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1 대한내과학회지 : 제 77 권부록 2 호 2009 증례 완전포상기태에서발생한 HELLP 증후군 1 예 충남대학교의과대학 1 내과학교실, 2 산부인과학교실, 3 병리학교실 김은미 1 김석현 1 성재규 1 이병석 1 이헌영 1 고영복 2 서광선 3 A case of HELLP syndrome in a patient with complete hydatidyform mole Eun-Mi Kim, M.D. 1, Seok Hyun Kim, M.D. 1, Jae Kyu Sung, M.D. 1, Byung Seok Lee, M.D. 1, Heon Young Lee, M.D. 1, Young-Bok Ko, M.D. 2, and Kwang-Sun Suh, M.D. 3 Departments of 1 Internal Medicine, 2 Obsterics and Gynecology and 3 Pathology, Chungnam National University College of Medicine, Daejeon, Korea A 47-year-old woman was admitted to our emergency department with seizure and gross hematuria. Her blood pressure was 220/130 mmhg on admission. On abdominal examination, a firm mass reaching the umbilicus was felt arising from the pelvis. An ultrasound examination revealed a huge snow storm-appearing mass filling the uterine cavity but no fetus. Laboratory tests showed a high ß-hCG (>225,000 mu/ml), proteinuria (3+), elevated liver enzymes, low platelet count, and an abnormal peripheral blood smear. We diagnosed HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets) with eclampsia in a patient with a complete hydatidiform mole. She underwent an emergency suction curettage for the hydatidiform mole. The liver enzymes and platelet count normalized about 2 weeks after the suction curettage. HELLP syndrome in a patient with hydatiform mole is very rare. Here, we report a patient who presented with a combination of HELLP syndrome, eclampsia, and a complete hydatidiform mole. (Korean J Med 77:S263-S267, 2009) Key Words: HELLP syndrome; Eclampsia; Hydatidiform mole 서론 HELLP 증후군은임신과관련되어나타나는전자간증및자간증질환중에서용혈, 간효소치의상승, 저혈소판증의소견을보이는비교적드문산과적합병증이다. 외국의보고에서는 HELLP 증후군의발생빈도는전체임산부의 0.2~ 0.6% 이며, 전자간증이나자간증의환자에서는 2~12% 에서 HELLP 증후군이발생한다 1). 정상임신이아닌포상기태에서 HELLP 증후군이발생한국외보고는매우드물게있으 나국내에는보고된사례가없다. 이에저자들은완전포상기태에서자간증과 HELLP 증후군이발생하고, 이외에도신기능이상, 폐부종, 범발성혈관내응고증등의내과적합병증이동반된 1예를경험하였기에문헌고찰과함께보고하는바이다. 증례환자 : 김, 47세여자 Received: Accepted: Correspondence to Seok Hyun Kim, M.D., Department of Internal Medicine, Chungnam National University Hospital, 33 Munhwa-ro, Jung-gu, Daejeon , Korea midoctor@cnuh.co.kr - S 263 -

- The Korean Journal of Medicine: Vol. 77, Suppl. 2, 2009 - 주소 : 경련및육안적혈뇨현병력 : 내원 5시간전에발생한경련과육안적혈뇨로응급실에내원하였다.

진찰소견 : 내원시혈압 220/130 mmhg, 맥박수 114회 / 분, 호흡수 24회 / 분, 체온 36.4 였고, 급성병색을보였다. 흉부진찰에서양폐야에서수포음이들렸고, 복부진찰에서 Figure 1. Peripheral blood smear findings.

5 g/dl, 혈소판 26,000/mm 3, AST 904 IU/L, ALT 522 IU/L, alkaline phosphatase 94 IU/L, γ-gtp 25 IU/L, 총빌리루빈 2.5 mg/dl, 총단백 5.8 g/dl, 알부민 2.9 g/dl, BUN 31 mg/dl, Creatinine 1.

2 - The Korean Journal of Medicine: Vol. 77, Suppl. 2, 주소 : 경련및육안적혈뇨현병력 : 내원 5시간전에발생한경련과육안적혈뇨로응급실에내원하였다. 과거력및산과력 : 과거력상특이소견없었고, 산과력은 (term birth-preterm birth-abortion-living children) 이었으며마지막임신은 10년전으로인공유산하였다. 사회력 : 매일소주한병씩 3년동안마셨으며흡연은하지않았다. 진찰소견 : 내원시혈압 220/130 mmhg, 맥박수 114회 / 분, 호흡수 24회 / 분, 체온 36.4 였고, 급성병색을보였다. 흉부진찰에서양폐야에서수포음이들렸고, 복부진찰에서 Figure 1. Peripheral blood smear findings. There were a few schistocytes, many nucleated red blood cells, and a few platelets. 하복부에는커다란종괴가촉지되었으나압통이나반발압통은없었다. 검사소견 : 혈액검사상백혈구 12,600/mm 3, 혈색소 7.5 g/dl, 혈소판 26,000/mm 3, AST 904 IU/L, ALT 522 IU/L, alkaline phosphatase 94 IU/L, γ-gtp 25 IU/L, 총빌리루빈 2.5 mg/dl, 총단백 5.8 g/dl, 알부민 2.9 g/dl, BUN 31 mg/dl, Creatinine 1.3 mg/dl, LDH 7086 IU/L, ß-hCG는 225,000 mu/ml 이상으로매우상승되어있었다. 적색뇨를보였으며소변검사상 Erythrocyte 4+, 적혈구 many, 단백뇨가 3+ 였으며, 혈액응고검사결과 PT 113% (27초), aptt 28초였고, Fibrinogen 183 mg/dl, FDP 85 µg/ml, D-dimer 15.2 µg/mg으로범발성혈관내응고증을보였다. 간염표지자검사에서는 IgM anti-hav 음성, IgG anti-hav 양성, HBsAg 음성, anti-hbs 양성, anti-hcv 음성이었다. 망상적혈구산정은 5.3% 로증가되고 Haptoglobulin은 2 mg/dl로감소되어있으며, 말초혈액도말검사에서는분열적혈구, 다염성적혈구와유핵적혈구가관찰되고혈소판은감소되어있어서혈관내용혈에합당하였다 ( 그림 1). 방사선소견 : 단순흉부촬영상에서양폐야음영이증가된폐부종의소견을보였으며, 초음파상에서태아와양수등은관찰되지않고눈보라모양을한 10 cm 크기의종괴가자궁내강을가득채우고있었다 ( 그림 2). 복부 CT상에서는자궁안에조영증강되는포도송이모양의종괴가관찰되었고, 간에는특이소견이없었고, 신장주변에는체액저류가관찰되었다 ( 그림 3). Figure 2. Transabdominal sonography findings. There was a huge snow storm-appearing mass filling the uterine cavity but no a fetus or amniotic fluid. Figure 3. Contrast-enhanced abdominopelvic CT findings. The CT revealed a distended uterine cavity filled with an enhancing vesicular mass representing molar tissue. - S 264 -

3 - Eun-Mi Kim, et al. HELLP syndrome in a patient with complete hydatidyform mole - Figure 4. Hydatidiform mole histologic findings. The mole showed hydropically degenerated chorionic villi with a central cistern formation and trophoblastic cell proliferation (hematoxylin and eosin, 200). 세포학적소견 : 육안적으로출혈성소견과함께포도송이같은다양한크기의낭구조들이관찰되었다. 광학현미경소견상수포성퇴화 (hydrophic degeneration) 를보이는다수의융모가관찰되었으며, 융모외면에영양세포의증식이동반된완전포상기태의소견을보였다 ( 그림 4). 치료및경과 : 포상기태에서발생한자간증과 HELLP 증후군으로진단하고 hydralazine과 labetalol로혈압조절을시행하였으나내원 8시간후에한차례경련이더발생하였다. 응급으로자궁내종괴흡입제거술을시행받았으며이후에폐부종과전신상태는급속히호전되었고, 2주후에는간수치와혈소판수치가정상화되었으며단백뇨도더이상검출되지않았다. HELLP 증후군은완전히회복되었으나 ß- hcg 는수술 2주후에 3,152 mu/ml 까지감소하였다가 4주후에 8,342 mu/ml 로다시상승하여지속성임신융모성종양 (persistent gestational trophoblastic tumor) 로진단하여현재는항암치료중이다. 고 HELLP 증후군은임신과관련되어나타나는전자간증및자간증질환중에서용혈, 간효소치의상승, 저혈소판증의소견을보이는경우로, 1954년 Pritchard 등이최초로기술한이후 1982년 Weinstein 등이처음으로 HELLP 증후군이라명명하였다. 외국의보고에서는임신성고혈압환자의 2~ 12% 에서발생하며, 모성사망률은 1~25% 까지다양하게보 찰 고되고있다. 그러나최근적극적인치료로산모및신생아의이환율및사망률이감소하여국내의보고에서는전자간증및자간증에서는발생빈도는 4.2% 였으며사망한예는없었다 1-3). HELLP 증후군의발생기전은현재까지명확히밝혀지지는않았지만전자간증의심한변형으로여겨지며주요한원인으로는태반의허혈손상과염증반응으로인한 cytokines 이나여러가지보체의비정상적인활성화에의한혈전성미세혈관병증으로설명되고있다. 이러한혈전성미세혈관병증의다른원인으로태아에대한모성의면역거부반응 (immune rejection) 으로생각되기도하고혈소판의플라즈미노겐활성화 (Platelet plasminogen activation) 의증가, 태아의지방산산화과정에서의오류 (inborn error of fatty acid oxidative mechanism) 와산화적스트레스 (Oxidative stress) 등이원인으로제시되기도한다. 혈전성미세혈관병증은미세혈관내피세포의활성화 (microvascular endothelial activation), 세포손상 (cell injury) 과혈전생성 (thrombosis) 을특징으로한다. 혈소판과피브린에의한미세혈전은혈관의부분적폐쇄를유발하고와류를형성하여전단응력 (shear stress) 을유발시켜적혈구의용혈을유발한다. HELLP 증후군에는여러장기를침범하는전신성염증반응이지만이러한혈전성미세혈관병증은주로간에서발생하고, CD95 (APO-1, Fas) 에의한간세포의자멸 (apoptosis) 이간손상의기전으로제시되기도하며, 실제로 HELLP 증후군환자의간초음파에서는간으로가는혈류가감소되어있으며이로인해간의허혈성손상이나괴사를유발하고간수치도상승한다. 또한혈소판감소증은혈소판이활성화되어손상된혈관내피세포에혈소판이과도하게응집소모됨으로서발생한다 4-6). 따라서 HELLP 증후군에서간괴사, 간경색, 간피막하혈종과간파열등이동반될수있고, 심한경우에는간파열로인한복강내출혈과쇼크상태로수술적치료가시행되거나사망한예도있다 7). HELLP 증후군의간이외의합병증으로급성신부전, 폐부종, 흉수, 복수, 파종성혈관내응고, 급성호흡곤란증후군등이있고드물게뇌출혈, 비장파열, 미만성폐포출혈, 척수손상과, 골괴사등이보고되어있다 8-12). Stefos 등과 Andreas 등은이러한 HELLP 증후군이정상임신이아닌불완전포상기태임신에서발생하여태아와종괴의흡입적출술후에완전히호전된예를보고하였다 12,13). 포상기태는영양배엽의증식과융모막의부종을수반하는비정상적인임신에서기인한일종의종양성질환으로, 조직 - S 265 -

4 - 대한내과학회지 : 제 77 권부록 2 호 학적으로완전포상기태와부분포상기태로구분된다. 완전포상기태는태아조직이없고, 포상기태변화나융모조직의과성장이전반적으로나타나며, 융모막융모의조개모양변화 (scalloping of chorionic villi) 나영양배엽실질의침투 (trophoblastic stromal inclusion) 가존재하지않는다. 반면부분포상기태는태아조직이있고, 포상기태변화나융모조직의과성장이부분적으로나타나며, 융모막융모의조개모양변화나영양배엽실질의침투가존재한다 14). 포상기태임신에서는과도한영양배엽세포의증식으로 ß-hCG가과다분비되고, 제태연령보다커진자궁이나, 임신오조 (hypermesis gravidarum), 난포막황체낭종 (theca lutein cyst), 갑상선기능항진증과전자간증이발생한다 18). 포상기태의발생빈도는지역에따라매우다양하며특히동양에서호발하는것으로알려져있고, 전체임신중 0.6~2명 /1,000명의빈도로발생한다. 포상기태임신중발생하는전자간증은 1970년대에는 27% 에서발생하는것으로보고되었으나초음파의발달과혈청 ß-hCG 검사가용이해지면서포상기태가조기에진단되고치료되어서최근의연구에서는전자간증의발생률은 1~3% 정도로매우감소되었다. 그리고정상임신에서전자간증은주로임신 3기에발생하나포상기태임신에서는정상임신에서보다좀더일찍 20주이전에전자간증발생하며, HELLP 증후군이외에도확장성심근병증과신증후군등의발생이보고되었다. 또한정상임신에서 HELLP 증후군이분만후대개후유증없이완전하게회복되는것처럼포상기태임신에서도포상기태의적출에의해이러한합병증들은특별한치료없이대부분호전된다 16-20). 전신경련과육안적혈뇨로내원한환자에서자간증과 HELLP 증후군이동반된완전포상기태로진단하고, 종괴의흡입제거후에특별한치료없이 HELLP 증후군의완전회복되고, 전신상태의극적인호전을보인 1예를경험하였기에문헌고찰과함께보고하는바이다. 요약 HELLP 증후군은혈전성미세혈관병증으로인하여용혈, 간효소치상승, 저혈소판증을나타내고자간증혹은전자간증등임신성고혈압성질환에서대부분발생한다. 그러나정상임신이아닌포상기태에서자간증과 HELLP 증후군발생하고이외에도범발성혈관내응고, 폐부종, 신기능이상등의심각한내과적합병증이동반된환자에서포상기태 의흡입적출술후에특별한치료없이극적인호전을경험하였다. 포상기태에서발생한 HELLP 증후군은극히드물고아직국내보고가없어서문헌고찰과함께보고하는바이다. 중심단어 : HELLP 증후군 ; 자간증 ; 포상기태 REFERENCES 1) Hay JE. Liver disease in pregnancy. Hepatology 47: , ) Weinstein L. Syndrome of hemolysis, elevated liver enzymes, and low platelet count: a severe consequence of hypertension in pregnancy. Am J Obstet Gynecol 142: , ) Kim JW, Park TC, Lee JW, Kwon JC, Kang YN, Hing SH, Kim YS, Yoon SA, Kim YO. Incidence and clinical course of HELLP syndrome in pregnant women. Korean J Med 67: , ) Fang CJ, Richards A, Liszewski MK, Kavanagh D, Atkinson JP. Advances in understanding of pathogenesis of ahus and HELLP. Br J Haematol 143: , ) Baumwell S, Karumanchi SA. Pre-eclampsia: clinical manifestations and molecular mechanisms. Nephron Clin Pract 106:c72-c81, ) Tranquilli AL, Landi B, Corradetti A, Giannubilo SR, Sartini D, Pozzi V, Emanuelli M. Inflammatory cytokines patterns in the placenta of pregnancies complicated by HELLP (hemolysis, elevated liver enzyme, and low platelet) syndrome. Cytokine 40:82-88, ) Sutton BC, Dunn ST, Landrum J, Mielke G. Fatal postpartum spontaneous liver rupture: case report and literature review. J Forensic Sci 53: , ) Ezri T, Abouleish E, Lee C, Evron S. Intracranial subdural hematoma following dural puncture in a parturient with HELLP syndrome. Can J Anaesth 49: , ) Manda P, Dorman E, Olagbaiye F, Akinfenwa O. A case report of spontaneous splenic capsular rupture associated with atypical presentation of haemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome. J Obstet Gynaecol 24: , ) Jeong WJ, Huh JW, Yu HM, Choi YJ, Jeon MH, Sim JY, Hong SB. A case of diffuse alveolar hemorrhange complicated by HELLP syndrome. Tuberc Respir Dis 59: , ) Groothuis JT, van Kuppevelt DH. Postpartum spinal cord injury in a woman with HELLP syndrome. J Spinal Cord Med 31: , ) Jäger M, Wild A, Krauspe R. Osteonecrosis and HELLPsyndrome. Z Geburtshilfe Neonatol 207: , ) Stefos T, Plachouras N, Mari G, Cosmi E, Lolis D. A case of partial mole and atypical type I triploidy associated with severe HELLP syndrome at 18 weeks' gestation. Ultrasound Obstet Gynecol 20: , S 266 -

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386-390.hwp 386 HANYANG MEDICAL REVIEWS Vol. 29 No. 4, 2009 우리나라 미숙아의 통계와 의료비용 Statistics and Medical Cost of Preterm in Korea 윤혜선 을지대학교 노원을지병원 소아청소년과학교실 Hye Sun Yoon, M.D., Ph.D., Department of Pediatrics, Nowon