한산소유지와폐보호환기법을포함한인공환기전략이중요한치료이다 12. 또한 HELLP syndrome 이합병된임신에서임상경과중수술, 출혈및파종성혈관내응고발생으로대량수혈이필요할수있어급성호흡곤란증후군발생시에는수혈연관급성폐손상 (transfusion related acute lung injury, TRALI) 도고려해야한다 13. 이런경우수혈을극히제한적으로시행해야할것이다. 미만성폐포출혈인경우응고장애교정및적극적인혈액투석등의보조요법이 HELLP syndrome 환자에서주된치료이나, 중증의경우고용량의스테로이드나혈장분리반출술등을치료로시도한보고도있다 14,15. 본환자의경우수혈이주된원인으로폐출혈이발생하였을가능성은낮다. 첫째로적혈구수혈은수술당일과다음날동안 5units 로대량수혈이아니였다. 수혈연관폐손상의경우대량수혈은 4일이상혈량전체를 (total blood volume) 수혈하는것으로되어있다. 잘유발하는종류도전혈, 신선동결혈장등순서인데, 첫 2일동안은신선동결혈장조차수혈되지않았다. 호흡곤란증상역시대부분수혈 1-2 시간안에발생하나, 본증례는수술다음날부터시작되었다. 둘째로수혈은진행경과중계속투여되었지만환자는 6일이후서서히회복의경과를보였다. 그래서본증례는내원당시파종성혈관내응고소견이있었던환자였고, 파종성혈관내응고가계속진행하면서증상이악화되었다가병의자연경과과정을거친수일후부터회복의경과를보였던증례로해석된다. 급성호흡곤란증후군과미만성폐포출혈간의이와같은상이한치료로두질환을감별하는것이중요할 것으로생각되며 HELLP syndrome 환자에서양측성폐침윤이보이는경우필요시기관지폐포세척술을시행하여이들질환들을감별해야하겠다. 요 HELLP syndrome에서여러출혈합병증이보고되었으나, 아직미만성폐포출혈에대한보고는없었다. HELLP syndrome이합병된임신 36주임산부에서분만후혈담과단순흉부방사선촬영상양측성폐침윤이관찰되어기관지폐포세척술을통해서미만성폐포출혈을진단및치료후호전된예를경험하였기에문헌과함께보고하는바이다. 약 참고문헌 1. Weinstein L. Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension. Am J Obstet Gynecol 1982;142:159-67. 2. Sibai BM, Ramadan MK, Usta I, Salama M, Mercer BM, Friedman SA. Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets(hellp syndrome). Am J Obstet Gynecol 1993;169:1000-6. 3. Sibai BM. Diagnosis, contraversies, and management of the syndrome of hemolysis, elevated liver enzymes, and low platelet count. Obstet Gynecol 2004;103:981-91. 4. Schhwarz MI, Cherniack RM, King JR. Diffuse alveolar hemorrhage and other rare infiltrative disorders. In: Murray, Nadel, editors. Textbook of respiratory me dicine. 3rd ed. W.B. Saunders Company; 2000. p. 1733-51. 5. Collard HR, Schwarz MI. Diffuse alveolar hemorrhage. Clin Chest Med 2004;25:583-92. 6. Van Dam PA, Renier M, Backland M, Buytaert P, Uyttenbroeck F. Disseminated intravascular coagula tion and the syndrome of hemolysis, elevated liver enzymes, and low platelets in severe preeclampsia. Obstet Gynecol 1989;73:97-102. 7. Robboy SJ, Minna JD, Colman RW, Birndorf NI, Lopas H. Pulmonary hemorrhage syndrome as a manifestation of disseminated intravascular coagulation: analysis of ten cases. Chest 1973;63:718-21. 8. Saka H, Ito T, Ito M, Watanabe A, Shimokata K. Di ffuse pulmonary alveolar hemorrhage in acute pro 421
WJ Jeong et al. : A case of diffuse alveolar hemorrhage complicated by HELLP ( hemolysis, elevated liver enzymes, and low platelets ) syndrome myelocytic leukemia. Intern Med 1992;31:457-8. 9. Katsumura Y, Ohtsubo K. Incidence of pulmonary thr omboembolism, infarction and haemorrhage in diss eminated intravascular coagulation: a necroscopic an alysis. Thorax 1995,50:160-4. 10. Albelda SM, Gefter WB, Epstein DM, Miller WT. Di ffuse pulmonary hemorrhage: a review and classifica tion. Radiology 1985;154:289-97. 11. Nava S, Carbone G, DiBattista N, Bellone A, Baiardi P, Cosentini R, et al. Noninvasive ventilation in cardi ogenic pulmonary edema. Am J Respir Crit Care Med 2003;168:1432 7. 12. The Acute Respiratory Distress Syndrome Network. Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome. N Engl J Med 2000;342:1301-8. 13. Silliman CC, Ambruso DR, Boshkov LK. Transfusionrelated acute lung injury. Blood 2005;105:2266-73. 14. Martin JN Jr, Thigsen BD, Rose CH, Cushman J, Moore A, May WL. Maternal benefit of high dose intravenous corticosteroid therapy for HELLP syndr ome. Am J Obstet Gynecol 2003;189:830-4. 15. Martin JN Jr, Files JC, Blake PG, Perry KG Jr, Mo rrison JC, Norman PH. Postpartum plasma exchange for atypical preeclampsia-ecclampsia as HELLP syn drome. Am J Obstet Gynecol 1995;172:1107-27. 422